Health Evidence Review Commission's Value-Based Benefits Subcommittee

Health Evidence Review Commission's Value-based Benefits Subcommittee

October 4, 2018 8:30 AM - 1:00 PM

Clackamas Community College Wilsonville Training Center, Room 111-112 29373 SW Town Center Loop E, Wilsonville, Oregon, 97070

Section 1.0 Call to Order AGENDA VALUE-BASED BENEFITS SUBCOMMITTEE October 4, 2018 8:30am - 1:00pm Clackamas Community College 29373 SW Town Center Loop E, Wilsonville Training Center, Rooms 111-112 Wilsonville, Oregon A working lunch will be served at approximately 12:00 PM All times are approximate

I. Call to Order, Roll Call, Approval of Minutes – Kevin Olson 8:30 AM

II. Staff report – Ariel Smits, Cat Livingston, Darren Coffman 8:35 AM

III. Straightforward/Consent agenda – Ariel Smits 8:45 AM A. Consent table B. S86 code review C. Coding issues for gender dysphoria

IV. Previous discussion items 8:50 AM A. F39 Unspecified Mood Disorder B. Brow ptosis repair C. Blepharoplasty

V. 2020 Biennial Review 9:30 AM A. Neonatal circumcision

VI. New discussion items 10:00 AM A. Medical indications for circumcision B. Items carried over from August VBBS meeting A. Postpartum depression screening B. Cardiac MRI C. Allergy testing for eczema D. MRI Guided Focused Ultrasound (MRgFUS) E. Human donor breast milk F. SI joint dysfunction prioritization G. Testosterone hypofunction H. iStent for open angle glaucoma I. Humeral osteotomy for recurrent shoulder dislocation

VII. Coverage guidances 12:00 PM A. CarioMEMs

Health Evidence Review Commission (503) 373-1985

VIII. Public comment 12:55 PM

IX. Adjournment – Kevin Olson 1:00 PM

Health Evidence Review Commission (503) 373-1985

Value-based Benefits Subcommittee Recommendations Summary For Presentation to: Health Evidence Review Commission on August 9, 2018

For specific coding recommendations and guideline wording, please see the text of the 8/9/2018 VbBS minutes.

RECOMMENDED CODE MOVEMENT (effective 10/1/2018 unless otherwise noted) • Add neuropsychological testing done by computer or technician to various covered mental health lines • Add 2019 ICD-10 codes to various covered and uncovered lines • Add acne fulminans to a covered line (effective January 1, 2019) • Add procedure codes for inserting drug eluting stents into coronary arteries to several heart disease lines • Add the procedure code for Eustachian tube inflation to an uncovered line • Makes the PET scan codes diagnostic and remove from lines; make the PET scan guideline into a diagnostic guideline • Add the code for prediabetes to Line 3 and recommend it be removed from the Diagnostic Procedures File. Add a series of temporary codes for the delivery of the Diabetes Prevention Program to Line 3. (effective January 1, 2019) • Move several developmental and speech delay codes to the dysfunction lines • Add the procedure code for nasal vestibular wall stenosis implants to an uncovered line • Add the procedure code for computer assisted musculoskeletal surgery to an uncovered line • Add procedure codes for insertion of buprenorphine implants to the substance disorder line (effective January 1, 2019) • Add the generic diagnosis code that can be used for adult human growth hormone deficiency to an uncovered line with a new coding specification that it is only on the uncovered line for that specific diagnosis (effective January 1, 2019) • Various straightforward coding and guideline note changes.

RECOMMENDED GUIDELINE CHANGES (effective 10/1/2018 unless otherwise noted) • Edit the guideline for chemodenervation with botulinum toxin for chronic migraine to require medication overuse to be addressed and to modify the requirements for pharmacotherapies • Edit the severe inflammatory skin disease line to update the step therapy requirements for atopic dermatitis • Edit the guideline note on biomarker tests of cancer tissue • Add a new diagnostic guideline note on urine drug testing • Edit the guideline for breast reconstruction after mastectomy to indicate that revision surgery is only covered for medical, not cosmetic, indications • Delete the guidelines regarding implantable buprenorphine and enzyme replacement therapy (effective January 1, 2019) • Edit the human growth hormone guideline to remove the restrictions on types of childhood diseases that are covered for treatment (effective January 1, 2019) • Add a new guideline to clarify coverage for the treatment of prediabetes with the Diabetes Prevention Program when delivered by CDC-certified programs (effective January 1, 2019)

Value-based Benefits Subcommittee Summary Recommendations, 8/9/2018

• Edit the guideline on overweight and obesity to make reference to the new Diabetes Prevention Program guideline (effective January 1, 2019)

BIENNIAL REVIEW CHANGES (effective 1/1/2020) • Create a new line for severe acne which will be in the funded region, with a new guideline • Reorganize the burn lines from 4 lines into 3

VALUE-BASED BENEFITS SUBCOMMITTEE Clackamas Community College Wilsonville Training Center, Rooms 111-112 Wilsonville, Oregon August 9, 2018 8:00 AM – 1:00 PM

Members Present: Kevin Olson, MD, Chair; Mark Gibson; Holly Jo Hodges, MD; Vern Saboe, DC; Gary Allen, DMD; Adriane Irwin, PharmD

Members Absent: Susan Williams, MD

Staff Present: Darren Coffman; Ariel Smits, MD, MPH; Cat Livingston, MD, MPH; Wally Shaffer, MD; Daphne Peck; Mark Altenhofen

Also Attending: Napua Catriz (OHA); Adam Obley, MD (Center for Evidence-based Medicine); Dr. Julie Dhossche and Dr. Tracy Funk (OHSU); Carolyn Concion, NP; Rob Twillman (Academy of Integrative Pain Medicine); Karen Yeargain; Edith Agoff; Ginevra Liptan MD (Frida Center for Fibromyalgia); Allan Chino, PhD; Windy Sinclair; Shane Sinclair; Amara McCarthy; Kim Martin Thanislaus; Karl Probst; Patrick Starnes; Steven Hix; Zane Six; Laura A Dolph; Rick Schmitt; Amanda Siebe (Disables Americans for Change); Helen Turner; Kelly Howard; Leonard Ramey; Laura Stallard; BJ Cavnor (One in Four); Margaret Olmon and Laura Jeffcoat (Abbvie); Becky Harison (BioMartin); Deena Loughany and Jay Wurschev (DHS Child Welfare); Sara Gore (Millennium); David Balham (Genentech); David Barba.

 Roll Call/Minutes Approval/Staff Report

The meeting was called to order at 8:00 am and roll was called. Minutes from the May 17, 2018 VbBS meeting were reviewed and approved. Staff noted that the minutes included in the meeting packet had some typos in the line placements for the HCPCS “C” code issue; these line numbers have been corrected.

Smits brought the errata document to the attention of the subcommittee members. There were no comments or discussion.

 Topic: Straightforward/Consent Agenda

Discussion: There was no discussion about the consent agenda items.

Recommended Actions: 1) Add ICD-10 Z45.42 (Encounter for adjustment and management of neuropacemaker) to line 250 PARKINSON'S DISEASE 2) Remove ICD-10 N43.4 series (Spermatocele of epididymis) from line 327 FUNCTIONAL AND MECHANICAL DISORDERS OF THE GENITOURINARY SYSTEM INCLUDING BLADDER OUTLET OBSTRUCTION 3) Add G0270-G0271 (Medical nutrition therapy) to line 320 OBESITY IN ADULTS AND CHILDREN; OVERWEIGHT STATUS IN ADULTS WITH CARDIOVASCULAR RISK FACTORS

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4) Add H0023 (Behavioral health outreach service (planned approach to reach a targeted population)) to line 4 SUBSTANCE USE DISORDER 5) Add N18.5 (Chronic kidney disease, stage 5) to line 59 END STAGE RENAL DISEASE 1) Remove N18.5 from line 339 CHRONIC KIDNEY DISEASE 6) Add 50389 (Removal of nephrostomy tube, requiring fluoroscopic guidance), 50432 (Placement of nephrostomy catheter, percutaneous), 50435 (Exchange nephrostomy catheter, percutaneous) and 50695 (Placement of ureteral stent, percutaneous) to line 25 VESICOURETERAL REFLUX 7) Add 11004 (Debridement of skin, subcutaneous tissue, muscle and fascia for necrotizing soft tissue infection; external genitalia and perineum), 11006 (Debridement of skin, subcutaneous tissue, muscle and fascia for necrotizing soft tissue infection; external genitalia, perineum and abdominal wall, with or without fascial closure), 11042 (Debridement, subcutaneous tissue (includes epidermis and dermis, if performed); first 20 sq cm or less), 13131-1313 (Repair, complex, forehead, cheeks, chin, mouth, neck, axillae, genitalia), 15004-15005 (Surgical preparation or creation of recipient site by excision of open wounds, burn eschar, or scar) and 55150 (Resection of scrotum) to line 47 DEEP ABSCESSES, INCLUDING APPENDICITIS AND PERIORBITAL ABSCESS 8) Add 57420-57421 (Colposcopy of the entire vagina, with cervix if present) to line 25 DYSPLASIA OF CERVIX AND CERVICAL CARCINOMA IN SITU, CERVICAL CONDYLOMA 9) Add 49020 (Drainage of peritoneal abscess or localized peritonitis, exclusive of appendiceal abscess, open), 49322 (Laparoscopy, surgical; with aspiration of cavity or cyst (eg, ovarian cyst)) and 49406-49407 (Image-guided fluid collection drainage by catheter) to line 51 ACUTE PELVIC INFLAMMATORY DISEASE 10) Revise Guideline Note 148 as shown in Appendix A 11) Modify GN173 as shown in Appendix A

MOTION: To approve the recommendations stated in the consent agenda. CARRIES 6-0.

 Topic: Behavioral Health Advisory Panel report

Discussion: Smits reviewed the summary documents. There was no discussion regarding the general recommendations.

There was discussion regarding the recommendations about a guideline for ICD-10 F39 (Unspecified mood [affective] disorder). Hodges felt that adopting the proposed guideline would make the exceptions process more streamlined. Gibson felt that the relative lack of use for more than a few visits did not require the adoption of a new guideline note. There were questions about whether the CCOs would find this guideline useful. Staff reported that the medical directors and CCOs were not specifically consulted on this topic. Staff were directed to consult with the CCO medical directors and see if the proposed guideline would be helpful and bring back this topic for further discussion in October.

Recommended Actions: 1) Add HCPCS H2014 (Skills training and development, per 15 minutes) to line 121 ABUSE AND NEGLECT 2) Add ER CPT codes (99281-99285) to lines 204 DEPRESSION AND OTHER MOOD DISORDERS, MILD OR MODERATE, 290 ACUTE STRESS DISORDER, and 391 PANIC DISORDER; AGORAPHOBIA

Value-based Benefits Subcommittee Minutes, 8/9/2018 Page 4 3) Remove ER CPT codes (99281-99285) from line 521 SEXUAL DYSFUNCTION 4) Remove inpatient CPT codes (99218-99226, 99331-99239) from lines 204 DEPRESSION AND OTHER MOOD DISORDERS, MILD OR MODERATE, 448 REACTIVE ATTACHMENT DISORDER OF INFANCY OR EARLY CHILDHOOD, 468 ENCOPRESIS NOT DUE TO A PHYSIOLOGICAL CONDITION, and 521 SEXUAL DYSFUNCTION 5) Add CPT 96118 (Neuropsychological testing (eg, Halstead-Reitan Neuropsychological Battery, Wechsler Memory Scales and Wisconsin Card Sorting Test), per hour of the psychologist's or physician's time, both face-to-face time administering tests to the patient and time interpreting these test results and preparing the report) to line 173 POSTTRAUMATIC STRESS DISORDER 6) Add a new guideline note to line 173 as shown in Appendix B 7) Add CPT 96119 (Neuropsychological testing… administered by technician, per hour of technician time, face-to-face) and 96120 (Neuropsychological testing (eg, Wisconsin Card Sorting Test), administered by a computer, with qualified health care professional interpretation and report) to lines 92 SEVERE/MODERATE HEAD INJURY: HEMATOMA/EDEMA WITH PERSISTENT SYMPTOMS, 173 POSTTRAUMATIC STRESS DISORDER, 193 AUTISM SPECTRUM DISORDERS, and 202 CHRONIC ORGANIC MENTAL DISORDERS INCLUDING DEMENTIAS 8) Remove CPT 96119 (Neuropsychological testing… administered by technician, per hour of technician time, face-to-face) and 96120 (Neuropsychological testing (eg, Wisconsin Card Sorting Test), administered by a computer, with qualified health care professional interpretation and report) from line 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS and remove entry to GN173. 9) Staff to review the proposed guideline for ICD-10 F39 with CCO medical directors and bring back to the October 2018 VBBS meeting

MOTION: To recommend the code and guideline note changes as presented other than those related to ICD-10 F39. CARRIES 6-0.

 Topic: Chronic Pain Task Force report Discussion: Smits gave an overview of the Task Force recommendations, including details of the proposed new line for fibromyalgia and chronic pain (diagnoses and treatments), the proposed accompanying guideline note, and changes recommended to the opioid guideline. She also summarized the major themes in the large number of public comments received on this topic. Saboe then commented on reports lack of inclusion of chiropractic care. ”So, on the original recommendations of non-pharmaceutical interventions you mentioned that chiropractic is not covered, that they had recommended. And again, the mistake is being made that chiropractic is synonymous with a single-modality -- spinal manipulation. And so the recommendation is also physical therapy. That’s a broad brush. That’s not only a profession, but there’s a whole cascade of interventions that fall under physical therapy. Might just as well say “Physical medicine.” So, passive/active, supervised exercise, therapeutic procedures, neuromuscular education, the modalities of mobilization, manipulation, manual traction. And then all the modalities all follow under physical therapy. And so to make the statement chiropractic’s not covered is an error. We provide most of all of these things are within our scope of license to provide, not just manipulation. So there needs to be some type of rewording

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that, in fact, when they say they’ve done the evidence and physical therapy is effective… that’s a broad brush. What modalities, what interventions are they speaking of? And so, in most all of those, I’m certain, are within the scope of the licensure of naturopathic physicians as well. So there needs to be some amendment of that language of those recommendations, because we would not want this going through and, and… the connotations of those interventions that fall under physical therapy or physical medicine are only to be provided by a physical therapist.”

Smits responded that the spinal manipulation CPT codes were not proposed for inclusion on the new line; however, if a chiropractor did PT services or office visit care, those CPT codes would be covered.

Kim Jones, PhD gave a presentation regarding the state of the evidence supporting coverage for treatments for fibromyalgia.

Public testimony Carolyn Concion, NP, testified that patients are stabilized on opioids for years. Then providers taper medications, frequently involuntarily. Patients are also rejected by providers due to their chronic pain.

Rob Twillman, Academy of Integrated Pain Management, testified in support of moving chronic pain above the current funding line, but opposes forcing opioid tapers. He requested that the subcommittee look at outcomes for chronic back pain patients tapered off opioids: functionality, suicides, mental health issues, etc. He noted that improved function is a criterion for the first 90 days of opioids in the opioid guideline, but improved function is not considered after 90 days. He feels that the opioid guideline needs criteria for pausing, stopping or reversing tapers.

Karen Yeargain, patient/public health nurse from Prineville, testified that it’s not diverted prescription drugs that are causing overdose problems, but rather street drugs. Oregon has decreased prescribing of opioids and is seeing increased suicides, but no increase in street drugs in chronic pain patients. Opioids increase functionality.

Ginevra Liptan, MD, an internal medicine physician with a focus on fibromyalgia, testified, noting that she is also a chronic pain patient. Opioids are imperfect. She agreed that the HERC should cover fibromyalgia and noted that Oregon is the only state without Medicaid funding for fibromyalgia care. She requested that the commission add tools that are helpful but do not take away the tool that has been helpful (opioids).

Allan Chino, PhD, a clinical health psychologist and pain specialist, testified about the need to move fibromyalgia above the line and have tools to help these patients. He noted that outcomes are superior when a range of treatment options are available, including opioids. Decisions should be based on individual patients. He noted that he has never seen hyperalgesia in his practice.

Karl Probst, a VA patient, testified about the new VA policy that requested patients get off opioids. Patients are offered suboxone instead. He feels that he has a better quality of life though opioids.

Patrick Starnes, an independent candidate for Oregon Governor, testified. He asked that the Committee not lump addicts with chronic pain sufferers. He stated that the commission needs more pain patient representation on the Task Force.

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Steven Hix, a patient, testified. He is very frightened about what is happening locally and nationally with opioids. He has tried all of the proposed modalities without success. Hydrotherapy was the most successful. He notes that it is very easy to lose hope, and become depressed. The most vulnerable people in this country are suffering. Taking away people’s medicine will not magically make their pain go away. This is a matter of human decency. There is a huge problem when one is labeled as a drug seeker. Health care insurance is a huge expense.

Helen Turner, a clinical nurse specialist caring for children with chronic pain, testified that opioids help children go to school and have improved quality of life. Evidence for opioids is messy at best, and does not apply to all patients. She is trying to get as many kids off opioids as she can, but some cannot be taken off.

Amanda Siebe, a patient with complex regional pain syndrome, testified. She brought in boxes of medical records, which include her treatment with all types of modalities. Only methadone helps her pain. Taking away opioids drives patients to suicide and street drugs. This takes away hope and functionality, giving nothing in exchange. <3% of patients on opioids become addicted.

BJ Cavnor, the executive director of One in Four, testified about his concern about restrictions on opioids in the guideline note. Pain patients are not addicts. Chronic pain patients are stigmatized. The PDMP database monitors drugs. Patients and providers should decide the best treatment strategy between them. This is a reactive policy at the state and national level, and does not help the overall opioid crisis.

Julia (no last name given) testified that this conversation was not public knowledge. She has tried all non-opioid medications, procedures and modalities; none work other than opioids.

Coffman gave the next steps in the process, as well as how to find out public meeting information, materials for public meetings, and how to provide written and oral testimony. The next meeting of the Chronic Pain Task Force will be September 20, 2018. The Task Force will have one or more meetings, and then forward their revised recommendations to VBBS at a future meeting. Any changes regarding chronic pain will need to be made by the March 2019 HERC meeting and would take effect with the January 1, 2020 Biennial Review changes.

Recommended Actions: 1) HERC staff will take the public testimony, subcommittee input, and HERC input to the September Chronic Pain Task Force meeting and work with the Task Force to revise their recommendations

 Topic: 2019 ICD-10 Code Review Discussion: There was no discussion of the straightforward code placements or the codes on the code issues summary.

There was discussion regarding the staff recommendations around brow ptosis repair and blepharoplasty. Hodges stated that the ophthalmologic jargon in these guidelines make them very difficult to interpret by non-ophthalmology medical reviewers and medical directors. The group requested that VBBS staff work with ophthalmology experts to rewrite the blepharoplasty guideline

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and the proposed brow ptosis repair guideline to clarify the requirements in non-jargon type language.

Recommended Actions: 1) Add 2019 ICD-10 code placements as shown in Appendix C 2) Staff to work the ophthalmology experts on the brow ptosis code placement and repair issues, as well as the blepharoplasty guideline

MOTION: To recommend the code placements as presented. CARRIES 6-0.

 Topic: 2020 Biennial Review – Severe Acne

Discussion: Smits reviewed the summary document. There was public testimony heard about hydranitis supporativa, which is a future review topic. There was no subcommittee discussion about the severe acne proposal.

Recommended Actions: Effective January 1, 2019 1) Change line title for line 373 ACNE CONGLOBATA (SEVERE CYSTIC ACNE) AND ACNE FULMINANS 2) Add ICD-10 L70.0 (acne vulgaris) to line 373 3) Modify GN 132 as shown in Appendix A

Effective January 1, 2020 1) Create a new line and guideline for severe acne as shown below 2) Score this new line as shown below 3) Change the line title for line 520 to ROSACEA; MILD/MODERATE ACNE

Line XXX SEVERE CYSTIC ACNE Treatment: MEDICAL AND SURGICAL TREATMENT a. ICD-10 codes: L70 (acne) b. CPT/HCPCS codes: all included currently on line 373 ACNE CONGLOBATA (SEVERE CYSTIC ACNE)

GUIDELINE NOTE XXX SEVERE CYSTIC ACNE Line XXX,520 Acne is only included on Line XXX if it is severe, defined as the presence of the following characteristics: persistent or recurrent inflammatory nodules and cysts AND ongoing scarring. Otherwise, acne diagnoses are included on line 520.

Note that acne with recurrent abscesses or communicating sinuses is covered according to Guideline Note 132 ACNE CONGLOBATA AND ACNE FULMINANS.

Line scoring Category 7 Impact on Healthy Life Years 1

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Impact on Pain and Suffering 3 Population effects 0 Vulnerable populations 0 Tertiary prevention 0 Effectiveness 4 Need for treatment 0.8 Net cost 3 SCORE 256, PUTS ON LINE 451

MOTION: To recommend the code and guideline note changes as presented. To recommend the biennial review changes for the severe acne line as presented. CARRIES 6-0.

 Topic: 2020 Biennial Review – Burn Line Reorganization

Discussion: Smits reviewed the proposed burn line reorganization. There was no discussion.

Recommended Actions: Effective January 1, 2020 1) Modify line 57 BURN, FULL THICKNESS GREATER THAN 10% OF BODY SURFACE as shown below 2) Merge lines 72 BURN, PARTIAL THICKNESS GREATER THAN 30% OF BODY SURFACE OR WITH VITAL SITE; FULL THICKNESS, LESS THAN 10% OF BODY SURFACE and 197 BURN, PARTIAL THICKNESS WITHOUT VITAL SITE REQUIRING GRAFTING, UP TO 30% OF BODY SURFACE into a new line as shown below with the line scoring as shown below 3) Modify line 602 MINOR BURNS as shown below 4) Delete the newly adopted GUIDELINE NOTE XXX MODERATE/SEVERE BURNS

Line 57 SEVERE BURNS BURN, FULL THICKNESS GREATER THAN 10% OF BODY SURFACE Treatment: FREE SKIN GRAFT, MEDICAL THERAPY ICD-10 All currently on line 57 (third degree burn and corrosion codes; burns of eyes, trachea, larynx, GI tract, ears) CPT: all currently on line 57 HCPCS: all currently on line 57

LINE XXX MODERATE BURNS Treatment: FREE SKIN GRAFT, MEDICAL THERAPY ICD-10: all second degree burn codes [remove all 3rd degree burn codes, L00 (Staphylococcal scalded skin syndrome) and L49.7 (Exfoliation due to erythematous condition involving 70-79 percent of body surface) and leave only on line 57] [Add L55.1 (Sunburn of second degree)] CPT: all currently on line 72 or 197 HCPCS: all currently on line 72 or 197

Line scoring for LINE XXX MODERATE BURNS Category 6 Impact on Healthy Life Years 7 Impact on Pain and Suffering 3 Population effects 0

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Vulnerable populations 0 Tertiary prevention 3 Effectiveness 4 Need for treatment 1 Net cost 2 SCORE 2080, PUTS ON LINE 127

602 MINOR BURNS Treatment: MEDICAL THERAPY ICD-10 All first degree and unspecified degree burn codes [remove all 2nd degree burn codes, L00 (Staphylococcal scalded skin syndrome) and L55.1 (Sunburn of second degree)] CPT: all currently on line 602 HCPCS: all currently on line 602

MOTION: To recommend the biennial review changes for the burns as presented. CARRIES 6-0.

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 Topic: Drug eluting stents

Discussion: Smits reviewed the summary document. Gibson asked whether the final evidence review concluded that drug eluting stents were more cost effective than bare metal stents. Smits replied that the evidence supported that drug eluting stents were at least no more expensive, and likely more cost effective based on the evidence reviewed.

Recommended Actions: 1) Add HCPCS C9600-C9608 (Drug eluting stent percutaneous coronary interventions) to lines a. 45 CORONARY ARTERY ANOMALY b. 69 ACUTE AND SUBACUTE ISCHEMIC HEART DISEASE, MYOCARDIAL INFARCTION, 98 HEART FAILURE c. 189 CHRONIC ISCHEMIC HEART DISEASE d. 285 COMPLICATIONS OF A PROCEDURE ALWAYS REQUIRING TREATMENT

MOTION: To recommend the code changes as presented. CARRIES 6-0.

 Topic: Eustachian tube inflation

Discussion: Smits reviewed the summary document. There was discussion about whether this procedure belonged on line 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS or line 652 SENSORY ORGAN CONDITIONS WITH NO OR MINIMALLY EFFECTIVE TREATMENTS OR NO TREATMENT NECESSARY. The argument in favor of line 660 was that this procedure was experimental. Line 652 might be easier to administer, because it clearly shows that the pairing of Eustachian tube inflation with Eustachian tube dysfunction was not covered. Hodges reported that her CCO had no issues with administering these types of codes when they are on line 660.

Recommended Actions: 1) Add Eustachian tube dilation (HCPCS C9745) to line 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS 2) Add an entry to GN173 as shown in Appendix A

MOTION: To recommend the code and guideline note changes as presented. CARRIES 6-0.

 Topic: Severe inflammatory skin disease guideline

Discussion: Smits reviewed the summary document. There was no discussion.

Recommended Actions: 1) Modify GN21 as shown in Appendix A

MOTION: To recommend the guideline note changes as presented. CARRIES 6-0.

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 Topic: Diagnostic indications and the PET guideline

Discussion: Smits reviewed the summary document. There was no discussion.

Recommended Actions: 1) Remove PET scan CPT codes (CPT 78608-78609, 78811-78816) from all current lines on the Prioritized List a. Advise HSD to place on the Diagnostic Procedures File 2) Change the current PET guideline to a diagnostic guideline as shown in Appendix A

MOTION: To recommend the code and guideline note changes as presented. CARRIES 6-0.

 Topic: Absorbable implants for nasal vestibular wall stenosis

Discussion: Smits reviewed the summary document. There was no discussion.

Recommended Actions: 1) Add HCPCS C9749 Repair of nasal vestibular lateral wall stenosis with implant(s)) to line 660 CONDITIONS FOR WHICH CERTAIN TREATMENTS HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS; UNPROVEN TREATMENTS 2) Add an entry to GN173 as shown in Appendix A

MOTION: To recommend the code and guideline note changes as presented. CARRIES 6-0.

 Topic: Migraine and botulinum toxin guideline edit

Discussion: Livingston presented the issue summary. Irwin queried how the requirement for failing 3 medications would be evaluated. For example, riboflavin and magnesium could be a good choice for some patients, and if these were used, would the 3 additional pharmacotherapies be required to have been tried. Livingston mentioned it may be variably interpreted by plans. Hodges clarified that each of the 3 pharmacotherapies would have to be evidence-based to count against the 3 required pharmacotherapies. They amended the staff recommendations to include the use of “e.g.” demonstrating that additional therapies could be an option, if evidence-based (and/or if there are contraindications to some of the drug classes).

Recommended Actions: 1) Modify Guideline Note 42 as shown in Appendix A

MOTION: To recommend the guideline note changes as amended. CARRIES 6-0.

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 Topic: Computer assisted musculoskeletal surgery

Discussion: Smits reviewed the summary document. There was no discussion.

Recommended Actions: 1) Place CPT 20985 (Computer-assisted surgical navigational procedure for musculoskeletal procedures, image-less) on line 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS a. Advise HSD to remove CPT 20985 from the Ancillary File 2) Add an entry to GN173 as shown in Appendix A

MOTION: To recommend the code and guideline note changes as presented. CARRIES 6-0.

 Topic: Prioritization of FDA-approved drugs on unfunded lines on the Prioritized List; Human Growth Hormone Deficiency

Discussion: Smits reviewed the summary document. There was no discussion.

Recommended Actions: Changes effective January 1, 2019 1) Remove an entry to GN172 as shown in Appendix A 2) Remove an entry to GN173 as shown in Appendix A 3) Add buprenorphine implant insertion procedure codes to line 4 SUBSTANCE USE DISORDER a. CPT 11981-11983 (Insertion, removal, and removal with re-insertion, non- biodegradable drug delivery implant) b. HCPCS G0516-G0518 (Insertion removal, and removal with re-insertion, of non- biodegradable drug delivery implants, 4 or more) 4) Delete GN67 5) Delete the following ICD-10 codes from Line 650, ENDOCRINE AND METABOLIC CONDITIONS WITH NO OR MINIMALLY EFFECTIVE TREATMENTS OR NO TREATMENT NECESSARY. a. E75.21 Fabry (-Anderson) disease b. E75.22 Gaucher disease c. E75.24 Niemann-Pick disease d. E76 series (Disorders of glycosaminoglycan metabolism) 6) Add ICD-10 E23.0 (Hypopituitarism) to line 650 ENDOCRINE AND METABOLIC CONDITIONS WITH NO OR MINIMALLY EFFECTIVE TREATMENTS OR NO TREATMENT NECESSARY 7) Add the following coding specifications to lines 40 PANHYPOPITUITARISM, IATROGENIC AND OTHER PITUITARY DISORDERS and 386 PITUITARY DWARFISM a. “ICD-10 E23.0 is included on this line for conditions other than adult human growth hormone deficiency.” 8) Add the following coding specification to line 650 a. “ICD-10 E23.0 is included on this line only for adult human growth hormone deficiency.” 9) Modify GN74 as shown in Appendix A

MOTION: To recommend the code and guideline note changes as presented. CARRIES 6-0.

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 Topic: Diabetes Prevention Program (DPP)

Discussion: Livingston reviewed the summary document. There was minimal discussion.

Recommended Actions: Effective January 1, 2019 1. Add R73.03 Prediabetes to Line 3 PREVENTION SERVICES WITH EVIDENCE OF EFFECTIVENESS a. Recommend HSD remove R73.03 from the Diagnostic File 2. Add Z86.32 Personal history of gestational diabetes to Line 3 3. Add 98962 Education and training for patient self-management by a qualified, nonphysician health care professional using a standardized curriculum, face-to-face with the patient (could include caregiver/family) each 30 minutes; 5-8 patients to Line 3 4. Add the temporary codes for DPP to Line 3 a. 0403T Preventive behavior change, intensive program of prevention of diabetes using a standardized diabetes prevention program curriculum, provided to individuals in a group setting, minimum 60 minutes, per day b. 0488T Preventive behavior change, online/electronic intensive program of prevention of diabetes using a standardized diabetes prevention program curriculum, provided to an individual, per 30 days 5. Adopt GUIDELINE NOTE XXX Diabetes Prevention Program as shown in Appendix B 6. Modify the Guideline Note on overweight and obesity as shown in Appendix A

MOTION: To recommend the code and guideline note changes as presented. CARRIES 6-0.

 Topic: Coverage of developmental diagnoses

Discussion: Livingston reviewed the summary document. There were questions about how many children the code changes may impact. A data run suggested that there is significant utilization of these codes, despite being currently located in the Diagnostic File. Staff clarified that this is helping to correct a wrong with schools, but will have impact in community settings as well. Irwin discussed the importance of prioritizing treatment for children. The group agreed that F88 was also appropriate to move into the funded region.

Recommended Actions: 1) Add R62.0 Delayed milestone in childhood to dysfunction lines: 292, 345, and 377. a. Add a coding specification as follows: “R62.0 is included on lines 292, 345, and 377 for children 8 and under.” 2) Add F80.9 Developmental disorder of speech and language, unspecified to dysfunction line 345. 3) Add F88 Other disorders of psychological development to lines 292, 345, and 377. a. Add a coding specification as follows: “F88 is included on these lines for developmental delay. When it is used to indicate sensory integration disorder or sensory processing disorder, it is included on Line 659.” 4) HSD staff to work with schools to help with identifying appropriate diagnoses 5) Place F82 Specific developmental disorder of motor function on Line 659 rather than in the Undefined File.

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MOTION: To recommend the coding and coding specification changes as presented. CARRIES 6-0.

 Topic: Postpartum depression screening

Discussion: This topic was tabled until October 2018

 Topic: Revisions to breast reconstruction guideline

Discussion: Smits reviewed the summary document. There was no discussion.

Recommended Actions: 1) Revise GN79 as shown in Appendix A

MOTION: To recommend the guideline note changes as presented. CARRIES 6-0.

 Topic: Cardiac MRI

Discussion: This topic was tabled until October 2018

 Topic: Coverage Guidance— Single fraction radiation for palliation of bone metastases

Discussion: Shaffer introduced the summary document. Obley reviewed the evidence report. There was no discussion.

Recommended Actions: 1) Guideline Note 12 was modified as shown in Appendix A 2) Statement of Intent 1 was modified as shown in Appendix A

MOTION: To approve the recommended changes to the Prioritized List based on the draft Single Fraction Radiotherapy for Palliation of Bone Metastases coverage guidance scheduled for review by HERC at their August 9, 2018 meeting. CARRIES 6-0. Note: Discussion by HERC was postponed until their October 4, 2018 meeting.

 Topic: Coverage Guidance— Urine drug testing

Discussion: Obley, Gingerich, and Livingston presented the information in the meeting materials. Olson asked about the limit on definitive tests of 7 substances per day. Gingerich clarified that the coding for these definitive tests is based on the number of drug classes examined per day. Livingston confirmed there is no evidence that looking for 20 drug classes is more effective than looking for seven; in fact, there is no evidence of effectiveness for urine drug testing at all—the recommendations are guideline-driven. Irwin asked about testing for various opioids and metabolites. She has seen separate charges for various drugs and metabolites within a class (e.g., hydrocodone and each norhydrone and other metabolites).

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After discussion, David Barba, a representative of Millennium Health, a urine drug testing lab, clarified that for Oregon Medicaid, tests are billed according to the number of drug classes assayed (e.g., opiates) but the results may, for instance, report on 5 metabolites within a class. He said an older billing methodology charged separately per substance tested for, but this methodology is no longer used by most payers. He suggested changing the language to refer to drug classes rather than drugs. For example, a test might test for ten benzodiazepines, which would be counted as a single drug class. With opioids, there is one class for most opioids, but there are separate classes for each synthetic opioid. Drugs such as fentanyl and tramadol aren’t picked up in presumptive tests. He said that many labs offer standard panels of tests which allows a provider to test for many classes by checking a single box on the order form. He said Millennium moved away from panels three years ago.

Based on this discussion, the subcommittee agreed to change the recommendation language to refer to seven drug classes rather than seven drugs.

Deena Loughany, Child Safety Program Manager for the Oregon Department of Human Services Child Welfare, offered public testimony. She also introduced Jay Wurscher, who works in her office. She said parental substance use is the number one child safety issue in Oregon and nationally, and the primary reason her agency is forced to terminate parental rights is the inability of parents to enter substance used disorder treatment. DHS uses urine drug tests as a key component in determining whether it is safe for a child to be in parent’s home. All tests must be confirmed because of the negative consequences that could result from a false positive test. All these drug tests are medically necessary from the child’s perspective. She recommended excluding tests related to child welfare from the coverage limits. DHS does not abuse testing or test excessively, but DHS parents need more testing than most patients in the health system. DHS child welfare already has administrative rules which govern these tests. She said there have been many rash and harmful decisions related to child placement made based upon testing that did not include confirmations. If not covered by Medicaid, funding for these tests would come out of the state budget without federal matching funds.

In response to clarifying questions, Wurscher said that the vast majority of testing goes to Legacy Laboratories. There is a six-panel test, and no variation from that test can happen without his approval. He said almost all the tests ordered are for OHP recipients; last year only $60,000 worth of testing was done for people who were not OHP recipients. He said DHS put caps on testing years ago; total testing went down to about $35,000 per month, but has risen recently due to better partnerships with drug courts and substance use disorder treatment providers. Testing is requested by DHS and performed at Legacy Lab and then billed to OHP, whether fee-for-service or for CCOs.

Olson asked how much this was considered at EbGS. Livingston said there was more discussion about drug courts, but this discussion was included as well. EbGS felt that drug courts were outside the purview, but did not discuss child welfare testing extensively. Olson suggested excluding child welfare testing. After discussion, the subcommittee recommended excluding these tests. Because of time limitations, the subcommittee did not draft this language in the meeting but recommended that HERC draft specific language. Hodges asked Wurscher for the document showing the DHS limits on testing. Wurscher said he would provide it.

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Hodges asked about using the term “medically necessary” when there is no doctor involved. What changes medically based on the result? Gibson said this scenario also arises in drug court. Wurscher said that people who test positive are offered or ordered to receive treatment. They have whole groups of staff pushing people towards treatment. Olson suggested that HERC take up this discussion in the afternoon.

Recommended Actions: 1) Advise the Health Systems Division to move codes G0659 and G0477-G0480 to the Diagnostic Procedures File and remove them from the Ancillary File. 2) Add HCPCS codes G0481 (definitive testing of 8-14 drug classes), G0482 (definitive testing of 15- 21 drug classes) and G0483 (definitive testing of 22 or more drug classes) to Line 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS. Advise HSD to remove these codes from the Ancillary File. 3) Add a diagnostic guideline note as shown in Appendix A, with the expectation that HERC will consider addition of language excluding tests related to child welfare from the limits.

MOTION: To approve the recommended changes to the Prioritized List, as amended, based on the draft coverage guidance on Urine Drug Testing, with continued discussion of specific language related to child welfare at HERC. CARRIES 6-0.

 Public Comment:

Andy Kranenburg, MD from Medford, called in to testify regarding the treatment of sacroiliac joint pain and dysfunction. Currently, there is a guideline on the Prioritized List regarding when treatment is appropriate, but the diagnosis is on an uncovered line. He requested reconsideration of the prioritization of sacroiliac joint dysfunction to a line above the funding line. He reviewed the HERC prioritization methodology, and SI joint dysfunction ended up with a very high score according to him and his colleagues, higher than many conditions that are currently covered. SI joint pain is a highly burdensome health state.

HERC staff will provide subcommittee members with Dr. Kranenburg’s written testimony, with review of the proposed and current line scoring. Smits will provide Dr. Kranenburg with the current scoring for this line.

 Issues for next meeting: • Chronic Pain Task Force updates • Coverage of ICD-10 F39 • Brow ptosis repair • Blepharoplasty • Postpartum depression screening • Cardiac MRI • SI joint dysfunction prioritization

 Next meeting:

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October 4, 2018 at Clackamas Community College, Wilsonville Training Center, Wilsonville, Oregon, Rooms 111-112.

 Adjournment:

The meeting adjourned at 1:17 PM.

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Revised Guideline Notes

Effective October 1, 2018

STATEMENT OF INTENT 1: PALLIATIVE CARE [Editor’s note: HERC did not review this recommendation for inclusion on the 10/1/2018 Prioritized List. HERC will review it at a later date.] It is the intent of the Commission that palliative care services are covered for patients with a life- threatening or serious progressive illness to alleviate symptoms and improve quality of life.

Palliative care services should include culturally appropriate discussions and medical decision making aligned with patient’s personal goals of therapy, assessment of symptom burden, assistance with advance care planning, care coordination, emotional, psychosocial and spiritual support for patients and their families. Palliative care services may be provided concurrently with life prolonging/curative treatments.

Some examples of services associated with an encounter for palliative care (ICD-10 Z51.5) that should be available to patients without regard to Prioritized List line placement: A) Inpatient palliative care consultations 1) Hospital Care E&M (CPT 99218-99233) B) Outpatient palliative care consultations provided in either the office or home setting 1) E&M Services (CPT 99201-99215) 2) Transitional Care Management Services (CPT 99495-6) 3) Advance Care Planning (CPT 99497-8) 4) Chronic Care Management (CPT 99487-99490) C) Psychological support and grief counseling (CPT 99201-99215) D) Medical equipment and supplies for the management of symptomatic complications or support activities of daily living E) Medications or acupuncture to reduce pain and symptom burden F) Surgical procedures or therapeutic interventions (for example, palliative radiation therapy) to relieve pain or symptom burden

Other services associated with palliative care includes: A) Social Work B) Clinical Chaplain/ Spiritual Care C) Care Coordination

It is NOT the intent of the Commission that coverage for palliative care encompasses those treatments that seek to prolong life despite substantial burdens of treatment and limited chance of benefit. See Guideline Note 12 PATIENT-CENTERED CARE OF ADVANCED CANCER TREATMENT OF CANCER WITH LITTLE OR NO BENEFIT.

GUIDELINE NOTE 19 DIAGNOSTIC GUIDELINE XX, PET SCAN GUIDELINES Lines 113,116,133,135,157,158,163,174,200,201,211,230,260,263,276,287,314 PET Scans are covered for diagnosis of the following cancers only: • Solitary pulmonary nodules and non-small cell lung cancer

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• Evaluation of cervical lymph node metastases when CT or MRI do not demonstrate an obvious primary tumor.

For diagnosis, PET is covered only when it will avoid an invasive diagnostic procedure, or will assist in determining the optimal anatomic location to perform an invasive diagnostic procedure.

PET scans are covered for the initial staging of the following cancers: • Cervical cancer only when initial MRI or CT is negative for extra-pelvic metastasis • Head and neck cancer when initial MRI or CT is equivocal • Colon cancer • Esophageal cancer • Solitary pulmonary nodule • Non-small cell lung cancer • Lymphoma • Melanoma

For staging, PET is covered when clinical management of the patient will differ depending on the stage of the cancer identified and either: A) the stage of the cancer remains in doubt after standard diagnostic work up, OR B) PET replaces one or more conventional imaging studies when they are insufficient for clinical management of the patient.

Restaging is covered only for cancers for which staging is covered and for thyroid cancer if recurrence is suspected and l131 scintography is negative. For restaging, PET is covered after completion of treatment for the purpose of detecting residual disease, for detecting suspected recurrence or to determine the extent of a known recurrence. PET is not covered to monitor tumor response during the planned course of therapy. PET scans are NOT indicated for routine follow up of cancer treatment or routine surveillance in asymptomatic patients.

PET scans are also indicated for preoperative evaluation of the brain in patients who have intractable seizures and are candidates for focal surgery. PET scans are NOT indicated for cardiac evaluation.

GUIDELINE NOTE 12, PATIENT-CENTERED CARE OF ADVANCED CANCER TREATMENT OF CANCER WITH LITTLE OR NO BENEFIT [Editor’s note: HERC did not review this recommendation for inclusion on the 10/1/2018 Prioritized List. HERC will review it at a later date.]

Cancer is a complex group of diseases with treatments that vary depending on the specific subtype of cancer and the patient’s unique medical and social situation. Goals of appropriate cancer therapy can vary from intent to cure, disease burden reduction, disease stabilization and control of symptoms. Cancer care must always take place in the context of the patient’s support systems, overall heath, and core values. Patients should have access to appropriate peer-reviewed clinical trials of cancer therapies. A comprehensive multidisciplinary approach to treatment should be offered including palliative care services (see STATEMENT OF INTENT 1, PALLIATIVE CARE).

Treatment with intent to prolong survival is not a covered service for patients who have progressive metastatic cancer with

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A) Severe co-morbidities unrelated to the cancer that result in significant impairment in two or more major organ systems which would affect efficacy and/or toxicity of therapy; OR B) A continued decline in spite of best available therapy with a non-reversible Karnofsky Performance Status or Palliative Performance score of <50% with ECOG performance status of 3 or higher which are not due to a pre-existing disability.

Treatments with intent to relieve symptoms or improve quality of life are covered as defined in STATEMENT OF INTENT 1, PALLIATIVE CARE. Examples include: A) Single-dose radiation therapy for painful bone metastases with the intent to relieve pain and improve quality of life. Single fraction radiotherapy should be given strong consideration for use over multiple fraction radiotherapy when clinically appropriate (e.g., not contraindicated by risk of imminent pathologic fracture, worsening neurologic compromise or radioresistant histologies such as sarcoma, melanoma, and renal cell carcinoma). B) Surgical decompression for malignant bowel obstruction. C) Medication therapy such as chemotherapy with low toxicity/low side effect agents with the goal to decrease pain from bulky disease or other identified complications. Cost of chemotherapy and alternative medication(s) should also be considered.

To qualify for treatment coverage, the cancer patient must have a documented discussion about treatment goals, treatment prognosis and the side effects, and knowledge of the realistic expectations of treatment efficacy. This discussion may take place with the patient’s oncologist, primary care provider, or other health care provider, but preferably in a collaborative interdisciplinary care coordination discussion. Treatment must be provided via evidence-driven pathways (such as NCCN, ASCO, ASH, ASBMT, or NIH Guidelines) when available.

The development of the single fraction radiotherapy portion of this guideline note was informed by a HERC coverage guidance. See http://www.oregon.gov/oha/HPA/CSI-HERC/Pages/Evidence-based- Reports.aspx.

GUIDELINE NOTE 21, SEVERE INFLAMMATORY SKIN DISEASE Lines 424,480,502,530,539,654 Inflammatory skin conditions included in this guideline are: A) Psoriasis B) Atopic dermatitis C) Lichen planus D) Darier disease E) Pityriasis rubra pilaris F) Discoid lupus

The conditions above are included on line 424 if severe, defined as having functional impairment (e.g. inability to use hands or feet for activities of daily living, or significant facial involvement preventing normal social interaction) AND one or more of the following: A) At least 10% of body surface area involved B) Hand, foot or mucous membrane involvement.

Otherwise, these conditions above are included on Lines 480, 502, 530, 539 and 654.

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For severe psoriasis, first line agents include topical agents, phototherapy and methotrexate. Second line agents include other systemic agents and oral retinoids and should be limited to those who fail, or have contraindications to, or do not have access to first line agents. Biologics are included on this line only for the indication of severe plaque psoriasis; after documented failure of first line agents and failure of (or contraindications to) a second line agent.

For severe atopic dermatitis/eczema, fist line agents include topical moderate to high potency corticosteroids, and narrowband UVB cyclosporine, methotrexate, and azathioprine. Second line agents include topical calcineurin inhibitors (e.g. pimecrolimus and topical, tacrolimus), topical phosphodiesterase (PDE)-4 inhibitors (e.g. crisaborole), and oral immunomodulatory therapy (e.g. cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, or oral corticosteroids). Use of the topical second line agents (e.g. calcineurin inhibitors and phosphodiesterase (PDE)-4 inhibitors) and should be limited to those who fail or have contraindications to first line agents. Biologic agents are included on this line for atopic dermatitis only after failure of or contraindications to at least one agent from each of the following three classes: 1) moderate to high potency topical corticosteroids, 2) topical calcineurin inhibitors or topical phosphodiesterase (PDE)-4 inhibitors, and 3) oral immunomodulator therapy first and second line agents.

GUIDELINE NOTE 42, CHEMODENERVATION FOR CHRONIC MIGRAINE Line 409 Chemodenervation for treatment of chronic migraine (CPT 64615) is included on this line for prophylactic treatment of adults who meet all of the following criteria:

A) have chronic migraine defined as headaches on at least 15 days per month of which at least 8 days are with migraine B) has not responded to or have contraindications to at least three prior pharmacological prophylaxis therapies (e.g. beta-blocker, calcium channel blocker, anticonvulsant, or tricyclic antidepressant) C) their condition has been appropriately managed for medication overuse D) treatment is administered in consultation with a neurologist or headache specialist.

Treatment is limited to two injections given 3 months apart. Additional treatment requires documented positive response to therapy. Positive response to therapy is defined as a reduction of at least 7 headache days per month compared to baseline headache frequency.

GUIDELINE NOTE 79, BREAST RECONSTRUCTION Line 191 Breast reconstruction is only covered after mastectomy as a treatment for breast cancer or as prophylactic treatment for the prevention of breast cancer in a woman who qualifies under Guideline Note 3, and must be completed within 5 years of initial mastectomy. Revision of previous reconstruction is only covered in cases where the revision is required to address complications of the surgery (wound dehiscence, fistula, chronic pain directly related to the surgery, etc.). Revisions are not covered solely for cosmetic issues.

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Breast reconstruction may include contralateral reduction mammoplasty (CPT 19318) or contralateral mastopexy (CPT 19316). Mastopexy is only to be covered when contralateral reduction mammaplasty is inappropriate for breast reconstruction and mastopexy will accomplish the desired reconstruction result.

GUIDELINE NOTE 148, BIOMARKER TESTS OF CANCER TISSUE Lines 157,184,191,230,263,271,329,660 The use of multiple molecular testing tissue of origin testing to select targeted cancer therapy (e.g., CPT 81504) is included on line 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS.

For early stage breast cancer, the following breast cancer genome profile tests are included on Line 191 when the listed criteria are met. One test per primary breast cancer is covered when the patient is willing to use the test results in a shared decision-making process regarding adjuvant chemotherapy. Lymph nodes with micrometastases less than 2 mm in size are considered node negative. • Oncotype DX Breast Recurrence Score (CPT 81519) for breast tumors that are estrogen receptor positive, HER2 negative, and either lymph node negative, or lymph node positive with 1-3 involved nodes. • EndoPredict (using CPT 81599) and Prosigna (CPT 81520 or PLA 0008M) for breast tumors that are estrogen receptor positive, HER2 negative, and lymph node negative. • MammaPrint (using CPT 81521 or HCPCS S3854) for breast tumors that are estrogen receptor or progesterone receptor positive, HER2 negative, lymph node negative, and only in those cases categorized as high clinical risk. EndoPredict, Prosigna, and MammaPrint are not included on Line 191 for early stage breast cancer with involved axillary lymph nodes. Oncotype DX Breast Recurrence Score is not included on Line 191 for breast cancer involving four or more axillary lymph nodes or more extensive metastatic disease.

Oncotype DX Breast DCIS Score (CPT 81479) and Breast Cancer Index (may use CPT 81479, 81599, 84999, S3854) are included on Line 660.

For melanoma, BRAF gene mutation testing (CPT 81210) is included on Line 230 MALIGNANT MELANOMA OF SKIN.

For lung cancer, epidermal growth factor receptor (EGFR) gene mutation testing (CPT 81235) is included on Line 263 CANCER OF LUNG, BRONCHUS, PLEURA, TRACHEA, MEDIASTINUM AND OTHER RESPIRATORY ORGANS only for non-small cell lung cancer. KRAS gene mutation testing (CPT 81275) is not included on Line 263.

For colorectal cancer, KRAS gene mutation testing (CPT 81275) is included on Line 157. BRAF (CPT 81210) and Oncotype DX (81525) are not included on Line 157. Microsatellite instability (MSI) is included on line 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS.

For bladder cancer, Urovysion (88120, 88121) testing is included on line 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS.

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For prostate cancer, Oncotype DX Genomic Prostate Score (81479), Prolaris Score Assay (81541), and Decipher RP (81479) are included on Line 660.

The development of this guideline note was informed by a HERC coverage guidance. See http://www.oregon.gov/oha/HPA/CSI-HERC/Pages/Evidence-based-Reports.aspx.

GUIDELINE NOTE 173, INTERVENTIONS THAT ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS FOR CERTAIN CONDITIONS Line 660 The following Interventions are prioritized on Line 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS:

Procedure Code Intervention Description Rationale Last Review C9745 Nasal endoscopy, surgical; Insufficient evidence of May, 2018 balloon dilation of effectiveness Eustachian tube C9749 Repair of nasal vestibular Unproven treatment August, 2018 lateral wall stenosis with implant(s) 20985 Computer-assisted Insufficient evidence of August 2018 surgical navigational effectiveness procedure for musculoskeletal procedures, image-less G0481-G0483 Urine drug testing, (Note: Not specified at August, 2018 definitive for >7 drug this time; see will be classes addressed in future errata) Breast Cancer Gene • Mammostrat Unproven Intervention May, 2018 (breast Expression tests • Oncotype DX Breast cancer) billed with DCIS Score nonspecific codes • Breast Cancer Index Coverage Guidance (e.g. 81479, 81599, • IHC4 Blog (Breast) 84999, S3854)

Prostate Cancer • Oncotype DX Genomic Unproven Intervention January, 2018 Gene Expression Prostate Score (prostate) tests billed with • Decipher RP for prostate nonspecific codes cancer Coverage Guidance (e.g. 81479, 81599, Blog (Prostate) 84999)

81301 Microsatellite instability Unproven Intervention August, 2015 (MSI) for colorectal cancer Coverage Guidance Blog

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81479 • Oncotype DX Breast Unproven Intervention May, 2018 (breast) DCIS Score • Breast Cancer Index Coverage Guidance • Oncotype DX Genomic Blog (Breast) Prostate Score • Decipher RP for prostate January, 2018 cancer (prostate) 81504 Oncology (tissue of origin), Unproven Intervention August, 2015 microarray gene expression profiling of > 2000 genes, utilizing formalin-fixed paraffin- embedded tissue, algorithm reported as tissue similarity scores) 81525 Oncotype DX for colon Insufficient evidence of November, 2015 cancer effectiveness 88120, 88121 Urovysion for bladder Insufficient evidence of cancer effectiveness 96119 Neuropsychological No evidence of January, 2014 testing (eg, Halstead- effectiveness Reitan Neuropsychological Battery, Wechsler Memory Scales and Wisconsin Card Sorting Test) 96120 Neuropsychological testing (eg, Wisconsin Card Sorting Test)

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For implementation January 1, 2019

GUIDELINE NOTE 5, OBESITY AND OVERWEIGHT Line 320 Medical treatment of overweight (with known cardiovascular risk factors) and obesity in adults is limited to intensive counseling on nutrition and physical activity, provided by health care professionals. Intensive counseling is defined as face-to-face contact more than monthly. A multidisciplinary team is preferred, but a single clinician could also deliver intensive counseling in primary care or other settings.

Intensive counseling visits are included on this line for 6 months. Intensive counseling visits may continue for an additional 6 months (up to 12 months) as long as there is evidence of continued weight loss or improvement in cardiovascular risk factors based on the intervention. Maintenance visits at the conclusion of the intensive treatment are included on this line no more than monthly after this intensive counseling period. The characteristics of effective behavioral interventions include: high intensity programs; multicomponent (including at a minimum diet and exercise), group-based commercial programs; Mediterranean diet; and the following sub-elements -- calorie counting, contact with a dietician, and comparison to peers.

Known cardiovascular risk factors in overweight persons for which this therapy is effective include: hypertension, dyslipidemia, prediabetes, or the metabolic syndrome. Treatment of prediabetes with the Diabetes Prevention Program (DPP) is addressed on Line 3 in Guideline Note 179.

Medical treatment of obesity in children is limited to comprehensive, intensive behavioral interventions. For treatment of children up to 12 years old, interventions may be targeted only to parents, or to both parents and children.

Pharmacological treatments and devices (e.g. gastric balloons, duodenal jejunal bypass liners, and vagus nerve blocking devices) for obesity are not intended to be included as services on this line or any other line on the Prioritized List.

GUIDELINE NOTE 67, ENZYME REPLACEMENT THERAPY Lines 60,147,660 Enzyme replacement therapy for infantile Pompe’s disease is included on Line 147. All other enzyme replacement therapies for inborn errors of metabolism are included on Line 660.

GUIDELINE NOTE 74, GROWTH HORMONE TREATMENT Lines 40,386,467,650 Treatment with growth hormone is included only for children with: pituitary dwarfism, Turner’s syndrome, Prader-Willi-syndrome, Noonan’s syndrome, short stature homeobox-containing gene (SHOX), chronic kidney disease (stages 3, 4, 5 or 6) and those with renal transplant. Treatment with growth hormone should continue only until adult height as determined by bone age is achieved. Treatment is not included for isolated deficiency of human growth hormone or other conditions in adults.

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GUIDELINE NOTE 132, ACNE CONGLOBATA AND ACNE FULMINANS Line 373 Acne conglobata is only included on Line 373 if it involves recurrent abscesses or communicating sinuses. ICD-10 L70.0 is included on line 373 only for acne fulminans.

GUIDELINE NOTE 172, INTERVENTIONS WITH MARGINAL CLINICAL BENEFIT OR LOW COST- EFFECTIVENESS FOR CERTAIN CONDITIONS Line 500 The following interventions are prioritized on Line 500 CONDITIONS FOR WHICH INTERVENTIONS RESULT IN MARGINAL CLINICAL BENEFIT OR LOW COST-EFFECTIVENESS:

Procedure Intervention Description Rationale Last Review Code 11981 Implantable buprenorphine for Not cost effective compared November, 2017 G0516, opioid use disorder for patients to equally efficacious G0518 who are clinically stable on 8 mg alternative formulations daily or less of buprenorphine or equivalent for at least 6 months

Procedure Code Intervention Description Rationale Last Review S9357 Enzyme replacement therapy No clinically August, 2012 (e.g. idursulfase and similar important benefit medications) for all inborn error of metabolism conditions except infantile Pompe’s disease 11981 Implantable buprenorphine Unproven November, 2017 G0516, G0518 for opioid use disorder for treatment patients other than those who are clinically stable on 8 mg daily or less of buprenorphine or equivalent for at least 6 months

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New Guideline Notes

Effective October 1, 2018

DIAGNOSTIC GUIDELINE D23 URINE DRUG TESTING [Editor’s Note: The language in green below was adopted at the HERC meeting later the same day]

Urine drug testing (UDT) using presumptive testing is a covered diagnostic benefit when the results will affect treatment planning. Definitive testing is covered as a confirmatory test only when the result of the presumptive testing is inconsistent with the patient’s history, presentation, or current prescribed medication plan, and the results would change management.

Definitive testing other than to confirm the results of a presumptive test as specified above is not covered, unless the clinician suspects use of a substance that is inadequately detected by presumptive UDT (e.g., fentanyl). Definitive testing is limited to no more than seven drug classes per date of service.

For patients receiving treatment for a substance use disorder, presumptive testing on up to 36 dates of service and definitive testing on up to 12 dates of service per year are covered. These limits must be applied in accordance with mental health parity law.

For patients receiving chronic opioid therapy for chronic pain, frequency of testing depending on the patient’s risk level (using a validated opioid risk assessment tool). Definitive testing should be conducted only for confirmatory purposes as described above and should not exceed 12 dates of service per year: • Low Risk: Random presumptive testing on up to two dates of service per year • Moderate Risk: Random presumptive testing on up to four dates of service per year • High Risk: Random presumptive testing on up to 12 dates of service per year

In patients with unexplained alteration of mental status and when knowledge of drug use is necessary for medical management (e.g., emergency department evaluation for altered mental status), UDT (presumptive and confirmatory definitive testing, if indicated) is covered in excess of the above limitations.

Urine drug testing conducted in accordance with policy of the DHS Office of Child Welfare Programs, when medically necessary, is also covered in excess of these limitations.

GUIDELINE NOTE 19 NEUROPSYCHOLOGICAL TESTING FOR PTSD Line 173 Neuropsychological testing is included on this line only when there is question of cognitive deficit or impairment and such testing is required to assist in making the correct diagnosis.

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Effective January 1, 2019

GUIDELINE NOTE XXX DIABETES PREVENTION PROGRAM Line 3 Prediabetes (R73.03) and personal history of gestational diabetes (Z86.32) are included on this line only for the Diabetes Prevention Program (DPP). The only programs included are CDC-recognized lifestyle change programs for DPP.

To be eligible for referral to a CDC-recognized lifestyle change program, patients must meet the following requirements: . Be at least 18 years old and . Be overweight (body mass index ≥25; ≥23 if Asian) and . Have no previous diagnosis of type 1 or type 2 diabetes and . Not have end-stage renal disease and . Have a blood test result in the prediabetes range within the past year: ◦ Hemoglobin A1C: 5.7%–6.4% or ◦ Fasting plasma glucose: 100–125 mg/dL or ◦ Two-hour plasma glucose (after a 75 gm glucose load): 140–199 mg/dL or ◦ Be previously diagnosed with gestational diabetes

Effective January 1, 2020

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2019 ICD-10 Code Placement [insert Excel document from the minutes folder here]

Value-based Benefits Subcommittee Minutes, 8/9/2018 Appendix C Section 3.0 Consent Agenda- Straightforward Items Consent Agenda Issues—October 2018

Code Code Description Line(s) Involved Issue Recommendation(s) H93.8X Other specified disorders of ear 444 HEARING LOSS - OVER AGE H93.8X is found on line 311 for Add ICD-10 H93.8X to line 444 OF FIVE hearing loss under the age of 5, but not on line 444. A similar code (H94.8) is on both lines. This code has few subdiagnoses. Z87.891 Personal history of nicotine INFORMATIONAL DIAGNOSIS FILE Z87.891 is informational, but it is Add Z87.891 to Line 3 Preventive dependence used as a primary diagnosis when Services ordering a screening lung CT for people with a history of 30 pack years of smoking. This is a USPSTF recommendation. G0297 Low dose ct scan (ldct) for lung cancer screening is on Line 3. 58541- Laparoscopy, surgical, 395 ENDOMETRIOSIS AND Line 395 is missing several Add 58541-58544 to line 395 58544 supracervical hysterectomy ADENOMYOSIS hysterectomy CPT codes; other hysterectomy codes appear on this line. 33724 Repair of isolated partial 105 TETRALOGY OF FALLOT ICD10 Q26.8 (Other congenital Add 33724 to line 105 anomalous pulmonary (TOF); CONGENITAL VENOUS malformations of great veins) venous return (eg, Scimitar ABNORMALITIES which, which is used for Syndrome) Scimitar Syndrome, is on line 105. CPT 33724 is on line 130 TOTAL ANOMALOUS PULMONARY VENOUS CONNECTION. These codes should pair. L55.2 Sunburn of third degree 57 SEVERE BURNS In August, 2018, HERC created a Add ICD-10 L55.2 to the new line 181 CONDITIONS INVOLVING new third degree burn line, 57 SEVERE BURNS effective Jan 1, EXPOSURE TO NATURAL effective Jan 1, 2020. L55.2 was 2020; remove from line 181 at ELEMENTS (E.G., LIGHTNING not considered. It’s currently on that time. STRIKE, HEATSTROKE) line 181 but should be on new line 57.

1 Consent Agenda Issues—October 2018

Code Code Description Line(s) Involved Issue Recommendation(s) L73.0 Acne keloid 373 ACNE CONGLOBATA ICD-10 L73.0 was mistakenly Remove ICD-10 L73.0 from line (SEVERE CYSTIC ACNE) added to line 373 and should be 373 removed. It should remain on line 520 ROSACEA; ACNE

2 Straightforward Guideline Note Changes October 2018

1) Guideline note 65 lists a series of telephone and email consultation CPT codes (CPT 98966- 98969 Telephone assessment and management service provided by a qualified nonphysician health care professional to an established patient, parent, or guardian….). There is another set of telephone consultation codes not included in this guideline that are appropriate, CPT 99441- 99443 (Telephone evaluation and management service by a physician or other qualified health care professional who may report evaluation and management services provided to an established patient, parent, or guardian…). These codes should be added to the GN as shown below.

GUIDELINE NOTE 65, TELEPHONE AND EMAIL CONSULTATIONS Included on all lines with evaluation & management (E&M) codes Telephone and email consultations (CPT 98966-98969, 99441-99443) must meet the following criteria: 1) Patient must have a pre-existing relationship with the provider as demonstrated by at least one prior office visit within the past 12 months. 2) E-visits must be provided by a physician or licensed provider within their scope of practice. 3) Documentation should model SOAP charting; must include patient history, provider assessment, and treatment plan; follow up instructions; be adequate so that the information provided supports the assessment and plan; must be retained in the patient’s medical record and be retrievable. 4) Telephone and email consultations must involve permanent storage (electronic or hard copy) of the encounter. 5) Telephone and email consultations must meet HIPAA standards for privacy. 6) There needs to be a patient-clinician agreement of informed consent for E-visits by email. This should be discussed with and signed by the patient and documented in the medical record.

2) Add GN166 to line 401 CONDITIONS OF THE BACK AND SPINE. GN166 is currently only attached to line 558 MACROMASTIA, which has raised questions by some providers.

GUIDELINE NOTE 166, BREAST REDUCTION SURGERY FOR MACROMASTIA Line 401, 558 Breast reduction surgery for macromastia is not covered as a treatment for neck or back pain resulting from the macromastia due to lack of high quality evidence of effectiveness.

S86 Series Review

Issue: The orthopedic ICD-10 review never completed their review of all orthopedic-related codes. The S86 series was never reviewed and several diagnoses appear to be on inappropriate lines. This topic was brought to our attention by a CCO medical director question.

The lines proposed for placement have a guideline which determines when the diagnosis is on the covered line and when on the lower line.

GUIDELINE NOTE 98, SIGNIFICANT INJURIES TO LIGAMENTS, TENDONS AND MENISCI Lines 376,430,605 Significant injuries to ligaments, tendons and/or menisci are those that result in clinically demonstrable joint instability or mechanical interference with motion. Significant injuries are covered on Line 376 or Line 430 for both medical and surgical interventions and non-significant injuries are included on Line 605.

Iliotibial (IT) band syndrome (ICD10 M76.3) is included on Line 376 only for pairing with 2 physical therapy visits with a provider licensed to provide physical therapy services, anti-inflammatory medications, and primary care office visits. Otherwise, it is included on Line 605.

HERC staff recommendation: 1) Move the codes below to the recommended line(s)

ICD-10 Code Description Current line(s) Recommended Line(s) Code S86.11 Strain of other muscle(s) 430 Internal derangement of 376 DISRUPTIONS OF THE and tendon(s) of knee and ligamentous LIGAMENTS AND TENDONS OF posterior muscle group disruptions of the knee, THE ARMS AND LEGS, at lower leg level resulting in significant EXCLUDING THE KNEE, injury/impairment RESULTING IN SIGNIFICANT 605 Sprains and strains of INJURY/IMPAIRMENT adjacent muscles and joints, 605 minor S86.21 Strain of muscle(s) and 430, 605 376, 605 tendon(s) of anterior muscle group at lower leg level S86.31 Strain of muscle(s) and 430, 605 376, 605 tendon(s) of peroneal muscle group at lower leg level, right le S86.81 Strain of other muscle(s) 430, 605 376, 605 and tendon(s) at lower leg level S86.91 Strain of unspecified 430, 605 376, 605 muscle(s) and tendon(s) at lower leg level

Gender Dysphoria Coding Issues October 2018

Question: Should various procedures be added to the gender dysphoria line?

Question source: Various providers

Issue: Various non-pairings have arisen with line 312 GENDER DYSPHORIA/TRANSEXUALISM. These questions mainly involve the types of PT included on the line, as well as lack of inclusion for several urethral procedures. These procedures have been discussed with gender dysphoria experts. The expert and HERC staff recommendations are shown below. These CPT codes all appear on a variety of other covered lines.

Urethroplasty codes not appearing on line 312: 53405 Urethroplasty; second stage (formation of urethra), including urinary diversion 53410 Urethroplasty, 1-stage reconstruction of male anterior urethra

PT codes not appearing on line 312: 97112 Therapeutic procedure, 1 or more areas, each 15 minutes; neuromuscular reeducation of movement, balance, coordination, kinesthetic sense, posture, and/or proprioception for sitting and/or standing activities 97116 Therapeutic procedure, 1 or more areas, each 15 minutes; gait training (includes stair climbing) 97535 Self-care/home management training (eg, activities of daily living (ADL) and compensatory training, meal preparation, safety procedures, and instructions in use of assistive technology devices/adaptive equipment) direct one-on-one contact, each 15 minutes

Expert input: Daniel Dugi, MD, OHSU surgery All of the gender-affirming genital surgeries (vaginoplasty/vulvoplasty, metoidioplasty, phalloplasty) involve extensive operation on the urethra, hence a urethroplasty code, which captures time and effort not described by other codes. The 2nd stage code is used particularly with phalloplasty—in the first stage phalloplasty we create the phallus for the penile portion, but we don’t connect it to the native urethral position until a second stage surgery. Additional, for phalloplasty patients who have complications of fistula or stricture, we often need to address that in 2 stages, hence the need for a 2nd stage procedure code.

These other PT codes seem to relate to physical therapists more holistic approach to rehab, especially after a major surgery that requires people to limit their walking. I don’t think they are really specific to gender dysphoria treatment but helpful instead for recovery after these major surgeries.

HERC staff recommendations: 1) Add CPT 53405 (Urethroplasty; second stage (formation of urethra), including urinary diversion) and 53410 (Urethroplasty, 1-stage reconstruction of male anterior urethra) to line 312 GENDER DYSPHORIA/TRANSEXUALISM 2) Do not add the PT codes as they are not indicated for gender dysphoria treatment

Section 4.0 Previously Discussed Items Unspecified Mood Disorder

Question: Should restrictions be placed on the utilization of ICD-10 F39 (Unspecified mood disorder)?

Question source: Lea Forsman; OHA behavioral health team

Issue: Until 2015, F39 (Unspecified mood [affective] disorder) had a guideline note restricting use to children 18 years and under, with pairings allowed only with a few procedure codes (see the historical GN28 below). This guideline was removed in 2015 due to concerns that under the ACA, such restrictions would be considered age discrimination without a medical justification. Additionally, HERC staff felt that mental health parity rules would not allow restriction of use of the F39 code to only a few services. F39 is currently on line 204 DEPRESSION AND OTHER MOOD DISORDERS, MILD OR MODERATE.

There was discussion at the August 2018 VBBS meeting regarding this topic. Hodges felt that the staff proposed guideline note would make the exceptions process more streamlined. Gibson felt that a guideline note was not needed based on what appeared to be generally appropriate utilization. HERC staff was directed to consult the CCO medical directors to determine if a guideline note was desirable and useful for the CCOs.

Material included in August 2018 issue summary: BHAP discussed this topic at their June 2018 meeting. It was noted that this code is often used when a patient is developing a disorder, but has not had enough symptoms to meet diagnostic criteria for any specific disorder. Bradshaw, however, noted that he sees this diagnosis used for years on end and no more specific diagnosis is ever made. There was agreement that this diagnosis could be overused. Savicki recalled that this diagnosis had a guideline to initially restrict to kids due to not wanting to give diagnosis to kids like bipolar disorder or other disorder which might lead to overtreatment, etc. Cobb reflected that overuse might not be a problem if it reflects more people getting into initial treatment.

BHAP requested that HERC staff reach out to the OHA team to get additional information about the overutilization they reported. Is the overuse just more initial diagnoses of more patients, or is it being used for a long time for single patients, which would be sloppy coding. Staff reached out to the OHA behavioral health team and did a utilization review (below).

BHAP members were divided on the need for a guideline for F39. In general, members were supportive of a guideline; however, some felt that there should be somewhat broad leeway for clinicians to see a patient multiple times to determine an exact diagnosis. Rural areas may have more need for this code due to a relative lack of behavioral health workforce to assist in making a definitive diagnosis.

Utilization data: 2017 data, FFS and CCO Of 4220 individuals. 1 had 106 unique dates of service (DOS). 14 had >30; 142 had >10, 358 had >5, 967 had 3 or more. 2472 had 1, 781 had 2. Therefore 77% of patients had this diagnosis used 1 or 2 times The majority of claims were for outpatient clinic visits. Psychotherapy, lab tests, ER visits, and inpatient treatment were also billed with this code.

Unspecified Mood Disorder

Proposed guideline note:

GUIDELINE NOTE XXX UNSPECIFIED MOOD DISORDER Line 204 ICD-10 F39 (Unspecified mood [affective] disorder) is included on line 204 only when 1) A person is in the diagnostic phase of a workup, OR 2) A person is seen in an urgent/emergency care setting where the focus is on directing the person to the correct provider, OR 3) Used for services for pre-verbal children or patients who are non-verbal, OR 4) It is not possible to give a more specific diagnosis due to cultural/stigma considerations.

CCO responses: 1) CareOregon: our consensus is that use of F39 does not present enough of a problem to warrant an intervention by HERC, either a new guideline note or visit limit 2) Pacific Source: recommended adoption of the guideline with removal of #4 3) FFS: did not recommend adoption of the guideline as limits may not be appropriate

HERC staff summary BHAP and the CCOs were split on the need for a new guideline for F39 Unspecified mood disorder. Given this split in opinion, HERC staff recommend no guideline at this time, with review of utilization in a year or two. If utilization is seen as problematic, then a guideline can be considered at that time.

BHAP/HERC staff recommendation: 1) Do not adopt a new guideline regarding F39 (unspecified mood disorder) for line 204 DEPRESSION AND OTHER MOOD DISORDERS, MILD OR MODERATE

Brow Ptosis 2019 ICD-10 Code Placement Issues

Issue: ICD10 H57.81 (Brow ptosis) was discussed at the August 2018 VBBS meeting. The staff recommendation was to add the new code to 3 lines with appropriate CPT codes, with a new guideline to specify when the diagnosis is on each line. One covered line would be for congenital cases in children, the second covered line would be for acquired cases in older patients that caused significant visual issues, and the uncovered line would be for cosmetic brow ptosis. The proposed guideline was written with the assistance of pediatric and adult ophthalmologists.

At the August meeting, VBBS members felt that the pediatric placement and section of the guideline were appropriate. However, the wording of the guideline for the adult acquired section was felt to be too “jargon-y” and difficult to understand by non-ophthalmology reviewers. HERC staff was instructed to work with ophthalmologists to try to make the wording more understandable by the average reviewer.

HERC staff have worked with CCO medical directors and ophthalmologists. There has been a dichotomy of thoughts on simplifying the brow ptosis guideline. Some medical directors and all the ophthalmologists thought that using the common wording that is included in CMS guidelines and most private insurer guidelines is preferable, as this is what ophthalmologists are used to documenting. Other CCO medical directors felt that simplification would be preferable and assist in reviewing these types of claims.

There was also a couple of responses from CCO medical directors who felt that brow ptosis was a low priority issue and who objected to the placement on a covered line.

Definition: Brow ptosis is decent of the brow and brow fat pad and typically occurs with advancing age. Drooping of the eyebrows can occur to such an extent that excess tissue is pushed into the upper eyelid that may cause mechanical blepharoptosis and/or dermatochalasis. In the most severe cases, the drooping can obstruct the visual field and cause positional head changes. There are 2 types of ptosis: acquired and congenital. Ptosis in early childhood can lead to amblyopia. Ptosis may occur because the levator muscle's attachment to the lid is weakening with age. Acquired ptosis can also be caused by a number of different things, such as disease that impairs the nerves, diabetes, injury, tumors, inflammation, or aneurysms. Congenital ptosis may be caused by a problem with nerve innervation or a weak muscle. Drooping eyelids may also be the result of diseases such as myotonic dystrophy or myasthenia gravis. It is considered a cosmetic issue unless the visual field is impacted. The treatment is surgical repair (blepharoptosis).

Similar Codes: 1) CPT 67900 (Repair of brow ptosis (supraciliary, mid-forehead or coronal approach)) is on lines 351 STRABISMUS DUE TO NEUROLOGIC DISORDER and 469 ACQUIRED PTOSIS AND OTHER EYELID DISORDERS WITH VISION IMPAIRMENT. 2) ICD-10 Q10.0 (Congenital ptosis) is on lines 393 STRABISMUS WITHOUT AMBLYOPIA AND OTHER DISORDERS OF BINOCULAR EYE MOVEMENTS; CONGENITAL ANOMALIES OF EYE; LACRIMAL DUCT OBSTRUCTION IN CHILDREN and 469. 3) GN130 details criteria for the similar procedure of blepharoplasty (upper eyelid surgery)

Brow Ptosis 2019 ICD-10 Code Placement Issues

GUIDELINE NOTE 130, BLEPHAROPLASTY Line 469 Blepharoplasty is covered when 1) visual fields demonstrate an absolute superior defect to within 15 degrees of fixation, 2) upper eyelid position contributes to difficulty tolerating a prosthesis in an anophthalmic socket, 3) essential blepharospasm or hemifacial spasm is present, OR 4) when there is significant ptosis in the downgaze reading position.

HERC staff recommendations: 1) Place H57.81 (Brow ptosis) on line 393 STRABISMUS WITHOUT AMBLYOPIA AND OTHER DISORDERS OF BINOCULAR EYE MOVEMENTS; CONGENITAL ANOMALIES OF EYE; LACRIMAL DUCT OBSTRUCTION IN CHILDREN for congenital brow ptosis and on lines 469 ACQUIRED PTOSIS AND OTHER EYELID DISORDERS WITH VISION IMPAIRMENT Treatment PTOSIS REPAIR and line 652 SENSORY ORGAN CONDITIONS WITH NO OR MINIMALLY EFFECTIVE TREATMENTS OR NO TREATMENT NECESSARY for acquired brow ptosis a. Will pair with repair CPT codes 2) Remove ICD-10 Q10.0 (Congenital ptosis) from line 469 and leave only on line 393 3) Adopt one of the two options below as a new guideline note:

OPTION 1: preferred by ophthalmology as consistent with other payer guidelines:

GUIDELINE NOTE XXX BROW PTOSIS Lines 393,469,652 Brow ptosis repair is included on line 393 for congenital brow ptosis in children only when ALL the following criteria are met: 1) The condition developed within the first year of life, and 2) Ptosis interferes with field of vision, and 3) The child has abnormal head posture (e.g., head tilt or turn, chin up or chin down), amblyopia or strabismus or is at high risk for development of amblyopia.

Brow ptosis repair is included on line 469 for acquired brow ptosis only when ALL the following criteria are present: 1) Brow ptosis is causing a functional impairment of upper/outer visual fields with documented complaints of interference with vision or visual field related activities such as difficulty reading or driving due to upper brow drooping, looking through eyelashes, or seeing the upper eyelid skin, and 2) Photographs show the eyebrow below the supraorbital rim, and 3) Overhanging skin due to brow ptosis is sufficiently low to produce a visually significant field restriction of approximately 30 degrees or less from fixation or a central "pseudo- margin to reflex distance" of 2.0 mm or less, and 4) The visual field impairment cannot be corrected by an upper lid blepharoplasty alone.

Otherwise, brow ptosis repair is included on line 652.

Brow Ptosis 2019 ICD-10 Code Placement Issues

OPTION 2: suggested by medical directors with simplified language

Brow ptosis repair is included on line 469 for acquired brow ptosis only when ALL the following criteria are present: 1) Brow ptosis is causing a functional impairment of upper/outer visual fields with documented complaints of interference with vision or visual field related activities such as difficulty reading or driving due to upper brow drooping, looking through eyelashes, or seeing the upper eyelid skin, and 2) Photographs show the eyebrow below the supraorbital rim, and 3) The visual field impairment cannot be corrected by an upper lid blepharoplasty alone.

Otherwise, brow ptosis repair is included on line 652.

Blepharoplasty

Question: Should the blepharoplasty guideline be clarified and brought into alignment with the CMS coverage criteria?

Question source: Holly Jo Hodges, CCO medical director

Issue: Recently, dermatochalasis was added to a covered line to pair with blepharoplasty. The blepharoplasty guideline was written by the ophthalmology ICD-10 reviewers, but never utilized as the diagnosis code needed for pairing with blepharoplasty was not added to the line in error. In May 2018, the HERC added the dermatochalasis diagnosis code to the blepharoplasty line. Dr. Hodges requested that the blepharoplasty guideline be reviewed. In particular, the first clause of the guideline was found to be confusing. CMS national coverage determination language has been updated since the ICD-10 ophthalmology review and Dr. Hodges suggested substituting in the current LCD language. The new language requires that the eyelid droop is “sufficiently low to produce a visually significant field restriction considered by this policy to be approximately 30 degrees or less from fixation.” Changing the current language requiring “visual fields demonstrate an absolute superior defect to within 15 degrees of fixation” to language requiring “30 degree loss of visual field” will allow ease of reviewing and reduce confusion among ophthalmologists.

This change was discussed at the August, 2018 VBBS meeting. HERC staff were directed to clarify the wording in the guideline with ophthalmology to allow non-ophthalmologists to better understand what the guideline is requiring. HERC staff consulted with ophthalmologists, who noted that the current wording is what CMS requires and what they are used to documenting. The ophthalmologists could not come up with different wording for item #1. Opthalmology and CCO medical directors agreed that item #4 in the guideline should be removed.

HERC staff recommendation: 1) Modify GN130 as shown below

GUIDELINE NOTE 130, BLEPHAROPLASTY Line 469 Blepharoplasty is covered when 1) visual fields demonstrate an absolute superior defect to within 15 degrees of fixation a minimum of 30 degrees of visual field loss exists with upper lid skin/margin in repose, 2) upper eyelid position contributes to difficulty tolerating a prosthesis in an anophthalmic socket, OR 3) essential blepharospasm or hemifacial spasm is present., OR 4) when there is significant ptosis in the downgaze reading position.

Section 5.0 Biennial Review Newborn Circumcision 2020 Biennial Review

Question: Should elective newborn circumcision be moved to a higher priority position on the Prioritized List?

Question sources: Dr Rick Wopat, family physician; Dr. Steven Skoog, OHSU Pediatric Urology; Dr. Kim Wentz and Dr. Allan Merritt, HSD; various CCO medical directors

Issue: Newborn elective circumcision is currently prioritized to line 623 REDUNDANT PREPUCE Treatment ELECTIVE CIRCUMCISION. Medically indicated circumcision is found on several higher priority lines, 327 FUNCTIONAL AND MECHANICAL DISORDERS OF THE GENITOURINARY SYSTEM INCLUDING BLADDER OUTLET OBSTRUCTION, 412 BALANOPOSTHITIS AND OTHER DISORDERS OF PENIS, and 496 PHIMOSIS. Medical conditions of the foreskin are also on higher priority lines without pairing with circumcision, such as balanitis on line 412 BALANOPOSTHITIS AND OTHER DISORDERS OF PENIS.

Historically, the OHP has never covered elective newborn circumcision. Review of minutes finds no discussion in the past 20 years on coverage of routine circumcision in newborns. When the Prioritized List was created, the American Academy of Pediatrics had a policy statement that routine newborn circumcision was not medically justified. The AAP has since changed this policy to a more pro newborn circumcision stance.

Recently, HERC staff undertook a review of medical indications for circumcision. As part of that review, HERC staff received considerable feedback regarding the need to review evidence published in the past 10 years regarding the benefits of newborn circumcision and the need to reconsider OHP policy to not cover routine newborn circumcision. As a result of this feedback, HERC staff has conducted an evidence review of the health benefits of circumcision and a policy review of expert groups regarding newborn circumcision.

Evidence General 1) Friedman 2016, evidence-based review of circumcision a. Lowered risk of HIV infection, based on 3 large RCTs conducted in Africa in areas of high HIV endemicity. Lowered risk of STI infection in males in settings of high STI endemicity i. These conclusions are limited by the lack of high-quality data from areas outside of Africa. ii. Evidence outside of Africa comes mostly from observational studies. Such studies were conducted in the USA and Israel, where circumcision rates are high and HIV burden is relatively low, and similarly showed an inverse association between circumcision and HIV acquisition b. When the effects of adult circumcision on sexual function and satisfaction of men are examined, high-quality evidence strongly supports lack of harm. c. Circumcision rarely causes serious complications if practiced by trained practitioners, in a sterile setting, and with a proper follow-up. d. Conclusion: a definite pro or con recommendation, based on a risk-benefit ratio, cannot be made

Reduction in HIV acquisition

Newborn Circumcision 2020 Biennial Review

1) Sigfried 2013, Cochrane review on male circumcision and reduction in HIV acquisition a. N=3 RCT i. Conducted in South Africa (N = 3 274), Uganda (N = 4 996) and Kenya (N = 2 784) between 2002 and 2006. All three trials were stopped early due to significant findings at interim analyses. b. The incidence risk ratio (IRR) was 0.50 at 12 months with a 95% confidence interval (CI) of 0.34 to 0.72; and 0.46 at 21 or 24 months (95% CI: 0.34 to 0.62). These IRRs can be interpreted as a relative risk reduction of acquiring HIV of 50% at 12 months and 54% at 21 or 24 months following circumcision. c. We conducted a meta-analysis of the secondary outcomes measuring sexual behaviour for the Kenyan and Ugandan trials and found no significant differences between circumcised and uncircumcised men. For the South African trial the mean number of sexual contacts at the 12-month visit was 5.9 in the circumcision group versus 5 in the control group, which was a statistically significant difference (p < 0.001). This difference remained statistically significant at the 21-month visit (7.5 versus 6.4; p = 0.0015). No other significant differences were observed. d. Incidence of adverse events following the surgical circumcision procedure was low in all three trials. e. the potential for significant biases affecting the trial results was judged to be low to moderate given the large sample sizes of the trials, the balance of possible confounding variables across randomised groups at baseline in all three trials, and the employment of acceptable statistical early stopping rules. f. The quality of the evidence was moderate to high, downgraded for unreliable randomization methods in two of the trials and early discontinuation in all three trials a. Authors’ conclusions There is strong evidence that medical male circumcision reduces the acquisition of HIV by heterosexual men by between 38% and 66% over 24 months. Incidence of adverse events is very low, indicating that male circumcision, when conducted under these conditions, is a safe procedure. Inclusion of male circumcision into current HIV prevention measures guidelines is warranted, with further research required to assess the feasibility, desirability, and cost-effectiveness of implementing the procedure within local contexts.

Reduction in UTI 1) Jagannath 2012, Cochrane review of circumcision for prevention of UTI a. Authors’ conclusions We were unable to identify any randomised controlled trials on the use of routine neonatal circumcision for prevention of UTI in male infants. Until further evidence becomes available, clinicians should continue to base their decisions on position statements and recommendations and in conjunction with the opinions of the children’s parents 2) Morris 2013, systematic review and meta-analysis of circumcision for the prevention of UTI a. N=22 studies, 250,000+ patients i. 1 RCT (Turkey), 4 cohort studies (not specified prospective or retrospective), 2 prospective cohort studies, 1 retrospective cohort study, 11 case-control studies, 1 cross sectional study, 2 “retrospective analysis” studies ii. UTI definition varied across studies

Newborn Circumcision 2020 Biennial Review

b. For age 0 to 1 year the relative risk of UTI was 9.91 (95% CI 7.49–13.1), for age 1 to 16 years RR was 6.56 (95% CI 3.26–13.2) and for older than 16 years it was 3.41-fold (95% CI 0.916–12.7) higher in uncircumcised males. c. 32.1% (95% CI 15.6–49.8) of uncircumcised males experience a urinary tract infection in their lifetime compared with 8.8% (95% CI 4.15–13.2) of circumcised males (RR 3.65, 95% CI 1.15–11.8). d. The number needed to treat was 4.29 (95% CI 2.20–27.2). e. Conclusions: The single risk factor of lack of circumcision confers a 23.3% chance of urinary tract infection during the lifetime. This greatly exceeds the prevalence of circumcision complications (1.5%), which are mostly minor. The potential seriousness of urinary tract infection supports circumcision as a desirable preventive health intervention in infant males. 3) Singh-Grewal D 2005, Systematic review of circumcision for the prevention of UTI a. N=402,908 children from 12 studies (1 RCT, 4 cohort studies, 7 case-control studies) b. Circumcision was associated with a significantly reduced risk of UTI (OR = 0.13; 95% CI, 0.08 to 0.20; p,0.001) with the same odds ratio (0.13) for all three types of study design. c. Conclusions: Circumcision reduces the risk of UTI. Given a risk in normal boys of about 1%, the number needed-to-treat to prevent one UTI is 111. In boys with recurrent UTI or high grade vesicoureteric reflux, the risk of UTI recurrence is 10% and 30% and the numbers-needed-to-treat are 11 and 4, respectively. Haemorrhage and infection are the commonest complications of circumcision, occurring at rate of about 2%. Assuming equal utility of benefits and harms, net clinical benefit is likely only in boys at high risk of UTI.

Complications 1) Weiss 2010, systematic review of complications of elective circumcision https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835667/pdf/1471-2490-10-2.pdf a. N=16 studies of neonatal or infant circumcision i. 12 countries, variety of circumcision methods b. The median frequency of any adverse event was 1.5% (range 0-16%), and median frequency of any serious adverse event was 0% (range 0-2%). Nine studies reported no serious adverse events, but three studies reported that 1-2% of boys had a serious complication c. Complications included infection, ulceration, urethral laceration, amputation of the glans penis, bleeding, excess residual foreskin, hematoma, and meatal stenosis

Expert recommendations 1) CDC 2017, Male Circumcision and the Prevention of HIV Infection, Sexually Transmitted Infections, and other Health Outcomes https://stacks.cdc.gov/view/cdc/58456 a. Expert symposium, evidence review, and review of public comments b. Health benefits i. During infancy, circumcised infants are less likely than uncircumcised infants to experience urinary tract infections (UTIs); an estimated 7% of infant males presenting with fever in outpatient clinics and emergency rooms had UTIs, including 20% of uncircumcised febrile infants and 2% of circumcised febrile infants aged younger than3 months of age.

Newborn Circumcision 2020 Biennial Review

ii. An estimated 32% of uncircumcised males compared with 9% of circumcised males will experience a UTI in their lifetime, suggesting that circumcision is associated with a 23% absolute decreased lifetime risk of UTI. iii. Although most UTIs are treatable, serious complications may occur when UTIs are not diagnosed, recurrent, difficult to treat, or left untreated. Such complications may include sepsis, pyelonephritis, and renal scarring and have been associated with an increased risk for long-term consequences, including hypertension, build-up of kidney waste products (uremia), and end-stage renal disease. iv. An estimated 14% of uncircumcised boys compared with 6% of circumcised boys experienced balanitis, irritation, adhesions, phimosis or paraphimosis, suggesting that circumcision is associated with an 8% absolute decreased risk of these conditions v. During adulthood, circumcised males were less likely than uncircumcised males to experience penile cancer. vi. Other anticipated health benefits derive in part from future prevention of HIV and some STIs acquired through heterosexual sex. Eight percent of annual HIV diagnoses in the United States are among persons with infection attributed to heterosexual contact. STIs are very common, with human papilloma virus (HPV) infection of the anus or genitals occurring in many sexually active persons, although HPV vaccination is highly effective against many serotypes. Current risks for either HIV or other non-HIV STIs may not remain constant in the future and the future risk for any individual neonate, child, or adolescent cannot be definitively defined at the time that a circumcision decision is made. c. Complications i. Complications of medically performed male circumcision in the United States are typically uncommon and easily managed. Severe complications are rare in all age groups and occur in 0.23% of all circumcised males overall. ii. Among newborns and children aged 1–9 years, most frequently reported complications include bleeding and inflammation of the penis or incomplete wound healing or adhesions requiring corrective procedures. iii. Complications occur (according to age at circumcision) in 0.2% of infants aged ≤ 1 month, 0.4% of infants aged<1 year, and approximately 9% in children aged 1– 9 years. 2) American Academy of Pediatrics 2012 www.pediatrics.org/cgi/doi/10.1542/peds.2012-1990 a. Systematic evaluation of English-language peer-reviewed literature from 1995 through 2010 indicates that preventive health benefits of elective circumcision of male newborns outweigh the risks of the procedure. Benefits include significant reductions in the risk of urinary tract infection in the first year of life and, subsequently, in the risk of heterosexual acquisition of HIV and the transmission of other sexually transmitted infections. b. The procedure is well tolerated when performed by trained professionals under sterile conditions with appropriate pain management. Complications are infrequent; most are minor, and severe complications are rare. Male circumcision performed during the newborn period has considerably lower complication rates than when performed later in life.

Newborn Circumcision 2020 Biennial Review

c. Although health benefits are not great enough to recommend routine circumcision for all male newborns, the benefits of circumcision are sufficient to justify access to this procedure for families choosing it and to warrant third-party payment for circumcision of male newborns. It is important that clinicians routinely inform parents of the health benefits and risks of male newborn circumcision in an unbiased and accurate manner. Parents ultimately should decide whether circumcision is in the best interests of their male child. They will need to weigh medical information in the context of their own religious, ethical, and cultural beliefs and practices. The medical benefits alone may not outweigh these other considerations for individual families. 3) American Academy of Family Practice 2018 a. There are potential health benefits from neonatal circumcision. The evidence is strongest for the prevention of UTI in newborn males. The number needed to treat to prevent one UTI is about 140 and to prevent one hospitalization for UTI is 195. Circumcision also prevents penile cancer, but this is a rare disease (0.6/100,000), and the number needed to treat to prevent one case is approximately 300,000. In addition, about 1/3 of penile cancers are caused by human papilloma virus and may be prevented by HPV vaccine. There is also evidence that circumcision can prevent some other STDs, including the acquisition of HIV, but the evidence for this comes from studies of adult circumcision in Africa and may not be generalizable to neonatal circumcision in the U.S. b. Circumcision can also result in complications. Acute complications can include bleeding (0.8-1.8/1,000), infection (6/10,000), and injury to the penis (4/10,000). Late complications can include incomplete circumcision, excessive skin removal, adhesions, meatal stenosis, phimosis, inclusion cysts. The rate at which these late complications occur is not well defined. c. The potential health benefits from circumcision justify it being a covered medical service by third-party payers, and it should be an available service for those who desire it. 4) American Urologic Association 2017 a. The risks and disadvantages of circumcision are encountered early whereas the advantages and benefits are prospective. When circumcision is being discussed with parents and informed consent obtained, medical benefits and risks, and ethnic, cultural, religious and individual preferences should be considered 5) Canadian Paediatric Society 2018 a. While there may be a benefit for some boys in high-risk populations and circumstances where the procedure could be considered for disease reduction or treatment, the Canadian Paediatric Society does not recommend the routine circumcision of every newborn male. 6) Royal Australasian Society of Physicians 2010 https://www.racp.edu.au/docs/default- source/advocacy-library/circumcision-of-infant-males.pdf a. Circumcision is generally a safe procedure but there are risks of minor complications and some rare but serious complications b. The most important conditions where benefits may result from circumcision are recurrent urinary tract infections in children; and Human Immunodeficiency Virus (HIV) plus some other sexually transmitted infections in adults from populations with a high prevalence of these conditions; cancer of the penis in men with a history of phimosis, and cancer of the cervix in women whose partners engage in sexual practices known to increase the risk of Human Papilloma Virus (HPV) infection. The protection against

Newborn Circumcision 2020 Biennial Review

Sexually Transmitted Infections (STIs) and HIV is less clear-cut in Australia and New Zealand than in high prevalence countries. c. Ethical and human rights concerns have been raised regarding elective infant male circumcision because it is recognised that the foreskin has a functional role, the operation is non-therapeutic and the infant is unable to consent. d. After reviewing the currently available evidence, the RACP believes that the frequency of diseases modifiable by circumcision, the level of protection offered by circumcision and the complication rates of circumcision do not warrant routine infant circumcision in Australia and New Zealand.

Other Medicaid coverage: There are several CCOs in Oregon that are currently covering newborn circumcision due to patient and provider demand.

As of 2009 (Clark 2011) newborn male circumcision was not covered for Medicaid enrollees in fifteen states: Arizona, California, Florida, Idaho, Louisiana, Maine, Minnesota, Mississippi, Missouri, Montana, North Carolina, North Dakota, Oregon, Utah, and Washington. Two states had variable policies. In Nevada, Medicaid managed care plans in two urban areas covered routine newborn male circumcision, while fee-for-service elsewhere in the state covered male circumcision only if medically necessary. In Tennessee, one of two Medicaid managed care plans covered routine newborn male circumcision, while the other covered male circumcision only when medically necessary. The remaining thirty-three states covered newborn circumcision for all Medicaid enrollees.

State coverage for adult male circumcision is variable.

Current line prioritization scoring Line 623 REDUNDANT PREPUCE Category: 9 HL: 0 Suffering: 0 Population effects: 0 Vulnerable population: 0 Tertiary prevention: 0 Effectiveness: 5 Need for service: 0 Net cost: 2 Score: 0 Approximate line placement: 623

Newborn Circumcision 2020 Biennial Review

HERC staff summary Neonatal circumcision remains a controversial topic. Studies have found that neonatal circumcision reduces the rate of HIV and other STI acquisition; however, this conclusion is based on data from high prevalence countries, is limited to heterosexual patients, and it is not clear how it translates to areas of lower HIV/STI prevalence. Neonatal circumcision reduces the risk of UTI in infants and young boys, with a NNT of between 4 and 111 (the literature is highly variable on this estimate). The reason for the variation in NNT for prevention of UTI may be in the study methods (higher NNT came from a review that specifically excluded high risk boys). Boys with vesicoureteral reflux appear to have greater benefit in UTI prevention with circumcision given their higher prevalence of UTI. The complications of circumcision are generally minor, but can include rare serious adverse events. The rate of complications is estimated to be 1.5% overall, with 0.23% rate of serious complications. The risks of circumcision are much higher when done outside of the neonatal period, due to need for general anesthesia, etc. There appears to be no impact on sexual satisfaction with circumcision. Coverage for routine neonatal circumcision is highly variable among Medicaid programs. Desire for circumcision varies widely among families, depending on religious and cultural norms and other factors.

HERC staff recommendation: 1) Rescore line 623 as shown below a. Change category from 9 (Inconsequential care) to 7 (non-fatal condition with treatment aimed at disease modification or cure) b. Change population effects from 0 to 1 (possible prevention of HIV/STIs in low prevalence setting; scale 0 to 5) c. Change tertiary prevention from 0 to 2 (prevention of UTI and penile cancer; possible prevention of HIV/STIs in low prevalence setting; scale 0 to 5) d. Change need for service from 0 to 0.1 (scale 0 to 1)

Recommended line prioritization scoring (current scores in parentheses) Line 623 REDUNDANT PREPUCE Category: 7 (9) HL: 0 Suffering: 0 Population effects: 1 (0) Vulnerable population: 0 Tertiary prevention: 2 (0) Effectiveness: 5 Need for service: 0.1 (0) Net cost: 4 (2) Score: 30 Approximate line placement: 569

Clinical Microbiology and Infection 22 (2016) 768e774

Contents lists available at ScienceDirect

Clinical Microbiology and Infection

journal homepage: www.clinicalmicrobiologyandinfection.com

Review Pros and cons of circumcision: an evidence-based overview

* B. Friedman 1, J. Khoury 2, 3, N. Petersiel 2, 3, T. Yahalomi 2,M.Paul2, 4, A. Neuberger 2, 3, 4,

1) Department of Urology, Lady Davis Carmel Medical Center, Haifa, Israel 2) Unit of Infectious Diseases, Rambam Medical Center, Haifa, Israel 3) Internal Medicine B, Rambam Medical Center, Haifa, Israel 4) Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel article info abstract

Article history: Based on three large randomized controlled trials (RCTs) conducted in Africa, it can clearly be stated that Available online 4 August 2016 circumcision lowers the risk of infection with the human immunodeficiency virus (HIV) and some sexually transmitted infections (STIs) among males in settings of high HIV and STI endemicity. Similar Editor: D. Raoult effects on STI risk may exist for females, although this may result from an indirect effect of decreasing risk of infection among male partners. It is unknown whether circumcision prevents HIV acquisition in Keywords: Benefits men who have sex with men (MSM), although there might be a protective effect for men who engage Circumcision mainly in insertive anal intercourse. When the effects of adult circumcision on sexual function and Effect satisfaction of men are examined, high-quality evidence strongly supports lack of harm. Whether HIV circumcision alters sexual satisfaction of female partners is not known as fewer and smaller studies Impact reported conflicting results. Circumcision rarely causes serious complications if practiced by trained Infections practitioners, in a sterile setting, and with a proper follow-up. These conclusions are limited by the lack Male circumcision of high-quality data from areas outside of Africa. RCTs have not been conducted to assess the effects of Sexually transmitted infections circumcising infants or MSM. Circumcision has well-proven benefits for people residing in areas with high prevalence of STIs, including HIV, and is not unethical for those who choose to be circumcised or have their children circumcised on religious, social, or cultural grounds. For many others, a definite pro or con recommendation, based on a risk-benefit ratio, cannot be made. B. Friedman, CMI 2016;22:768 © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Introduction discussion of the pros and cons of circumcision for those who have to make a very personal decision. Few procedures generate as much controversy as male circumcision. While religious and social factors strongly influence Methods the decision of many adults and parents about circumcision, others seek to understand in what ways, medically speaking, this pro- We searched PubMed and the Cochrane Library for the term fi cedure can bring bene ts or cause harm. While reviewing the ‘circumcision’, filtering in PubMed for clinical trials and systematic fi literature for this review we have made two observations: rst, the reviews. We addressed primarily systematic reviews of randomized abundance of very low-quality research, some of which is clearly controlled trials (RCTs). Where unavailable, we searched for RCTs, biased unreservedly for or against circumcision; second, the bulk of and when RCTs were unavailable or insufficient we included trials and systematic reviews concentrate on one aspect of possible observational studies in the literature review. We rated the quality fi bene ts or harms, but do not provide a general overview [1]. Thus, of the evidence as very low, low, moderate, or high. We based the fi we have tried to lter out bad science, and provide a balanced rating primarily on the study design (high quality for RCTs and low quality for observational studies) and then downgraded or upgra- ded according to the internal validity of each study, following the GRADE recommendations [2]. We accepted the quality rating from * Corresponding author. A. Neuberger, Rambam Medical Center, Unit of Infectious Diseases, 8 Haalya Hashnya St., Haifa, 3109601, Israel. systematic reviews using the GRADE system and risk of bias E-mail address: [email protected] (A. Neuberger). assessment from other systematic reviews. We used the http://dx.doi.org/10.1016/j.cmi.2016.07.030 1198-743X/© 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. B. Friedman et al. / Clinical Microbiology and Infection 22 (2016) 768e774 769 terminology ‘affected’ for high-quality evidence, ‘probably affected’ showed mixed results regarding the possibility of disinhibition for moderate-quality evidence, ‘may be affected’ for low-quality following circumcision. Recently, a cohort study from Uganda evidence, and ‘effect not known’ for very low-quality or no evi- found that, while the circumcision programme attracts more dence [3]. sexually active males, it does not alter their sexual behaviour [11e13]. Evidence outside of Africa comes mostly from observational Circumcision and the risk of HIV acquisition studies. Such studies were conducted in the USA and Israel, where circumcision rates are high and HIV burden is relatively low, and Heterosexual men similarly showed an inverse association between circumcision and HIV acquisition [14,15]. A systematic review of studies conducted in The inner surface of the foreskin contains Langerhans cells with India included 13 observational studies, showing that circumcision human immunodeficiency virus (HIV) receptors, which explains may reduce HIV acquisition by approximately 40% (OR 0.66; 95% CI the biological rationale for using male circumcision to decrease 0.53e0.83) [16]. As circumcision in India is almost exclusively rates of HIV acquisition among men [4]. Early non-randomized practiced by Muslims, bias is likely (low-quality evidence). studies attempting to assess the effects of circumcision on HIV Following the publication of the RCTs from Africa, the Center for could not control for religion and tradition as confounding factors. Disease Control and Prevention (CDC) announced in 2007 that Three major RCTs comparing immediate and delayed there is ‘sufficient evidence to inform heterosexually active males (21e24 months) circumcision, and assessing HIV acquisition in the about the significant, albeit partial, efficacy of medical circumcision interval, were conducted in South-Africa, Kenya, and Uganda in the in reducing the risk of HIV infection’ [17]. Similarly, the WHO/ 2000s. All were stopped early when male circumcision was shown UNAIDS recommends male circumcision as an efficacious inter- to decrease the rates of HIV acquisition in planned interim-analysis vention for HIV prevention in countries with high HIV incidence e [5 7] (Table 1). A Cochrane review of these RCTs, which included a and low male circumcision prevalence [18]. total of 11 500 men, showed that circumcision reduced HIV acquisition with an incidence risk ratio (IRR) of 0.46 (95% CI Women 0.34e0.62) at the end of follow-up. The number needed to treat (NNT) at 21e24 months was 56 (95% CI 41e90). Circumcision As male circumcision reduces the incidence of HIV among men, prevented 17 HIV infections (95% CI 11e24) over 2 years per 1000 it may indirectly reduce the risk of exposure to women. Whether men, with a control event rate of 2.5% translating to a population circumcision can directly prevent the acquisition of HIV by female yearly incidence of HIV acquisition of 1.25% [8]. The quality of the partners of HIV-infected men is uncertain. Only one RCT, conducted evidence was moderate to high, downgraded for unreliable in Uganda in 2009, addressed this issue and was discontinued early randomization methods in two of the trials and early discontinu- because of futility [19]. In this trial 922 discordant couples were ation in all three trials (although discontinuation rules were enrolled and randomized either to circumcision or control (delayed defined in all three). circumcision for 24 months). Surprisingly, there was a small in- The public health implications of male circumcision have not crease in the risk of HIV acquisition among women in the inter- been studied adequately, as all RCTs assessed the effects of the vention group, mainly because of early resumption of sexual intervention on individuals rather than on populations. A few activity before wound healing, and an increase in the viral load mathematical models have been proposed aiming at estimating the shortly after circumcision (high-level evidence). A systematic re- potential impact of increased circumcision coverage on the inci- view summarizing this RCT and a few longitudinal observational dence of HIV in Africa. A dynamical simulation model, for example, studies showed that male circumcision probably does not reduce suggested that full coverage of circumcision could avert 0.3 the risk for HIV among women (relative risk 0.80, 95% CI 0.53e1.36) (0.1e0.5) million deaths in the first 10 years and a further 2.7 [20]. (1.5e5.3) million in the next 10 years, in sub-Saharan Africa [9]. However, by definition, models can never account for all additional factors that can influence the impact of a specific intervention on Men who have sex with men (MSM) disease incidence [10]. Increasing rates of antiretroviral coverage make impossible long-term assessment of the procedure itself, and To the best of our knowledge, no RCT assessed the impact of the effect of circumcision on sexual risk-taking is unknown. In the circumcision on the risk of HIV acquisition among MSM. A three RCTs described above, circumcised males practiced riskier sex Cochrane systematic review published in 2011 included 20 obser- behaviours, leading to concerns about disinhibition and higher vational studies in high- and middle-income countries with a total transmission rates of HIV. Other observational studies from Africa of 65 784 participants. The meta-analysis showed that circumcision

Table 1 Randomized controlled trials of immediate vs. delayed surgical circumcision in Africa

Auvert 2005 [5] Bailey 2007 [6] Gray 2007 [7]

Location Orange Farm, South Africa Kisumu, Kenya Rakai, Uganda Study years 2002e2005 2002e2005 2002e2006 Age range (years) 18e24 18e24 15e49 N patients 3274 2784 4996 Duration of follow-up 21 months 24 months 24 months Risk of bias a Selection bias b High risk Unclear High risk Other None None None

a All trials stopped early based on pre-defined stopping rules. As the primary outcome (HIV acquisition) was objective, blinding was deemed less relevant and is not addressed. b Based on the highest risk of random sequence generation and allocation concealment. 770 B. Friedman et al. / Clinical Microbiology and Infection 22 (2016) 768e774 may reduce HIV acquisition among MSM reporting an insertive anal 0.18e0.81), whereas a nonsignificant reduction in the incidence role (seven studies), but might not have an effect among MSM of syphilis was observed among men without HIV (0.64, practicing a receptive role (three studies), low-quality evidence 0.36e1.11) [31]. [21]. Similar results were reported in another systematic review, Herpes Simplex Virus (HSV): RCTs from Uganda [24] and South highlighting that a protective effect was demonstrated only in Africa [32] showed a significant reduction in HSV infection rates studies conducted before the highly active antiretroviral therapy after circumcision. Two other trials conducted in Kenya failed to era [22]. Recently, an observational study of the risk of HIV acqui- show such a reduction [30e33]. The discrepancy between these sition conducted among MSM in China, involving 1155 men, trials was attributed to lack of specificity of the assay used in showed that circumcised MSM were less likely to acquire HIV (aOR, some trials, different prevalence of HSV at baseline, different age 0.46; 95% CI 0.24e0.89). Again, this protective effect was most groups, and different numbers of sexual partners. pronounced among MSM who predominantly practiced insertive anal intercourse [23]. Finally, STIs whose incidence is probably not affected by circumcision include: Adult circumcision and sexually transmitted infections Gonorrhoea: one RCT [34] and one observational study [35], To provide an overview of the evidence on the effect of both performed in Africa, did not show a risk reduction of circumcision on the risk of acquisition of various sexually trans- gonorrhoeal infection after circumcision. mitted infections (STIs), we will separate infections into those in Chlamydia: one RCT did not show a relationship between which incidence is decreased, those in which incidence is possibly circumcision status and Chlamydia infection [34]. decreased, and those in which incidence is unaffected by circumcision. The evidence summarized above derives mostly from an analysis of secondary outcomes in the circumcision RCTs conducted in Heterosexual men Africa, performed to assess its effect on HIV acquisition. The effects of circumcision on STIs in non-African countries have not been STIs whose incidence is decreased or likely to be decreased studied rigorously. Based on observational studies conducted in the following circumcision include: USA, it is likely that circumcision both prevents HPV and increases the likelihood for clearing existing HPV infections [36,37]. Data on Human papilloma virus (HPV), high-quality evidence: large RCTs HSV are conflicting as a cohort study conducted in Australia showed of immediate versus deferred circumcision, all of which were a protective effect of circumcision, whereas trials in America and performed in Africa, included a total of 3921 and 3815 men in India failed to demonstrate such an effect [38e40]. Studies con- the intervention and control arms, respectively. These trials ducted in the USA, India, and Austria demonstrated conflicting re- clearly demonstrate that circumcision decreases HPV infection sults with regard to the effect of circumcision on the incidence of rates among HIV-negative heterosexual men. Overall infection HSV and syphilis [38e41]. rates were 14.8e18% in the intervention group and 23.3e27.8% in the control group [24e27]. Among HIV-positive men included Female partners in an RCT performed in Uganda, circumcision decreased the risk of high-risk multiple HPV genotype infections (RR 0.40, 95% CI STIs whose incidence is decreased or likely to be decreased: 0.19e0.84), control event rate 24.7% [28]. Mycoplasma (moderate-quality evidence): in one RCT from HPV: based on three RCTs conducted in Uganda, there is strong Kenya, which included 2784 men, the prevalence of Mycoplasma evidence that male circumcision decreases HPV infection rates genitalium was 13.4% among uncircumcised men versus 8.2% in female partners of circumcised HIV-negative males [42,43], among circumcised men. After adjustment for other risk factors but does not affect HPV transmission among couples when the for infection, being circumcised nearly halved the odds of My- men are HIV positive [44]. Outside of Africa, a meta-analysis on coplasma genitalium infection (aOR 0.54; 95% CI 0.29e0.99) [29]. 1913 couples included in case-control studies, showed that Genital ulcer disease (GUD): the clinical syndrome of GUD is circumcision is associated with a lower risk of cervical cancer caused mainly by STIs, and its incidence is assessed as a general among monogamous female partners of men with multiple estimate of STI incidence when specific microbiologic diagnoses sexual partners (aOR 0.42, 95% CI 0.23e0.79) [45]. are not available. Two large RCTs, which included 8315 participants, showed that GUD incidence was halved among circum- STIs whose incidence is possibly decreased by circumcision: cised men, with a risk ratio of 0.51e0.52 [30]. Similarly, a prospective observational study of 746 men showed that an GUD and bacterial vaginosis: based on a single RCT, the risk for uncircumcised status was an independent risk factor for GUD GUD, bacterial vaginosis, and trichomonas infection may be (hazard rate ratio ¼ 2.5) [31]. reduced in female partners of circumcised males [46]. Circum- cision was not associated with a lower risk for bacterial vagi- STIs whose incidence is possibly decreased by circumcision: nosis in one retrospective study conducted in the USA [47]. Chlamydia trachomatis: in a multinational retrospective study, Syphilis: one large RCT from Uganda, which included 5534 men, circumcision was associated with a lower risk for Chlamydia showed no significant difference between circumcised and un- trachomatis infection in female sexual partners of circumcised circumcised men in new acquisition of syphilis (adjusted hazard males [48]. ratio 1.10, 95% CI 0.75e1.65, p ¼ 0.44) [24]. On the other hand, another RCT, performed on 4761 males in Kenya and Uganda, STIs whose incidence is probably not affected by circumcision: showed that circumcision was associated with a 42% reduction in the incidence of syphilis (adjusted hazard ratio 0.58, 95% CI HSV and genital mycoplasma: the risk of HSV and genital my- 0.37e0.91). In a subgroup analysis among HIV-infected men, a coplasma infections is probably not reduced in females whose 62% reduction in the incidence of syphilis was noted (0.38, sexual partners have been circumcised [49,50]. B. Friedman et al. / Clinical Microbiology and Infection 22 (2016) 768e774 771

Men who have sex with men had either equal or improved sexual satisfaction following circumcision [60,61]. To the best of our knowledge, no RCT has assessed the effect of Evidence in middle- or high-income countries is mostly derived circumcision on the risk of STIs among MSM. In several observa- from low-quality observational trials, the majority of which did not tional trials no association has been found between male circum- account sufficiently for confounders. Such studies were conducted cision and STIs [51e54]. The STIs assessed included HSV-2, syphilis, in China [62], Taiwan [63], Korea [64], several European countries urethral gonorrhoea, and urethral Chlamydia infection. One study [65,66], Australia [67], and the USA. Most studies reported either no reported a significant, protective effect of circumcision on the risk harm or increased sexual satisfaction, while fewer studies reported of syphilis acquisition, and no association for other STIs [55], while some degree of sexual dysfunction. In one relatively large obser- another reported no association for most STIs, but a significantly vational trial conducted among MSM in Australia, sexual dysfunc- greater risk of acquiring non-chlamydial non-gonococcal urethritis tion or decreased sexual satisfactions were similar among [56]. circumcised and non-circumcised participants [67].

Effects of circumcision on sexual function and satisfaction Women

Men Few studies examined women's preferences regarding the status of partner circumcision. In the trial conducted in Uganda, nearly Two of the RCTs conducted in Africa primarily to assess the ef- all women (97.1%) reported either no change or improved sexual fects of circumcision on HIV, also analysed outcomes related to satisfaction after their partners were circumcised [68]. The vast sexual function and satisfaction. In the trial conducted in Uganda, majority of women partners of male participants in the trial from decreased sexual satisfaction or sexual dysfunction were reported Kenya reported that they were very satisfied (92%) or somewhat equally by <2% of participants in both study arms [57]. In the trial satisfied (5%) with the outcome of circumcision [59]. Other large from Kenya, circumcision similarly did not affect sexual dysfunc- observational trials conducted in Africa reported similar results: in tion. Men in the intervention group reported increased penile Malawi, women were more likely to report greater sexual pleasure sensitivity and enhanced ease of reaching orgasm, with 99.5% of with a circumcised partner [61], and similar results were observed circumcised participants reporting that they were ‘very satisfied’ in Zambia [60]. The only relatively large study conducted in a high- with the outcome [11,58,59]. Participants in several large non- income country reported that circumcision might decrease sexual randomized trials conducted in Africa similarly reported that they satisfaction among female partners. This analysis is limited by a

Table 2 Effect of circumcision on the risk of acquiring human immunodeﬁciency virus (HIV) and other sexually transmitted infections (STIs) in randomized controlled trials (RCTs)

Pathogen or syndrome Countries Effect of circumcision Comments

HIV HIV among heterosexual men South Africa [5] RR 0.4 (0.24e0.68) Relative risk similar in all three large RCTs Kenya [6] RR 0.47 (0.28e0.78) Uganda [7] RR 0.43 (0.24e0.75) HIV among females Uganda [19] HR 1.49 (0.62e3.57) Circumcision of HIV-infected males did not reduce HIV-transmission to female partners HIV among MSM South Africa [21] Circumcision prevented HIV only in MSM practicing mainly insertive anal sex - Insertive role OR 0.27 (0.17e0.44) - Receptive role OR 1.2 (0.63e2.29) STIs among heterosexual men HPV Uganda [24] aRR 0.65 (0.46e0.90) Circumcision reduced HPV infection in both HIV-positive [22] and Uganda [25] RR 0.67 (0.51e0.89) HIV-negative men Uganda [28] RR 0.4 (0.19e0.84) South Africa [26] PRR 0.66 (0.51e0.86) Kenya [27] RR 0.34 (0.13e0.86) Mycoplasma Kenya [29] OR 0.54 (0.29e0.99) Genital ulcer disease (GUD) Kenya [24] RR 0.52 (0.37e0.73) Uganda [31] - HSV-negative PRR 0.51 (0.43e0.74) - HSV-positive PRR 0.66 (0.51e0.69) Syphilis Uganda [24] aHR 1.1 (0.75e1.65) In a subgroup analysis of the Ugandan trial, circumcision was protective against Uganda [31] RR 0.58 (0.37e0.91) syphilis among HIV-positive, but not among HIV-negative men HSV Uganda [24] aHR 0.72 (0.56e0.92) In some, but not all trials there was a reduction in HSV incidence. Trials differed South Africa [32] IRR 0.45 (0.24e0.82) in prevalence of HSV at baseline, age groups, number of sexual partners, and assays used Kenya [30] RR 0.94 (0.70e1.25) Kenya [33] HR 0.88 (0.77e1.10) Gonorrhoea Kenya [28] IRR 0.95 (0.68e1.34) No effect South Africa [29] OR 0.97 (0.71e1.32) Chlamydia Kenya [34] IRR 0.87 (0.65e1.16) No effect South Africa [35] OR 0.58 (0.33e1.03) STIs among females HPV Uganda [42] RR 0.72 (0.60e0.85) Circumcision reduced HPV infection rates of female partners of HIV negative Uganda [43] RR 0.66 (0.50e0.87) men [36,37], but not of HIV positive men [38] Uganda [44] RR 1.07 (0.86e1.32) Genital ulcer disease Uganda [46] RR 0.78 (0.63e0.97) Mycoplasma Uganda [50] PRR 1.0 (0.48e2.12) aRR, adjusted risk reduction; HPV, human papilloma virus; HSV, herpes simplex virus; IRR, incidence rate ratio; MSM, men who have sex with men; PRR, prevalence risk ratio. 772 B. Friedman et al. / Clinical Microbiology and Infection 22 (2016) 768e774 cross-sectional design, and a low number of circumcised partici- Conclusions pants (125 out of 2345 participants) [69]. The effects of circumcision are still largely debated, and conflicting conclusions have been drawn from existing data. It can be clearly stated that adult circumcision decreases the rate Complications of the circumcision procedure of HIV acquisition among men in settings with a high incidence of HIV and therefore indirectly reduces risk of exposure to women Surgical circumcision (Table 2). We do not know whether there is a direct effect of male circumcision on women's risk for HIV. There may be a transient Conventional circumcision by surgical removal of the foreskin is increase in HIV acquisition risk if sexual intercourse occurs the standard procedure used in most circumcision programmes. immediately after the procedure, before wound healing. It is also Circumcision may result in early (intraoperative) or late (post- uncertain whether circumcision prevents HIV acquisition in MSM, operative) complications [70e72]. Early complications tend to be although there might be a protective effect for men who mainly minor and treatable: pain, bleeding, swelling, or inadequate skin engage in insertive anal intercourse. The RCTs conducted in Africa removal [70,73]. Serious complications, such as amputation of the provide ample evidence of the effect of circumcision for the pre- glans penis, occur only rarely [74,75]. Late complications may vention of several, albeit not all, STIs among men. Evidence among include pain, wound infection, oedema, and urinary retention, female sexual partners is of lower quality, but also seems to show a meatal ulcer, meatal stenosis, foreskin adhesions, fistulas, and loss beneficial effect for some STIs. Evidence among MSM comes from of penile sensitivity [76]. Rates of reported complications vary observational trials, which may be inadvertently biased, so that no greatly between studies, as these rates are affected by the setting of definite conclusions can be drawn. Severe adverse events after the surgical procedure and data collection methods [77,78]. adult and infant circumcision are rare. Complication rates correlate with age, occurring least often in All these beneficial effects of circumcision are relevant for high neonates and infants. In a systematic review the median frequency HIV- and STI-endemicity settings. Additional proven benefits of of any serious adverse event following neonatal or infantile circumcision such as the prevention of balanitis and phimosis were circumcision performed by medically trained providers was 1.5% beyond the scope of this review. Whether circumcision carries (range 0e16%) and 0% (range 0e2%), respectively. In children aged benefit outside of Africa is unknown. We do not know the effects of 1 year old or older, the median frequency of any or serious adverse circumcision following infant or child circumcision performed as event was 6% (range 2e14%), and 0% (range 0e3%), respectively part of religious or social ceremonies. In this setting the relevant [79]. The simpler nature of the procedure among neonates e no outcomes might be UTIs in infants and life-long STI acquisition. In need for suturing, and better healing - was hypothesized to un- addition, the scope of this review does not allow for a full discus- derlie the lower rate of complications in this age group. In high- and sion of the epidemiological impact of a circumcision policy in high- middle-income countries, but not in Africa, adverse events were income countries, and in Africa. Such impact was estimated to be observed most commonly among boys circumcised for medical, significant even outside of Africa [92]. rather than religious or cultural reasons [80e82]. In a study that Deciding whether to perform the procedure is easier for people included boys circumcised mainly for phimosis in the UK, the fre- residing in areas with high prevalence of STIs, including HIV, and quency of any adverse events was 6.4%, and 2.8% required re- for those who choose to be circumcised or have their children admission to hospital [80]; similar frequencies of readmissions circumcised on religious, social, or cultural grounds. For many were reported in a Danish study [81]. others, a definite pro or con recommendation, based on a risk- In middle- to high-income countries (Iran and Israel), some benefit ratio, cannot be made. case-control studies found that UTIs were more likely to occur following circumcision by a traditional, rather than a medical Transparency declaration provider [83e86]. In this context it should be noted that the lifelong risk of UTI is reduced by the procedure [87]. Data from African There was no funding for this study. All authors report no con- countries clearly show that the rate of complications is higher flicts of interests. when conducted in a traditional setting [11,76,88e90]. A systematic review of complications after traditional male circumcision in References South African found rates of 35% to 48%, and a mortality rate of 0.2%. Poor postoperative care by traditional circumcisers is likely to [1] Morris BJ, Hankins CA, Tobian AA, Krieger JN, Klausner JD. Does male contribute to increased complication rates [89,90]. circumcision protect against sexually transmitted infections? Arguments and meta-analyses to the contrary fail to withstand scrutiny. ISRN Urol 2014;2014:684706. [2] Guyatt G, Oxman A, Vist G. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924e6. Non-surgical circumcision [3] Glenton C, Santesso N, Rosenbaum S, Nilsen ES, Rader T, Ciapponi A, et al. 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Male circumcision for HIV prevention in young men in Kisumu, Kenya: a rando- was observed in the device group in comparison with the con- e e mised controlled trial. Lancet (London, England) 2007;369:643 56. ventional technique group (RR 0.54, 95% CI 0.39 0.74). This dif- [7] Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, Nalugoda F, et al. Male ference was largely driven by lower bleeding and higher healing circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. rates. Nevertheless, the expertise of the provider may be much Lancet 2007;369:657e66. fl [8] Siegfried N, Muller M, Deeks JJ, Volmink J. Male circumcision for prevention of more in uential on the incidence of complications than the tech- heterosexual acquisition of HIV in men. Cochrane Database Syst Rev 2009: nique used [79,90]. CD003362. B. Friedman et al. / Clinical Microbiology and Infection 22 (2016) 768e774 773

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Nandi Siegfried1, Martie Muller2, Jonathan J Deeks3, Jimmy Volmink4,5

1Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. 2Department of Mathematics, Faculty of Science, University of Copenhagen, Copenhagen Ø, Denmark. 3Public Health, Epidemiology and Biostatistics, University of Birmingham, Birmingham, UK. 4Centre for Evidence-based Health Care, Stellenbosch University, Cape Town, South Africa. 5South African Cochrane Centre, South African Medical Research Council, Cape Town, South Africa

Contact address: Nandi Siegfried, Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. [email protected].

Editorial group: Cochrane HIV/AIDS Group. Publication status and date: Edited (no change to conclusions), comment added to review, published in Issue 5, 2013. Review content assessed as up-to-date: 10 September 2008.

Citation: Siegfried N, Muller M, Deeks JJ, Volmink J. Male circumcision for prevention of heterosexual acquisition of HIV in men. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD003362. DOI: 10.1002/14651858.CD003362.pub2.

ABSTRACT

Background

Male circumcision is deﬁned as the surgical removal of all or part of the foreskin of the penis and may be practiced as part of a religious ritual, as a medical procedure, or as part of a traditional ritual performed as an initiation into manhood. Since the 1980s, over 30 observational studies have suggested a protective effect of male circumcision on HIV acquisition in heterosexual men. In 2002, three randomised controlled trials to assess the efﬁcacy of male circumcision for preventing HIV acquisition in men commenced in Africa. This review evaluates the results of these trials, which analysed the effectiveness and safety of male circumcision for preventing acquisition of HIV in heterosexual men.

Objectives

To assess the evidence of an interventional effect of male circumcision for preventing acquisition of HIV-1 and HIV-2 by men through heterosexual intercourse

Search methods

We formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress). In June 2007 we searched the following electronic journal and trial databases: MEDLINE, EMBASE, and CENTRAL. We also searched the electronic conference databases NLM Gateway and AIDSearch and the trials registers ClinicalTrials.gov and Current Controlled Trials. We contacted researchers and relevant organizations and checked reference lists of all included studies.

Selection criteria

Randomised controlled trials of male circumcision versus no circumcision in HIV-negative heterosexual men with HIV incidence as the primary outcome.

Two review authors independently assessed study eligibility, extracted data, and graded methodological quality. Data extraction and methodological quality were checked by a third author who resolved differences when these arose. Data were considered clinically homogeneous and meta-analyses and sensitivity analyses were performed.

Main results

Three large RCTs of men from the general population were conducted in South Africa (N = 3 274), Uganda (N = 4 996) and Kenya (N = 2 784) between 2002 and 2006. All three trials were stopped early due to significant findings at interim analyses. We combined the survival estimates for all three trials at 12 months and also at 21 or 24 months in a meta-analysis using available case analyses using the random effects model. The resultant incidence risk ratio (IRR) was 0.50 at 12 months with a 95% confidence interval (CI) of 0.34 to 0.72; and 0.46 at 21 or 24 months (95% CI: 0.34 to 0.62). These IRRs can be interpreted as a relative risk reduction of acquiring HIV of 50% at 12 months and 54% at 21 or 24 months following circumcision. There was little statistical heterogeneity between the trial results (χ² = 0.60; df = 2; p = 0.74 and χ² = 0.31; df = 2; p = 0.86) with the degree of heterogeneity quantified by the I² at 0% in both analyses. We investigated the sensitivity of the calculated IRRs and conducted meta-analyses of the reported IRRs, the reported per protocol IRRs, and reported full intention-to-treat analysis. The results obtained did not differ markedly from the available case meta-analysis, with circumcision displaying significant protective effects across all analyses.

We conducted a meta-analysis of the secondary outcomes measuring sexual behaviour for the Kenyan and Ugandan trials and found no significant differences between circumcised and uncircumcised men. For the South African trial the mean number of sexual contacts at the 12-month visit was 5.9 in the circumcision group versus 5 in the control group, which was a statistically significant difference (p < 0.001). This difference remained statistically significant at the 21-month visit (7.5 versus 6.4; p = 0.0015). No other significant differences were observed.

Incidence of adverse events following the surgical circumcision procedure was low in all three trials.

Reporting of methodological quality was variable across the three trials, but overall, the potential for signiﬁcant biases affecting the trial results was judged to be low to moderate given the large sample sizes of the trials, the balance of possible confounding variables across randomised groups at baseline in all three trials, and the employment of acceptable statistical early stopping rules.

Authors’ conclusions

There is strong evidence that medical male circumcision reduces the acquisition of HIV by heterosexual men by between 38% and 66% over 24 months. Incidence of adverse events is very low, indicating that male circumcision, when conducted under these conditions, is a safe procedure. Inclusion of male circumcision into current HIV prevention measures guidelines is warranted, with further research required to assess the feasibility, desirability, and cost-effectiveness of implementing the procedure within local contexts.

PLAIN LANGUAGE SUMMARY

Male circumcision for prevention of heterosexual acquisition of HIV in men

Results from three large randomised controlled trials conducted in Africa have shown strong evidence that male circumcision prevents men in the general population from acquiring HIV from heterosexual sex. At a local level, further research will be needed to assess whether implementing the intervention is feasible, appropriate, and cost-effective in different settings.

BACKGROUND childhood; as a medical procedure to treat or prevent infections, Male circumcision is deﬁned as the surgical removal of all or part injury, or anomalies of the foreskin; or as part of a traditional ritual of the prepuce (foreskin) of the penis and may be practiced as performed as an initiation into manhood (Horizons 2000). Since part of a religious ritual usually conducted shortly after birth or in the 1980s, observational studies have suggested an association be-

Male circumcision for prevention of heterosexual acquisition of HIV in men (Review) 2 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Review] Routine neonatal circumcision for the prevention of urinary tract infections in infancy

Vanitha A Jagannath1, Zbys Fedorowicz2, Vikas Sud3, Abhishek Kumar Verma3, Sakineh Hajebrahimi4

1Department of Paediatrics, American Mission Hospital, Manama, Bahrain. 2UKCC (Bahrain Branch), The Cochrane Collaboration, Awali, Bahrain. 3MBBS, Kasturba Medical College, Manipal, India. 4Urology, Tabriz University of Medical Sciences, Tabriz, Iran

Contact address: Zbys Fedorowicz, UKCC (Bahrain Branch), The Cochrane Collaboration, Box 25438, Awali, Bahrain. [email protected]. [email protected].

Editorial group: Cochrane Neonatal Group. Publication status and date: New, published in Issue 11, 2012. Review content assessed as up-to-date: 30 August 2011.

Citation: Jagannath VA, Fedorowicz Z, Sud V, Verma AK, Hajebrahimi S. Routine neonatal circumcision for the prevention of urinary tract infections in infancy. Cochrane Database of Systematic Reviews 2012, Issue 11. Art. No.: CD009129. DOI: 10.1002/14651858.CD009129.pub2.

ABSTRACT

Background

Neonatal circumcision is a fairly common surgical procedure that may be carried out for medical reasons, one of them being prevention of urinary tract infections (UTI) in male infants. Circumcision could help in reducing the incidence of UTI by reducing periurethral bacterial colonization, which is accepted as a potential risk factor in UTI. Evidence is needed to inform the beneﬁts or harm for the routine use of this intervention.

Objectives

To assess the effectiveness and safety of routine neonatal circumcision for the prevention of UTIs in infancy.

Search methods

We searched the Cochrane Neonatal Review Group Trials Register comprising references identiﬁed from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We completed this search 30 June 2011.

Selection criteria

Randomised controlled trials and quasi-randomised controlled trials.

Data collection and analysis

Two review authors had planned to independently screen studies, extract data and assess risk of bias using standard Cochrane Collab- oration methodologies. We did not identify any studies for inclusion in this review.

Main results

We did not identify any relevant studies after a comprehensive search of the literature.

Routine neonatal circumcision for the prevention of urinary tract infections in infancy (Review) 1 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Authors’ conclusions We were unable to identify any randomised controlled trials on the use of routine neonatal circumcision for prevention of UTI in male infants. Until further evidence becomes available, clinicians should continue to base their decisions on position statements and recommendations and in conjunction with the opinions of the children’s parents.

PLAIN LANGUAGE SUMMARY Newborn circumcision for the prevention of urinary tract infections in infancy Routine neonatal circumcision is a fairly common surgical procedure that may be carried out for medical or religious reasons. The incidence of urinary tract infection (UTI) is greater in uncircumcised babies. Circumcision is a relatively simple procedure and is associated with minimal complications when carried out in neonates rather than in later life. We did not ﬁnd any trials to support or refute the effectiveness of routine neonatal circumcision to prevent UTI in infancy. Although limited data from previous studies have shown that this intervention might be beneﬁcial, questions regarding the safety and effectiveness of routine neonatal circumcision for the prevention of UTIs in infancy remain unanswered.

BACKGROUND may not be justified. The conclusions from a more recent review ( Routine neonatal circumcision is a fairly common surgical proce- Singh-Grewal 2005) indicated that although circumcision reduces dure (To1998) that may be carried out for medical or religious rea- the risk of UTI there was an attendant risk of complications and sons. The potential medical benefits include reduced occurrence that the net clinical benefits are only achievable in boys at high of urinary tract infections (UTI) in infancy and a reduced risk of risk of UTI. Regular foreskin hygiene is important for all males to sexually transmitted diseases (STD) such as HIV, penile cancer, prevent UTI (Robson 1992), but there is no evidence that many of phimosis, human papilloma virus-related cervical cancer in female the potential medical benefits of circumcision can be achieved by sexual partners in later life, HSV2, genital ulcers, and bacterial simple daily penile hygiene (Wiswell 1990; Tobian 2010). While vaginosis (Alanis 2004). Circumcision is a relatively simple pro- the procedure appears to be beneficial in the prevention of UTI, cedure and is in general associated with minimal complications a number of studies have shown that UTI may itself present as a (Wiswell 1990). complication of circumcision (Cohen 1992). It has been suggested that newborn circumcision can be a valuable Neonatal circumcision rates vary widely at the global level, with preventive health measure for UTI in infancy (Schoen 2000). A rates as high as 64% in North America (American Academy of systematic review and meta-analysis (Amato 1992) of newborn Pediatrics 1999), between 10% and 20% in Australia (Royal circumcision concluded that the risk of UTI may decrease with Australasian College of Physicians 2002), and much lower rates circumcision but, given that the risk of UTI during the first year in Europe and Asia (American Academy of Pediatrics 1999). See of life is itself low, a recommendation for routine circumcision Figure 1.

Routine neonatal circumcision for the prevention of urinary tract infections in infancy (Review) 2 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Circumcision and Lifetime Risk of Urinary Tract Infection: A Systematic Review and Meta-Analysis

Brian J. Morris* and Thomas E. Wiswell

From the School of Medical Sciences and Bosch Institute, University of Sydney, New South Wales, Australia (BJM), and the Center for Neonatal Care, Orlando, Florida (TEW)

Abbreviations Purpose: Urinary tract infection is common in infant males who are uncircum- and Acronyms cised and can lead to renal parenchymal disease of the still growing pediatric UTI ϭ urinary tract infection kidney. Although the rate of urinary tract infection is highest in the ﬁrst year of life, the cumulative incidence during the rest of the lifetime is under-recognized, VUR ϭ vesicoureteral reﬂux but is expected to be nontrivial. Thus, any intervention that might prevent urinary tract infection would be expected to reduce suffering and medical costs. Accepted for publication November 15, 2012. Materials and Methods: We conducted a meta-analysis of 22 studies examining The complete list of references including numbers 31 through 77 is available at http:// the single risk factor of lack of circumcision, then determined the prevalence and jurology.com/. relative risk of urinary tract infection in different age groups (0 to 1, 1 to 16 and Nothing to disclose. older than 16 years). From these data we estimated the lifetime prevalence. * Correspondence: School of Medical Sci- ences, Sydney Medical School, University of Syd- Results: For age 0 to 1 year the relative risk was 9.91 (95% CI 7.49–13.1), for age ney, NSW 2006 Australia (telephone: ϩ61-2- 1 to 16 years RR was 6.56 (95% CI 3.26–13.2) and for older than 16 years it was 9351-3688; FAX: ϩ61-2- 9351-2227; e-mail: brian. 3.41-fold (95% CI 0.916–12.7) higher in uncircumcised males. We then calculated [email protected]). that 32.1% (95% CI 15.6–49.8) of uncircumcised males experience a urinary tract See Editorial on page 2022. infection in their lifetime compared with 8.8% (95% CI 4.15–13.2) of circumcised Editor’s Note: This article is the males (RR 3.65, 95% CI 1.15–11.8). The number needed to treat was 4.29 (95% CI fourth of 5 published in this issue 2.20–27.2). for which category 1 CME credits Conclusions: The single risk factor of lack of circumcision confers a 23.3% chance can be earned. Instructions for of urinary tract infection during the lifetime. This greatly exceeds the prevalence obtaining credits are given with of circumcision complications (1.5%), which are mostly minor. The potential the questions on pages 2398 and 2399. seriousness of urinary tract infection supports circumcision as a desirable preventive health intervention in infant males.

Key Words: circumcision, male; foreskin; urinary tract infections; meta-analysis; male

URINARY tract infections are common in Rushton and Majd found that 50% infancy1 and can lead to significant to 86% of children with febrile UTI morbidity.2 The younger the infant, the and presumed pyelonephritis had re- more likely and severe will be the UTI, nal parenchymal defects which per- and the greater the risk of sepsis and sisted.8 Others reported pyelonephri- death.3 By the age of 7 years 2% (defi- tis in 34% to 70% of febrile UTI cases nitely) and another 5% (probably) of boys in the first year of life9 and another have had at least 1 UTI.4 Apart from estimate was 90%.10 Nuclear scans in severe pain and fever, the infant kidney febrile infants after treatment for UTI is still growing, thus increasing suscepti- noted scarring in 10% to 30%.11 Acute bility to renal injury and scarring from pyelonephritis is a major cause of re- UTI.5,6 This exposes half to serious, life nal scarring12 and the likelihood of threatening conditions later in life.7 renal scarring after acute pyelone-

0022-5347/13/1896-2118/0 http://dx.doi.org/10.1016/j.juro.2012.11.114 ® 2118 www.jurology.com THE JOURNAL OF UROLOGY Vol. 189, 2118-2124, June 2013 © 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH,INC. Printed in U.S.A. CIRCUMCISION AND LIFETIME URINARY TRACT INFECTIONS 2119

phritis is 36% to 52%.10,13–15 The majority with re- attributable to circumcision. Moreover, not only is nal scarring do not have VUR.16 Moreover, recur- the prevalence of UTI highest in infancy, but it is a rent UTI can occur in the absence of VUR with an much more severe and generalized disease at this incidence of 36%.17 It is the parenchymal infection age, with fever the predominant sign due to pyelo- with inflammation rather than the VUR that is the nephritis. prerequisite for renal scarring.14–16 Roberts esti- Therefore, we generated estimates of the protec- mated that infant circumcision prevents 20,000 tive effect of circumcision against UTI during the cases of acute pyelonephritis annually.18 A 27-year lifetime of a male. We devised a strategy to 1) gen- followup study of pyelonephritis in childhood noted erate best estimates of the relative risk among un- a 10% to 20% risk of hypertension associated with circumcised males through a meta-analysis of pub- hyperreninemia and hypernatremia, consistent with lished data, and 2) use these figures, in addition to renal involvement.19 Post-infection scarring may occa- estimates of lifetime risk and circumcision rates for sionally progress to renal insufficiency and end stage populations in which these were known, to generate renal disease. As a result, measures that can be put in projected risk of UTI by circumcision status. place to prevent UTI would seem worthy of consideration. The first evidence that infant male circumcision MATERIALS AND METHODS might protect against UTI emerged in the early 20 The inclusion criteria for our meta-analysis were publica- 1980s, although the association had been sus- tion in a peer reviewed journal, publication before Sep- 21 pected since 1972. The studies that followed, in- tember 9, 2011, the presence of an adjusted RR or odds volving a variety of designs including a small ran- ratio or sufficient data to allow the calculation of crude or domized controlled trial,22 attested to the protection adjusted RR or OR for UTI by circumcision status. Articles afforded by circumcision against UTI in infancy. The were identified by searching the PubMed® database and Pediatric Research in Office Settings Febrile Infant by hand searching the bibliographies of published reports, Study of 219 United States practices found that including those of previously published meta-analyses. being uncircumcised was the strongest multivariate We searched for articles matching 1 or more of the key- predictor of UTI (OR 11.6, 95% CI 5.9–22.6).23 Among words circumcision, circumcised or uncircumcised plus 1 boys with UTI one study demonstrated that 19% ex- or more of the keywords UTI, urinary tract infection or bacteriuria. The abstracts of papers were used to judge perienced recurrent UTIs if not circumcised com- 24 whether they met our inclusion criteria (for convenience, pared with zero for the circumcised. In another the “Limits” facility was used to exclude articles without study recurrent UTI was seen in 34% of those with abstracts).33 We retrieved the full text of every article nonretractile foreskins compared with 18% of those except when this was not possible or it was in a language 17 whose foreskin could be retracted. Acute pyelone- other than English. Previously published meta-analyses phritis increased the likelihood of recurrent UTI by and systematic reviews of circumcision and UTIs were 4.6,17 nonretractile foreskin and acute pyelonephri- examined in full. No attempt was made to contact authors tis being the greatest risk factors for recurrent UTI. to identify additional studies they might have performed In premature uncircumcised boys whose risk of UTI or of which they might have been aware. was increased elevenfold, Cason et al found that We performed random effects inverse variance meta- circumcision eliminated the risk of recurrence.25 analyses using the natural logarithm of the OR as the effect size. Adjusted measures were considered more reli- Previously published meta-analyses have noted a able than crude effect estimates since they partially con- consistent protective effect of circumcision against 26–28 trolled for confounding factors and, therefore, were used in UTIs of approximately tenfold. Most studies our analysis where available. Otherwise we calculated the have been of infants, with only a few examining the appropriate crude measure and CI from published fre- prevalence of UTIs in children. Studies in men are quencies. When frequencies of zero were shown we added scarce.29 To our knowledge an estimate of the prev- 0.5 to the relevant cell. For one study we estimated RR alence of UTI by circumcision status during the en- using the quotient of published means and standard error tire lifetime has never been done. This deficit poses of the mean for UTI incidence.34 When data in 1 report particular difficulties for evidence-based decision represented a subset of data reported in another, we used making. Authors attempting to weigh risks vs ben- the most complete report. efits have tended to use the cumulative incidence in To assess the impact of age we created 3 binary valued infancy as an approximation of the lifetime risk. variables representing participant age, namely 0 to 1 year, 1 to 16 years and 16ϩ years. These particular boundaries Typical estimates of the risk of UTI among uncircum- 27 30 were chosen largely for convenient analysis rather than cised males have been 1% to 2%, 1.4% to 1.6% and for any biological reason. When studies presented data for 31 2.5%. Although the risk of UTI in males is greatest current UTI and history of UTI, we preferred the former 32 during the first month of life, the risk after infancy is as this facilitated classification of participant age. The age not zero and, therefore, such analyses would inevita- ranges for some studies included 2 of these categories, bly have underestimated the absolute risk reduction meaning that age groups were poorly isolated. 2120 CIRCUMCISION AND LIFETIME URINARY TRACT INFECTIONS

We estimated lifetime risk by circumcision status using we obtained incidence by circumcision status through meta-regression results for the 3 previously mentioned meta-analysis of the 4 cohort studies following infants age groups. This analysis provided RR estimates by age during this period.26,35–37 A random effects inverse vari- groups, which were then used as inputs in the model ance model was used, using the logit function for normal described. For the ﬁrst age group (subjects age 0 to 1 year) approximation of rate data. Data for later groups were

Table 1. Characteristics of studies included in analysis

Circumcision References Location Design Population Age Range UTI Deﬁnition Classiﬁcation

Wiswell et al36 USA Army hospitals Cohort 1975–1984 Birth-1 yr Not stated (92% of cultures Birth records suprapubic) Herzog41 Boston Children’s Case-control 1985–1986 Birth-1 yr 105 cfu/ml or Greater Medical records letter Hospital to parents Kashani and Taradag51 UCSD Medical Center Case-control 1980–1985 1 Mo-2 yrs 105 cfu/ml or Greater Medical records (catheter or suprapubic aspiration) Crain and Gershel42 New York Case-control 1982–1987 Younger than 8 wks 104 cfu/ml or Greater (bag/ Medical records catheter), greater than 102 (suprapubic) Rushton and Majd5 Washington, DC Case-control 1987–1988 2 Wks–6 mos 105 cfu/ml or Greater (clean Medical records catch), greater than 104 (prospectively for (catheterized) circumcised) Spach et al29 Seattle, WA Case-control (sexually Adult (median age pts 105 cfu/ml or Greater mid Examination transmitted disease 30, controls 32) stream plus 1 or more clinic urine culture) symptoms Wiswell and Hachey26 USA Army hospitals Cohort 1985–1990 Birth-1 yr Not stated Birth records Craig et al43 Sydney, Australia Case-control 1993–1994 Birth-4 yrs 105 or Greater (suprapubic or Parents or examination catheter), greater than 108 (midstream urine) Kim44 Seoul, Korea Case-control Younger than 15 yrs 105 cfu/ml or Greater Examination Shaw et al45 Philadelphia, PA Case-control 1995–1996 1 yr or younger (84% 105 cfu/ml or Greater (sterile Not stated (1 yr) African-American) urethral catheterization) To et al35 Ontario, Canada Cohort 1993 (fiscal yr) Birth-3 yrs ICD-9 codes 590, 595, 597, Canadian Classification 599 Code 76.0 (in 1st month) Herndon et al46 USA, 3 sites Case-control 1993–1998 ЉBoysЉ Society for Fetal Urology Society for Fetal data sheets Urology data sheets Schoen et al37 Kaiser Hospitals, CA Retrospective cohort Birth-1 yr ICD-9 coding or outpatient ICD-9 coding 1996–1997 clinic record Nayir22 Istanbul, Turkey Randomized controlled 3 Mos-10 yrs who had 105 cfu/ml or Greater ϩ Performed as part of trial UTI symptoms trial Newman et al23 USA, 219 sites Case-control 1995–1998 Birth-98 days 102 cfu/ml or Greater Not stated (suprapubic), 2 ϫ 104 or greater (catheter), 105 or greater (bag, clean voided) Kwak et al47 Seoul, Korea Cohort 1985–1993 4.2–174 Mos 105 cfu/ml or Greater Performed during study Zorc et al48 USA, 8 sites Cross-sectional 60 Days or younger 103 cfu/ml or Greater Examination (suprapubic), 5 ϫ 104 or greater (catheter), 105 or greater (catheter) ϩ pos urinalysis) Ghaemi et al49 Isfahan, Iran Case-control July 2001– Neonates (mean age Any cfu in suprapubic Examination February 2002 10.8 days) specimen, or 104 or greater in clean voided specimen Mukherjee et al34 Birmingham Children’s Retrospective cross- 1–18 Yrs (mean age Proven pure bacterial culture Not stated Hospital, UK sectional case-note 6.7) (organisms tabulated) review Roth et al50 Children’s Hospital of Retrospective analysis 1–11 Mos (mean age Pos urine culture Not stated Oklahoma 6.1) Alsaywid et al52 Children’s Hospital Prospective cohort study 1 Day–8.8 yrs Urine culture, organisms Performed during Westmead, Sydney 1995–2006 identified study Simforoosh et al53 Tehran, Iran Prospective cohort study Neonatal followed for 105 cfu/ml or Greater if pos Performed neonatally 2004–2008 15 mos or equivocal rechecked by as part of study suprapubic catheter CIRCUMCISION AND LIFETIME URINARY TRACT INFECTIONS 2121

derived from published figures for cumulative incidence to different age groups indicated that for ages 0 to 1 age 16 years and during a lifetime.38–40 To combine these year, RR of UTI was 9.91-fold (95% CI 7.49–13.1) figures it was necessary to first adjust them for hypothet- higher for uncircumcised boys, for age 1 to 16 years ical populations with standardized circumcision rates. We the RR of UTI was 6.56-fold higher (95% CI 3.26– did this by creating a simple mathematical model using 13.2) and for males older than 16 years the RR was the formula, p ϭ Cc ϩ (1-C)Rc, where p is the overall risk 3.41-fold higher (95% CI 0.916–12.7, table 3). We for a population, C the proportion of circumcised males, R is the relative risk for uncircumcised vs circumcised males then used these data to estimate risk during the and c is the risk among circumcised males. We were then entire lifetime according to circumcision status, able to estimate risk by circumcision status for each age finding RR to be 3.65 (95% CI 1.15–11.8) higher for group using the same model. The sum of these figures was uncircumcised (32.1%, 95% CI 15.6–49.8) vs circum- used as an estimate of lifetime risk. Monte Carlo simula- cised males (8.8%, 95% CI 4.15–13.2). The differ- tions (using 10,000 samples) were used to find 95% CIs. ence, 23.2 (ie 32.1 minus 8.8), represents the per- All statistical analyses were performed using the R centage of UTIs during the lifetime attributable to statistical language and environment version 2.14.1 the single risk factor of lack of circumcision. From (http://www.r-project.org/). The metafor package (version our data we calculated that the number needed to 1.6–0) was used to perform meta-analyses and meta-re- treat was 4.29 (95% CI 2.20–27.2). gressions.

DISCUSSION RESULTS Our analysis shows that during the entire lifetime Our PubMed search resulted in 163 articles. Most the adjusted risk of UTI is 3.7 times higher in un- were reviews or opinion pieces but 19 met the inclu- circumcised vs circumcised males. Infant males had sion criteria.5,22,23,26,29,34–37,41–50 Another article a 9.9 times higher risk of UTI if uncircumcised. This was identified by a review of bibliographies51 and 2 decreased to 6.6-fold for age 1 to 16 years and 3.4- further articles were identified from the authors’ fold beyond age 16 years. Lifetime UTI risk was 32% libraries.52,53 Table 1 shows the characteristics of in uncircumcised males and 8.8% in circumcised the studies included in the analysis. males. Table 2 shows the frequencies of UTIs in circum- Previous meta-analyses found risk of UTIs in un- cised and uncircumcised boys, together with RR, circumcised boys to be twelvefold (95% CI 11–14, ARR or OR as reported in each study. The figure is range 5 to 89-fold)26 and eightfold (95% CI 5–13)27 a forest plot of these data as ORs. An analysis by greater than in circumcised boys. UTI is especially

Table 2. The included studies showing frequency of UTI

References No./Total No. Circumcised No./Total No. Uncircumcised AOR,a ARR,b ORc* Notes*

Wiswell et al36 151/173,663 459/46,112 11.4 (9.53–13.8) ehij Herzog41 0/52 36/60 156 (9.22–26.60) cdehij Kashani and Faraday51 1/43 16/83 10 (1.28–78.4) cefhi Crain and Gershel42 4/96 18/103 4.87 (1.58–15) cehi Rushton and Majd5 2/37 21/49 13.1 (2.83–60.8) cehi Spach et al29 18/64 8/14 3.41 (1.04–11.2) cghi Wiswell and Hachey26 112/80,279 384/27,319 10.1 (8.17–12.4) ehij Craig et al43 2/49 142/837 5.6 (1.4–20) aefhi Kim44 0/19 8/70 5.3 (0.293–96.1) cdefi Shaw et al45 6/497 6/75 7.12 (2.23–22.7) c e i To et al35 55/29,217 205/29,217 3.7 (2.8–5) befhi Herndon et al46 7/37 10/19 4.76 (1.41–16.1) c e i Schoen et al37 22/9,668 132/5,225 11.1 (7.08–17.4) ehij Nayir22 0/35 3/35 7 (0.375–131) defi Newman et al23 15/572 41/197 9.76 (5.26–18.1) c e i Kwak et al47 6/27 18/50 1.97 (0.672–5.77) c f i Zorc et al48 6/262 62/291 10.4 (4.7–31.4) a e i Ghaemi et al49 2/105 16/148 6.24 (1.4–27.8) c e i Mukherjee et al34 Ϫ/Not available Ϫ/Not available 12 (6.4–23.6) a f i Roth et al50 0/41 2/24 9.22 (0.424–201) cdei Alsaywid et al52 5/74 62/137 11.4 (4.33–30) cefi Simforoosh et al53 0/2,000 20/1,000 83.7 (5.05–1,380) cdefhi

The studies are listed in chronological order. * a, adjusted odds ratio. b, adjusted relative risk. c, odds ratio. d, small sample correction. e, infant. f, child. g, adult. i, systematic search. j, USA. When a, b or c does not appear, the study did not report one of these. 2122 CIRCUMCISION AND LIFETIME URINARY TRACT INFECTIONS

Wiswell 1987 11.55 [ 9.61 , 13.89 ] Wiswell 1993 10.20 [ 8.26 , 12.60 ] Schoen 2000 11.36 [ 7.23 , 17.87 ] To 1998 3.70 [ 2.77 , 4.94 ] Nayir 2001 7.65 [ 0.38 , 153.75 ] Herzog 1989 156.43 [ 9.22 , 2655.08 ] Kashani 1989 10.03 [ 1.28 , 78.44 ] Crain 1990 4.87 [ 1.58 , 14.97 ] Rushton 1992 13.12 [ 2.83 , 60.81 ] Craig 1996 5.60 [ 1.48 , 21.17 ] Spach 1992 3.41 [ 1.04 , 11.21 ] Newman 2002 9.76 [ 5.26 , 18.10 ] Kwak 2004 1.97 [ 0.67 , 5.77 ] Zorc 2005 10.40 [ 4.02 , 26.88 ] Shaw 1998 7.12 [ 2.23 , 22.68 ] Herndon 1999 4.76 [ 1.41 , 16.13 ] Mukherjee 2009 12.00 [ 6.25 , 23.04 ] Kim 1996 5.30 [ 0.29 , 96.12 ] Ghaemi 2007 6.24 [ 1.40 , 27.76 ] Roth 2009 9.22 [ 0.42 , 200.54 ] Alsaywid 2010 11.41 [ 4.33 , 30.04 ] Simforoosh 2010 83.65 [ 5.05 , 1384.52 ]

0.05 1.15 27.94 678.58 Odds ratio

Forest plot showing odds ratios derived from studies included in meta-analysis. Mean is shown as square symbol and as ﬁrst number in column on right. Horizontal bars and numbers in brackets depict 95% CIs.

common in uncircumcised boys with underlying uri- There were 3 major limitations of our analysis. nary tract abnormalities.34,54 The conservative rec- 1) Inclusion of circumcision (and related terms) as ommendation by Singh-Grewal et al27 that circum- keywords may have introduced bias since authors cision should only be recommended in boys with might have been more likely to mention circumci- recurrent UTI or VUR is ﬂawed.3 Moreover, it ig- sion in the abstracts of papers in which associations nores other disorders that circumcision protects were found. However, if we had searched by UTI and against.55,56 Although the overall UTI rate of 1.1% related terms and had not included circumcision and was stated in that particular meta-analysis,27 the related terms, our search would have returned ap- cumulative incidence was 2.2% by age 2 years in a proximately 47,000 articles. Scrutiny of all of these Swedish study,57 6% in uncircumcised and 1% (sam- was unrealistic. 2) Bag specimens or clean catch urine ple size of 2) in circumcised boys younger than 5 samples were used in several studies. The organisms years old in Western Sydney,43 and 3.6% to age 16 identiﬁed in these samples were typically pure cul- years in a United Kingdom study.38 tures of known pathogens in great quantities (cfu/ml).

Table 3. UTI risk estimates for circumcised and uncircumcised males of different age groups

Age Group (yrs) RR (95% CI) % Circumcised Risk (95% CI) % Uncircumcised Risk (95% CI)

0–1 9.91 (7.49–13.1) 0.127 (0.072–0.223) 1.26 (0.737–2.14) 1–16 6.56 (3.26–13.2) 0.409 (0.221–0.704) 2.68 (1.67–4.13) 16ϩ 3.41 (0.916–12.7) 8.26 (3.61–12.7) 28.2 (11.6–45.7) Lifetime 3.65 (1.15–11.8) 8.8 (4.15–13.2) 32.1 (15.6–49.8)

Does not include results for meta-regression and stratiﬁed meta-analysis models, nor an analysis of various subsets such as studies of a general population vs those with VUR. CIRCUMCISION AND LIFETIME URINARY TRACT INFECTIONS 2123

However, the findings were similar to those of studies Our ability to fully explore the influence of age in which the majority of samples were obtained by was limited by the fact that some studies included suprapubic aspiration or bladder catheterization. 3) In wide age ranges. Future studies of UTI and circum- our estimates of lifetime risk we relied on combining cision in populations with wide age ranges, particu- risk data from dissimilar populations. While we ad- larly when younger children are included, should be justed for different circumcision rates, it is likely that careful to stratify by age. other differences among countries limited the accuracy Our analysis is the first to estimate the lifetime of such calculations. Cumulative rates from a British prevalence of UTI by circumcision status and, thus, study were for specialist referrals38 and, thus, may may represent the most realistic estimate of the have underestimated the true risk since many UTIs number needed to treat to date. A previous system- may be treated by a general practitioner. There are atic review compared the risk of complications from relatively few studies of UTI incidence in males, and circumcision with the absolute reduction in UTI risk most focus on infancy and early childhood. A 1974 during the first year of life.27 Since circumcision study reported a minimum risk of 1.1% by age 11 must be performed once but its benefits last for a 58 years, but more recent studies reported 2.2% by lifetime, complications should be compared with the 57 59 60 age 2, 1.9% by age 5 and 1.8% by age 6 years. sum of all benefits and not just a reduction in UTI. Lifetime prevalence data in a nationally represen- When data for UTIs are combined with data on tative American sample relied on self-reported protection against balanoposthitis, phimosis, para- 39,40 history of UTI diagnosis. These might under- phimosis, various sexually transmitted infections, estimate or overestimate the true rate of UTI. penile cancer, and other conditions and infections, Although our lifetime risk estimates were based the benefits were found to exceed the risks by more on the best available data, they remain projections than 100 to 1.56,71 based on mathematical models. A previous meta-analysis noted significant differences among studies,27 primarily from 1 large cohort CONCLUSIONS study. That study was notable for its long followup period (to 3 years). RR among uncircumcised males The present meta-analysis is the first to estimate was greatest in infancy, decreasing from 4.5 in the the lifetime risk of UTI in circumcised and uncir- first month to 3.0 during the first 3 years.35 A compa- cumcised males. Our finding that the single risk rable association with age was reported in one37 but factor of lack of circumcision accounts for 23% of not in another43 cohort study. Phimosis may be a risk UTIs during the lifetime of males compares favor- factor for UTI,17,61–64 supporting the view that patho- ably with the 1.5% complication rate associated with 72 genesis involves pathogens ascending from the prepu- infant circumcision in a meta-analysis. While most tial sac.65–67 Retractability of the foreskin is low complications are minor, UTIs can be associated 1 among newborns but common in adolescence.68 Al- with long-term morbidity and potential mortality. though the prevention of phimosis has been invoked in By protecting against UTIs the cost savings are con- explaining the protective effect of circumcision, a re- siderable.73 Prevention of UTIs in infancy was em- cent Canadian study found a similar UTI prevalence phasized in the 2012 American Academy of Pediat- in uncircumcised boys with a completely, partially or rics policy recommendations.55 Coupled with other nonvisible urethral meatus.69 lifetime benefits, the circumcision of all infant males The circumcision rate is 71% for United States would seem desirable. Newborn circumcision is as men born in the 1940s and 78% for those born in the protective against UTIs as are many vaccines given 1980s.70 However, we did not break down UTI risk to children to prevent other infections and dis- in adulthood by age. We believe that further age eases.37 For example, the level of protection deemed adjustments would have introduced an excess of acceptable against influenza vaccines74,75 justifies complexity into the analysis without a sufficient in- claims that infant male circumcision be regarded as crease in accuracy. a surgical vaccine.71,76,77

REFERENCES 1. Koyle MA, Barqawi A, Wild J et al: Pediatric 3. Schoen EJ: Circumcision for preventing urinary 5. Rushton HG and Majd M: Pyelonephritis in male urinary tract infections: the role of ﬂuoroquinolo- tract infections in boys: North American view. infants: how important is the foreskin? J Urol nes. Pediatr Infect Dis J 2003; 22: 1133. Arch Dis Child 2005; 90: 772. 1992; 148: 733. 4. Sureshkumar P, Jones M, Cumming RG et al: Risk 2. Chon CH, Lai FC and Shortliffe LM: Pediatric factors for urinary tract infection in children: a 6. Stull TL and LiPuma JJ: Epidemiology and natural urinary tract infections. Pediatr Clin North Am population-based study of 2856 children. J Pae- history of urinary tract infections in children. Med 2001; 48: 1441. diatr Child Health 2009; 45: 87. Clin North Am 1991; 75: 287. 2124 CIRCUMCISION AND LIFETIME URINARY TRACT INFECTIONS

7. Wiswell TE: The prepuce, urinary tract infections, acute pyelonephritis. Acta Paediatr 1993; 82: Research in Office Settings’ Febrile Infant Study. and the consequences. Pediatrics 2000; 105: 1061. Arch Pediatr Adolesc Med 2002; 156: 44. 8602. 16. Rushton HG: The evaluation of acute pyelonephri- 24. Conway PH, Cnaan A, Zaoutis T et al: Recurrent 8. Rushton HG and Majd M: Dimercaptosuccinic tis and renal scarring with technetium 99m-di- urinary tract infections in children: risk factors acid renal scintigraphy for the evaluation of py- mercaptosuccinic acid renal scintigraphy: evolv- and association with prophylactic antimicrobials. elonephritis and scarring: a review of experimen- ing concepts and future directions. Pediatr JAMA 2007; 298: 179. tal and clinical studies. J Urol 1992; 148: 1726. Nephrol 1997; 11: 108. 25. Cason DL, Carter BS and Bhatia J: Can circumci- 9. Zorc JJ, Kiddoo DA and Shaw KN: Diagnosis and 17. Shim YH, Lee JW and Lee SJ: The risk factors of sion prevent recurrent urinary tract infections in management of pediatric urinary tract infections. recurrent urinary tract infection in infants with hospitalized infants? Clin Pediatr (Phila) 2000; 39: Clin Microbiol Rev 2005; 18: 417. normal urinary systems. Pediatr Nephrol 2009; 699. 10. Rushton HG: Urinary tract infections in children. 24: 309. Epidemiology, evaluation, and management. Pe- 18. Roberts JA: Neonatal circumcision: an end to the 26. Wiswell TE and Hachey WE: Urinary tract infec- diatr Clin North Am 1997; 44: 1133. controversy? South Med J 1996; 89: 167. tions and the uncircumcised state: an update. Clin Pediatr (Phila) 1993; 32: 130. 11. Hoberman A, Wald ER, Hickey RW et al: Oral 19. Jacobson SH, Eklof O, Eriksson CG et al: Devel- versus initial intravenous therapy for urinary tract opment of hypertension and uraemia after pyelo- 27. Singh-Grewal D, Macdessi J and Craig J: Circum- infections in young febrile children. Pediatrics nephritis in childhood: 27 year follow up. BMJ cision for the prevention of urinary tract infec- 1999; 104: 79. 1989; 299: 703. tions in boys: a systematic review of randomized 12. Elder JS: Urinary tract infections. In: Nelson Text- trials and observational studies. Arch Dis Child book of Pediatrics, 18th ed. Edited by RM Klieg- 20. Ginsburg CM and McCracken GH: Urinary tract 2005; 90: 853. man, RE Behrman, HB Jenson et al. Philadelphia: infections in young children. Pediatrics 1982; 69: Saunders 2007. 409. 28. Amato D and Garduño-Espinosa J: Circumcision in the newborn child and risk of urinary tract 21. Mann PG: Proteus urinary infections in childhood. 13. Jakobsson B, Berg U and Svensson L: Renal infection during the first year of life. A meta- J Clin Pathol 1972; 25: 551. scarring after acute pyelonephritis. Arch Dis Child analysis. Bol Med Hosp Infant Mex 1992; 49: 652. 1994; 71: 386. 22. Nayir A: Circumcision for the prevention of sig- 14. Benador D, Benador N, Slosman D et al: Are nificant bacteriuria in boys. Pediatr Nephrol 2001; 29. Spach DH, Stapleton AE and Stamm WE: Lack of younger children at highest risk of renal sequelae 16: 1129. circumcision increases the risk of urinary tract after pyelonephritis? Lancet 1997; 349: 17. infections in young men. JAMA 1992; 267: 679. 23. Newman TB, Bernzweig JA, Takayama JI et al: 15. Wallin L and Bajc M: Typical technetium di- Urine testing and urinary tract infections in fe- 30. Van Howe RS: A cost-utility analysis of neonatal mercaptosuccinic acid distribution patterns in brile infants seen in office settings: the Pediatric circumcision. Med Decis Making 2004; 24: 584. 853

ORIGINAL ARTICLE Arch Dis Child: first published as 10.1136/adc.2004.049353 on 12 May 2005. Downloaded from Circumcision for the prevention of urinary tract infection in boys: a systematic review of randomised trials and observational studies D Singh-Grewal, J Macdessi, J Craig ......

Arch Dis Child 2005;90:853–858. doi: 10.1136/adc.2004.049353

Objective: To undertake a meta-analysis of published data on the effect of circumcision on the risk of urinary tract infection (UTI) in boys. Data sources: Randomised controlled trials and observational studies comparing the frequency of UTI in circumcised and uncircumcised boys were identified from the Cochrane controlled trials register, See end of article for authors’ affiliations MEDLINE, EMBASE, reference lists of retrieved articles, and contact with known investigators...... Methods: Two of the authors independently assessed study quality using the guidelines provided by the MOOSE statement for quality of observational studies. A random effects model was used to estimate a Correspondence to: Jonathan Craig, Centre for summary odds ratio (OR) with 95% confidence intervals (CI). Kidney Research, Clinical Results: Data on 402 908 children were identified from 12 studies (one randomised controlled trial, four Sciences Building, Locked cohort studies, and seven case–control studies). Circumcision was associated with a significantly reduced Bag 4001, Westmead , NSW 2145, Sydney, risk of UTI (OR = 0.13; 95% CI, 0.08 to 0.20; p 0.001) with the same odds ratio (0.13) for all three types Australia; jonc@health. of study design. usyd.edu.au Conclusions: Circumcision reduces the risk of UTI. Given a risk in normal boys of about 1%, the number- needed-to-treat to prevent one UTI is 111. In boys with recurrent UTI or high grade vesicoureteric reflux, the risk Accepted 9 August 2004 Published Online First of UTI recurrence is 10% and 30% and the numbers-needed-to-treat are 11 and 4, respectively. Haemorrhage 12 May 2005 and infection are the commonest complications of circumcision, occurring at rate of about 2%. Assuming equal ...... utility of benefits and harms, net clinical benefit is likely only in boys at high risk of UTI.

ircumcision is the commonest surgical procedure by two of us (JM and DSG) without blinding to authorship. carried out on children.1 Neonatal circumcision rates Resolution of discrepancies was by consensus and the vary widely between different cultures, with rates as involvement of the third author (JC) when necessary. C 2 high as 64% in North America, between 10% and 20% in 3 2 Australia, and far lower rates in Europe and Asia. Data sources http://adc.bmj.com/ Boys have been circumcised for thousands of years and The Cochrane controlled trials register (issue 4, November circumcision plays a significant cultural and religious role in 2002), MEDLINE (1966 to November 2002), and EMBASE many societies. It is also undertaken on medical grounds (1980 to November 2002) databases were searched. with benefits thought to include improved hygiene, a reduced MEDLINE and EMBASE were searched using ‘‘circumci- incidence of urinary tract infection (UTI),4–6 sexually trans- sion’’ as both a text word and medical subject heading mitted diseases,7 penile cancer,8 and phimosis,9 and a (MeSH) term. The search was not limited by language, and reduction in the incidence of human papilloma virus related bibliographies of identified publications were examined for cervical cancer in female sexual partners.10 any relevant material that may have been overlooked. Details on 11 September 2018 by guest. Protected copyright. The overall complication rate of circumcision is between of any additional published or unpublished data were sought 2% and 10%,11 12 and most complications are minor.11 13 14 from authors identified in the literature search. While haemorrhage is the most frequent acute complication, Following the computerised database search, all titles were infection, glandular ulceration, urethral fistula formation, screened and abstracts of relevant or possibly relevant articles and penile amputation can also occur.11 Long term complica- were reviewed in full. Studies in languages other than tions include meatal stenosis and poor cosmetic results.11 English were translated before assessment. When more than Various paediatric societies have developed position state- one report of the same data was found, data were extracted ments on circumcision. These statements generally conclude only from the paper containing the most complete data. that there is insufficient evidence to recommend routine neonatal circumcision but consider it justified in recurrent Study selection 2315 balanitis, true phimosis, and UTI. All studies examining the effect of male circumcision on UTI Lack of a clear consensus on the magnitude of the benefits were included. The population of interest was male without of circumcision may reflect the variability in the different any age restriction, and the intervention evaluated was methods used to search and critically appraise the available circumcision. Diagnosis with UTI was the only outcome 16 reports. As the most frequently cited benefit of circumcision investigated. Studies were included only if they provided is a reduced incidence of UTI, we have undertaken a sufficient information for a 262 contingency table to be systematic review of the available data on the effect of constructed, so that the odds of UTI in the circumcised group circumcision on UTI in male subjects of all ages. could be compared with those in the uncircumcised group.

METHODS Abbreviations: CONSORT, consolidated standards for reporting trials; All steps of the review, including literature search, data MOOSE, meta-analysis of observational studies in epidemiology; UTI, extraction, and data analysis, were carried out independently urinary tract infection

www.archdischild.com 854 Singh-Grewal, Macdessi, Craig

20 Data extraction 50% indicating significant heterogeneity. Heterogeneity Arch Dis Child: first published as 10.1136/adc.2004.049353 on 12 May 2005. Downloaded from Randomised studies were assessed using the guidelines between and within subgroups, and between individual provided by the CONSORT statement.17 Aspects of study studies when combined, was assessed. Possible sources of design including allocation concealment, blinding, follow up, heterogeneity included study type, setting, study population, outcome measurement, and analysis by intention to treat and follow up. were assessed. There were insufficient studies to construct a funnel plot to Quality assessment for observational studies was carried assess for publication bias. out using the guidelines provided by the MOOSE statement.18 The quality of studies identified was assessed according to RESULTS the study setting, completeness and duration of follow up, Literature search validity and completeness of exposure and outcome ascer- The study selection process is outlined in fig 1. From 2166 tainment, comparability of the control group, and adjustment titles and abstracts retrieved, 12 fulfilled the inclusion criteria for known confounding variables. (one randomised trial, four cohort studies, and seven case– control studies). Data synthesis Statistical analysis was done with Review Manager (version Characteristics of the studies included 4.2).19 An odds ratio (OR) with 95% confidence interval (CI) The characteristics of the studies included are outlined in was calculated for each individual study and a summary OR table 1. All were published between 1987 and 2001. Most using a random effects model was first calculated for originated from North America and relied on hospital subgroups based on study type (that is, randomised inpatient and outpatient data. These 12 studies provided data on 402 908 children and 1953 separate episodes of UTI. controlled trial, cohort study, or case–control study) and Most of the studies included examined UTI in infants. One then an overall OR was calculated across all study types if no included adults and four others included boys beyond the heterogeneity was present. first year of life. Studies generally reported episodes of UTI Consistency of the intervention effects across studies was rather than patients with UTI, and only one reported evaluated using the Cochran Q statistic for heterogeneity recurrent episodes of UTI in individual patients. with n21 degrees of freedom and an a of 0.05. This method The single randomised controlled trial by Nayir21 was a calculates a x2 statistic, with p,0.05 suggesting that the study of recurrent UTI. Seventy uncircumcised patients with observed variation in the OR is unlikely to be a result of proven UTI were recruited and then randomised into chance alone.20 The I2 statistic was calculated as an estimate circumcision and non-circumcision groups. UTI was defined of the percentage of the variability in the OR due to as a positive urine culture with .108/l pure growth from a heterogeneity rather than chance, with an I2 of greater than bag or clean catch specimen in the presence of urinary symptoms. The presence of urinary tract abnormality was the only exclusion criterion. Although this trial ran for Citations retrieved from MEDLINE and EMBASE (n = 2166) 12 months, only the six months of parallel follow up was included in the systematic review as the boys randomised to UTI outcome not reported (n = 2030) the no circumcision group were circumcised at six months.

Abstracts retrieved (n = 130) Quality of the included studies http://adc.bmj.com/ For the single randomised trial,21 follow up was complete and UTI outcome not reported (n = 86) analysis was by intention to treat but no details were provided about the method of randomisation, concealment of allocation, or blinding. No demographic details other than Full text retrieval (n = 44) age were available for comparison between the two groups. The quality of these studies the case–control and cohort Articles excluded after full appraisal studies was variable, with variable UTI definitions used and (n = 33) different methods employed to ascertain circumcision status on 11 September 2018 by guest. Protected copyright. – Reviews (n = 19) and UTI outcome. Exclusion criteria and adjustment for – Cost-benefit analyses (n = 4) – Position statements (n = 4) confounding also varied among the studies. Only one of the – Meta-analyses (n = 1) cohort studies followed patients beyond one year, and in the – Other (n = 5) case–control studies all controls were obtained from hospital based populations (tables 2 and 3). The confounding variables that were adjusted for included Articles included in the age, socioeconomic status, and ethnicity. Both socioeconomic systematic review (n = 11) status and ethnicity were associated with circumcision status in several studies but there was no evidence of an association Additional studies identified through between these factors and UTI outcome between the reference lists and contact with circumcised and uncircumcised groups. authors (n = 3) Association between circumcision and UTI Duplicate studies excluded (n = 2) Figure 2 summarises the results of our meta-analysis.

Included in final analysis (n = 12) Randomised controlled trial – Randomised controlled trial (n = 1) The randomised study from Nayir21 had an OR of 0.13 (95% – Cohort studies (n = 4) CI, 0.01 to 2.63). – Case-control studies (n = 7) Cohort studies 15622 Figure 1 Flow chart outlining the study selection process for the effect of All four cohort studies showed benefit with a summary circumcision on urinary tract infection. OR of 0.13 (95% CI, 0.07 to 0.23). There was significant

www.archdischild.com Circumcision to prevent urinary tract infection in boys 855

Table 1 Characteristics of included studies that have examined the effect of circumcision on urinary tract infection in male Arch Dis Child: first published as 10.1136/adc.2004.049353 on 12 May 2005. Downloaded from subjects

No of UTI Age (months, Study design Reference Year Country Setting n episodes years)

RCT Nayir21 2001 Turkey Hospital outpatients 70 3 3 months to 10 years

Cohort studies Schoen et al22 2000 USA Hospital in/outpatient 14 893 154 ,1 year To et al1 1998 Canada Hospital in/outpatient* 58 434 330 ,3 years Wiswell and Hachey6 1993 USA Hospital inpatient 107 598 496 ,1 year Wiswell et al5 1987 USA Hospital inpatient 219 775 610 ,1 year

Case–control studies Craig et al23 1996 Australia Hospital in/outpatient 886 144 ,5 years Newman et al24 2002 USA Non-hospital outpatients 769 56 ,3 months Rushton and Majd25 1992 USA Hospital inpatient 86 23 ,6 months Spach et al26 1992 USA Community sexually 78 26 Adult transmitted diseases clinic Crain and Gershel27 1990 USA Hospital outpatient 81 22 ,2 months Kashani and Faraday28 1989 USA Hospital inpatient 126 17 1 month to 2 years Herzog29 1989 USA Hospital outpatient 112 36 ,1 year

*Outpatient data not included in analysis as they did not accurately define UTI events. RCT, randomised controlled trial; UTI, urinary tract infection.

heterogeneity between the cohort studies (x2 = 82.48, df = 3, circumcisions carried out beyond the neonatal inpatient p,0.001), with the study by To et al1 being the outlier. When the period, these studies would underestimate UTI occurrence in study by To was excluded, the heterogeneity between cohort the circumcised group and thus result in misclassification. studies was non-significant (x2 = 0.88, df = 2, p = 0.64). The reasons for the observed heterogeneity are uncertain but Follow up duration may reflect varying methods of circumcision and UTI ascertain- The study by To1 extended follow up to as long as three years ment, and the differing follow up periods of the studies. compared with a maximum of one year for the other cohort In relation to circumcision status, To et al1 were able to studies. To showed a progressive reduction in the protective access information regarding circumcision beyond the effect of circumcision on UTI with increasing age. Thus the neonatal period and excluded subjects circumcised after inclusion of older subjects may have contributed to the the age of one month. The three other cohort studies were difference in results. The Craig study,23 however, which unable to account for circumcisions undertaken after the stratified for age, found no such difference, but was small neonatal inpatient stay. If there were significant numbers of and may have been subject to type II error. http://adc.bmj.com/ Table 2 Quality of cohort studies examining the effect of circumcision on urinary tract infection in male subjects

Adjustment for confounding variables Determination of Reference Definition of UTI circumcision status Exclusion criteria Follow up Age SES Ethnicity

Schoen .108/l pure growth in 90% Inpatients: ICD-9 coding for Patient not within health plan for full ,1 year No No No et al22 from any means of collection circumcision in neonatal duration of study

hospital stay on 11 September 2018 by guest. Protected copyright. Source unknown in 4% Outpatients: ICD-9 from Determined by retrospective KPNC database for database search and outpatient circumcision confirmed by review of case records of random selection of 52 cases

To et al1 Inpatients: ICD-9 coding The Canadian classification Older than 1 month of age at time 2–3 years for No Yes No (kidney infection, cystitis, procedure code during the of circumcision, multiple birth, inpatient urethritis or urinary tract first month of life stillbirth, birth complications and cases infection) lack of health care number Outpatients: OHIP data ,1 year for Determined by retrospective outpatient database search cases

Wiswell and Not specified US Army patient Bag urine specimen, congenital ,1 year No No No Hachey6 Determined by retrospective administration systems and abnormality, or predisposition to database search biostatistics activity UTI (not specified) database

Wiswell Not specified US Army patient Congenital abnormality or ,1 year No No No et al5 Determined by retrospective administration systems and predisposition to UTI (not specified) database search biostatistics activity database

ICD-9, International Classification of Diseases, 9th revision; KPNC, Kaiser Permanente Medical Care Program, Northern California, USA; OHIP, Ontario Health Insurance Plan; SES, socioeconomic status.

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Table 3 Quality of case–control studies examining the effect of circumcision on urinary tract infection in male subjects Arch Dis Child: first published as 10.1136/adc.2004.049353 on 12 May 2005. Downloaded from

Adjustment for confounding variables Determination of Reference Definition of UTI circumcision status Exclusion criteria Origin of controls Age SES Ethnicity

Newman et al24 Bag urine or clean catch Standard questionnaire No fever .38˚C or urine Patients presenting to No No No >107/l collected at presentation non-hospital outpatients CSU >26106/l Uncertain circumcision with a fever SPA >104/l status

Craig et al23 CSU/SPA >106/l Direct questioning of Past history of UTI or Patients presenting to Yes No No parents or direct urinary tract abnormality; hospital emergency examination neurological or skeletal department for any MSU >108/l abnormality predisposing reason other than those to UTI diagnosed with UTI

Rushton and MSU >108/l Cases: ‘‘prospectively’’ Prolonged neonatal Patients admitted with No Yes Yes Majd25 found but not specified hospital admission or febrile upper respiratory CSU >107/l Controls: documentation uncertain circumcision tract infection. Matched in medical record but no status for age, race, and SES further details given

Spach et al26 MSU .106/l growth Examination No clear exclusion Patients without Yes No Yes along with one or more criteria bacteriuria presenting to symptoms outpatient clinic

Crain and Bag urine >104/l Documentation in medical Absence of fever Patients presenting to No No No Gershel27 CSU >104/l records no further details hospital with fever and SPA >102/l given without a discharge diagnosis of UTI

Kashani and CSU/SPA >108/l Documentation in medical Urinary tract abnormality, Patients presenting to No No Yes Faraday28 record inadequate outpatients clinics for documentation of unrelated reasons specimen type or age ,1 month

Herzog29 CSU/SPA >107/l Documentation in medical Anatomical abnormality, Patients who presented to Yes Yes Yes record or direct contact past history of UTI, emergency with a febrile with family if unclear in myelodysplasia, illness and had a SPA or medical records uncertain circumcision CSU which was negative status or race, and equivocal culture results

CSU, catheter specimen of urine; MSU, midstream urine; SES, socioeconomic status; SPA, suprapubic aspirate; UTI, urinary tract infection. http://adc.bmj.com/

UTI diagnostic criteria DISCUSSION The Wiswell studies56 did not specify diagnostic criteria for The odds of UTI in circumcised boys are about 0.1 when defining UTI, while the study by To et al1 used International compared with uncircumcised boys. This represents a Classification of Diseases, 9th revision and Ontario Health reduction in odds of nearly 90%. Insurance Plan data coding, and the Schoen study22 used What is striking from these results is the level of laboratory data. These differing definitions of UTI are an homogeneity in the effect across a variety of settings and on 11 September 2018 by guest. Protected copyright. unlikely source of variability in the results. the three different study designs. An OR of 0.13 reflects a The study by To was also the only one to account for repeat substantial reduction and makes residual confounding an episodes of UTI in individual patients and showed that the unlikely source of the observed association. contributory effect of these repeat episodes was minimal. The The temporal and biological plausibility of circumcision (by other studies recorded the overall number of UTI episodes modifying preputial colonisation28 30 and thus decreasing the rather than the number of patients with UTI. potential source of bacteria causing UTI) adds weight to the association being a genuine effect of circumcision on UTI. Case–control studies However, colonisation may also increase the risk of contam- All seven case–control studies included23–29 showed benefit, ination of bag urine collections, leading to false positive urine with a combined OR of 0.13 (95% CI, 0.07 to 0.23). There was cultures in uncircumcised boys. The method of urine no significant heterogeneity between the studies within this collection was poorly defined or included bag urine collec- group (x2 = 8.15, df = 6, p = 0.2). tions in a significant number of the studies in this systematic review,156222327 thus potentially overestimating the rate of All studies UTI in the uncircumcised group. In the remaining studies, The summary OR across study types when all three were clean catch urine or suprapubic tap was the method of urine combined was 0.13 (95% CI, 0.08 to 0.20). There was no collection and the favourable odds ratio was maintained even significant heterogeneity between the three subgroups when the above bias was minimised. (x2 = 0.16, df = 2, p = 0.9). However, significant heterogene- The principal weakness of this systematic review is that it ity was observed between the individual studies (x2 = 90.63, is dominated by observational studies of variable quality. The df = 11, p,0.00001) owing to the inclusion of the To study.1 one randomised controlled trial identified had a small sample Without To1there was no significant heterogeneity between size and failed to achieve independent statistical significance. the remaining studies (x2 = 10.92, df = 10, p,0.4). However, the point estimate of OR for this randomised

www.archdischild.com Circumcision to prevent urinary tract infection in boys 857 Arch Dis Child: first published as 10.1136/adc.2004.049353 on 12 May 2005. Downloaded from Study Circumcised Uncircumcised OR (random) Weight OR (random) or subcategory (n/N) (n/N) (95% CI) (%) (95% CI)

01 Randomised trials Nayir21 0/35 3/35 1.96 0.13 (0.01 to 2.63) Subtotal (95% CI) 35 351.96 0.13 (0.01 to 2.63) Total events: 0 (circumcised), 3 (uncircumcised) Test for heterogeneity: not applicable Test for overall effect: z = 1.33 (p = 0.18)

02 Cohort studies Wiswell et al 5 151/173663 459/46112 14.24 0.09 (0.07 to 0.10) Wiswell & Hachey6 112/80279 384/27319 14.13 0.10 (0.08 to 0.12) To et al 1 83/29217 247/29217 13.96 0.33 (0.26 to 0.43) Schoen et al 22 22/9668 132/5225 12.71 0.09 (0.06 to 0.14) Subtotal (95% CI) 292827 10787355.04 0.13 (0.07 to 0.24) Total events: 368 (circumcised), 1222 (uncircumcised) Test for heterogeneity: χ2 = 82.69, df = 3 (p < 0.00001), I2 = 96.4% Test for overall effect: z = 6.28 (p < 0.00001)

03 Case–control studies Herzog29 0/52 36/60 2.16 0.01 (0.00 to 0.11) Kashani et al 28 1/43 16/93 3.62 0.10 (0.01 to 0.78) Crain & Gershel27 4/35 18/46 7.19 0.20 (0.06 to 0.66) Rushton & Majd25 2/37 21/49 5.43 0.08 (0.02 to 0.35) Craig et al 23 2/49 142/837 5.93 0.21 (0.05 to 0.87) Spach et al 26 18/64 8/14 7.23 0.29 (0.09 to 0.97) Newman et al 24 15/572 41/197 11.45 0.10 (0.06 to 0.19) Subtotal (95% CI) 852 128643.00 0.13 (0.07 to 0.23) Total events: 42 (circumcised), 282 (uncircumcised) Test for heterogeneity: χ2 = 8.56, df = 6 (p = 0.20), I2 = 29.9% Test for overall effect: z = 6.85 (p < 0.00001)

Subtotal (95% CI)293714 109194100.00 0.13 (0.08 to 0.20) Total events: 410 (circumcised), 1507 (uncircumcised) Test for heterogeneity: χ2 = 90.63, df = 11 (p < 0.00001), I2 = 87.9% Test for overall effect: z = 8.99 (p < 0.00001)

0.001 0.01 0.1 1 10 100 1000 Favours treatment Favours control

Figure 2 Meta-analysis of studies examining the effect of circumcision on urinary tract infection in male subjects. controlled trial was identical to that of the other studies since the earlier meta-analyses. We also excluded duplicate included, and to our combined result. data from our analysis and examined heterogeneity between Another shortcoming is that the majority of studies the available data. http://adc.bmj.com/ measured episodes of UTI rather than the number of patients While circumcision is protective for UTI, the overall risk– experiencing UTI. Thus the prevalence of repeat UTI in these benefit derived from circumcision in preventing UTI is not populations is not known and may have biased the observed easily quantifiable, as the incidence of important sequelae of results if the distribution of patients with repeat UTI was UTI (sepsis, permanent renal damage, hypertension, and unequal between the two treatment groups. However, as chronic renal failure) are not known. The complication rate seen in the To study,1 the number of recurrences is likely of circumcision is documented to be between 2% and 10%,11 12 to be small and an unlikely explanation for the large and no data are available on the relative risks and benefits of difference observed between the circumcised and uncircum- circumcision. Thus we have used a conservative estimate of on 11 September 2018 by guest. Protected copyright. cised groups. circumcision complications of 2% and assumed equal utility Existing systematic reviews on the association between for benefits and harms in the following analysis. circumcision and UTI by Amato in 19924 and Wiswell in19936 Existing studies suggest that from 1% to 2% of boys can be also concluded that circumcision was associated with a expected to experience a UTI within the first 10 years of protective effect on UTI, with ORs of 0.07 (95% CI, 0.06 to life.23 31 32 From the data included in this meta-analysis, the 0.09) and 0.08 (0.07 to 0.09), respectively, being obtained. UTI rate in the uncircumcised group was approximately 0.5% These results imply a more protective effect than we found in and may reflect a shorter follow up period than other studies. our analysis. This difference may be explained by the fact that Furthermore, studies32 33 have shown a recurrence rate of UTI we included several additional studies11 21 23 24 26 published in preschool children of around 10% in the absence of

Table 4 Benefit versus harm for circumcision in preventing urinary tract infection in boys at different levels of risk for UTI per 1000 boys, assuming a complication rate of 2% and an odds ratio of 0.13

UTI in UTI in Risk of uncircumcised circumcised UTI prevented by Complications of Patient group UTI (n) (n) circumcision (n) circumcision (n)

Normal 1% 10 1 9 20 Past UTI 10% 100 13 87 20 High grade VUR 30% 300 39 261 20

OR, odds ratio; UTI, urinary tract infection; VUR, vesicoureteric reflux.

www.archdischild.com 858 Singh-Grewal, Macdessi, Craig

Competing interests: none declared Arch Dis Child: first published as 10.1136/adc.2004.049353 on 12 May 2005. Downloaded from What is already known on this topic REFERENCES N Various paediatric societies have developed position 1 To T, Agha M, Dick PT, et al. Cohort study on circumcision of newborn boys statements on circumcision. These statements generally and subsequent risk of urinary-tract infection. Lancet 1998;352:1813–16. 2 American Academy of Pediatrics. Circumcision policy statement. American conclude that there is insufficient evidence to recom- Academy of Pediatrics. Task Force on Circumcision. Pediatrics mend routine neonatal circumcision but consider it 1999;103:686–93. justified in recurrent balanitis, true phimosis, and 3 Royal Australasian College of Physicians. Paediatrics and Child Health Division. Policy statement on circumcision, 2002, www.racp.edu.au/hpu/ urinary tract infection paed/circumcision/index.htm#toc. N Lack of a clear consensus on the magnitude of the 4 Amato D, Garduno-Espinosa J. Circumcision in the newborn child and risk of urinary tract infection during the first year of life. A meta-analysis. Bol Med benefits of circumcision may reflect variability in the Hosp Infant Mexico 1992;49:652–8. different methods used to search and critically appraise 5 Wiswell TE, Enzenauer RW, Holton ME, et al. Declining frequency of the available reports circumcision: implications for changes in the absolute incidence and male to female sex ratio of urinary tract infections in early infancy. Pediatrics 1987;79:338–42. 6 Wiswell TE, Hachey WE. Urinary tract infections and the uncircumcised state: an update. Clin Pediatr 1993;32:130–4. 7 Cook LS, Koutsky LA, Holmes KK. Circumcision and sexually transmitted What this study adds diseases. Am J Public Health 1994;84:197–201. 8 Schoen EJ. The relationship between circumcision and cancer of the penis. Cancer J Clin 1991;41:306–9. N Meta-analysis of existing research shows that circumci- 9 Dewan PA, Tieu HC, Chieng BS. Phimosis: is circumcision necessary? sion substantially reduces the risk of urinary tract J Paediatr Child Health 1996;32:285–9. infection (UTI) 10 Castellsague´X, Bosch FX, Mun˜oz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med N The data do not support the routine circumcision of 2002;346:1105–12. normal boys to prevent UTI 11 Williams N, Kapila L. Complications of circumcision. Br J Surg 1993;80:1231–6. N Circumcision should be considered in boys with a past 12 Kaplan GW. Complications of circumcision. Urol Clin North Am history of recurrent UTI or high grade (grade 3 and 1983;10:543–9. above) vesicoureteric reflux, as the benefit outweighs 13 Griffiths DM, Atwell JD, Freeman NV. A prospective survey of the indications and morbidity of circumcision in children. Eur Urol 1985;11:184–7. the risk of complications in these cases 14 Harkavy KL. The circumcision debate. Pediatrics 1987;79:649–50. 15 Canadian Paediatric Society. Neonatal circumcision revisited. Fetus and Newborn Committee, Canadian Paediatric Society. Can Med Assoc J 1996;154:769–80. significant urinary tract abnormality. The recurrence rate 16 Shaneyfelt TM, Mayo-Smith MF, Rothwangl J. Are guidelines following increases to 30% in children with vesicoureteric reflux of guidelines? The methodological quality of clinical practice guidelines in the peer-reviewed medical literature. JAMA 1999;281:1900–5. 32 33 grade 3 and above. We have used these estimates of UTI 17 Begg C, Cho M, Eastwood S, et al. CONSORT statement – improving the incidence and circumcision complication rate to construct a quality of reporting of randomized controlled trials. JAMA 1996;276:637–9. table of harms and benefits of circumcision (table 4). 18 Stroup DF, Morton SC, Olkin I, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational This shows that the benefit of circumcision on UTI only Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008–12. outweighs the risk in boys who have had UTI previously and 19 RevMan Analyses [Computer program]. Version 1.0 for Windows. In: Review have a predisposition to repeated UTI. As this analysis has Manager (RevMan) 4.2. Oxford: The Cochrane Collaboration, 2002. http://adc.bmj.com/ used a conservative circumcision complication rate of 2%, if 20 Higgins JPT, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta- analysis. BMJ 2003;327:557–60. the complication rate were in reality higher the risk–benefit 21 Nayir A. Circumcision for the prevention of significant bacturia in boys. analysis may not favour circumcision even in the higher risk Paediatr Nephrol 2001;16:1129–34. populations. 22 Schoen EJ, Colby CJ, Ray GT. Newborn circumcision decreases incidence and costs of urinary tract infections during the first year of life. Pediatrics In conclusion, the data we present do not support the 2000;105:789–93. routine circumcision of normal boys with standard risk in 23 Craig JC, Knight JF, Sureshkumar P, et al. Effect of circumcision on incidence order to prevent UTI. However, our data suggest that of urinary tract infection in preschool boys. J Pediatr 1996;128:23–27. circumcision of boys with higher than normal risk of UTI 24 Newman TB, Bernzweig JA, Takayama JI, et al. Urine testing and urinary tract on 11 September 2018 by guest. Protected copyright. infections in febrile infants seen in office settings: The Paediatric Research should be considered. As there is no direct evidence of the Office Settings’ Febrile Infant Study. Arch Pediatr Adolesc Med effect of circumcision on UTI in this group, confirmation 2002;156:44–54. through a randomised trial of circumcision in high risk 25 Rushton HG, Majd M. Pyelonephritis in male infants: how important is the patients would be beneficial. Using an OR of 0.2 (the upper foreskin? J Urol 1992;148:733–6. 26 Spach DH, Stapleton AE, Stamm WE. Lack of circumcision increases the risk of limit of the 95% CI of the combined OR found in this study) urinary tract infection in young men. JAMA 1992;267:679–81. and a power of 80%, the sample size required to study this 27 Crain EF, Gershel JC. Urinary tract infections in febrile infants younger than hypothesis would be 140 (70 in each treatment arm), 8 weeks of age. Pediatrics 1990;86:363–7. 28 Kashani IJ, Faraday MS. The risk of urinary tract infection in uncircumcised assuming a recurrence risk of 10%. male infants. Int Pediatr 1989;4:44–5. Until this additional information is available, the present data 29 Herzog LW. Urinary tract infections and circumcision. A case-control study. do not support the routine circumcision of boys to prevent UTI. Am J Dis Child 1989;143:348–50. However, circumcision should be considered in those with 30 Wiswell TE, Miller GM, Gelston HM, et al. Effect of circumcision status on periurethral bacterial flora during the first year of life. J Pediatr recurrent UTI or significantly increased risk of UTI. 1988;113:442–6. 31 Hellstrom A, Hanson E, Hansson S, et al. Association between urinary ...... symptoms at 7 years old and previous urinary tract infection. Arch Dis Child Authors’ affiliations 1991;66:232–4. D Singh-Grewal, J Macdessi, Department of Paediatrics and Child 32 Winberg J, Anderson HJ, Bregstom T, et al. Epidemiology of symptomatic urinary tract infection in childhood. Acta Paediatr Scand Health, The Children’s Hospital at Westmead, Sydney, Australia 1974;252(suppl):1–20. J Craig, Centre for Kidney Research, The Children’s Hospital at 33 Panaretto KS, Craig JC, Knight JF, et al. Risk factors for recurrent urinary tract Westmead, Sydney, Australia infection in preschool children. J Paediatr Child Health 1999;35:454–9.

www.archdischild.com AAFP 2018 Policy on Neonatal Circumcision

Neonatal Circumcision

There are potential health benefits from neonatal circumcision. The evidence is strongest for the prevention of UTI in newborn males. The number needed to treat to prevent one UTI is about 140 and to prevent one hospitalization for UTI is 195. Circumcision also prevents penile cancer, but this is a rare disease (0.6/100,000), and the number needed to treat to prevent one case is approximately 300,000. In addition, about 1/3 of penile cancers are caused by human papilloma virus and may be prevented by HPV vaccine. There is also evidence that circumcision can prevent some other STDs, including the acquisition of HIV, but the evidence for this comes from studies of adult circumcision in Africa and may not be generalizable to neonatal circumcision in the U.S.

Circumcision can also result in complications. Acute complications can include bleeding (0.8- 1.8/1,000), infection (6/10,000), and injury to the penis (4/10,000). Late complications can include incomplete circumcision, excessive skin removal, adhesions, meatal stenosis, phimosis, inclusion cysts. The rate at which these late complications occur is not well defined.

The potential health benefits from circumcision justify it being a covered medical service by third-party payers, and it should be an available service for those who desire it.

The decision whether to circumcise a newborn male is affected by parents’ values and beliefs and should be made by parents after a discussion of the benefits and harms. Family physicians should provide this information in an unbiased manner, and the parents’ decision should be respected.

Circumcision is preferably performed in the newborn period. When circumcision is performed, topical or local anesthesia techniques should be used to minimize newborn discomfort. (2013 COD) (April 2018 BOD) Circumcision The American Urological Association, Inc.® (AUA) believes that neonatal circumcision has potential medical benefits and advantages as well as disadvantages and risks. Neonatal circumcision is generally a safe procedure when performed by an experienced operator. There are immediate risks to circumcision such as bleeding, infection and penile injury, as well as complications recognized later that may include buried penis, meatal stenosis, skin bridges, chordee and poor cosmetic appearance. Some of these complications may require surgical correction. Nevertheless, when performed on healthy newborn infants as an elective procedure, the incidence of serious complications is extremely low. The minor complications are reported to be three percent. Properly performed neonatal circumcision prevents phimosis, paraphimosis and balanoposthitis, and is associated with a markedly decreased incidence of cancer of the penis among U.S. males. In addition, there is a connection between the foreskin and urinary tract infections in the neonate. For the first three to six months of life, the incidence of urinary tract infections is at least ten times higher in uncircumcised than circumcised boys. Evidence associating neonatal circumcision with reduced incidence of sexually transmitted diseases is conflicting depending on the disease. While there is no effect on the rates of syphilis or gonorrhea, studies performed in African nations provide convincing evidence that circumcision reduces, by 50-60 percent, the risk of transmitting the Human Immunodeficiency Virus (HIV) to HIV negative men through sexual contact with HIV positive females. There are also reports that circumcision may reduce the risk of Human Papilloma Virus (HPV) infection. While the results of studies in other cultures may not necessarily be extrapolated to men in the United States at risk for HIV infection, the AUA recommends that circumcision should be presented as an option for health benefits. Circumcision should not be offered as the only strategy for HIV and/or HPV risk reduction. Other methods of HIV and/or HPV risk reduction, including safe sexual practices, should be emphasized. Circumcision may be required in a small number of uncircumcised boys when phimosis, paraphimosis or recurrent balanoposthitis occur and may be requested for ethnic and cultural reasons after the newborn period. Circumcision in these children usually requires general anesthesia. The risks and disadvantages of circumcision are encountered early whereas the advantages and benefits are prospective. When circumcision is being discussed with parents and informed consent obtained, medical benefits and risks, and ethnic, cultural, religious and individual preferences should be considered. Board of Directors, May 1989 Board of Directors, October 1996 (Revised) Board of Directors, February 1998 (Revised) Board of Directors, February 2003 (Revised) Board of Directors, May 2007 (Revised) Board of Directors, May 2012 (Reaffirmed) Board of Directors, May 2017 (Revised)

Position statement Newborn male circumcision Posted: Sep 8 2015 | Reaffirmed: Feb 28 2018 Hide right menu

The Canadian Paediatric Society gives permission to print single copies of this document from our website. For permission to reprint or reproduce multiple copies, please see our copyright policy. Principal author(s) S Todd Sorokan, Jane C Finlay, Ann L Jefferies; Canadian Paediatric Society, Fetus and Newborn Committee, , Infectious Diseases and Immunization Committee Paediatr Child Health 2015;20(6):311-15 Abstract The circumcision of newborn males in Canada has become a less frequent practice over the past few decades. This change has been significantly influenced by past recommendations from the Canadian Paediatric Society and the American Academy of Pediatrics, who both affirmed that the procedure was not medically indicated. Recent evidence suggesting the potential benefit of circumcision in preventing urinary tract infection and some sexually transmitted infections, including HIV, has prompted the Canadian Paediatric Society to review the current medical literature in this regard. While there may be a benefit for some boys in high-risk populations and circumstances where the procedure could be considered for disease reduction or treatment, the Canadian Paediatric Society does not recommend the routine circumcision of every newborn male. Key Words: Circumcision; HIV; HPV; HSV; Infant; STI; UTI The cultural and religious ritual of male circumcision has been practiced for thousands of years. Circumcision as a medical procedure arose in Britain and the United States in the late 19th century. The historical medical benefits of neonatal circumcision have included ease of genital hygiene, diminished risk of disease and avoidance of circumcision later in life. In the middle of the last century, most Canadian boys were circumcised. However, the rate of neonatal circumcision has declined over time to the current Canadian average of 32%, with significant regional variability.[1] The Canadian Paediatric Society (CPS) published a position statement in 1996 stating that circumcision was not recommended as a routine procedure for male newborns because the benefits and harms were evenly balanced. A similar viewpoint was expressed by the American Academy of Pediatrics (AAP) in 1999 and reaffirmed in 2005.[2] More recent evidence regarding the beneficial role of male circumcision in preventing urinary tract infection (UTI) in infancy and some sexually transmitted diseases (STIs) in adult life has prompted the CPS to review the current medical information on the circumcision of newborn males. The AAP updated its own policy statement in 2012.[3] The goal of the present statement is to provide guidance to health care providers and up-to-date information for the parents of newborn boys, to enable them to make informed decisions regarding circumcision. Male Circumcision

By Sarah J. Clark, Peter H. Kilmarx, and Katrina Kretsinger doi: 10.1377/hlthaff.2011.0776 HEALTH AFFAIRS 30, NO. 12 (2011): 2355–2361 Coverage Of Newborn And Adult ©2011 Project HOPE— The People-to-People Health Male Circumcision Varies Among Foundation, Inc. Public And Private US Payers Despite Health Benefits

Sarah J. Clark (saclark@ ABSTRACT Studies have shown that male circumcision greatly reduces the med.umich.edu) is the risk for heterosexual transmission of HIV, other sexually transmitted associate director of the Child Health Evaluation and infections, infant urinary tract infections, penile cancer, and other Research Unit and an associate research scientist in adverse health outcomes. Given recent data regarding these health theDepartmentofPediatrics benefits and the cost-effectiveness of newborn male circumcision, and Communicable Diseases, University of Michigan, in Ann national policy makers are developing new recommendations regarding Arbor. circumcision for newborn, adolescent, and adult males. To investigate the Peter H. Kilmarx is the implications, this study assessed insurance coverage and reimbursement Zimbabwe country director for for routine newborn and adult male circumcision in private and public the Centers for Disease Control and Prevention, in health plans in 2009. We found that coverage varies across private and Atlanta, Georgia. public payers. Private insurance provides far broader coverage than state Katrina Kretsinger is the Medicaid programs for routine newborn male circumcision. Specifically, team leader for the Africa Medicaid programs in seventeen states do not cover it, even though region in the Disease Eradication and Elimination low-income populations have a higher risk of HIV and other sexually Branch, Global Immunization transmitted diseases compared to higher-income groups. For adult male Division, Center for Global Health, Centers for Disease circumcision, coverage is generally sparse across public and private plans. Control and Prevention. Presentation of evidence-based recommendations—for example, from the Centers for Disease Control and Prevention—may be necessary if coverage for newborn and adult male circumcision is to be expanded.

andomized controlled clinical tri- slightly in recent years, from about 60 percent in als conducted in Africa in recent the late 1990s to about 55 percent in the late years have demonstrated that 2000s.3,4 male circumcision greatly reduces Hospital-derived estimates underrepresent ac- the risk among men for heterosex- tual circumcision rates because of inconsistent ualR acquisition of HIV and other sexually trans- reporting on hospital records, the exclusion of mitted infections.1 Previous studies also indi- newborn circumcisions performed in commu- cated that male circumcision reduces the risk nity settings, and the exclusion of circumcisions for infant urinary tract infection, penile cancer, performed at older ages. Although data are lim- and other adverse health outcomes.1 Cost-effec- ited, estimates from 1996 indicate that of the tiveness analysis shows that given the HIV- 142,000 postneonatal male circumcisions—that preventive effect alone, newborn male circum- is, circumcisions on males older than one year— cision in the United States would be cost saving, performed that year, 49,000 were for males older with a discounted lifetime HIV-related health than fifteen years.5 The overall prevalence of cir- care savings of $427 per male.2 However, esti- cumcision among adult men in the United States mated rates of newborn male circumcision dur- for the period 1999–2004 was 79 percent, with ing the hospitalization for birth have declined substantially lower rates among black and His-

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panic males than among whites and lower rates fully insured plans covered infant male circum- in the West than in the Midwest and Northeast.6 cision (the categories were as follows: all/almost Lack of reimbursement may be an important all, most, some, and few or none); the reimburse- barrier to male circumcision. In a 1995 review, ment amount and whether it was bundled with 61 percent of newborn male circumcisions were labor and delivery reimbursement; time limits paid for by private insurance, 36 percent were for coverage; whether infant male circumcision paid for by Medicaid, and 3 percent were paid for fell under capped payments for preventive care; by the parents of the infant. Infants covered by coverage guidelines for adult male circumcision; private insurance were 2.5 times more likely to whether adult male circumcision was covered in be circumcised than infants whose parents paid general or only for specific conditions; and for the birth hospitalization.7 whether fully insured plans would cover adult In 1999, before the clinical trial data from circumcision for the prevention of sexually Africa were available, the American Academy transmitted infections, including HIV. of Pediatrics issued a policy statement saying The instrument for Medicaid officials included that newborn male circumcision had potential the policy for covering infant male circumcision; medical benefits. However, the data at that time the reimbursement amount and whether it was were not sufficient to support a recommendation bundled with labor and delivery reimbursement; of routine neonatal circumcision.8 After the pol- time limits for coverage; and policies for reim- icy statement was issued, several states elimi- bursing adult male circumcision, including nated Medicaid payment for male circumcisions whether reimbursement was general or only that were not deemed medically necessary. A for specific conditions. subsequent analysis found that after other fac- Sampling Frame We deliberately sought a na- tors were controlled for, hospitals in states in tional sample of large private insurance carriers. which Medicaid covered routine male circumci- To determine the sampling frame, we first se- sion had circumcision rates that were 24 percent lected eighteen states to include variation in higher than hospitals in states without such geography and HIV prevalence: Alabama, Ari- coverage.9 zona, California, Florida, Illinois, Louisiana, A new policy is forthcoming from an American Maryland, Massachusetts, Michigan, Missis- Academy of Pediatrics panel that was convened sippi, Nebraska, Nevada, New Jersey, New York, in 2008 to reconsider its male circumcision pol- North Carolina, Ohio, Oregon, and Texas. We icy in light of the results of the African clinical identified the five largest insurance carriers in trials and other data now available. In addition, each of the eighteen states, through either infor- the Centers for Disease Control and Prevention is mation from state insurance commissioners or a developing its first recommendations regarding search of the group accident and health data in male circumcision for newborns as well as for the market share reports of the National Associ- adults and adolescents.10 ation of Insurance Commissioners.11 We then Given the potential for revised recommenda- randomly selected three of the five largest car- tions on male circumcision for both newborns riers in each state, for a total sample of fifty-four and older males, there is a need for data on the carriers. extent to which the procedure is covered by pub- During data collection, we found that twenty- lic and private payers in the United States. Such nine of the fifty-four carriers were affiliated with information will help prepare both public health five large, national health insurance companies. officials and administrators from public and pri- State-level personnel at the companies indicated vate payers for effective and efficient implemen- that they operated under the same policies as the tation of any new guidelines that emerge. With national office. Therefore, we contacted the na- that in mind, the objective of this national study tional corporate offices to obtain coverage infor- was to provide new or updated information on mation, and we reclassified the twenty-nine state coverage for routine newborn male circumcision plans under their national company. and for adult male circumcision in both private Data Collection We obtained contact infor- and public health plans. mation for insurance carriers and state Medicaid offices from public sources. During the period May–August 2009 we placed calls to these organ- Study Data And Methods izations, requesting to speak with someone Study And Instrument Design The study was a knowledgeable about coverage policies. Once cross-sectional survey of large, private insurance we reached a knowledgeable person, we ex- carriers and all state Medicaid programs.We de- plained the study and provided a study informa- signed two standardized data collection instru- tion sheet via e-mail or fax. People were given the ments. The instrument for private carriers in- option of providing coverage and reimburse- cluded a crude estimate of how many of their ment information by phone, e-mail, or fax; most

2356 Health Affairs December 2011 30:12 Downloaded from HealthAffairs.org on July 17, 2018. Copyright Project HOPE—The People-to-People Health Foundation, Inc. For personal use only. All rights reserved. Reuse permissions at HealthAffairs.org. Study Results Lack of Payment For Newborn Male Circumcision ▸▸PRIVATE SECTOR: In the private sector, all reimbursement may five large national companies and eleven of twelve state carriers reported that “all/almost be an important all” of their plans covered routine newborn cir- barrier to male cumcision. The remaining state carrier reported that “most” of its plans covered the procedure. circumcision. None of the national companies and only three of the state carriers bundled reimbursement for newborn circumcision with labor and delivery reimbursement. The reimbursement amount for physician fees ranged from $84 to $399 for state carriers; the national companies did not chose to use e-mail or fax. We followed up by provide reimbursement ranges. However, car- phone and e-mail to clarify information, as rier representatives noted that reimbursement needed. often varies even within a payer because carriers All five of the national companies we contacted have different contracts with provider groups. and twelve of the twenty-five state carriers pro- One national company and two state carriers vided data for the study. We collected data from indicated that newborn circumcision had to be forty-one of the fifty-four carriers originally se- performed within the first month of life to lected for the study, for an overall response rate qualify for routine coverage. of 76 percent. Forty-one of the fifty Medicaid ▸▸PUBLIC SECTOR: At the time of data collec- programs participated in the survey, for a re- tion, newborn male circumcision was not sponse rate of 82 percent. For the nine programs covered for Medicaid enrollees in fifteen states: that did not respond within the time frame for Arizona, California, Florida, Idaho, Louisiana, data collection, we reviewed publicly available Maine, Minnesota, Mississippi, Missouri, Mon- information for beneficiaries and providers to tana, North Carolina, North Dakota, Oregon, identify each state’s general policy for covering Utah, and Washington. Two states had variable infant male circumcision; information on re- policies. In Nevada, Medicaid managed care imbursement and adult male circumcision cover- plans in two urban areas covered routine new- age was not available from these sources. born male circumcision, while fee-for-service Data Analysis For private payers, we calcu- elsewhere in the state covered male circumcision lated the number and proportion of national and only if medically necessary. In Tennessee, one of state plans that covered newborn and adult male two Medicaid managed care plans covered rou- circumcision, and we categorized them by spe- tine newborn male circumcision, while the other cific coverage parameters. For Medicaid, we cal- covered male circumcision only when medically culated the number and proportion of states that necessary. The remaining thirty-three states covered newborn and adult male circumcision as covered newborn circumcision for all Medicaid a general policy.We categorized Medicaid cover- enrollees. age by parameters for adult male circumcision. In states that covered newborn circumcision, Limitations This study, using private insur- Medicaid reimbursement ranged from $33 to ers’ data, is limited by its design, which focused $375 (the mean was $158, the median $146). on the largest payers in each state. Thus, results Several respondents explained that Medicaid cannot be generalized to small insurers. Re- managed care plans could establish their own sponse bias is also a consideration. Although rates that were independent from Medicaid 100 percent of the large national insurance com- fee-for-service rates, and twenty-eight states re- panies we contacted participated in the study, ported that at least half of their enrolled children only 48 percent of the single-state carriers par- were in managed care plans. Medicaid re- ticipated. In addition, we asked about coverage imbursement for newborn male circumcision policies in general. Individual plans might vary was bundled with labor and delivery reimburse- in their specific coverage parameters. ment in only two states, Kentucky and Texas. Finally, we collected the data at a single point Payment For Adult Male Circumcision in time. Two states—Colorado and South Caro- ▸▸PRIVATE SECTOR: Only one of the five na- lina—discontinued Medicaid coverage of cir- tional companies and four of the twelve state cumcision in 2011, and coverage may also have carriers reported covering adult male circum- changed in other states after the study was com- cision irrespective of medical indication. The pleted. other four national companies and eight state carriers said that they covered adult male circum-

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cision if it met one or more conditions or medical indications. Four national companies and three Access to circumcision state carriers covered recurrent balanitis, or inflammation of the penis; symptomatic phimosis, is greatly reduced for or inability to retract the foreskin resulting in pain, irritation, or other symptoms; preputial low-income neoplasm, or tumors in the foreskin; and surgical repair of a congenital defect. Four national populations, who companies and two state carriers covered para- would derive greater phimosis, a condition in which the retracted foreskin becomes trapped behind the penis. benefit from its Three national companies and three state carriers covered repeated tears in the frenulum, protective effects. the tissue that helps contract the foreskin over the penis. Four national companies and one state carrier covered recurrent urinary tract infection, while three national companies and two state carriers covered trauma to the foreskin. Three national medical necessity varied considerably across companies and one state carrier covered asymp- states. tomatic phimosis, or inability to retract the fore- For example, Louisiana reimbursed for male skin with no symptoms. circumcisions related to specific International Fewer carriers covered other conditions: geni- Classification of Diseases, Ninth Revision, Clinical tal warts (two national companies, one state car- Modification (ICD-9-CM) codes; claims that did rier); sexual impairment (one national, one not carry these codes were forwarded for medical state); and problems with hygiene (also one na- review. Missouri reimbursed only when two tional and one state). Only one carrier covered physicians documented in writing that a disease, cosmetic problems (a national company) or pathology, or other abnormality existed that re- psoriasis or other dermatoses—that is, skin de- quired circumcision. Mississippi required medi- fects—affecting the foreskin (a state carrier). cal necessity to be fully documented in the medi- Even conditions that were not specifically listed cal record by a physician’s notes and office by a carrier might still be covered if a physician records, not just a pathology report. Additional reported that circumcision was medically nec- requirements were that the patient had failed to essary. respond to conservative treatment, the condi- All of the national and state carriers reported tion was recurrent, and phimosis could not be that there was usually no difference in coverage the sole diagnosis. parameters between self-insured and fully in- When adult male circumcision was covered, sured plans. Medicaid reimbursement for it ranged from In response to our question about whether $39 to $2,500. Removing the $2,500 outlier pay- prevention of sexually transmitted infections ment, the mean reimbursement amount was would be a basis for coverage of adult male cir- $132, and the median was $128. cumcision, officials from one national company With regard to prevention of sexually trans- and four state carriers said that circumcision mitted infections, officials from three state would not be covered for this reason, while rep- Medicaid programs thought that male circum- resentatives of six state carriers thought that it cision would be covered for this reason, while would be covered. Officials from four national representatives of thirteen programs reported companies and two state carriers were unsure of that it would not be covered. Officials from eight- whether it would be covered. een programs were unsure whether it would be ▸▸PUBLIC SECTOR: Medicaid officials in thirty- covered. four states provided information on adult male During data collection, several representatives circumcision coverage. Three Medicaid proof private and public payers made unsolicited grams—those in Michigan, New Hampshire, comments to the effect that changes in their cov- and Pennsylvania—had no policy of restricting erage policy would depend on the issuance of an coverage of adult male circumcision to specific evidence-based recommendation by the Centers diagnoses or conditions or of requiring specific for Disease Control and Prevention or another documentation from physicians. The other credible federal health agency. thirty-one programs reported covering adult male circumcision when medically necessary. However, requirements for documentation of

2358 Health Affairs December 2011 30:12 Downloaded from HealthAffairs.org on July 17, 2018. Copyright Project HOPE—The People-to-People Health Foundation, Inc. For personal use only. All rights reserved. Reuse permissions at HealthAffairs.org. Discussion riers commented that the overall number of The results from this study show that coverage adult male circumcisions was small, and thus for male circumcision varies across private and extensive restrictions were not warranted. More public payers. of the private carriers reported that they would Newborn Male Circumcision With regard to cover only certain diagnoses, which included in- routine newborn male circumcision, private infection, inflammation, and injury to the foreskin surance provides far broader coverage than state or head of the penis as well as recurrent urinary Medicaid programs. Following the policy tract infections. Not typically covered were diag- changes in South Carolina in February 2011 noses related to hygiene, sexual impairment, and in Colorado in July 2011, seventeen state and cosmetic reasons. Medicaid programs now provide no coverage Public coverage for adult male circumcision for newborn male circumcision. In two addi- was similar. A small number of states covered tional states, coverage depends on managed care the procedure without restriction, while most enrollment. The irony of these findings is that required a specific diagnosis or physician docu- access to circumcision is greatly reduced for low- mentation of medical necessity. However, income populations, who have a higher risk of some Medicaid programs—unlike the private HIV12 and other sexually transmitted infec- carriers—placed stringent requirements on ei- tions,13 and who thus would derive greater ben- ther the specific diagnosis or the process of efit from the protective effects of circumcision, physician documentation. Thus, the same con- compared to higher-income populations. dition could be covered by some private carriers During data collection, a number of respon- and state Medicaid programs, yet not covered by dents in states not covering routine newborn others. male circumcision commented on the estimated We received a range of responses to the ques- costs of reinstating coverage. Using the median tion of whether adult male circumcision would reimbursement across Medicaid programs, be covered for the prevention of sexually trans- reinstating coverage would add $150 for roughly mitted infections. Private plan representatives 35 percent of the state’s Medicaid-enrolled new- frequently indicated that their coverage policy borns. Given the current economic climate in would depend on whether an evidence-based rec- most states, any movement toward broader ommendation were passed by a credible federal Medicaid coverage of newborn male circumci- health agency, such as the Centers for Disease sion would need to address these cost concerns. Control and Prevention. It is essential that enti- As noted above, a cost-effectiveness analysis ties developing recommendations understand indicates that newborn male circumcision is cost that the strength and presentation of the evi- saving for HIV prevention.2 However, there is a dence they use will have a direct bearing on cov- long delay between the cost of the procedure and erage decisions by public and private payers. any cost-saving benefit accrued through preven- In the United States, most HIV transmission is tion of HIV or other sexually transmitted in- through male-male sex. Although circumcision fections. may reduce the risk of HIV transmission in men In the shorter term, cost benefits would be who engage primarily in insertive male-male expected because circumcision reduces the risk sex,18–19 to date there is no robust evidence that of urinary tract infections by as much as 90 per- circumcision prevents HIV among men who have cent.14 These infections are a common cause of sex with men. Furthermore, no cost-effective- hospitalization in infants. Moreover, up to half ness analysis of adult male circumcision for of male infants with febrile urinary tract infec- the prevention of HIV and other sexually trans- tions—that is, infections that produce a fever— mitted infections in US adolescent and adult will exhibit subsequent renal scarring or other males has been conducted. Such cost data may adverse effects, including long-term kidney dis- be especially influential for Medicaid policy con- ease.15,16 These benefits have not been added up siderations. to establish their cost savings during the period Conclusion Coverage for both newborn and of Medicaid enrollment. However, in one study adult male circumcision is variable across the of the cost-effectiveness of neonatal male cir- United States. Coverage is typically broader cumcision, the decision to perform the pro- among private insurance carriers than state cedure in infancy and thus avert subsequent cost- Medicaid programs. Under current reimburse- lier circumcision of adolescents and adults was a ment policies, male circumcision is not equally significant driver of cost benefit.17 available for all newborns, adolescents, or adults AdultMaleCircumcisionIn a subset of car- who might benefit from the procedure. riers, including one large national company, Given the emerging evidence on the benefits of adult male circumcision is covered without re- circumcision, future recommendations support- striction. Several representatives from these caring the role of male circumcision in preventing

December 2011 30:12 Health Affairs 2359 Downloaded from HealthAffairs.org on July 17, 2018. Copyright Project HOPE—The People-to-People Health Foundation, Inc. For personal use only. All rights reserved. Reuse permissions at HealthAffairs.org. Male Circumcision

HIV and other sexually transmitted infections ing potential cost benefits, should be clearly out- should provide a clear evidence base. In addition, lined and widely disseminated in order to pro- data on the benefits of newborn circumcision mote policy changes that will lead to equitable beyond sexually transmitted infections, includ- access to circumcision for all males. ▪

This work was funded by the Centers for Disease Control and Prevention (CDC). The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the CDC.

NOTES

1 Kilmarx PH, Kretsinger K, 7 Mansfield CJ, Hueston WJ, Rudy M. reach nonclinic populations in the Millett GA. Considerations in the Neonatal circumcision: associated community: risk factors for infection role of male circumcision in the factors and length of hospital stay. J in men. Sex Transm Dis. 2010; prevention of HIV transmission in Fam Pract. 1995;41(4):370–6. 37(12):756–63. the USA. HIV Ther. 2009;3(3): 8 American Academy of Pediatrics. 14 Zorc JJ, Levine DA, Platt SL, 241–54. Circumcision policy statement. Dayan PS, Macias CG, Krief W, et al. 2 Sansom SL, Prabhu VS, Pediatrics. 1999;103(3):686–93. Clinical and demographic factors Hutchinson AB, An Q, Hall HI, 9 Leibowitz AA, Desmond K, Belin T. associated with urinary tract infec- Shrestha RK, et al. Cost-effectiveness Determinants and policy implica- tion in young febrile infants. Pedi- of newborn circumcision in reducing tions of male circumcision in the atrics. 2005;116(3):644–8. lifetime HIV risk among U.S. males. United States. Am J Public Health. 15 Zorc JJ, Kiddoo DA, Shaw KN. Di- PloS One. 2010;5(1):e8723. 2009;99(1):138–45. agnosis and management of pediat- 3 Merrill CT, Nagamine M, Steiner C. 10 Centers for Disease Control and ric urinary tract infections. Clin Mi- Circumcisions performed in U.S. Prevention. Male circumcision and crobiol Rev. 2005;18(2):417–22. community hospitals, 2005 [Inter- risk for HIV transmission and other 16 Rushton HG. The evaluation of acute net]. Rockville (MD): Agency for health conditions: implications for pyelonephritis and renal scarring Healthcare Research and Quality; the United States [Internet]. Atlanta with technetium 99m-dimercapto- 2008 Jan [cited 2011 Oct 20]. (HCUP (GA): CDC; [updated 2008 Feb; cited succinic acid renal scintigraphy: Statistical Brief No. 45). Available 2011 Oct 20]. Available from: http:// evolving concepts and future direc- from: http://www.hcup-us.ahrq www.cdc.gov/hiv/resources/ tions. Pediatr Nephrol. 1997;11: .gov/reports/statbriefs/sb45.jsp factsheets/circumcision.htm 108–20. 4 Centers for Disease Control and 11 National Association of Insurance 17 Schoen EJ, Colby CJ, To TT. Cost Prevention. Trends in in-hospital Commissioners. 2009 market share analysis of neonatal circumcision in newborn male circumcision—United reports for the top 125 accident and a large health maintenance organi- States, 1999–2010. MMWR Morb health insurers by state and zation. J Urol. 2006;175(3 Pt 1): Mortal Wkly Rep. 2011;60(34): countrywide. Kansas City (MO): 1111–5. 1167–8. NAIC; 2009. 18 Millett GA, Flores SA, Marks G, 5 Owings MF, Kozak LJ. Ambulatory 12 Centers for Disease Control and Reed JB, Herbst JH. Circumcision and inpatient procedures in the Prevention. Characteristics associ- status and risk of HIV and sexually United States, 1996. Vital Health Stat ated with HIV infection among het- transmitted infections among men 13. 1998;(139):1–119. erosexuals in urban areas with high who have sex with men: a meta- 6 Xu F, Markowitz LE, Sternberg MR, AIDS prevalence—24 cities, United analysis. JAMA. 2008;300:1674–84. Aral SO. Prevalence of circumcision States, 2006–2007. MMWR Morb 19 Wiysonge CS, Kongnyuy EJ, Shey M, and herpes simplex virus type 2 in- Mortal Wkly Rep. 2011;60(31): Muula AS, Navti OB, Akl EA, et al. fections in men in the United States: 1045–9. Male circumcision for prevention of the National Health and Nutrition 13 Chai SJ, Aumakhan B, Barnes M, homosexual acquisition of HIV in Examination Survey (NHANES), Jett-Goheen M, Quinn N, Agreda P, men. Cochrane Database Syst Rev. 1999–2004. Sex Transm Dis. 2007; et al. Internet-based screening for 2011;(6):CD007496. 34(7):479–84. sexually transmitted infections to

2360 Health Affairs December 2011 30:12 Downloaded from HealthAffairs.org on July 17, 2018. Copyright Project HOPE—The People-to-People Health Foundation, Inc. For personal use only. All rights reserved. Reuse permissions at HealthAffairs.org. ABOUT THE AUTHORS: SARAH J. CLARK, PETER H. KILMARX & KATRINA KRETSINGER

Research Unit at the University of program in medicine. He Michigan and an associate research completed an internship and scientist in the Department of residency in internal medicine and Sarah J. Clark is Pediatrics and Communicable a fellowship in infectious diseases the associate director of the Diseases. Her main research at Johns Hopkins Hospital. Child Health interests include immunization Evaluation and policy at the state and federal Research Unit at levels; immunization attitudes and the University of behavior among providers, Michigan. patients, and parents; Medicaid Katrina Kretsinger In this month’s Health Affairs, policy and utilization patterns; and is the team leader ’ Sarah Clark and coauthors report parents perspectives on health for the Africa on their study assessing insurance care. region in the CDC’s coverage and reimbursement for Clark earned her master of public Disease Eradication and Elimination routine newborn and adult male health degree in health behavior Branch. circumcision in private and public and health education from the health plans in 2009. The authors University of North Carolina at Katrina Kretsinger is the team found that private insurance Chapel Hill. leader for the Africa region in the provided far broader coverage than Disease Eradication and state Medicaid programs for Elimination Branch, Global routine newborn male Immunization Division, Center for circumcision. For adult male Global Health, CDC. Previously she circumcision, coverage was served as a medical epidemiologist generally rare across public and Peter H. Kilmarx is for the CDC, first for the private plans. the Zimbabwe Meningitis and Vaccine-Preventable Of special interest was the fact country director for Diseases Branch and then in the that Medicaid programs in the Centers for HIV Vaccine and Special Studies Disease Control and seventeen states did not cover Team in the National Center for Prevention. circumcision, even though low- HIV/AIDS, Viral Hepatitis, STD, income populations have a higher Peter Kilmarx is the Centers for and TB Prevention. For the HIV risk of HIV and other sexually Disease Control and Prevention’s Vaccine and Special Studies Team, transmitted diseases. Clark says (CDC’s) Zimbabwe country her research focused mainly on that the finding may reflect the director, implementing the US HIV prevention, including severe budgetary problems facing President’sEmergencyPlanfor antiretroviral therapy, HIV vaccine the states. She and her coauthors AIDS Relief and the Obama trials, and male circumcision. Her conclude that clear evidence-based administration’s Global Health recent work has focused on the recommendations will probably Initiative. From 2006 to 2010 he design, implementation, and have to be made before coverage is was chief of the epidemiology evaluation of immunization expanded for newborn and adult branch in the CDC Division of HIV/ projects in Africa. male circumcision, whether among AIDS Prevention. Kretsinger earned her master’s public or private health plans. Kilmarx earned his medical degree in government from Cornell Clark is the associate director of degree through the Dartmouth- University and her medical degree the Child Health Evaluation and Brown Universities combined from Harvard Medical School.

December 2011 30:12 Health Affairs 2361 Downloaded from HealthAffairs.org on July 17, 2018. Copyright Project HOPE—The People-to-People Health Foundation, Inc. For personal use only. All rights reserved. Reuse permissions at HealthAffairs.org. Section 6.0 New Discussion Items Medically Indicated Circumcision

Questions: 1) Should circumcision be paired with balanitis xerotica obliterans (BXO)? 2) Should circumcision be paired with balanitis? 3) What other medical indications need to be paired with circumcision on the Prioritized List?

Question sources: 1) HSD appeals 2) Holly Jo Hodges, CCO medical directors 3) HERC staff, various urology providers

Issues: Balanitis xerotica obliterans (BXO) is also known as penile lichen sclerosis. It is coded with ICD-10 N48.0 (Leukoplakia of penis). It is an atrophic and sclerotic condition of the head of the penis (glans penis). Sometimes it leads to stenosis and occasionally obliteration of the external meatal orifice. It can also lead to the inability to fully pull back the foreskin over the glans or the inability to return the pulled- back foreskin back over the glans (paraphimosis). Currently N48.0 is on line 243 DERMATOLOGICAL PREMALIGNANT LESIONS AND CARCINOMA IN SITU and not paired with circumcision, which is a standard treatment if the foreskin is involved. Other treatments for this condition include topical steroids and topical tacrolimus, which are covered. The surgical treatments for this condition include urethral surgery if the urethra becomes stenotic and circumcision if the foreskin becomes involved; neither of these surgeries currently pair. Experts (see Clouston 2011) indicate that circumcision is required in most cases.

Balanitis is an inflammation of the glans penis. When the foreskin is also affected, it is termed balanoposthitis. The condition causes rashes and pain in the penis. Recurrent bouts of balanitis may cause scarring of the preputial orifice; the reduced elasticity may lead to pathologic phimosis. Balanitis is a common condition affecting 11% of adult men seen in urology clinics and 3% of children in the United States; globally, balanitis may occur in up to 3% of uncircumcised males. Initial treatment in adults often involves simply pulling back the foreskin and cleaning the penis. If cleaning is not effective, then topical steroids or other topical medications may be required. Circumcision is only indicated when the patient has recurrent bouts of balanitis. Balanitis is coded with ICD-10 N48.1 and is currently on line 412 BALANOPOSTHITIS AND OTHER DISORDERS OF PENIS.

Phimosis was reviewed in 2007, and felt that it should be paired with circumcision when medically indicated, such as when it caused ischemia. Further research was suggested to identify the medical indications for circumcision and ensure they were included on a covered line with a guideline. This later review did not appear to have been completed. HERC staff have determined that a complete review of medical indications for circumcision should be undertaken.

Evidence 1) Malone 2007, review of medical indications for circumcisions a. Preputial adhesions and physiological phimosis i. No: Resolve with puberty b. Paraphimosis i. No. Reduction under local or general anaesthesia is nearly always possible with several minimally invasive methods; a literature review that included the Cochrane database and Medline searches failed to show that any one was

1 Medically Indicated Circumcision

better than the others. There is no evidence that circumcision is subsequently necessary. c. Balanoposthitis i. Antibiotic treatment is the first line treatment, ii. Circumcision should be reserved for those with recurrent balanoposthitis, although alternative methods, such as preputioplasty (an operative technique to widen the preputial ring), may achieve the same effect in preventing further episodes of balanoposthitis and leaving a retractile foreskin. d. Preputial pearls i. No. Always resolve spontaneously. e. redundant foreskin i. No medical need for circumcision f. Physiological phimosis i. No. Self resolves with age g. Pathological phimosis i. Almost always associated with balanitis xerotica obliterans, requires circumcision h. Prevention of UTI in boys with urologic abnormalities i. A metaanalysis of the effect of circumcision in boys suggested that only those at high risk of urinary tract infection—that is, those with recurrent infections or with abnormal urinary tracts such as high grade vesicoureteric reflux— would benefit from circumcision. However, a note of caution must be struck on the benefit of circumcision, even in the presence of an underlying abnormality of the urinary tract, as shown in a controlled trial published a few years ago. No benefit was found for circumcision when it was performed at the same time as antireflux surgery for severe vesicoureteric reflux irrespective of the age of the patient. a. Hypospadias repair ii. Circumcision may be required to provide tissue for reconstruction b. Medical indications for circumcision are generally accepted as phimosis secondary to balanitis xerotica obliterans and recurrent balanoposthitis, which occur in 1.5% and 1% of boys respectively c. Summary: The only absolute medical indications for circumcision are balanitis xerotica obliterans and a scarred foreskin. Firm evidence for relative indications is limited to recurrent balanitis and to the prevention of urinary tract infection in boys with vesicoureteric reflux or other urological abnormalities. Many other “medical indications” have little or no evidence base, including a long foreskin, balanoposthitis, preputial concretions, physiological phimosis, and preputial adhesion 2) Singh-Grewal D 2005, Systematic review of circumcision for the prevention of UTI a. N=402,908 children from 12 studies (1 RCT, 4 cohort studies, 7 case-control studies) b. Conclusions: In boys with recurrent UTI or high grade vesicoureteric reflux, the risk of UTI recurrence is 10% and 30% and the numbers-needed-to-treat are 11 and 4, respectively.

Medically Indicated Circumcision

Expert input Dr. Steven Skoog, OHSU pediatric urology He agreed with the staff proposed indications (Balanitis xerotica obliterans, recurrent balanoposthitis, severe foreskin scarring causing physiologic complications, or vesicoureteric reflux or other urological abnormalities). In addition, he proposed a few additional indications: “we will at times call severe scarring, cicatrix formation, also boys with severe dysuria and alteration of urinary stream deserve a circumcision. Boys with recurrent urinary infection and ballooning of the prepuce with voiding need circumcision. Older pre-adolescent boys with painful erections and persistent adhesions need circumcision. Boys with prenatally diagnosed moderate to severe hydronephrosis benefit from circumcision to prevent UTI.“ Dr. Skoog recommended defining recurrent balanoposthitis as 2 or more bouts.

CCO medical directors The CCO medical directors objected to the addition of circumcision for prevention of UTI even in high risk patients, including patients with vesicoureteric reflux. The evidence of benefit is not strong, and these cases can be approved through the exceptions process.

Medically Indicated Circumcision

Diagnoses for possible consideration for pairing with medical circumcision Code Code description Current line(s)

N13.7 Vesicoureteral-reflux 21 VESICOURETERAL REFLUX

N47.5 Adhesions of prepuce and glans penis 496 PHIMOSIS

N47.6 Balanoposthitis 412 BALANOPOSTHITIS AND OTHER DISORDERS OF PENIS

N47.8 Other disorders of prepuce (includes 623 REDUNDANT PREPUCE ballooning of the prepuce)

N48.0 Leukoplakia of penis [includes balanitis 243 DERMATOLOGICAL PREMALIGNANT xerotica obliterans] LESIONS AND CARCINOMA IN SITU

N48.1 Balanitis 412

Z87.440 Personal history of urinary (tract) infections Informational File

Circumcision is currently found on the following lines: Code Code description Lines 54150 Circumcision, using clamp or other device 496 PHIMOSIS with regional dorsal penile or ring block 623 REDUNDANT PREPUCE 54160 Circumcision, surgical excision other than 496,623 clamp, device, or dorsal slit; neonate (28 days of age or less) 54161 Circumcision, surgical excision other than 327 FUNCTIONAL AND MECHANICAL clamp, device, or dorsal slit; older than 28 DISORDERS OF THE GENITOURINARY SYSTEM days of age INCLUDING BLADDER OUTLET OBSTRUCTION 496,623

Medically Indicated Circumcision

HERC staff summary Circumcision is medically necessary for balanitis xerotica obliterans causing phimosis and for recurrent balanoposthitis, and severe foreskin scarring causing medical issues (not simply cosmetic issues). There also appears to be benefit in the prevention of urinary tract infection in boys with abnormal urinary tracts, such as high grade vesicoureteric reflux.

HERC staff recommendations: 1) Add CPT 54150 (Circumcision, using clamp or other device with regional dorsal penile or ring block), 54160 (Circumcision, surgical excision other than clamp, device, or dorsal slit; neonate (28 days of age or less)) and 54161 (Circumcision, surgical excision other than clamp, device, or dorsal slit; older than 28 days of age) to lines 21 VESICOURETERAL REFLUX and 412 BALANOPOSTHITIS AND OTHER DISORDERS OF PENIS 2) Add CPT 54150 (Circumcision, using clamp or other device with regional dorsal penile or ring block) and 54160 (Circumcision, surgical excision other than clamp, device, or dorsal slit; neonate (28 days of age or less)) to line 327 FUNCTIONAL AND MECHANICAL DISORDERS OF THE GENITOURINARY SYSTEM INCLUDING BLADDER OUTLET OBSTRUCTION a. CPT 54161 is already on this line 3) Remove ICD-10 N48.0 (Leukoplakia of penis) from line 243 DERMATOLOGICAL PREMALIGNANT LESIONS AND CARCINOMA IN SITU and add to line 412 BALANOPOSTHITIS AND OTHER DISORDERS OF PENIS 4) Add ICD-10 Z87.440 (Personal history of urinary (tract) infections) to line 327 FUNCTIONAL AND MECHANICAL DISORDERS OF THE GENITOURINARY SYSTEM INCLUDING BLADDER OUTLET OBSTRUCTION a. Advise HSD to remove ICD-10 Z87.440 from the Informational File 5) Keep circumcision CPT codes on line 496 PHIMOSIS and on line 623 REDUNDANT PREPUCE; however, these lines should remain below the funding line as circumcision is elective for these conditions a. See separate evidence review for redundant prepuce 6) Add a new guideline note regarding circumcision as shown below

GUIDELINE NOTE XXX MEDICALLY INDICATED CIRCUMCISION Lines 327, 412 Circumcision (CPT 54150, 54161) is included on these lines only for patients with 1) Balanitis xerotica obliterans, or 2) Recurrent balanoposthitis (2 or more bouts), or 3) Severe foreskin scarring causing physiologic complications, or 4) Vesicoureteric reflux or other urologic abnormalities, or 5) Recurrent urinary tract infections (2 or more with documented positive urine cultures). Balanitis (ICD-10 N48.1) does not pair with circumcision.

Penile lichen sclerosus (balanitis xerotica obliterans) David Clouston * , Anthony Hall † and Nathan Lawrentschuk ‡ * Focus Pathology, Melbourne, † Skin and Cancer Foundation, Carlton, and ‡ University of Melbourne, Department of Surgery, and Ludwig Institute for Cancer Research, Austin Hospital, Melbourne, Australia

SUMMARY What ’s known on the subject? and What does the study add? The clinical presentation and complications of lichen sclerosus are well known. What is Penile lichen sclerosus, also known as less well known is the true incidence of the condition. The published fi gures are all balanitis xerotica obliterans, is a chronic based on attendance at general medical clinics or specialist clinics, but it is likely that infl ammatory condition of the penis which the true incidence is much higher than this reported incidence as many men will not can occur at all ages. The infl ammation present to the doctor for treatment. The other uncertainty is the relationship of lichen leads to the formation of white plaques sclerosus to the subsequent development of cancer of the penis. As pointed out in the most commonly on the foreskin or penis, paper, it is likely that between 4% and 8% of men with this condition will develop and can lead to inability to retract the squamous cell cancer of the penis. However, it is unclear if lichen sclerosus itself foreskin or blockage to the fl ow of urine. causes the development of squamous cell cancer or if it is due to coexistent infection Cancer may occur rarely. with human papillomavirus. Penile lichen sclerosus is a progressive, This review provides a concise summary of the clinical and pathological features of the sclerosing, infl ammatory dermatosis disease and describes its current medical and surgical treatment. It brings together a of the glans penis and foreskin which number of papers which have addressed the association of lichen sclerosus with is of uncertain aetiology. Recent studies squamous cell carcinoma of the penis and shows that the likely incidence of have shown a link between lichen sclerosus carcinoma is approximately 4 – 8% in men with this condition. and squamous cell carcinoma of the penis. In this review, we discuss the clinical presentation, pathology and KEYWORDS current approach to treatment of this condition. penile , lichen , sclerosus

INTRODUCTION glans penis and prepuce and less commonly presenting to an outpatient clinic in Brookes on the scrotum. Perianal involvement is Army Medical Centre in the USA. Penile Penile lichen sclerosus is a progressive, extremely rare in male patients with lichen lichen sclerosus occurs across all ages from sclerosing, infl ammatory dermatosis of the sclerosus. In up to 20% of patients, there as early as 6 months of age. glans penis and foreskin (prepuce) of may be extragenital lesions, particularly on uncertain aetiology that results in signifi cant the upper trunk, shoulders and upper arms. Penile lichen sclerosus accounts for a morbidity. Lichen sclerosus was originally Extragenital lesions are not seen in penile signifi cant proportion of patients with penile described by Stuhmer in 1928 as balanitis lichen sclerosus occurring in boys [ 2 ] . disease. In a study of 357 men presenting to xerotica obliterans (BXO), a term of Greek a specialist penile dermatosis clinic, penile derivation, with xeros meaning dry and In this review, we will discuss the lichen sclerosus was present in 52 men obliterare , to efface. However, penile or male pathogenesis and clinical presentation of (15%), of whom 51 were uncircumcised [ 4 ] . genital lichen sclerosus is the preferred penile lichen sclerosus and the current Similarly, Yardley et al . [ 5 ] found penile terminology, as lichen sclerosus occurs in approach to treatment. lichen sclerosus in 34% of circumcision both males and females, and in anogenital specimens from boys between the ages of 3 and extragenital sites. In a review of the months and 16 years. literature, Meffert et al . [ 1 ] found lichen INCIDENCE sclerosus was reported in 4280 women compared with 691 men, with 4308 cases The true incidence of penile lichen sclerosus AETIOLOGY AND PATHOGENESIS involving the genitals, 805 in extragenital is unknown but is likely to be more common sites and 355 cases involving both genital than the quoted fi gures. Kizer et al . [ 3 ] The aetiology of male genital lichen and extragenital sites. In men, lichen found an incidence of 0.07% in an sclerosus is unknown, but it is most sclerosus occurs most commonly on the unselected cohort of 153 432 patients probably multifactorial. Like most penile

Medical aspects of male circumcision Padraig Malone, Henrik Steinbrecher

Southampton University Hospital, Why should I read this review? circumcision, including the prevention of penile and Department of Paediatric Urology, Circumcision is the commonest surgical procedure in cervical cancer, the prevention of sexually transmitted Southampton SO16 6YD males, because routine infant circumcision is practised in infection, particularly HIV, and the prevention of Correspondence to: P Malone [email protected] many countries for religious and cultural reasons. It urinary tract infection. Many surgeons would also originated over 15 000 years ago, being performed for perform a circumcision during surgery for hypospadias. BMJ 2007;335:1206-9 religious, ritualistic, and cultural reasons, and it was not doi:10.1136/bmj.39385.382708.AD until the 19th century that the procedure was “medica- Paraphimosis lised.” It is one of the most controversial surgical Paraphimosis occurs when the foreskin is notpulled back interventions: proponents claim benefits such as over the glans after retraction. A tight constricting band improved hygiene and reduced risks of infection ensues, causing swelling of the distal penis and acute (urinary and sexually transmitted) and of penile and discomfort (see fig A on bmj.com). Reduction under cervical cancer, whereas opponents deny or minimise local or general anaesthesia is nearly always possible with these benefits and cite substantial complication rates and several minimally invasive methods; a literature review reduced penile sensation. Many parents and patients that included the Cochrane database and Medline have firmly held beliefs, placing medical workers under searches failed to show that any one was better than the extreme pressure at times when dealing with requests for others.3 There is no evidence that circumcision is circumcision. It is vital for all medical staff to be aware of subsequently necessary. the various indications for circumcision and the operative techniques and their complications to cope Balanoposthitis and balanitis with these consultations with an evidence base. Balanoposthitis affects about 1% of boys and occurs This review concentrates solely on the medical when there is erythema and oedema of the prepuce and indications for circumcision and does not address the glans (in balanitis the inflammation is confined to the issues of routine, religious, or ritual infant circumci- glans). The foreskin is usually non-retractile. It is often sion. It highlights clinical conditions frequently accompanied by purulent discharge, and the inflamma- referred for circumcision but which are normal physio- tion may spread along the shaft of the penis associated logical variants and do not require surgery. It also lists with dysuria. Culture of the preputial discharge has the absolute medical indications for circumcision and shown that E coli and Proteus are the commonest the complications of the procedure. The various organisms and that Candida is rare.4 Antibiotic treatment surgical techniques are listed in the table. is the first line treatment, and most boys do not have a further attack. Circumcisionshould be reserved for those What is the normal anatomy of the penis and foreskin? with recurrent balanoposthitis, although alternative Preputial adhesions and physiological phimosis methods, such as preputioplasty (an operative technique During development, the epithelium lining the prepuce to widen the preputial ring), may achieve the same effect and the glans are contiguous, such that preputial in preventing further episodes of balanoposthitis and adhesions represent a normal feature of foreskin leaving a retractile foreskin. development. Epidemiological data from two seminal papers in the past century show that, at the age of 5 years, Preputial “pearls” and redundant foreskin almost 75% of boys still have preputial adhesions and this These conditions are completely benign and do not figure drops steadily until puberty.12 Preputial adhe- require circumcision. Preputial pearls (fig 1) are retained sions, therefore, are not an indication for circumcision. In sebaceous secretions (smegma) produced by the inner addition, it was noted that 8% of 7 year olds have a foreskin layer that fail to be released because of preputial physiological phimosis which resolves spontaneously, adhesions. They always resolve spontaneously. A leaving a 1% incidence at puberty.2 redundant foreskin causes only pooling of urine and is treated by gently pulling the foreskin back to take up any What are the relative indications for circumcision? “slack” when passing urine, and then drying the foreskin Circumcision is performed for various conditions, but at the end of micturition. A single study examined the their natural course suggests that this is not always foreskin length and risk of penile cancer and concluded necessary. There are also many relative indications for that the presence of a long foreskin increased the risk

1206 BMJ | 8DECEMBER2007| VOLUME 335 Postpartum Depression Screening

Question: How should coverage of postpartum depression screening be clarified on the Prioritized List?

Question source: Dana Hargunani, CMO; HSD

Issue: Postpartum depression has major impacts on child and maternal health. Currently, it is not clear that postpartum depression screening is explicitly intended to be covered on the Prioritized List. Also, there is a lack of clarity about the coverage of this screening when provided during the child’s appointment rather than during the mother’s visit.

Perinatal depression (encompassing pregnancy and 12 months postpartum) or postpartum depression (typically up to 6 weeks postpartum) are both underassessed and treated.

The American Academy of Pediatrics (AAP) developed a new CPT code to allow reporting of the administration of a caregiver-focused health risk assessment (eg, maternal depression inventory) for the benefit of the patient.

Metrics and Scoring have approved a postpartum visit metric for 2019-2020 with a future plan to include quality measures such as postpartum depression screening in 2021.

Prioritized List Status Fee Code Code Description Current List Placement Schedule Z13.32 Encounter for screening for maternal depression New ICD 10 code, just reviewed by BHAP, recommended placement on Line 3 96127 Brief emotional/behavioral assessment (eg, Diagnostic Procedures $4.42 depression inventory, attention- File deficit/hyperactivity disorder [ADHD] scale), with scoring and documentation, per standardized instrument 96150 Health and behavior assessment (eg, health- 1,3,4,5,8,9,10,12 and 184 $15.04- focused clinical interview, behavioral observations, other lines. 17.23 psychophysiological monitoring, health-oriented questionnaires), each 15 minutes face-to-face with the patient; initial assessment 96151 Health and behavior assessment (eg, health- 1,3,4,5,8,9,10,12 and 184 $14.53- focused clinical interview, behavioral observations, other lines. 16.68 psychophysiological monitoring, health-oriented questionnaires), each 15 minutes face-to-face with the patient; re-assessment 96152 Health and behavior intervention, each 15 minutes, 1,3,4,5,8,9,10,12 and 184 $13.77- face-to-face; individual other lines. 15.85 96153 Health and behavior intervention, each 15 minutes, 1,3,4,5,8,9,10,12 and 184 $2.98-

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Postpartum Depression Screening

Fee Code Code Description Current List Placement Schedule face-to-face; group (2 or more patients) other lines. 3.52 96154 Health and behavior intervention, each 15 minutes, 1,3,4,5,8,9,10,11 and 194 $13.27- face-to-face; family (with the patient present) other lines. 15.81 96155 Health and behavior intervention, each 15 minutes, 1,3,4,5,8,9,10,11 and 194 $15.95- face-to-face; family (without the patient present) other lines. 17.42 96160 Administration of patient-focused health risk Diagnostic Procedures $3.23 assessment instrument (eg, health hazard File appraisal) with scoring and documentation, per standardized instrument 96161 Administration of caregiver-focused health risk Diagnostic Procedures $3.23 assessment instrument (eg, depression inventory) File for the benefit of the patient, with scoring and documentation, per standardized instrument G8431 Screening for depression is documented as being Ancillary Procedures File positive and a follow-up plan is documented G8432 Depression screening not documented, reason not Ancillary Procedures File given G8433 Screening for depression not completed, Ancillary Procedures File documented reason G8510 Screening for depression is documented as Ancillary Procedures File negative, a follow-up plan is not required G8511 Screening for depression documented as positive, Ancillary Procedures File follow-up plan not documented, reason not given

Evidence Summary USPSTF, 2016 https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFi nal/depression-in-adults-screening1 The USPSTF recommends screening for depression in the general adult population, including pregnant and postpartum women. Screening should be implemented with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up. • “B” Recommendation

O’Connor, 2016 https://jamanetwork.com/journals/jama/fullarticle/2484344 • Systematic review for USPSTF • Pregnant and postpartum women 18 years and older • 6 trials (n = 11 869) showed 18% to 59% relative reductions with screening programs, or 2.1% to 9.1% absolute reductions, in the risk of depression at follow-up (3-5 months) after participation in programs involving depression screening, with or without additional treatment components, compared with usual care. • Based on 23 studies (n = 5398), a cutoff of 13 on the English-language Edinburgh Postnatal Depression Scale demonstrated sensitivity ranging from 0.67 (95% CI, 0.18-

Postpartum Depression Screening, Issue #1450 Page 2

Postpartum Depression Screening

0.96) to 1.00 (95% CI, 0.67-1.00) and specificity consistently 0.87 or higher. Data were sparse for Patient Health Questionnaire instruments. • Pooled results for the benefit of CBT for pregnant and postpartum women with screen- detected depression showed an increase in the likelihood of remission (pooled relative risk, 1.34 [95% CI, 1.19-1.50]; with absolute increases ranging from 6.2% to 34.6%. • Author conclusions: Direct and indirect evidence suggested that screening pregnant and postpartum women for depression may reduce depressive symptoms in women with depression and reduce the prevalence of depression in a given population.

MED, 2016 • Policy brief on screening for postpartum depression and linkage to care o Some states allow only PHQ-9, EPDS, or Beck, and others allow any validated screen

• o Some allow for billing on mom’s or child’s Medicaid ID (Colorado, Illinois), others only on mom (New York) or only child (Minnesota) o Several states used 99420 which has been replaced with 96160 o Key issues identified in the MED report – resources need to be available for screening tools, referral pathways need to be in place, provider and telephonic support can be important.

Other state strategies Minnesota • Developed clinical pathways for postpartum depression screening and follow up • Postpartum depression screening is covered in well child checks, up to 3 times in the first 12 months of life • Recommended 99420 which was reimbursed in 2015 at $8.67

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Postpartum Depression Screening

New York • Reimburses for screening for postpartum depression • When done during the infant visit, it is billed to the mother’s Medicaid number • Up to 3 screens in the 12 months postpartum are covered • Providers are instructed to have a plan in place to address positive screens • 99420 is to be used, reimbursement $15.60

Illinois • Created metrics around prenatal and postpartum depression screening • 96127, with the HD modifier (96127 HD) for postpartum depression screening, up to a year after the infant’s birth; may be billed on the infant’s recipient number, if infant is the patient. • The University created a phone consultation service to connect providers to psychiatrists for advice about diagnosis, management, and medications • The creation of a hotline, staffed by mental health experts, for women to call for advice or resources • Provider education efforts across the state

Colorado • Any screen is acceptable but encourage PHQ9 and EPDS • Recently replaced 99420 with G8431- positive screen, G8510- negative screen • Reimbursement $10.28, yearly

National Guidance CMS, 2015 CMS Core Set of Children’s Health Care Quality Measures includes a maternity care behavioral risk assessment at the initial prenatal visit with depression screening listed along with alcohol, tobacco, drug use, and intimate partner violence screening

CMS, 2016 Informational Bulletin on Postpartum Depression • Maternal depression screening during the well-child visit is considered a pediatric best practice and is a simple way to identify mothers who may be suffering from depression and may lead to treatment for the child or referral for mothers to other appropriate treatment. • States and managed care plans can promote uptake by: o Posting information about maternal depression screening on provider websites and publishing information in provider newsletters. o Delivering provider trainings to promote the use of maternal depression screening tools and proper billing codes. o Conducting in-person visits to clinics to train providers on how to implement screenings, help practices modify clinic flow, and discuss referral strategies. o Offering practitioners continuing medical education (CME) credits for participation. • States may cover maternal depression screening for non-Medicaid eligible mothers during the well-child visit. States may also cover treatment for the mother when both

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Postpartum Depression Screening

the child and the mother are present, treatment focuses on the effects of the mother’s condition on the child, and services are for the direct benefit of the child.

Recommendations from professional associations AAP Bright Futures https://www.aap.org/en-us/Documents/periodicity_schedule.pdf o Maternal depression screening is recommended during well child checks by 1 month, 2 months, 4 months, and 6 months

ACOG, 2015 https://www.acog.org/-/media/Committee-Opinions/Committee-on-Obstetric- Practice/co630.pdf?dmc=1&ts=20180710T0405387857 o ACOG recommends screening at least once during the perinatal period for depression and anxiety symptoms using a standardized, validated tool o Screening by itself is insufficient. It must be coupled with appropriate follow up and treatment o Systems should be in place to ensure follow up for diagnosis and treatment

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Postpartum Depression Screening

HERC Staff Summary Screening for postpartum depression is recommended by the USPSTF and is intended to be covered on the Prioritized List, during mom’s or a child’s visit, and clarity is needed.

The American Academy of Pediatrics has specifically been advocating for the use of the 96161 to be used during the child’s visit for maternal depression screening so clarifying this code is appropriate would be in alignment with national efforts.

The claim for maternal depression screening can be appropriately billed to mom when she is the patient, or to the infant when they are the patient.

HERC Staff Recommendations: 1. Add Z13.32 Encounter for screening for maternal depression to Line 3 (per BHAP recommendations), although pairing with this would not be necessary, any well child or postpartum visit would be appropriate pairing. 2. Add 96160, 96161, and 96127 to Line 3 (and continue to have them be Diagnostic as well) 3. Add a Guideline GUIDELINE NOTE XXX POSTPARTUM DEPRESSION SCREENING Line 3 Postpartum depression screening using a validated instrument (e.g. Edinburgh Postpartum Severity Score, PHQ-9) is included on this line during the child’s visit (CPT 96161) or during the mother’s visit (CPT 96160, 96127) when there is a plan in place to address positive depression screens. 4. HSD may need to clarify that this code can be billed in addition to other screens such as developmental screening 5. Recommend to HSD to review the reimbursement rate for these codes. Other states are reimbursing between $8.67 and $15.60. The current reimbursement rates for FFS are $3.23. 6. Other parts of OHA will need to work with partners on promoting the uptake of postpartum depression screening and additional resources to ensure adequacy of follow-up and access to appropriate treatment. There are excellent examples from other states.

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Clinical Guidelines for Implementing Universal Postpartum Depression

Screening in Well Child Checks

MATERNAL & CHILD HEALTH SECTION P.O. BOX 64882, ST. PAUL, MN 55164 PHONE: 651-201-3625 Topic Webpage Here: www.health.state.mn.us/divs/cfh/topic/pmad NOVEMBER 2015

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Clinical Guidelines for Implementing Universal Postpartum Depression Screening in Well Child Checks

Table of Contents Why screen for postpartum depression during well child checks? ...... 3 The consequences of maternal depression on child development ...... 4 Basic Implementation ...... 5 Work Flow ...... 5 Documenting and Charting for Postpartum Depression in Well Child Checks ...... 7 Scripts for Screening and Referral for PPD ...... 9 Key Issues ...... 12 Choosing Well-Child Visits for Postpartum Depression Screening ...... 12 Deciding Which Tool to Use ...... 14 Billing ...... 14 Resources ...... 15 For Parents ...... 15 For Providers ...... 16 Acknowledgements ...... 17 References ...... 19

This document was created by the Minnesota Department of Health as part of an Adult Medicaid Quality Grant from the Centers for Medicare and Medicaid Services (CMS), awarded to the Minnesota Department of Human Services. Disclaimer: The information included in this document is for informational and educational purposes only. Users of the guidelines should not substitute information contained herein for professional judgment, nor should they rely solely on the information provided. Furthermore, this document does not reflect the optimal medical practice for all circumstances. Users are advised to seek professional counsel on the issues raised by consulting with medical staff for matters involving clinical practice.

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Why screen for postpartum depression during well child checks?

Maternal postpartum depression (PPD) can have serious adverse effects on the mother and child relationship, resulting in an environment that can disrupt the infant’s development. Infants who live in a neglectful or depressed setting are likely to show delays in development and impaired social interaction. In a new clinical report by the American Academy of Pediatrics (AAP), “Incorporating Recognition and Management of Perinatal and Postpartum Depression Into Pediatric Practice,” published in the November print issue of Pediatrics (published online Oct. 25), pediatric practices are encouraged to screen mothers for postpartum depression, to use community resources for the treatment and referral of the depressed mother, and to provide support for the mother-child relationship. Estimated rates of depression among pregnant and postpartum women can range between 5 percent and 25 percent. A family history of depression, alcohol abuse and a personal history of depression increase the risk of perinatal depression. A prenatal visit in the pediatric medical home is an excellent opportunity to establish a relationship with the parents, assess for risk of depression and supports, and initiate preventive strategies. Postpartum depression can lead to increased medical costs, inappropriate medical care, discontinuation of breastfeeding and child abuse and neglect. Screening is recommended by Bright Futures and the AAP Mental Health Task Force, and is a best practice in caring for infants and their families. (American Academy of Pediatricians, 2015). Many mothers are screened for postpartum depression at their 6 week postpartum visit, as is recommended by the American College of Obstetricians and Gynecologists (American College of Obstetricians and Gynecologists, 2015). However, providers who deliver well child checks are likely to see the mothers more often and have an opportunity to screen for PPD during a wider range of dates. In addition, an infant is more likely to receive a 2 month well child check - 92% in Minnesota’s Medicaid population in 2012 (Minnesota Department of Health, 2014) - than a mother is likely to receive a postpartum visit. Nationally, 64% of mothers covered by a Medicaid health plan receive a postpartum care visit, compared with 82% covered by commercial health plans (Onstad, 2014). Effective, free, relatively quick, validated screening tools exist to identify mothers at risk for postpartum depression. Treatments exist and are accessible, with great variability depending on location and insurance, for mothers to treat postpartum depression. Untreated, postpartum depression can have a negative impact on a baby’s overall health and development.

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Providers administering well child checks are in a key position to interact with the baby’s primary caretaker and to universally screen for postpartum depression, as part of the care they provide for the child.

The consequences of maternal depression on child development (Canadian Paediatirc Society, 2004)

• Prenatal o Inadequate prenatal care, poor nutrition, higher preterm birth, low birth weight, pre-eclampsia and spontaneous abortion. • Infant o Behavioral: Anger and protective style of coping, passivity, withdrawal, self- regulatory behavior, and dysregulated attention and arousal o Cognitive: Lower cognitive performance • Toddler o Behavioral: Passive noncompliance, less mature expressions of autonomy, internalizing and externalizing problems, and lower interaction o Cognitive: Less creative play and lower cognitive performance • School Age o Behavioral: Impaired adaptive functioning, internalizing and externalizing problems, affective disorders, anxiety disorders and conduct disorders o Academic: Attention deficit/hyperactivity disorder and lower IQ scores • Adolescent o Behavioral: Affective disorders (depression), anxiety disorders, phobias, panic disorders, conduct disorders, substance abuse and alcohol dependence o Academic: Attention deficit/hyperactivity disorder and learning disorders

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Basic Implementation Work Flow In developing a work flow for implementing the PPD screen in well child checks, the key components are:

o Introduction and completion of the screen o Provider review of score and identification of next steps o Discussion of score and any necessary next steps with parent o Documentation and any necessary follow up Potential interventions that would be appropriate, depending on the score on the screening tool are:

• Very low score: Basic education regarding postpartum depression and maintaining positive mental health – Maternal Wellbeing Plan (found at http://www.health.state.mn.us/divs/cfh/topic/pmad/pmadfs.cfm ) • Mild to moderate score: Warm referral to see a provider regarding the mental health concern. Education regarding postpartum depression. Possibly other community supports. • High or crisis score: Immediate transfer to a provider for parent. Create a plan for this process before launching universal screening. The community resources and other interventions offered to a parent could be developed by clinic staff. They may include local public health, family home visiting, early childhood family education, and other social service supports.

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Documenting and Charting for Postpartum Depression in Well Child Checks When screening for postpartum depression in well child checks, the most essential documentation practices are:

• Have the results of the screen available, in the child’s chart, to the child’s provider. • Document the follow up that occurs following a positive score on the screen.

Finding the right way to accomplish these two essentials can be tricky. It may be done very differently in different settings and clinical systems. There is not one “recommended” practice, but the following are ways systems have met these priorities along with HIPAA and their unique clinic/system expectations.

“Provider” refers to child’s provider (not parent’s).

Options Details Advantages Disadvantages Clinic Types In the 1. Completed paper • All information • Parent may Systems Parent’s screening tool is scored, only in parents not have a file where Record – then used by provider file, only parent in system, parent sees Parent is during the well child and parent’s may not pop a provider in same check. provider have up at future in the same EMR 2. Well child check in record access. well child system, has a note that a tool was checks. especially used to complete a • Parent’s when screen. provider can do • May take provider is 3. Provider opens up follow up. more care same for parent’s record, puts coordination parent and score and follow up • May get easier time. baby. activities in parent’s as technology record only (not child’s). improves. 4. Tool may be scanned into parent’s record. 5. Internal message may be sent to parent’s provider to ask them to complete necessary follow up. In the 1. Completed paper • Information Mental health Systems Child’s screening tool is scored, regarding the information on where Record then used by provider child’s health is parent is available parent sees during the well child readily from child’s a provider check. accessible to record. in the same 2. Provider/support puts child’s provider system. information about the but is not clear tool being completed, to all readers score of tool, and follow (i.e. using up activities into child’s “pass” or other record. coded words). 3. Encounters in child’s record are used to track follow up.

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Options Details Advantages Disadvantages Clinic Types In the 4. Parent’s provider, if in • Tracking follow Child’s system, can be notified up from Record through internal pediatric visit is (cont.) messaging. easier. 5. Tool may be scanned into child’s record.

In a 1. Completed paper • Information on Difficult (maybe Systems stand- screening tool is scored, parent is not impossible) to do where the alone file then used by provider connected to flagging, parent is during the well child child’s record. reporting. not a check. patient. 2. WCC has a note that a • Information is tool was used to complete available, if you a screen. know where to 3. Care coordination staff look. put score and parent information, and follow up, into separate, stand- alone file—like Excel spread sheet. 4. Tool may be scanned into unattached folder on protected drive. Send to 1. Screening tool comes with • Information on Difficult (maybe Systems parent’s a consent form for parent is not impossible) to do where provider information to be shared connected to flagging, parent is with parent’s provider, child’s record. reporting. not a and spot to fill in provider patient. information. • Information is 2. Completed paper available, if you screening tool is scored, know where to then used by provider look. during the well child check. • Parent will (if it 3. WCC has a note that a works) receive tool was used to complete follow up care a screen. from own 4. Care coordination staff provider. forward screen information and recommendation for follow up care to parent’s provider.

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Other interesting options include:

• Obtaining consent from the parent to put the score into the child’s record. • Upload actual screening tool into parent’s chart. • Keep parent and baby linked in medical record (may expire after a certain amount of time after birth). • Only record if screen is high.

Scripts for Screening and Referral for PPD Training may be helpful for all of the staff involved in administering the postpartum depression screen and needed follow up. Here are scripts that could be used. These are scripts to be used as a guide by staff and providers to discuss postpartum depression. These scripts should NOT be given to patients. Segments of it could be adapted into written form if desired. The italics are recommended words to be used when speaking to the parent. Please review and adapt to the needs of the families in the clinic population. Handing out the Screen This block could be printed on the screen: Congratulations on your new baby! It’s a big adjustment and we would like to know how you are feeling. Please check the answer that comes closest to how you have been feeling in the past 7 days, not just how you feel today. Front desk staff: (The person handing the parent the screening tool.) Having a baby is a big adjustment and your provider would like to check in with you and find out how you are feeling. Please fill this out, thinking about how you have been feeling over the past week. Your (nurse/medical assistant) will collect it from you in the room.

Introducing the Screen to Patients:

• PROVIDER: As your child’s provider, I’m concerned about the wellbeing of your child and so I’m also concerned about the wellbeing of the people who take care of your child. I’d like to know how you are feeling and how you have been coping. Please take a few minutes to fill out this short survey. (OR – Thank you for filling this out.) Response to a positive PPD screen:

• PROVIDER: This is a screen for depression. I’m concerned because you have a high score. Have you been feeling down, depressed, or anxious lately? o PROVIDER: Would you be willing to see someone for help? . PROVIDER: Do you have someone you feel comfortable talking with, such as your clinician, doctor, midwife, or a therapist you already see?

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• Yes: PROVIDER: Can we help you make an appointment? • No: PROVIDER: Let’s talk about who you would like to talk with. o PROVIDER: Can we help you identify a provider or connect you to a therapist? Follow Up Plan: If the screen was high:

• A follow up phone call within hours or days after the initial screen was high o clinic should decide who will be the staff member who makes this call consistently use this staff member • A follow up appointment with the parent’s provider or therapist should take place within a week. Follow-up Call:

• PROVIDER: I wanted to follow up with you about the discussion we had when you were in last week. Have you been able to connect with your provider or therapist? o Yes: PROVIDER: How did everything go? . Things went well: PROVIDER: I am glad to hear that, please let us know if you need any additional information or referrals. . Things did not go well: PROVIDER: Can I help connect you to a different provider? o No: PROVIDER: What has prevented you from connecting with the referral? . Try to problem solve with the parent—if wait time is long provide second referral, if require childcare/transportation provide additional information. How to Respond to High Positive Screen:

• PROVIDER: This is a screen for depression. Based upon your response(s) and/or our discussion, I’m worried about your wellbeing. I believe you need to see someone today. I can help you set something up right now. o PROVIDER: Let’s talk about how this process will go. . Discuss how clinic handles crisis- walk parent through the process, and physically have a staff member get them to emergency room, OR bring in behavioral health OR find transportation for them to emergency room. . It’s very important that the clinic has a plan for the child while the parent receives care. Possible options in Minnesota include: • Clinic is connected to behavioral health/emergency room and can make arrangements for child care with family. • Clinic works with mom to contact Mother-Baby Program at Hennepin County Medical Center (612)873-6262, to create plan for family.

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• The place where parent is being transferred does not have child care: ask parent if they have someone they can call to come and be with them, who can also watch child (mother, sister, partner) . Help parent manage any additional responsibilities (Childcare, eldercare etc.) If the parent says they do not want to see someone today:

o PROVDIER: Is there a reason why you are hesitating? . Listen to parent, try to help parent deal with issues around why they don’t want to see someone. Try NOT to be confrontational, rather gently work with parent to help them feel safe visiting additional resources. . PROVIDER: Can I call someone to be with you? (Such as your mom, partner, sister, friend etc.) . If a parent absolutely refuses to seek further care today, work as hard as you can to have someone come meet them. Follow up for High Positive Screen: Make a follow up call to high positive screens within days or hours. Child’s clinic will make call to see if the mother has connected to care. It would be best to have mother make an appointment for herself within 1 week. If a patient refused further care, call them within 24 hours and continue trying to follow up call until reached. If having trouble reaching them use emergency contact to try and reach them (without breaking HIPAA-just ask if the emergency contact can help you reach the parent for follow up) • I wanted to follow up with you about the referral you received when you were in last week. Have you been able to connect with the referral? o Yes: Did everything go alright? . Yes: I am glad to hear that, please let us know if you need any additional information or referrals . No: Would you like a referral to a different provider? o No: What has prevented you from connecting with the referral? . Try to problem solve with the parent—if wait time is long provide second referral, if require childcare/transportation provide additional information.

Every clinic should have a Crisis Response Plan prepared. If clinic has no Crisis Resource in place at time of emergency call 911.

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Key Issues Choosing Well-Child Visits for Postpartum Depression Screening The best option for screening mothers for postpartum depression is to screen at all well child checks within the first year, or at least up to and including the 6 month check. In Minnesota, a maternal depression screen at a well child check in the first 12 months is billable, up to three times in a calendar year. It is a recommended part of a complete Child and Teen Check Up (Minnesota’s Early and Periodic Screening, Diagnostic, and Treatment) in visits within the first year. Some pediatric clinics choose specific well child checks at which to do the PPD screen. This may be useful for clinics who have significant differences between visits (i.e. other screens only done at certain visits) and but may not be helpful for clinics with patients who came for well child checks in a less than regular fashion. A practical suggestion: if you must pick only one visit (not recommended) than do it at the 2 month – unless you know all your moms are attending and getting screened at their 6 week postpartum visit, then do it at the 4 month. Here are some things to consider in deciding which well child visits to do PPD screening at:

Visit Advantages Disadvantages Data

Most parents are still in the middle of major Psychosis presents itself within adjustment to the 1 or 2 two weeks in 65% of all cases of hormonal changes and week If there is a concern, it is best to postpartum psychosis. (Heron, generally having a baby. (new catch it as early as possible. 2007), (MGH Center, 2008), Concerns over anxiety born) (Scotland, 2012). or depression are expected and not out of the ordinary.

• Most important time to catch this with a caregiver. Children who are younger • The initial “baby blues” have when first exposed to their passed and this is the point Many mothers will also mother’s depression may be where depression/anxiety attend their 6 week more vulnerable to the will start to have an effect 2 month postpartum visit, where development of on the child. they will (hopefully) be psychopathology than • Anxious or depressed moms screened. and moms in low-income children not exposed until communities are less likely later (Goodman, 2011), (AAP, to attend their 6 week 2010). check.

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Visit Advantages Disadvantages Data

There is a strong body of research on the impact of a depressed parent on children. Effects include increased risk of mood disorder in children, impaired cognitive functioning, and poor language development • If it hasn’t been caught yet, (Conroy, 2012) (Grace, 2003) this may be the last good Late, so if screening (Zajicek-Farber, 2009) (Scotland 4 or 6 chance to catch it and start here, should also be 2012), (AAP 2010). month to address the effect upon screening earlier. the baby. • No verified differences in screening at 4 or 6 month. One study suggests screening at 6 month is better than 4 (Sheeder, 2008).

One study notes no significant difference (Whichman, 2010).

Caregiver may tire of • Don’t have to remember the screen (no clear All visits which visit it is. • More chances to find research to support this caregivers with concerns. concern)

Additional Screening Advice:

• Parents with a previous mental health history should be screened at every well-child visit. • Parents with PPD/ or anxiety symptoms should be screened at every well-child visit. If the provider suspects PPD/ or anxiety, parent should be screened at every well-child visit (Heron , Robertson Blackmore, McGuinness, Craddock, & Jones, 2007).

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Deciding Which Tool to Use Factors to take into consideration when selecting a validated tool to use for the postpartum depression screen:

• Is the tool specifically designed for pregnant or postpartum mothers? EPDS is, PHQ9 is not. • Is the tool used within the medical community, outside of OB/GYN, and therefore the score and concern is easily communicated to a provider? PHQ9 is, EPDS is not. • Are there other providers in the clinic system who have already chosen a tool to use? Is consistency in the system important? • Is the tool billable within the state Medicaid rules? In Minnesota, the approved tools are the Beck, PHQ9, and EPDS. • Is the tool free and easily accessible? PHQ9 and EPDS are both free. • Is the tool available and verified, in other languages spoken in our patient population? • Is the tool already available for use in the clinic electronic health record? Billing This information is from the Minnesota Department of Human Services Child & Teen Checkups Provider Guide, as of 11/30/2015. It will likely be different in other states. When billing for a maternal depression screening, refer to the following criteria: • Use CPT code 99420 with modifier UC. • Use the child’s MHCP recipient ID number. • Bill it on the same claim as the C&TC screening or other pediatric visit. • May be billed on the same date as a child’s developmental screening (96110), and or a social-emotional screening (96127). When a maternal depression screening is performed using one of the standardized screening instrument during a well-child check, and reported on the claim, that line item on the claim will be paid at our fee schedule rate. The fee schedule rate for the CPT code 99420 is $8.67.

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Resources The Minnesota Department of Health has created an information sheet and a tool for helping plan for maternal wellbeing – the Maternal Wellbeing Plan. These are available online, in 7 languages (Amharic, English, Hmong, Karen, Russian, Somali, and Spanish) at http://www.health.state.mn.us/divs/cfh/topic/pmad/.

For Parents There are many sources for support and information regarding postpartum depression, including: For immediate help: Call 911 or Crisis Connection at 866-379-6363; TTY 612-379-6377 or Text “LIFE” to 61222 available in many rural areas. For resources and support: Pregnancy Postpartum Support Minnesota Resource List: www.ppsupportmn.org PPSM HelpLine call or TEXT to (612) 787-PPSM or [email protected] Support and information provided by peer volunteers 7days a week. Mother-Baby HopeLine at Hennepin County Medical Center (612) 873-HOPE or (612) 873-4673 Mental health support and resources. The HopeLine is not a crisis phone line. They will call you back within 2 days. Postpartum Support International www.postpartum.net

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For Providers Here are a few of the resources available for providers: Mother-Baby HopeLine at Hennepin County Medical Center: (612) 873-HOPE or (612) 873-4673 Mental health support and resources. The HopeLine is not a crisis phone line. They will call you back within 2 days. Staffed by trained professionals with experience providing technical assistance to other providers.

Depression in Mothers: More Than the Blues http://store.samhsa.gov/product/Depression-in-Mothers-More-Than-the-Blues/SMA14- 4878 A free toolkit designed for providers who come in contact with mothers experiencing depression. It includes facts about depression, screening tools, referrals, resources and handouts for mothers who are depressed. Substance Abuse and Mental Health Services Administration: Toolkit for providers.

Support and Training to Enhance Primary Care for Postpartum Depression (Step-PPD) http://www.step-ppd.com/step-ppd/home.aspx A free online training course for primary care providers designed to increase understanding of postpartum depression (PPD), and provide education on caring for women with postpartum depression. The course covers basic understanding of PPD, how to assess PPD, and how to treat PPD.

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Acknowledgements The Minnesota Department of Health Maternal and Child Health Section thanks the following people and organizations for their participation and contributions.

Advisory Work Group Cecilia Wachdorf, RN, CNM, PhD, Women’s Health Consultant, Maternal and Child Adar Kahin, CHW Health WellShare International

Ann Challas, RN Minnesota Department of Human Services Primewest Julie Pearson, MSW, Medicaid Services Brian Lynch, MD Policy Supervisor, Adult Mental Health Mayo Clinic Catherine Wright, PsyD, MS, LPCC, Early Childhood Mental Health Program Lynda Moerke, RN Coordinator, Children’s Mental Health Primewest Participants in the Postpartum Depression Shannon Neale, MD Screening Quality Improvement Project, Park Nicollet Parkside Clinic 2014 & 2015 Deb Rich, Broadway Family Medicine, University of Shoshana Center Minnesota Physicians Minnesota Department of Health Jerica Berge, PhD, MPH, LMFT, CFLE Grace Buezis, MPH, Maternal and Child Emily Kidd, MD Health Section Priscilla Lees, RN Laura Miller, MD Susan Castellano, Manager, Maternal and Tanner Nissly, DO Child Health Section Andrew Slattengren, DO Karla Decker Sorby, RN, Tribal Nurse Stephanie Trudeau-Hern, MS Consultant, Family Home Visiting Sheila Pelzel, FNP-C, WHNP-BC, MSN, Child Cass Lake Indian Health Services & Teen Checkups Barbara Nyberg, RN, CNW Nancy Grimsrud, RN, PHN, CPNP, Child & Matei Teodorescu, MD Teen Checkups Katy Schalla Lesiak, MSN/MPH, APRN, Child Children’s Hospitals and Clinics of MN Health Consultant, Maternal and Child Connie Smith, PNP Health Dakota Child and Family Clinic Bonika Peters, MPH, Assistant Section Angie Grabau, RN, MS, CPNP Manager, Maternal and Child Health Nikki Rose, CNA Section Tessa Wetjen, MPA, Maternal and Child Health Section

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Fridley Children and Teenagers Clinic HealthPartners White Bear Lake Jennifer Flick, RN Elsa Keeler, MD John R. Hollerud, MD HealthPartners Stillwater Medical Group Angela LaPointe Bijan Shayegan, MD Holly Meier, PPCNP-BC Sandra Broberg, RN Mary J. Pohl, MD Jennifer E. Rousseau, MD South Lake Pediatrics Fadel G. Sakkal, MD Liz Haas, APRN, CNP, IBCLC Stephen B. Sitrin, MD Maria McGannon, APRN, CNP, IBCLC Lisa Carlson, RN HealthPartners Melissa Rudolph Marshall Southside Family Clinic Nel Fuchs, FNP HealthPartners Arden Hills Sara Zumbado, CNA Leslie Ann Kummer, MD Heather Erickson St. Luke’s Pediatrics Heather Winesett, MD HealthPartners Roseville Krista Harju, MSW, LGSW, M.Ed Jamie Lyn Reinschmidt, MD Bree Kordiak The Duluth Clinic, Essentia Amy Colvet-Watkins, RN Julie Reichhoff, MD

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References American Academy of Pediatrics (2015). https://www.aap.org/en-us/about-the-aap/aap-press- room/pages/Managing-Maternal-Depression-Before-and-After-Birth.aspx as accessed 11/11/2015. American College of Obstetricians and Gynecologists (2015). “Screening for perinatal depression.” Committee Opinion No. 630. Obstet Gynecol 2015; 125: 1268–71. Canadian Paediatirc Society (2004). “Maternal Depression and Child Development.” Paediatrics & Child Health. 2004 Oct; 9(8): 575–583. Conroy, S. P. (2012). Maternal Psychopathology and Infant Development at 18 Months: The Impact of Maternal Personality Disorder and Depression. Journal of the American Academy of Child & Adolescent Psychiatry , 1, 51-61. Goodman, S. H., Rouse, M. H., Connell, A. M., Broth, M. R., Hall, C. M., & Heyward, D. (2011). Maternal Depression and Child Psychopathology: A Meta-Analytic Review. Clinical Child and Family Psychology Review , 1, 1-27. Grace, S. E. (2003). The effect of postpartum depression on child cognitive development and behavior: A review and critical analysis of the literature. Archives of Women’s Mental Health , 6 (4), 263-274. Heron , J., Robertson Blackmore, E., McGuinness, M., Craddock, N., & Jones, I. (2007). No ‘latent period’ in the onset of bipolar affective puerperal psychosis. Archives of Women's Mental Health , 10 (2), 79-81. Minnesota Department of Health, Child and Teen Check-up (EPDST) rates from Minnesota Medical Assistance billing data, 2012, as analyzed by the Minnesota Department of Health, November 2015. Onstad K, Khan A, Hart A, et al. Benchmarks for Medicaid Adult Health Care Quality Measures. Cambridge, MA: Mathematica Policy Research;2014. Sheeder, J., Kabir, K, & Stafford, B. (2009). Screening for Postpartum Depression and Well-Child Visits: Is Once Enough During the First 6 Months of Life? Pediatrics, 123 (982). Whichman, C.L., Angstman, K.B., Lynch, B., Whalen, D., Jacobson, N. (2010) Postpartum Depression Screening: Initial Implementation in a Multispecialty Practice with Collaborative Care Managers. Journal of Primary Care & Community Health, I(3) 158-163. Zajicek-Farber, M. L. (2009). Postnatal Depression and Infant Health Practices among High-Risk Women. Journal of Child and Family Studies , 18 (2), 236-245.

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Fall 0 8

Colorado Department Nationwide Initiatives of Public on Pregnancy-Related Health and Environment Depression

A Summary of 16 Key Informant Interviews

June 2013

Contents Introduction ...... 2 Background ...... 3 Method ...... 3 Notable Strategies ...... 4 Key Trends ...... 7 Challenges and Key Lessons Learned ...... 10 Conclusion ...... 11 Appendix A: List of State Interview Participants...... 12

The Colorado Maternal and Child Health Program wishes to thank the key informants nation-wide for their time and information; Marisol Erlacher, Project Consultant, for conducting and summarizing the interviews; and Colorado Department of Public Health and Environment staff members for preparation of this report.

Nationwide Initiatives on Pregnancy-Related Depression Page 2

Introduction

Pregnancy-related depression is depression that occurs either during pregnancy or up to one year postpartum. Also known as maternal, postpartum or perinatal depression, pregnancy- related depression can have devastating effects on a mother, her child and her family. The issue is complex and finding adequate support for individuals who suffer from it can be difficult.

Historically, the effects of depression during pregnancy or postpartum, or after a pregnancy loss, have been primarily associated with the mother. However, mounting evidence suggests that depression during this time in the life course also affects the child and other family members, often with delayed effects that impact the child’s developmental years. In response to this body of evidence, states working on pregnancy-related depression have moved toward a more comprehensive approach to address screening, referral and treatment barriers, as well as associated stigma. From home visitation to public awareness campaigns, the experiences of these states provide a wealth of information to help others successfully tackle this challenging issue.

Background

Depression is the most common complication of pregnancy for mothers, both in Colorado and nationwide. According to Colorado’s Pregnancy Risk Assessment Monitoring System (PRAMS), nearly one in every nine Colorado women who give birth (11.0 percent) will experience signs and symptoms of depression (PRAMS, 2009-2010). The Centers for Disease Control and Prevention have noted that anywhere from 8-19 percent of women nationwide report having postpartum depressive symptoms.1

Colorado’s 2011-2015 Maternal and Child Health Block Grant needs assessment identified pregnancy-related depression as one of nine priority areas for Colorado’s Maternal and Child Health program. The priority focuses on a population-level approach by promoting timely screening, referral and support for pregnancy-related depression through improvements to the health care and mental health systems. This priority also aligns with Colorado’s mental health and substance abuse “winnable battle,” one of 10 identified public health and environmental priorities Colorado has committed to addressing in the coming years.

The Maternal Wellness team at the Colorado Department of Public Health and Environment coordinates the state’s pregnancy-related depression efforts. As a foundation for multi-year program planning, Maternal Wellness staff members identified the need to learn more about other states’ experience in addressing the public health issue of pregnancy-related depression.

Method

During the summer of 2012, Colorado’s Maternal Wellness team developed and administered an online survey with every state and territorial maternal child health and behavioral/mental health director. Additionally, a handful of community-based support organizations were identified and included in the survey.

1 Centers for Disease Control and Prevention (2013). Depression among women of reproductive age. Retrieved April 2013 from http://www.cdc.gov/reproductivehealth/Depression/index.htm. Nationwide Initiatives on Pregnancy-Related Depression Page 3

A total of 125 individuals were invited to complete the survey. The survey received 61 individual responses representing 38 separate states and territories. Of those states and territories responding, 28 reported they were implementing, or had recently implemented, initiatives focused on pregnancy-related depression. A copy of the survey can be found here.

Results from the survey were then reviewed to prioritize states for key informant interviews. The Pregnancy-Related Depression State Advisory Committee, comprised of experts and key stakeholders from across Colorado, helped identify the 16 most relevant states to interview. Each state was contacted to participate in a brief telephone interview with an independent contractor. Interviews were completed primarily with representatives from state health departments. However, representatives from a community-based organization, insurance provider and mental health department were also included. A list of states and representatives interviewed can be found at the end of this report. Individual state interview summaries can be found by clicking here to access an addendum to this report.

For the purpose of this report, the term “pregnancy-related depression” will be used to encompass postpartum depression, perinatal depression and maternal depression. Individual states may have used various terms to describe strategies, but all survey and interview questions were framed using the term pregnancy-related depression.

This report discusses the notable strategies, key themes, challenges and successes identified by states during the interviews.

Notable Strategies

The 16 state representatives interviewed discussed a variety of strategies to strengthen pregnancy-related depression screening and referral systems. Many states worked within existing programs focused on maternal and child populations to implement screening, referral and in some cases treatment, at the service delivery level. The development of cross-sector collaborations, the use of hotlines as referral resources, the training of providers and public awareness campaigns were also common strategies.

Home Visitation

For many states, work in pregnancy-related depression began with the inception of home visitation programming. Recent funding for home visitation programs through the Affordable Care Act’s Maternal, Infant and Early Childhood Home Visitation program (MIECHV) expanded access to these services in many communities. States most often focused on the integration of screening and referral protocols into the existing framework. A handful of states integrated treatment into programming for mothers who screen positive for symptoms of depression, and who are receptive to a short intervention delivered by program staff members.

Iowa – This state instituted “listening visits” as part of its home visitation program. Public health nurses are trained to implement the listening visits curriculum when conducting home visits to help a mother identify at least two things causing stress in her life. These nurses then work with the new mother to develop solutions to these issues. The Edinburgh Postnatal Depression Scale is used to determine if a listening visit is indicated for a woman based on how she answered the questions. The intervention’s effectiveness has been evaluated using postpartum depression screenings directly after receiving the visit and at a one month follow-up visit. On average, women’s scores dropped up to 5 points after receiving the visits and continued to

Nationwide Initiatives on Pregnancy-Related Depression Page 4

decrease on future screens.

Louisiana and Massachusetts – These states have interdisciplinary teams that provide mental health support using licensed practitioners or social workers. Both states provide in- home interventions, referral and support for mothers exhibiting symptoms of depression. In Louisiana, infant mental health consultants serve a dual role of providing direct services to program participants and consulting with staff members.

Michigan – The Maternal Infant Health Program (MIHP) works in collaboration with obstetric and pediatric programs to coordinate care for mothers. MIHP is a direct-service, home visitation program that promotes healthy pregnancies to improve birth outcomes and supports the health of infants. It is administered by the Michigan Department of Community Health and available to all pregnant Medicaid beneficiaries and their infants statewide.

Healthy Start

Healthy Start is a national program funded by the Health Resources and Services Administration of the U.S. Department of Health and Human Services. The program focuses on decreasing health disparities and increasing access to health services to improve maternal and child health outcomes. Many states awarded this funding have integrated pregnancy-related depression screening and referral into program benchmarks.

Alaska – Its Healthy Start program operates in the northwest region of the state, largely comprised of Alaskan Natives/American Indians identified as experiencing high rates of perinatal and postpartum depression. The program requires perinatal and postpartum depression screenings as part of its case management and home visitation programs, and also provides community education classes that address depression and other behavioral health issues.

Florida – This state’s Healthy Start program operates through 32 coalitions statewide. The program provides universal screening to pregnant women enrolled in the program, using the Edinburgh Postnatal Depression Scale.

Cross-Sector Collaborations

Driven by a lack of targeted, sustainable funding streams, public and private agencies have collaborated to move pregnancy-related depression work forward in many states. Several states organized cross-sector workgroups and collaborations as a result of state-mandated legislation. States have found ways to maximize resources by networking across government agencies, education institutions, hospitals, private practices, health insurance providers, Medicaid providers and mental health agencies. For example, partnerships with local universities allow for collaboration on research and technical assistance programming for providers. This strategy has increased awareness of pregnancy-related depression among providers, and provided a more cohesive vision for state priorities through the inclusion of diverse partners.

Vermont – The Vermont Child Health Improvement Program (VCHIP) has provided a blueprint for cross-sector collaboration. VCHIP is a 10 year-old quality improvement arm operating from the University of Vermont’s College of Medicine that institutes protocols for high-quality pregnancy and postpartum care. VCHIP focuses on population-level maternal and child health services research and facilitates cross-functional partnerships between researchers, practitioners, insurers, professional organizations and government. The program empowers providers with the knowledge and skills needed to deliver high quality services and develops educational materials to better inform practitioners on how to integrate best practices into

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current systems. VCHIP supports the state’s focus on maternal and child health outcomes, including pregnancy-related depression.

Michigan – A group of statewide stakeholders met for several months and developed recommendations to improve access to mental health services for expectant and new mothers.

New Jersey – In 2005, this state formed a work group in collaboration with the Commissioner of Health to plan a statewide postpartum depression project in accordance with newly passed legislation.

Oregon – The Maternal Mental Health Work Group has a legislative mandate to review maternal mental health issues and develop recommendations for the legislature on how to improve statewide maternal and child mental health systems.

Hotlines

Often women and family members seek out information and referral resources in a time of crisis. For this reason, a number of states use hotlines to provide resources on pregnancy- related depression.

Illinois, Iowa, Nebraska and Missouri – These states provide guidance, support and resources to depressed mothers through a hotline staffed by volunteers, including trained mothers or professionals.

Oregon and Missouri – These states either provide specific depression-focused hotlines or work in collaboration with state-run, toll-free Maternal and Child Health information numbers to connect mothers directly with designated support hotlines and other resources.

New Jersey – A state-run, toll-free hotline provides multiple health resources for callers. Staff members screen callers and refer them to appropriate resources. Callers with insurance who desire mental health services are referred within their networks. Callers without insurance are connected to a referral source that serves uninsured clients. Three staff members are dedicated to postpartum depression phone calls.

Provider Education and Trainings

As part of the survey, states were asked to comment on technical assistance and training opportunities for providers, including how these opportunities were implemented and resulting successes. Many states developed comprehensive websites that not only provide accessible information for consumers and providers, but also serve as avenues for training. Providing continuing education credits was a critical element of successful training programs, most likely due to the incentive for the provider to attend.

Florida, Iowa, Massachusetts, Michigan, New Mexico, Nebraska and Ohio – These states use web-based trainings for providers. Florida’s webinars address the varying degrees of depression and different levels of intervention available to a mother. The goal is to help providers recognize other effective and available interventions beyond medication. New Mexico has provided interactive webinar trainings on pregnancy-related depression that have reached providers in Illinois, Oklahoma and Texas.

Louisiana – This state provides an introduction to perinatal depression within a comprehensive, 36-hour continuing education program. The program provides an overview of various topics, including segments on recognizing maternal depression, its impact on infants, interventions and other high-risk/co-occurring issues, such as substance abuse and domestic

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violence.

Michigan and Nebraska – Both states provide trainings that include continuing education credits. While Michigan offered continuing medical education credits for medical doctors, in addition to nursing and social worker continuing education credits, Nebraska recognized that the audience was largely comprised of nurses and social workers and chose to solely offer continuing nursing education credits. Both states’ curriculums are web-based and focus on the topic of depression during and after pregnancy, as well as the importance of screening, referral and treatment. Michigan’s training includes a curriculum on motivational interviewing and program intervention theories. Both initiatives measure training utilization through post-course surveys and regular reports identifying the number of users and licensure status.

Public Awareness Campaigns

Many of the states interviewed identify public awareness campaigns or consumer marketing initiatives as part of their efforts to address pregnancy-related depression. Communication channels included specialized websites, social media, informational packets and mass media, including billboards, bus ads, etc. The target audience for most efforts was general, with many states targeting moms who had suffered from pregnancy-related depression as a way to generate awareness.

Oklahoma – The Oklahoma Department of Health partnered with a local advertising agency to develop a public service announcement titled Quicksand. The campaign used actors of diverse ethnic backgrounds to create a visual and audio representation of symptoms associated with postpartum depression using language captured from mothers who had experienced the illness.

Nebraska – This state collaborated with local partners and a social marketing firm to develop the Moms Reach Out Campaign. This campaign uses a website as its communication outlet and peer stories to engage its audience.

Massachusetts – This state developed a comprehensive public awareness campaign to target providers and new parents. The New Parent Initiative uses peer stories from new parents and providers to build empathy, create support and share information about issues new parents may experience. Topics include parenting expectations, child development, maternal depression, substance abuse, premature birth, adoption and family planning.

Key Trends

States with successful pregnancy-related depression initiatives often had policy changes and/or legislation in place to help move the work forward. Reimbursement was also identified as a key factor in improving the uptake of screening efforts among practitioners. Additionally, recommending a screening tool (or tools) and bundling payment for depression screening with other risk factor screenings has improved the success of universal screening efforts either program-wide or system-wide.

Nationwide Initiatives on Pregnancy-Related Depression Page 7

Legislation and Policy

Numerous states have successfully leveraged legislation to increase statewide support for and impact of depression initiatives.

Illinois – Senate Bill 15: Postpartum Mood Disorders Prevention Act, enacted in 2008, supports the development of policies and procedures to address perinatal depression and calls for the early screening of women by health care workers. The Governor’s office each year proclaims May Perinatal Mood Disorders Awareness Month, to increase the public awareness of the impact perinatal mood disorders have on mothers, children and families.

Massachusetts – In 2010, the state enacted An Act Relative to Postpartum Depression. This legislation developed from the Perinatal Connections Program, a grant-funded program implemented to address policy implications, programming, data collection, systems and technical assistance for maternal depression. This legislation gave the Massachusetts Department of Public Health authority to improve the screening and treatment of perinatal depression. This authority allowed the department to develop effectiveness standards for depression screening, as well as regulate data submission by providers and health insurance carriers that conduct depression screenings.

New Jersey – The 2006 Postpartum Depression Screening Bill requires all health care professionals who provide prenatal care to educate women about postpartum depression and obtain a history of postpartum depression prior to delivery. Additionally, the law requires facilities and providers delivering postnatal care to screen new mothers for postpartum depression when leaving the birthing facility and at the postpartum check-up. Compliance is tracked through the Electronic Birth Certificate Program.

Oregon – This state successfully used legislative efforts to address stakeholder engagement, public awareness and provider education. House Bill 2666: Maternal Mental Health Work Group required the development of a statewide work group on maternal mental health disorders appointed by the Department of Human Services director. The work group was charged with identifying vulnerable populations and developing recommendations for accessible and effective strategies to improve maternal mental health. House Bill 3625: Maternal Mental Health Month declares May as Maternal Mental Health Month in Oregon. House Bill 2235: Maternal Mental Health Patient and Provider Education Program created a program to deliver provider education to help prevent the associated long-term negative outcomes of depression on women, children and families. Oregon’s ability to develop diverse legislation targeting a spectrum of pregnancy-related depression issues has successfully sustained momentum on improving maternal mental health.

Reimbursement for Screening

As part of the initial survey, each respondent was asked whether the state’s Medicaid program had an open Current Procedural Terminology (CPT) code or International Statistical Classification of Disease and Related Health Problems (ICD) code for any of the following: postpartum depression screening, adult depression screening or general preventative screening that can include depression. The goal of this question was to identify states that had successfully tied a reimbursement code(s) to screening and further discuss how this effort supported a state’s overall depression work.

Many of those surveyed were unclear on whether open reimbursement codes existed. This is likely due to the survey’s outreach to public health staff members rather than those in charge of public insurance programs. However, a small sample of states noted their efforts to achieve screening reimbursement codes, and this achievement, in combination with additional state

Nationwide Initiatives on Pregnancy-Related Depression Page 8

initiatives, clearly supported the increased use of screening by providers.

Oklahoma – A qualified Medicaid practitioner who provides prenatal care services may be reimbursed for a psychosocial assessment. Any traditional Oklahoma Medicaid member or SoonerCare Choice member (the state’s managed care plan) is eligible to receive the screening. The assessment includes two forms: the American Congress of Obstetricians and Gynecologist’s Obstetric Medical History Form and the Oklahoma Health Care Authority’s Prenatal Psychosocial Assessment Form. Providers have a reimbursement limit of one per pregnancy at a rate of $30. Medicaid members who change providers during pregnancy are limited to reimbursement for two assessments per pregnancy.

Virginia – As part of the BabyCare program, a Medicaid provider can use a universal screening form containing evidence-based questions to screen for interpersonal violence, substance abuse and maternal depression. Providers can use this screen during pregnancy and up to two years after delivery. Providers may screen under either the mother’s or infant’s plan, with as many as four screenings per pregnant member and four screenings per infant member per year.

Michigan – Women enrolled in the Maternal Infant Health Program, a Medicaid program for eligible pregnant women and women as much as 60 days postpartum, receive a risk identifier tool during pregnancy and immediately postpartum. This risk identifier tool includes the Edinburgh Postnatal Depression Scale and is reimbursable as part of the program.

Illinois – While not referenced on the survey, any physician or other provider enrolled in the state’s Medicaid program may complete a perinatal depression screening during a prenatal, postpartum, infant well-child or episodic visit. Reimbursement is available for this screening; it is classified as a “risk assessment” at $14.60. If a mother is no longer covered under Medicaid, a provider may bill the child’s Medicaid number.

Recommending Specific Screening Tools

Many of the states interviewed have conducted reviews of screening tools to improve screening standardization and increase use of evidence-based practices. The screening tool most commonly used by the states interviewed was the Edinburgh Postnatal Depression Scale.

Oklahoma and Vermont – Both states have completed studies evaluating the efficacy and relevance of the Edinburgh Postnatal Depression Scale. Vermont had a study published in the Journal of Women's Health illustrating that, while the professional understanding of the importance of screening has increased over time, confidence in delivering the screening has not. The article recommended training as a way to build confidence among practitioners2.

Oklahoma – An Oklahoma work group completed a five-month pilot project using the Edinburgh Postnatal Depression Scale in clinical settings. The goal of the pilot project was to determine the efficacy and logistics of using this screening tool in clinic settings statewide. The pilot project determined that the Edinburgh Postnatal Depression Scale was the most appropriate tool due to ease of use and accessibility.

Massachusetts – The Massachusetts Department of Public Health developed the Postpartum Depression Screening Grid to help providers determine the most effective screening tool for their purposes. The grid provides a listing of appropriate screening tools for postpartum depression and includes administration, completion time, validity and electronic availability for each tool.

2 Price, SK. et al. (2012). Perinatal depression screening and intervention: enhancing health provider involvement. Journal of Women’s Health, 21(4), 447-455. Nationwide Initiatives on Pregnancy-Related Depression Page 9

Bundling of Screening Assessments

Many states have been forward-thinking in the use of screening assessments by bundling depression screening with other associated risk screens. The two most notable pairings include substance abuse and domestic violence screening. Many states that bundled screening assessments were successful in obtaining reimbursement.

Louisiana – The state’s Birth Outcomes Initiative is developing a screening tool entitled La HART (Louisiana Health Assessment, Referral and Treatment). This screening tool currently focuses on substance use and domestic violence, but plans are underway to add depression screening and resources.

Michigan – All Medicaid-eligible women in Michigan’s Maternal Infant Health Program are administered the Edinburgh Postnatal Depression Scale, Perceived Stress Scale and T-ACE Substance Abuse Screen. These screens are embedded within the program’s risk identifier tools. The results of each screening are entered into a state database and a score is generated based on an algorithm. If a woman scores moderate or high risk, a set of interventions are provided by program staff.

Virginia – The Virginia Department of Health worked with an expert panel to effectively bundle screenings. This panel was part of a grant funding requirement and included Medicaid representation. It focused on screening and referral, and determined that a triad of issues commonly co-existed with mothers: interpersonal violence, substance abuse and depression. After three years of work, the panel was able to bundle screenings and seek reimbursement for this package.

Challenges and Key Lessons Learned

As part of the interview process, key informants were asked to share challenges encountered and recommendations for addressing those challenges. The most frequent barriers noted by states in effectively addressing the issue of pregnancy-related depression were related to health care providers incorporating the issue into their practice and the stigma associated with a mental health diagnosis.

Many states noted that health care providers have not been able to appropriately assist patients suffering from pregnancy-related depression, often due to a lack of awareness and skills to support women who express symptoms. In most cases, providers respond within their professional limitations or the limitations of their respective institutions or agencies. As previously described, many states have worked diligently to provide direct educational support through face-to-face trainings or web-based curriculum. Other states have invited health care providers to join collaborative efforts to continue to disseminate information through their professional channels. Ultimately, it appears that affecting cultural change among providers may mean legislation or policy mandating screening or screening reimbursement for health care providers who work with mothers of childbearing age.

The stigma associated with mental health diagnoses is a common national theme. The stigma of mental health is even greater among postpartum women due to the pressures and expectations associated with motherhood. This stigma, along with many other existing cultural norms and expectations, has made it difficult for mothers to accept a diagnosis and follow through with treatment — a common barrier noted by many of the interviewed states. Efforts to provide varying levels of intervention allow mothers with low to moderate depression to find

Nationwide Initiatives on Pregnancy-Related Depression Page 10

relief without the need for a referral to additional mental health services. This strategy addresses both stigma and lack of referral sources.

Conclusion

A great deal of innovative work in pregnancy-related depression is taking place around the country. Work groups and collaborations have helped move the work forward, pooling resources and talents to further initiatives in creative ways. Technology has become a cost- effective and accessible way to provide information to mothers and providers in the community. Many states use websites with peer stories to reach consumers. Others have developed web- based provider training modules, including continuing education credits, to provide incentives to attend. Partnerships with state Medicaid programs and administrators have proven successful as well. Whether combined with legislation or as an individual connection, these collaborations have been key to furthering universal and standardized screening, reimbursement and data collection efforts. Despite many of the stated successes, more work needs to be done to evaluate these strategies to ensure future efforts focus on those approaches with the greatest potential to improve the rates of pregnancy-related depression among new mothers.

Addressing maternal mental health is complex, but the various examples highlighted here demonstrate a critical role for public health in bringing awareness to the issue at the population level and promoting standard screening and referral throughout health systems. Successfully addressing pregnancy-related depression today is key to improving the health and mental health of women, children and their families tomorrow.

Nationwide Initiatives on Pregnancy-Related Depression Page 11

Appendix A: List of State Interview Participants

Alaska Perinatal Nurse Consultant Alaska Department of Health and Debra Golden Social Services

Florida Infant, Maternal and Florida Department of Health Susan Potts Reproductive Health

Illinois Founding Director and Clinical Postpartum Depression Alliance of Sarah Allen, D Clin Pysch Advisor Illinois

Iowa Coordinator of Maternal Health Iowa Department of Mental Health Stephanie Trusty Title V Grant

Louisiana Clinical Director of LA Nurse Louisiana Office of Public Health Paula Zeanah, PhD Family Partnerships (NFP) Maternal Child Health Program

Massachusetts Assistant Clinical Director Bureau of Family Health and Karin Downs MPH Director for Title V Program Nutrition

Michigan Public Health Consultant Michigan Department of Joni Detwiler, BS, SW Maternal Infant Health Community Health

Missouri Chief of Bureau of Genetics Department of Health Services Sharmini Rogers, MPH, MBBS Senior and Healthy Childhood

Nebraska Program Manager Maternal Child Adolescent Health Kathy Karsting, RN, MPH DHHS-Division of Public Health

New Jersey Public Health Consultant NJ Department of Health Elizabeth Dahms

New Mexico Nurse Case Manager Blue Salud Sharen Kimmet, RN, BSN, CCM

Ohio Office of Children and Families Ohio Department of Mental Health Maria Himmeger and Prevention

Oklahoma Public Health Social Work Oklahoma State Department of Julie Dillard Coordinator Health

Oregon MCH Systems and Policy Center for Prevention and Health Nurit Fischler, MS Specialist, Maternal and Child Promotion, Oregon Health Health Section Authority

Vermont Maternal and Child Health Vermont Department of Health Dr. Breena Holmes Director

Virginia Program Manager for Virginia Department of Health Joan Corder-Mabe Reproductive Health Unit

Nationwide Initiatives on Pregnancy-Related Depression Page 12

DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Medicare & Medicaid Services 7500 Security Boulevard, Mail Stop S2-26-12 Baltimore, MD 21244-1850

CMCS Informational Bulletin

DATE: May 11, 2016

FROM: Vikki Wachino, Director Center for Medicaid and CHIP Services

SUBJECT: Maternal Depression Screening and Treatment: A Critical Role for Medicaid in the Care of Mothers and Children

Introduction This Informational Bulletin discusses the importance of early screening for maternal depression and clarifies the pivotal role Medicaid can play in identifying children with mothers who experience depression and its consequences, and connecting mothers and children to the help they need. State Medicaid agencies may cover maternal depression screening as part of a well- child visit. In addition, states must cover any medically necessary treatment for the child as part of the Early and Periodic Screening, Diagnostic and Treatment (EPSDT) benefit.

Prevalence and Impact of Maternal Depression Maternal depression is a serious and widespread condition that not only affects the mother, but may have a lasting, detrimental impact on the child’s health. Maternal depression presents a significant early risk to proper child development, the mother-infant bond, and the family. Maternal depression screening and treatment is an important tool to protect the child from the potential adverse physical and developmental effects of maternal depression. According to the American Academy of Pediatrics (AAP), screening mothers for maternal depression is a best practice for primary care pediatricians caring for infants and their families1 and can be integrated into the well-child care schedule, as well as included in the prenatal visit. Maternal depression is characterized by a spectrum of severity: the common “maternity blues” or “baby blues” are usually gone after a few days or one to two weeks and are helped with reassurance and support for the mother. This is distinct from postpartum depression and postpartum psychosis (the most serious condition), which meet specific diagnostic criteria.2 According to AAP, it has been estimated that 5 percent to 25 percent of all pregnant, postpartum and parenting women have some type of depression depending on the population surveyed. “Maternal depression” in this guidance encompasses the full spectrum of severity, not only the most severe diagnoses. Mothers who have low incomes are more likely to experience some form of depression than the general population of mothers. For low-income women, rates of depressive symptoms are reported to be between 40 percent and 60 percent.3 There are estimates that 11 percent of infants in families with incomes below the federal poverty level live with a mother who has severe depression and that more than half (55 percent) of all infants living in poverty are being raised by mothers with some form of depression.4 In light of recent evidence that children living with mothers with depression may be at risk for long-term physical and behavioral health consequences, the importance of screening and treating CMCS Informational Bulletin - Page 2

maternal depression is clear. As Harvard University’s Center on the Developing Child indicated in 2009, children raised by a clinically depressed mothers may perform lower on cognitive, emotional, and behavioral assessments than children of non-depressed caregivers, and are at risk for later mental health problems, social adjustment difficulties, and difficulties in school.5 The risk to the child may depend on the severity of the maternal depression, but timely screening and appropriate treatment can reduce maternal depression and its consequences. According to the AAP, “If the maternal depression persists untreated and there is not intervention for the mother and the dyadic relationship, the developmental issues for the infant also persist and are likely to be less responsive to intervention over time.” 6 Recent research shows promising results for intensive interventions that focus specifically on mother-child interactions, suggesting that treatments designed to improve child well-being must attend both to relieving the mothers’ depression and focus on interactions with the child as central dimensions of the interventions. 7

Medicaid’s Role in Maternal Depression Screening and Treatment Screening Maternal depression screening is endorsed by several independent expert medical panels that impact services provided to Medicaid eligible children and adults. For example: The AAP-endorsed Bright Futures: Guidelines for Health Supervision of Infants, Children and Adolescents ™ is used by many states to implement their EPSDT well-child visits. Bright Futures includes recommendations for well-child visits at one week and one and two months of age, including a recommendation for “Parental (maternal) well-being,” which includes a postpartum checkup, with depression and substance abuse screening. Any suggestion of depression should trigger screening questions and providers furnishing these services as part of a well-child visit are guided to refer the mother to her obstetrician or other health care professional and appropriate community-based mental health services. In terms of Medicaid coverage, covering Bright Futures recommended services as part of the preventive benefit strengthens access to these services. In addition, the United States Preventive Services Task Force (USPSTF) recently published recommendations for screening for depression in the general adult population, including pregnant and postpartum women. 8 The recommendation was given a B grade, based on the quality and strength of the evidence about potential benefits and harm for screening for this purpose. For state Medicaid agencies, section 4106 of the Affordable Care Act (ACA) established a one percentage point increase in the Medicaid federal medical assistance percentage (FMAP) applied to expenditures for preventive services to states that cover all USPSTF grade A and B preventive services and the Advisory Committee on Immunization Practices (ACIP) recommended vaccines. The EPSDT benefit is Medicaid’s comprehensive child health benefit. Under the EPSDT benefit, eligible individuals under age 21 must be provided periodic screening services (well child exams).9 One required element of this screening is a comprehensive health and developmental history, including assessment of physical and mental health development. CMCS Informational Bulletin - Page 3

A maternal depression screening can be considered an integral part of a risk assessment for the child, in light of the evidence that maternal depression can place children at risk of adverse health consequences. There are several validated screening tools for depression which are simple to administer and can help identify maternal depression and potential risk to the child.10 Some of these screening tools are specific to postpartum women and some are more general. Some states cover maternal depression screening as part of a Medicaid well-child visit. These states may instruct providers to claim for this activity either as a service for the child or for the mother, depending on the mother’s Medicaid eligibility. The Centers for Medicare & Medicaid Services (CMS) wishes to clarify that, since the maternal depression screening is for the direct benefit of the child, state Medicaid agencies may allow such screenings to be claimed as a service for the child as part of the EPSDT benefit. State Medicaid agencies have discretion to determine reimbursement approaches available to the pediatric provider for furnishing the maternal depression screening. In keeping with the expert recommendations, several state Medicaid agencies have recognized the importance of the maternal depression screening and are allowing providers to perform and bill for this screening as part of the EPSDT well-child visit:

• Colorado: The Colorado Department of Health Care Policy and Financing issued Provider Bulletins with guidance on maternal depression screening. Starting January 2014, postpartum depression screening is covered as an annual depression screening and Medicaid primary care providers are encouraged to screen new mothers at a well-child visit using the mother’s Medicaid ID number. To facilitate screening in more settings, providers seeing an infant for a well-baby visit are alternatively allowed to bill for the service using the Medicaid ID of the infant.11 • Illinois: The Illinois Department of Healthcare and Family Services (HFS) covers perinatal depression screening when an approved screening instrument is used. If the postpartum depression screening (for the woman) occurs during a well-child visit or episodic visit for an infant (under age one) covered by HFS’ Medical Programs, the screening may be billed as a "risk assessment" under the infant’s Medicaid identification number. Alternatively, if the woman is postpartum and covered by HFS’ Medical Programs, the postpartum depression screening may be billed under the woman's identification number.12 • North Dakota: North Dakota Medicaid covers maternal depression screening as a separate service when performed in conjunction with a Health Tracks (EPSDT) screening or any other pediatric visit, and is considered a risk assessment for the child. Up to three maternal depression screenings are allowed for a child under the age of one. Providers are instructed to bill only when one of the standardized screening tools is used and to bill using the child’s North Dakota Medicaid ID Number.13 • Virginia: Virginia covers the Behavioral Health Risks Screening Tool developed for pregnant and non-pregnant women of child-bearing age through the Maternal, Infant, and Early Childhood Home Visiting Program. The state provided information to practitioners on how to bill Medicaid for using the screening tool as well as what treatment services are available to women who screen positive. The Edinburgh Postnatal Depression Anxiety Subscale is used to address depressive symptoms and risk of co-occurring anxiety. Pregnant women are eligible for additional services, including case management CMCS Informational Bulletin - Page 4

during pregnancy and up to the end of the month following their 60th day post-partum. Infants are eligible for case management services up to their second birthday.14

Diagnostic and Treatment Services If a problem is identified as a result of an EPSDT screen, states have an obligation to arrange for medically necessary diagnostic and treatment services to address the child’s needs.15 Diagnostic and treatment services directed solely at the mother would be coverable under the Medicaid program only if the mother is Medicaid eligible. Mothers who are not Medicaid eligible may receive some benefit from diagnostic and treatment services directed at treating the health and well-being of the child (such as family therapy services) to reduce or treat the effects of the mother’s condition on the child. Consistent with current policy regarding services provided for the “direct benefit of the child,” such diagnostic and treatment services must actively involve the child, be directly related to the needs of the child and such treatment must be delivered to the child and mother together, but can be claimed as a direct service for the child. Such services also must be coverable under one or more section 1905(a) benefit categories such as rehabilitative services or other licensed practitioner services.

State Medicaid agencies should encourage the child’s provider to refer mothers for other appropriate care, including diagnosis, therapy and/or medication. Mothers who are Medicaid eligible should be referred to their primary care providers or other appropriate providers. Mothers who are ineligible for Medicaid, or lose their eligibility 60 days postpartum, can be referred to community resources that offer appropriate mental health services, such as community mental health programs, federally qualified health centers or other programs that may exist in the community. For example, the Substance Abuse and Mental Health Services Administration (SAMHSA) offers a behavioral health treatment service locater at https://findtreatment.samhsa.gov/. Eligibility levels for parents in state Medicaid programs vary; in states that have taken up Medicaid’s expansion of eligibility to low income adults, significantly greater number of low income mothers will be eligible and can receive comprehensive coverage than in states that have not.

The Health Resources and Services Administration (HRSA) in partnership with the Administration for Children and Families (ACF), funds states, territories and tribal entities to create home visiting evidence-based programs that improve maternal and child health, prevent child abuse and neglect, encourage positive parenting, and promote child development and school readiness. Medicaid coverage authorities offer states the flexibility to provide services in the home, which may improve care and service delivery for eligible pregnant women, parents, and young children. The majority of evidenced-based home visiting programs deliver services such as screening, case management, family support, counseling, and skills training for pregnant women and parents with young children and many of these services are also Medicaid-coverable. CMS issued an Information bulletin on March 2, 2016 describing the intersection between home visiting models and Medicaid16.

Promoting Maternal Depression Screening Under Medicaid

Generally, experience in states has shown that there is broad agreement that communication to providers about screening tools, Medicaid billing codes, referral options and other information is CMCS Informational Bulletin - Page 5 central for successful uptake and continued use.17 States and managed care plans use a variety of approaches to promote maternal depression screening among providers, including:

• Posting information about maternal depression screening on provider websites and publishing information in provider newsletters. • Delivering provider trainings to promote the use of maternal depression screening tools and proper billing codes. • Conducting in-person visits to clinics to train providers on how to implement screenings, help practices modify clinic flow, and discuss referral strategies. • Offering practitioners continuing medical education (CME) credits for participation.

States that elect to cover this service utilizing a managed care delivery system must ensure that the service is appropriately reflected in the managed care plans’ contract, and can include performance standards to ensure that the service is widely performed. Activities designed to promote maternal depression screenings among Medicaid providers and to train them on how to incorporate maternal depression screening and treatment into the EPSDT well-child visit are generally eligible for Medicaid administrative matching funds.

Conclusion Maternal depression can take a substantial toll on the health and well-being of both mothers and children, and can increase related health costs, impede the development of the child, and create negative social consequences. Maternal depression screening during the well-child visit is considered a pediatric best practice and is a simple way to identify mothers who may be suffering from depression and may lead to treatment for the child or referral for mothers to other appropriate treatment. In addition to covering this screening for Medicaid eligible mothers, states may cover maternal depression screening for non-Medicaid eligible mothers during the well-child visit. States may also cover treatment for the mother when both the child and the mother are present, treatment focuses on the effects of the mother’s condition on the child, and services are for the direct benefit of the child. States interested in learning more on this topic and to request technical assistance may contact Kirsten Jensen, Director, Division of Benefits and Coverage at [email protected].

Endnotes

1 Managing Maternal Depression Before and After Birth, American Academy of Pediatrics, October 25, 2010 Managing Maternal Depression Before and After Birth, American Academy of Pediatrics, October 25, 2010 http://pediatrics.aappublications.org/cgi/reprint/peds.2010-2348v1 2 Earls, Marian, MD. Clinical Report – Incorporating Recognition and Management of Perinatal and Postpartum Depression into Pediatric Practice, American Academy of Pediatrics, 2010 http://pediatrics.aappublications.org/content/early/2010/10/25/peds.2010-2348 3 Earls, 2010 4 Veriker, Tracey, Jennifer Macomber, and Olivia Golden, Infants of Depressed Mothers Living in Poverty: Opportunities to Identify and Serve, The Urban Institute. August 2010 5 Maternal Depression Can Undermine the Development of Young Children, Working Paper 8, Center on the Developing Child, Harvard University, December 2009. http://www.developingchild.harvard.edu. CMCS Informational Bulletin - Page 6

6 Earls, 2010 7 Center on the Developing Child, Harvard University, December 2009 8http://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal /depression-in-adults-screening1#discussion1 9 Section 1905(r) of the Social Security Act. 10 Identifying and Treating Maternal Depression: Strategies and Considerations for Health Plans, National Institute for Health Care Management Foundation, June 2010. See Table 4. http://www.nihcm.org/pdf/FINAL_MaternalDepression6-7.pdf Tools like the Edinburgh Postpartum Depression Scale and Postpartum Depression Screening Scale have been developed specifically to measure postpartum depression. As part of their recommendation to screen adults for depression in primary care settings, the USPSTF concluded that asking two simple questions, such as those included in the Patient Health Questionnaire-2, may be as effective as more formal instruments. 11 Colorado Department of Health care Policy and Financing, Provider Bulletins: Postpartum Depression Screenings and Payment in the Pediatric Primary Care Office (March 2014) and Supplement (August 2014). 12 Handbook for Providers of Healthy Kids Services: Policies and Procedures for Healthcare for Children, Illinois Department of Healthcare and Family Services, January 2015. http://hfs.illinois.gov/html/010915n.html 13 North Dakota Department of Human Services, Medical Services Division, Medicaid Coding Guideline, effective July 1, 2011, revised June 11, 2013. https://www.nd.gov/dhs 14 Reimbursement Efforts to Address Depression Among Pregnant and Postpartum Women, Colorado Department of Public Health and the Environment, November 2013. https://www.colorado.gov/pacific/sites/default/files/PF_Reimbursement-Efforts-to-Address- Depression-Among-Pregnant-and-Postpartum-Women.pdf 15 EPSDT – A Guide for States: Coverage in the Medicaid Benefit for Children and Adolescents, Center for Medicaid and CHIP Services, CMS, June 2014 https://www.medicaid.gov/medicaid- chip-program-information/by-topics/benefits/downloads/epsdt_coverage_guide.pdf 16 Coverage of Maternal, Infant, and Early Childhood Home Visiting Services. Center for Medicaid and CHIP Services, CMS, March 2016. https://www.medicaid.gov/federal-policy- guidance/downloads/CIB-03-02-16.pdf 17 Reimbursement Efforts to Address Depression Among Pregnant and Postpartum Women, Colorado Department of Public Health and the Environment, November 2013. https://www.colorado.gov/pacific/sites/default/files/PF_Reimbursement-Efforts-to-Address- Depression-Among-Pregnant-and-Postpartum-Women.pdf

141 Northwest Point Blvd November 28, 2016 Elk Grove Village, IL 60007-1019 Phone: 847/434-4000 Fax: 847/434-8000 E-mail: [email protected] www.aap.org Dear Medical Director:

The American Academy of Pediatrics (AAP), representing over 66,000

Executive Committee pediatricians, pediatric medical sub-specialists and pediatric surgical specialists dedicated to the health, safety, and well-being of infants, children, adolescents and President Benard P. Dreyer, MD, FAAP young adults, is advocating for coverage and payment for new CPT codes and modifiers that are effective January 1, 2017.The AAP urges all payers to pay for President-Elect Fernando Stein, MD, FAAP health risk assessments as a separately reported service as well as live audio and

Immediate Past President video visits between the patient and the pediatrician as the same level as payment Sandra G. Hassink, MD, FAAP for in person office visits.

Executive Director/CEO Karen Remley, MD, FAAP Since the Health Insurance Portability and Accountability Act of 1996 (HIPAA) requires that the “version of the medical data code sets specified in the Board of Directors implementation specifications must be the version that is valid at the time the District I health care is furnished,” covered entities must incorporate the new codes into Carole E. Allen, MD, FAAP Arlington, MA their claims processing systems by January 1, 2017. We want to inform you of these new codes and ascertain how your claims systems and payment edits will District II Warren M. Seigel, MD, FAAP pay on claims reporting the following: Brooklyn, NY District III Health Risk Assessment: There will be new codes on Jan. 1 for reporting David I. Bromberg, MD, FAAP administration and scoring of a patient-centered health risk assessment and a Frederick, MD caregiver-focused health risk assessment. Following is additional information on District IV Jane M. Foy, MD, FAAP the new health risk assessment CPT codes: Winston Salem, NC ●96160 Administration of patient-focused health risk assessment instrument (e.g., District V Richard H. Tuck, MD, FAAP health hazard appraisal) with scoring and documentation, per standardized Zanesville, OH instrument. District VI Pamela K. Shaw, MD, FAAP Code 96160 replaces code 99420 (administration and interpretation of health risk Kansas City, KS assessment instrument, e.g., health hazard appraisal) for administration of a District VII patient-focused health risk assessment. Anthony D. Johnson, MD, FAAP Little Rock, AR ●96161 Administration of caregiver-focused health risk assessment instrument District VIII (e.g., depression inventory) for the benefit of the patient, with scoring and Kyle Yasuda, MD, FAAP Seattle, WA documentation, per standardized instrument. Code 96161 is new for 2017 and used to report use of a standardized instrument to District IX Stuart A. Cohen, MD, FAAP screen for health risks in the caregiver for the benefit of the patient. It is intended San Diego, CA that code 96161 will be reported to the patient’s health plan as it is a service for District X the benefit of the patient. Sara H. Goza, MD, FAAP Fayetteville, GA

November 28, 2016 Page 2

In 2017 RBRVS, CMS published both codes as status ‘A’ (Active), with the RUC-recommended RVUs as follows:

CPT Status Work Non- Facility Mal- Total Total Global RVUs Facility PE Practice Non- Facility PE RVUs RVUs Facility RVUs RVUs RVUs 96160 A 0.00 0.13 NA 0.00 0.13 NA ZZZ 96161 A 0.00 0.13 NA 0.00 0.13 NA ZZZ

CMS also designated both codes as ‘add on’ codes (i.e., ZZZ global period), meaning that the resources expended in providing these services is not presently accounted for in the base code (i.e., E/M code) and, therefore, should be reported separately.

A common scenario in pediatrics is the administration and scoring of a caregiver-focused health risk assessment, such as a recommended routine maternal depression screen conducted for the benefit of the infant and, as of 1/1/2017 would be reported with CPT code 96161. CMS is on record of encouraging state Medicaid agencies to allow such screenings to be claimed as a service for the child as part of the EPSDT benefit. As per the attached CMS Informational Bulletin dated May 11, 2016, state Medicaid agencies have discretion to determine reimbursement approaches available to the pediatric provider for furnishing the maternal depression screening. “In keeping with the expert recommendations, several state Medicaid agencies have recognized the importance of the maternal depression screening and are allowing providers to perform and bill for this screening as part of the EPSDT well-child visit." The AAP calls upon private carriers to pay separately for CPT codes 96160 and 96161.

Moderate Sedation: There are a number of changes to the moderate sedation codes, their guidelines and relative values. These revisions accommodate a change in the practice of medicine and provide instruction regarding report of moderate sedation services to reflect clarification regarding how time is reported for these services. The changes include: 1) the deletion of the existing moderate sedation codes that identify one hour or thirty-minute sedation periods (99143, 99144, 99145, 99148, 99149, and 99150); 2) the addition of six new codes to identify thirty or fifteen-minute increments for sedation (99151, 99152, 99153, 99155, 99156, 99157); 3) revision of the accompanying guidelines (including time requirements) and parentheticals associated with the moderate sedation codes and 4) published relative values for moderate sedation.

The Academy urges all payers to provide appropriate payment for reported moderate sedation codes that reflect the total relative value of the service as shown in the table below.

November 28, 2016 Page 3

2017 CMS National Physician Fee Schedule Relative Value for Moderate Sedation Codes CPT Short Work Non- Facility Mal- Total Total Global code Descrptn RVUs Facility PE Practice Non- Facility PE RVUs RVUs Facility RVUs RVUs RVUs 99151 Mod sed 0.50 1.63 0.12 0.05 2.18 0.67 XXX same phys/qhp <5 yrs 99152 Mod sed 0.25 1.18 0.08 0.02 1.45 0.35 XXX same phys/qhp 5/>yrs 99153 Mod sed 0.00 0.30 0.30 0.01 0.31 0.31 ZZZ same phys/qhp ea 99155 Mod sed 1.90 0.56 0.56 0.17 2.63 2.63 XXX oth phys/qhp <5 yrs 99156 Mod sed 1.65 0.35 0.35 0.15 2.15 2.15 XXX oth phys/qhp 5/>yrs 99157 Mod sed 1.25 0.27 0.27 0.11 1.63 1.63 ZZZ other phys/qhp ea

Modifier 95: CPT 2017 introduces a new modifier used to indicate that services represented by specific CPT codes were provided via synchronous (real-time) communication using audio and video telecommunications. The telemedicine modifier 95 is appended only to specific CPT codes included in the new CPT Appendix P. Appendix P includes codes for services commonly performed by pediatricians, including ■■ New and established patient office or other outpatient evaluation and management services (99201–99205, 99212–99215) ■■ Subsequent hospital care (99231–99233) ■■ Inpatient and outpatient consultations (99241–99245, 99251–99255) ■■ Subsequent nursing facility care (99307–99310) ■■ Prolonged services in the office or outpatient setting (99354, 99355) ■■ Individual behavior change interventions (99406–99409) ■■ Transitional care management services (99495, 99496) ■■ Remote real-time interactive video-conferenced critical care codes (0188T, 0189T)

November 28, 2016 Page 4

The Academy encourages all payers to provide coverage benefits and pay appropriately for these new codes as separately reported services, apart from the evaluation and management service. In addition, carriers are urged to pay for services reported with Modifier 95 at the same level of payment as in person office visits. We request your coverage and payment policy for the above listed CPT codes and modifier.

We look forward to your response on your coverage and payment policy for these new CPT codes. If you have questions or need additional information, please contact Lou Terranova, Senior Health Policy Analyst at [email protected] or 847-434-7633.

Sincerely,

/S/

Benard P. Dreyer, MD, FAAP President

BPD/lt

Attachment: CMSC Informational Bulletin (May 11, 2016) Maternal Depression Screening and Treatment: A Critical Role for Medicaid in the Care of Mothers and Children

DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Medicare & Medicaid Services 7500 Security Boulevard, Mail Stop S2-26-12 Baltimore, MD 21244-1850

CMCS Informational Bulletin

DATE: May 11, 2016

FROM: Vikki Wachino, Director Center for Medicaid and CHIP Services

SUBJECT: Maternal Depression Screening and Treatment: A Critical Role for Medicaid in the Care of Mothers and Children

during pregnancy and up to the end of the month following their 60th day post-partum. Infants are eligible for case management services up to their second birthday.14

Promoting Maternal Depression Screening Under Medicaid

Endnotes

Overview

 On May 11, 2016, the Centers for Medicare and Medicaid Services (CMS) issued an informational bulletin on maternal depression screening and treatment, emphasizing the importance of early screening for maternal depression and clarifying the pivotal role Medicaid can play in identifying children with mothers who experience depression and its consequences, and connecting mothers and children to the help they need.

 State Medicaid agencies may cover maternal depression screening as part of a well-child visit.

 In addition to screenings, states must also cover any medically necessary treatment for the child as part of the Early and Periodic Screening, Diagnostic and Treatment (EPSDT) benefit. Additionally, treatment for maternal depression that includes both the child and the parent, such as family counseling, may also be paid for under EPSDT.

 While Medicaid programs are permitted to pay for these services, states must affirmatively act to implement coverage. States also have discretion regarding the procedures used to pay pediatricians for providing maternal depression screening services.

Why Should AAP Chapters Take Action?

 Maternal depression can have a lasting impact on a child’s health and well-being if left untreated. When parents are depressed it can negatively impact a child’s development, impede their ability to learn, and have effects that can last into adulthood.

 The Bright Futures: Guidelines for Health Supervision of Infants, Children, and Adolescents, 3rd Edition, recommends a postpartum checkup as part of well-child visits, including depression and substance use disorder screenings and maternal depression screenings as a best practice for pediatricians.

Division of State Government Affairs | 1.800.433.9016, x7799 | [email protected]

 While CMS authorization to cover maternal depression screenings under EPSDT was in place prior to issuance of the bulletin, most states have not moved forward with paying pediatricians and other physicians for this service. The bulletin serves to remind states of this option while also providing stakeholders (like AAP chapters) with needed support for related advocacy work with state Medicaid programs.

What Can States Do?

 Currently, 13 state Medicaid programs (CO, DE, IA, IL, MA, MN, ND, NV, NY, OH, SC, VA, WA) already provided coverage of maternal depression screenings. While state Medicaid agencies are not required to cover maternal depression screenings, the bulletin reiterates their ability to do so. States must affirmatively act (ie, adopt policy or rules) to provide coverage of maternal depression screenings.

 States have discretion to determine the procedures used for paying pediatricians for maternal depression screenings. For example: o North Dakota Medicaid considers maternal depression screenings a risk assessment for the child and covers it as a separate service when provided in conjunction with an EPSDT screening or any other pediatric visit. Pediatricians are instructed to bill under the child’s Medicaid ID. o Medicaid primary care physicians in Colorado are “encouraged” to screen new mothers at a well-child visit using the parent’s Medicaid ID number, but are allowed to use the child’s in instances where the mother is not enrolled;

 States are permitted to require that a specific screening tool be used in order for pediatricians to be paid. They can also limit the number of screenings allowed.

What Should Pediatric Practices Know About Providing Maternal Depression Screenings?

 As currently noted in the AAP Bright Futures and Preventive Medicine Coding Fact Sheet, CPT code 99420: administration and interpretation of health risk assessment instrument (eg, health hazard appraisal), can be used for a postpartum screening administered to a mother as part of a routine newborn check and can be billed under the child’s name.

 Beginning January 1, 2017, 99420 will be revised and an additional new code will become effective. The AAP developed a new CPT code to allow reporting of the administration of a caregiver-focused health risk assessment (eg, maternal depression inventory) for the benefit of the patient.

 The October 2016 issue of the AAP Coding Newsletter will include member education on appropriate reporting of the new codes.

 Because state laws, managed care contracts, and liability coverage policies vary, pediatricians are encouraged to explore any potential concerns with care offered to adults in the context of delivery of care to a pediatric patient.

What Can AAP Chapters Do?

 AAP chapters can reach out to state Medicaid programs and/or policy makers to advocate for maternal depression screening coverage and payment as part of EPSDT when provided during a child’s well-visit. Implementation of coverage of depression screenings should include a plan for Medicaid agencies to communicate with physicians regarding screening tools, how to bill, options for patient referrals, etc.

 Work with state medical and specialty societies, parent and family advocates, and other stakeholders in your state to support increasing access to maternal depression screenings.

 Be aware of existing community resources to help refer parents to appropriate mental health services when necessary. This will be especially important in instances when the parent is ineligible for Medicaid coverage.

Additional Resources

 AAP Clinical Report: Incorporating Recognition and Management of Perinatal and Postpartum Depression Into Pediatric Practice  CMS: Medicaid: Keeping Mom Healthy  Bright Futures  Center for Law and Social Policy: Seizing New Policy Opportunities to Help Low-Income Mothers with Depression  AAP Division of State Government Affairs

Cardiac MRI for Indications other than Congenital Heart Disease

Question: Should cardiac MRI be included for indications other than evaluation of congenital cardiac disease?

Question source: Primary Health; HERC staff

Issue: Cardiac MRI CPT codes were new codes in 2007. Placement was debated over several meetings in 2007 and 2008. Ultimately, it was decided to put cardiac MRI codes only on the congenital heart disease lines. It was felt that other indications had less expensive imaging modalities available, such as ECHO. There was also concern that the test had not been proven as a valuable test in many areas.

Cardiac MRI has become a more common and accepted test over the past decade. CMS recently changed their guidelines regarding determination of ejection fraction (EF) for qualifying for an implantable cardiac defibrillator and included cardiac MRI as one modality for determining EF. Most private insurers cover cardiac MRI for evaluation of cardiomyopathy, and for determination of EF, although some restrict to when ECHO is non-diagnostic. CCO’s are increasingly getting requests for cardiac MRIs for evaluation of cardiomyopathy. Echocardiography, in particular trans-esophageal echocardiogram (TEE), remains the generally accepted modality for the evaluation of cardiac anatomy and function most of the time by most practitioners. However, there are patients who cannot be adequately imaged with ECHO.

Expert Guidelines THE NICE 2015 (https://www.nice.org.uk/guidance/qs99/resources/secondary-prevention-after-a- myocardial-infarction-pdf-2098977438661) guideline on Secondary Prevention after MI states that “Left ventricular function can be assessed using a variety of methods, including echocardiography, cardiac magnetic resonance imaging (MRI), angiography and nuclear imaging. [Expert opinion].” The NICE 2010 (https://www.nice.org.uk/guidance/cg108/resources/chronic-heart-failure-in-adults-management-pdf- 35109335688901) guideline on management of congestive heart failure states “Consider alternative methods of imaging the heart (for example, radionuclide angiography, cardiac magnetic resonance imaging or transoesophageal Doppler 2D echocardiography) when a poor image is produced by transthoracic Doppler 2D echocardiography. [2003].”

The ACCF/ACR/AHA/NASCI/SCMR 2010 Expert Consensus Document on Cardiovascular Magnetic Resonance (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042771/pdf/nihms268875.pdf) stated that “CMR may be used for assessment of LV and RV size and morphology, systolic and diastolic function, and for characterizing myocardial tissue for the purpose of understanding the etiology of LV systolic or diastolic dysfunction.” Additionally, “CMR may be useful for identifying coronary artery anomalies and aneurysms, and for determining coronary artery patency.”

Expert input Dr. Eric Stecker: My feeling is CMR is unlikely to be abused or overused since it is probably a money loser for cardiologists and health systems. Labor intensive by tech’s and cardiologists to protocol and conduct it. It is not used as first line for EF assessment – echo is. Rarely it’s used when echo images or precision of estimate of EF are insufficient. CMR is essential to evaluate for a non- ischemic etiology of cardiomoypathies, myocardial viability when needed to guide whether to

Cardiac MRI for Indications other than Congenital Heart Disease

revascularize or not, and evaluating for risk of sudden cardiac death among patients with unexplained arrhythmias (heart block, VT, VF) or family history of a genetic disorder predisposing to hypertrophic cardiomyopathy, fibrosis or cardiomyopathy. So I think it should just be covered as a standard diagnostic test and encourage echo first line when possible. Can look later to see if people are overusing it.

Current Prioritized List Placement CPT Code Description Current Lines 75557 Cardiac magnetic resonance imaging for Congenital heart disease lines: morphology and function without contrast 44,67,70,85,86,89,90,105,106, 111, 128, material; 130, 138, 176, 186, 188, 224, 233,258, 264, 651 75559 With stress imaging Same as above 75561 Cardiac magnetic resonance imaging for Same as above morphology and function without contrast material(s), followed by contrast material(s) and further sequences; 75563 with stress imaging Same as above 75565 Cardiac magnetic resonance imaging for Same as above velocity flow mapping

HERC staff summary Cardiac MRI (CMR) has become a standard imaging modality for a variety of cardiac indications. It does not appear to have potential for overuse according to our cardiology expert.

HERC staff recommendations: 1) Remove CMR from all current lines on the Prioritized List and add to the Diagnostic Procedures File a. CPT 75557-75565 (Cardiac magnetic resonance imaging) 2) Consider adopting a new diagnostic guideline as shown below

DIAGNOSTIC GUIDELINE DX CARDIAC MAGNETIC RESONANCE IMAGING Cardiac magnetic resonance imaging (CMR) is covered only after it has been determined that echocardiogram and Doppler studies are inconclusive or expected to be nondiagnostic.

Allergy Testing for Eczema

Questions: 1) Should specific IgE testing and skin allergy testing be paired with severe eczema? 2) Should specific IgE testing and skin allergy testing continue to be paired with mild eczema?

Question sources: 1) Thermo Fisher Scientific 2) HERC staff

Issue: IgE allergy testing (a blood test to see if there are antibodies to a specific protein) and skin patch testing are currently not paired with severe eczema (also known as atopic dermatitis) on line 424 SEVERE INFLAMMATORY SKIN DISEASE. However, various types of allergy testing are paired with mild/moderate eczema on line 530 MILD ECZEMA.

Termo Fisher Scientific contacted the HERC requesting a review of IgE testing for allergic rhinitis (currently paired but below the funding line) and for children with severe eczema. They provided guidelines from the American Academy of Dermatology indicating the children with severe eczema who are not responding to optimal medical therapy should have allergy testing. They also provided information from the National Institute of Allergy and Infectious Diseases indicating that children with severe eczema should receive IgE allergy testing for peanuts prior to introducing peanuts into their diet; similarly, children with egg allergy should have IgE testing for peanuts prior to introduction. The ICD-10 code for egg allergy (Z91.012 Allergy to eggs) is currently informational.

IgE blood tests were restricted to various lines based on the 2018 CPT code review; the lines included only those that included skin allergy testing. Previously, these tests were diagnostic, were widely used and paired with a variety of diagnoses. The other diagnoses on line 424, such as psoriasis, are not generally recommended for evaluation by allergy testing.

Expert guidelines 1) American Academy of Dermatology 2014, guideline for management of atopic dermatitis a. The role of allergens in eliciting and maintaining atopic dermatitis (AD) skin lesions is complex, further complicated by challenges in determining clinical relevance and their importance relative to other factors. b. In summary, allergens may be pertinent to some AD patients but require a detailed history, careful evaluation, and correlation of allergy test results to determine clinical relevance. It is extremely rare to find 1 allergen responsible for AD, which is a complex multifactorial disease in which nonallergic factors, such as climate and secondary infection, may also be implicated. a. Recommendations: a. Atopic dermatitis patients have an increased rate of environmental and food allergies, and physicians should assess for these conditions during history taking. If significant concerns for allergy are identified (hives, urticaria, etc) assessment can be undertaken. Allergy testing independent of history is not recommended. b. Patch testing should be considered in patients with atopic dermatitis who have persistent/recalcitrant disease and/or a history or physical examination findings consistent with allergic contact dermatitis. c. Level of Evidence: II; Strength of Recommendations: B

1 Allergy Testing for Eczema

b. Children <5 years of age with moderate to severe AD should be considered for food allergy evaluation for milk, egg, peanut, wheat, and soy if at least 1 of the following is met: (A) persistent AD in spite of optimized treatment or (B) having a reliable history of immediate reaction after ingestion of a specific food. (no level of evidence specified)

2) NICE 2007, guideline for diagnosis and treatment of eczema in children under 12 https://www.nice.org.uk/guidance/cg57/resources/atopic-eczema-in-under-12s-diagnosis-and- management-pdf-975512529349 a. Healthcare professionals should consider a diagnosis of food allergy in children with atopic eczema who have reacted previously to a food with immediate symptoms, or in infants and young children with moderate or severe atopic eczema that has not been controlled by optimum management, particularly if associated with gut dysmotility (colic, vomiting, altered bowel habit) or failure to thrive. b. Healthcare professionals should consider a diagnosis of inhalant allergy in children with seasonal flares of atopic eczema, children with atopic eczema associated with asthma or allergic rhinitis, and children aged 3 years or over with atopic eczema on the face, particularly around the eyes. c. Healthcare professionals should consider a diagnosis of allergic contact dermatitis in children with an exacerbation of previously controlled atopic eczema or with reactions to topical treatments. d. Healthcare professionals should reassure children with mild atopic eczema and their parents or carers that most children with mild atopic eczema do not need to have testing

3) NIAID 2017, guidelines for the prevention of peanut allergy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217343/ a. Expert consensus guideline i. Infants with severe eczema, egg allergy, or both: Strongly consider evaluation by IgE measurement of peanut antibody and/or skin prick test and, if necessary, an oral food challenge. Based on test results, introduce peanut-containing foods. ii. Quality of evidence noted to be moderate, with significant contribution of expert input

Expert Input Dr. Tracy Funke, OHSU Dermatology Allergy testing is not a routine part of eczema work-up or management. Allergy testing is unreliable in infants and can lead to food restriction based on false positives. It is also now recommended that infants with mild-moderate atopic dermatitis introduce peanut and egg into their diet between 4-6 months of age and that is where I focus my efforts in an attempt to reduce food allergy development. I find that the vast majority of infants fall into the mild- moderate eczema category and that very few really have severe atopic dermatitis by 6 months of age. I do not think that allergy testing should be a routine part of atopic dermatitis work-up or management and should be used only in select patients with allergy-specific symptoms (hives, etc).

Allergy Testing for Eczema

Dr Julie Dhossche, OHSU Dermatology …we do not routinely do any kind of allergy testing (blood, prick or patch) in patients with eczema/atopic dermatitis. I would say in adults more often than kids we do consider patch testing (which we do in dermatology clinic) in those with persistent/worsening/changing disease to tease out any component of allergic contact dermatitis which may be contributing to their rash.

HERC staff summary Allergy testing (either IgE blood testing or skin patch testing) is recommended by expert groups for patients with severe eczema with no or minimal improvement with optimal medical therapy or with concurrent hives or urticaria, or for infants with severe eczema prior to introducing peanuts. However, it does not appear to be common practice in Oregon and is not recommended by local dermatology experts except in situations where a patient has other signs of allergy (hives, etc.). It does not appear to have strong support for use in evaluation of patients with mild eczema, and NICE recommends against such testing for mild eczema.

Currently, allergy testing is paired with mild eczema but not severe eczema. There are multiple diagnoses on the line with severe eczema that are not appropriate for pairing; therefore, if allergy testing is added to this covered line then a guideline would need to be added to limit use to appropriate diagnoses.

HERC staff recommendations: 1) Remove allergy testing from line 530 MILD ECZEMA as NICE and expert groups do not recommend such testing for mild eczema a. CPT 86003 AND 86008 (Allergen specific IgE) b. CPT 86486, 95004, 95018, 95024-95028, 95044, 95052, 95056, 95060, 95065, 95070- 95071, 95076, 95079 (Allergy testing, skin, mucous membrane, inhalation) c. CPT 95115-95134 (Professional services for allergen immunotherapy) d. CPT 95144-95170 (Professional services for the supervision of preparation and provision of antigen) e. CPT 95180 (Rapid desensitization procedure) 2) Do not add IgE and skin patch testing for allergens to line 424 SEVERE INFLAMMATORY SKIN DISEASE a. Not recommended by local experts b. If patients have severe eczema that is affected by hives or another below the line diagnoses, the allergy testing can be done via pairing the allergy testing with the diagnoses of hives and using the comorbidity rule

FROM THE ACADEMY

Guidelines of care for the management of atopic dermatitis

Section 4. Prevention of disease ﬂares and use of adjunctive therapies and approaches

Work Group: Robert Sidbury, MD (Co-chair),a WynnisL.Tom,MD,b James N. Bergman, MD,c KevinD.Cooper,MD,d Robert A. Silverman, MD,e Timothy G. Berger, MD,f SarahL.Chamlin,MD,MSCI,g DavidE.Cohen,MD,h Kelly M. Cordoro, MD,f Dawn M. Davis, MD,i StevenR.Feldman,MD,PhD,j JonM.Hanifin,MD,k Alfons Krol, MD,k David J. Margolis, MD, PhD,l Amy S. Paller, MD,g Kathryn Schwarzenberger, MD,m Eric L. Simpson, MD,k Hywel C. Williams, DSc,n Craig A. Elmets, MD,o Julie Block, BA,p Christopher G. Harrod, MS,q Wendy Smith Begolka, MBS,q and Lawrence F. Eichenfield, MD (Co-chair)b Seattle, Washington; San Diego, San Francisco, and San Rafael, California; Vancouver, British Columbia, Canada; Cleveland, Ohio; Fairfax, Virginia; Chicago and Schaumburg, Illinois; New York, New York; Rochester, Minnesota; Winston-Salem, North Carolina; Portland, Oregon; Philadelphia, Pennsylvania; Memphis, Tennessee; Nottingham, United Kingdom; and Birmingham, Alabama

Atopic dermatitis is a common, chronic inflammatory dermatosis that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this final section, treatments for flare prevention and adjunctive and complementary therapies and approaches are reviewed. Suggestions on use are given based on available evidence. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2014.08.038.)

Key words: aeroallergens; allergy testing; atopic dermatitis; calcineurin inhibitors; complementary therapy; corticosteroids; diet; education; ﬂare; food allergy; topicals.

DISCLAIMER specific therapy must be made by the physician and Adherence to these guidelines will not ensure the patient in light of all the circumstances presented successful treatment in every situation. Furthermore, by the individual patient, and the known variability these guidelines should not be interpreted as setting a and biologic behavior of the disease. This guideline standard of care or be deemed inclusive of all proper reflects the best available data at the time the guideline methods of care nor exclusive of other methods of was prepared. The results of future studies may care reasonably directed to obtaining the same results. require revisions to the recommendations in this The ultimate judgment regarding the propriety of any guideline to reflect new data.

From the Department of Dermatology,a Seattle Children’s Nottingham University Hospitals National Health Service Trust, Hospital; University of California, San Diego and Division of Nottingham; Department of Dermatology,o University of Ala- Pediatric and Adolescent Dermatology,b Rady Children’s bama at Birmingham; National Eczema Association,p San Rafael; Hospital, San Diego; Department of Dermatology and Skin and the American Academy of Dermatology,q Schaumburg. Science,c University of British Columbia, Vancouver; Depart- Funding sources: None. ment of Dermatology,d Case Western University; private The management of conflict of interest for this guideline series practice,e Fairfax; Department of Dermatology,f University of complies with the Council of Medical Specialty Societies’ Code California San Francisco; Department of Dermatology,g North- of Interactions with Companies. The authors’ conflict of inter- western University Feinberg School of Medicine, Chicago; est/disclosure statements appear at the end of this article. Department of Dermatology,h New York University School of Accepted for publication August 22, 2014. Medicine; Department of Dermatology,i Mayo Clinic, Rochester; Reprint requests: Wendy Smith Begolka, MBS, American Academy Department of Dermatology,j Wake Forest University Health of Dermatology, 930 E Woodfield Rd, Schaumburg, IL 60173. Sciences, Winston-Salem; Department of Dermatology,k E-mail: [email protected]. Oregon Health & Science University, Portland; Department of Published online September 25, 2014. Biostatistics and Epidemiology,l University of Pennsylvania 0190-9622/$36.00 School of Medicine, Philadelphia; Kaplan-Amonette Depart- Ó 2014 by the American Academy of Dermatology, Inc. ment of Dermatology,m University of Tennessee Health Science http://dx.doi.org/10.1016/j.jaad.2014.08.038 Center, Memphis; Centre of Evidence-Based Dermatology,n

1 MRI Guided Focused Ultrasound for Treatment of Essential Tremor

Question: Should MRI guided focused ultrasound (MRgFUS) be paired with essential tremor?

Question source: Insightec

Issue: MRgFUS (CPT 0398T) is a non-invasive treatment alternative to deep brain stimulation for treatment of essential tremor that does not respond to medical therapy. Of note, deep brain stimulation is currently not paired with essential tremor on the Prioritized List.

Essential tremor is the most common cause of disabling tremor and is distinct from Parkinson's disease. It typically affects the arms and hands, although it may also involve the head, jaw, tongue and legs. Treatment for essential tremor includes medications such as beta blockers (for example, propranolol), anti-epileptics (for example, primidone) or sedatives (for example, clonazepam). Rarely, injections of botulinum toxin may be used. Surgery may be considered in people whose condition has not responded adequately to best medical therapy. Surgical treatments include deep brain stimulation and radiofrequency thalamotomy.

MRgFUS uses high-power focused ultrasound to irreversibly ablate target tissue that is causing the tremor. The potential benefits of unilateral MRI-guided focused ultrasound thalamotomy are that it: is less invasive than the other existing procedures; results in a faster recovery time; and allows for testing of the effects of sublethal doses before ablation. However, it is only done on 1 side.

Current Prioritized List status: ICD-10 G25.0 (Essential tremor) is on line 362 DYSTONIA (UNCONTROLLABLE); LARYNGEAL SPASM CPT 0398T is not currently in the HERC database as this type of code is generally not reviewed

From Insightec: National Government Services, the Medicare Administrative Contractor covering the States of NY, CT, RI, MA, ME, WI, IL, NH, VT, and MN has deemed MRI Guided Focused Ultrasound (CPT 0398T) to be medically reasonable and necessary to treat patients suffering from essential tremor (ICD-10: G25.0), and is a covered benefit for Medicare beneficiaries as of 4/1/2018…The Medicare Administrative Contractors for the States of OR, KT, OH, AL, GA, TN, NC, SC, VA, WV, CA, HI, NV, AK, AZ, ID, MT, ND, SD, UT, WA, WY, and US Commonwealth and Territories of American Samoa, Guam, Northern Mariana Islands also approved MRI Guided Focused Ultrasound for essential tremor as medically reasonable and necessary, currently in draft phase with an anticipated effective date for coverage of 11/2018…The covered treatment for individuals with essential tremor who are also non-responsive to medication therapy is Deep Brain Stimulation. This treatment is effective and appropriate in certain situations, however it is extremely invasive with a lower safety profile, requires follow up surgeries every few years to replace the batteries and/or to move the wiring, is expensive due to the hardware and inpatient hospital stay, recovery can be lengthy, and puts the patient at risk for infection, stroke and other complications. Alternatively, MRI Guided Focused Ultrasound is an outpatient procedure and the patient is in-and-out on the same day and this should be at minimum, an option for a physician and patient to choose if they feel that is the most patient centered, individualized and preferred course of treatment.

MRI Guided Focused Ultrasound for Treatment of Essential Tremor

Evidence 1) NICE 2018: Unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor a. The evidence on the safety of unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor raises no major safety concerns. However, current evidence on its efficacy is limited in quantity. Therefore, this procedure should not be used unless there are special arrangements for clinical governance, consent, and audit or research. b. The NICE evidence review found 11 articles on MRgUS for essential tremor: 1 systematic review, 1 randomised controlled trial (2 publications providing 1- and 2-year follow-up data), 2 non-randomised comparative studies and 6 case series 2) Ravikumar 2017, systematic review of MRgUS for essential tremor a. Data was obtained on 83 magnetic resonance-guided focused ultrasound thalamotomies b. Magnetic resonance-guided focused ultrasound thalamotomy resulted in significantly higher utility scores compared with deep brain stimulation (DBS; P < 0.001) or stereotactic radiosurgery (P < 0.001). Projected costs of magnetic resonance-guided focused ultrasound thalamotomy were significantly less than DBS (P < 0.001), but not significantly different from radiosurgery. c. Conclusions: Magnetic resonance-guided focused ultrasound thalamotomy is cost- effective for tremor compared with DBS and stereotactic radiosurgery and more effective than both. 3) Elias 2016, RCT of MRgUS for essential tremor a. N=76 patients b. Randomized to MRgUS vs sham procedure c. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort) as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively. d. CONCLUSIONS MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. .

MRI Guided Focused Ultrasound for Treatment of Essential Tremor

HERC staff summary: MRgUS is a promising but experimental procedure for treating essential tremor. To date, approximately 83 patients have had this procedure reported in the literature. NICE considers this procedure experimental. Alternative surgeries are currently not paired with essential tremor on the Prioritized List. Medications to treat essential tremor are available.

HERC staff recommendation: 1) Add CPT 0398T (MRgFUS) to line 660 2) Add the following entry to GN173

GUIDELINE NOTE 173, TREATMENTS THAT HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS FOR CERTAIN CONDITIONS; UNPROVEN TREATMENTS

The following treatments are prioritized on Line 660, CONDITIONS FOR WHICH CERTAIN TREATMENTS HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS; UNPROVEN TREATMENTS, for the conditions listed here:

CPT/HCPCS Code TREATMENT Rational Date of Last Review/Link to Meeting Minutes O398T MRI guided focused Insufficient October, 2018 ultrasound for the evidence of treatment of essential effectiveness tremor

MRI Guided Focused Ultrasound for Treatment of Essential Tremor

Disposition of manufacturer provided literature 1) CMS and private insurer policies—not medical literature 2) Chang 2018—follow up of study included in systematic reviews 3) Kim 2017—retrospective cohort study; high quality studies available 4) Langford 2018—only included trial with MRgUS was the Elias trial, which was already included in the literature review 5) Fishman 2017—clinical review 6) Fishman 2018—safety data only

Unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor

Interventional procedures guidance Published: 20 June 2018 nice.org.uk/guidance/ipg617

Your responsibility

This guidance represents the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, healthcare professionals are expected to take this guidance fully into account. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.

Commissioners and/or providers have a responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity, and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.

Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible.

1 Recommendations

1.1 The evidence on the safety of unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor raises no major safety concerns. However, current evidence on its efficacy is limited in quantity.

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Therefore, this procedure should not be used unless there are special arrangements for clinical governance, consent, and audit or research.

1.2 Clinicians wishing to do unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor should:

Inform the clinical governance leads in their NHS trusts.

Ensure that patients and their carers understand that this procedure is only done to treat tremor on 1 side of the body, and that the effect of this on the functional ability and quality of life of patients with bilateral disease is uncertain. Patients should be informed about alternative treatments, including those that can be done bilaterally. Provide patients with clear written information to support shared decision-making. In addition, the use of NICE's information for the public is recommended.

Audit and review clinical outcomes of all patients having unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).

1.3 Patient selection should be done by a multidisciplinary team experienced in managing essential tremor, including clinicians with specific training in the procedure.

1.4 Further research, which could include randomised controlled trials, should address patient selection, report on functional improvement and quality of life, and provide long-term follow-up data.

2 The condition, current treatments and procedure

The condition

2.1 Essential tremor is the most common cause of disabling tremor and is distinct from Parkinson's disease. It typically affects the arms and hands, although it may also involve the head, jaw, tongue and legs. The cause is not known but many patients have a family history of the condition. At first, the tremor may not be present all the time. However, it gradually worsens. Purposeful movement, stress, tiredness, hunger, heightened emotions or extremes in temperature make it worse.

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Current treatments

2.2 Treatment for essential tremor includes medications such as beta blockers (for example, propranolol), anti-epileptics (for example, primidone) or sedatives (for example, clonazepam). Rarely, injections of botulinum toxin may be used.

2.3 Surgery may be considered in people whose condition has not responded adequately to best medical therapy. Surgical treatments include deep brain stimulation and radiofrequency thalamotomy.

The procedure

2.4 This procedure is carried out with the patient lying supine inside an MRI scanner. The patient's head is shaved and a stereotactic head frame is attached. Patients are kept awake so they can report any improvement or adverse events to the operator during the procedure. However, they may be offered light sedation. Continuous MRI and thermal mapping are used to identify the target area of the brain and monitor treatment. Low power (sub-lethal) ultrasound is delivered to confirm the chosen location. Then, high-power focused ultrasound pulses are administered to irreversibly ablate target tissue. Chilled water is circulated around the head during the treatment to prevent thermal damage to the scalp caused by the increase in bone temperature. The procedure takes about 3 hours and symptom relief should be immediate.

2.5 The potential benefits of unilateral MRI-guided focused ultrasound thalamotomy are that it: is less invasive than the other existing procedures; results in a faster recovery time; and allows for testing of the effects of sublethal doses before ablation. However, it is only done on 1 side.

3 Committee considerations

The evidence

3.1 To inform the committee, NICE did a rapid review of the published literature on the efficacy and safety of this procedure. This comprised a comprehensive literature search and detailed review of the evidence from 11 sources, which was discussed by the committee. The evidence included 1 systematic review, 1 randomised controlled trial (2 publications providing 1- and 2-year follow-up

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data), 2 non-randomised comparative studies and 6 case series, and is presented in table 2 of the interventional procedures overview. Other relevant literature is in the appendix of the overview.

3.2 The specialist advisers and the committee considered the key efficacy outcomes to be: sustained reduction in tremor, improved quality of life and functional improvement.

3.3 The specialist advisers and the committee considered the key safety outcomes to be: unintentional neurological consequences and intracerebral bleeding.

3.4 No patient commentary was sought because this procedure is currently only done in research in the UK.

Committee comments

3.5 The committee noted that essential tremor can have major consequences on the quality of life for many people.

3.6 This procedure is an alternative to more invasive methods used to lesion the thalamus. The lesion produced is permanent.

3.7 While this procedure does not preclude subsequent treatments for essential tremor (such as deep brain stimulation), the effects on those subsequent treatments are unknown.

3.8 There is a comprehensive training programme offered by the company manufacturing the device used in this procedure.

ISBN: 978-1-4731-2834-7

Endorsing organisation

This guidance has been endorsed by Healthcare Improvement Scotland.

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Accreditation

Cost-Effectiveness of Focused Ultrasound, Radiosurgery, and DBS for Essential Tremor

Vinod K. Ravikumar, BS,1 Jonathon J. Parker, MD, PhD,1 Traci S. Hornbeck, PA,1 Veronica E. Santini, MD,2 Kim Butts Pauly, PhD,3 Max Wintermark, MD,3 Pejman Ghanouni, MD, PhD,3 Sherman C. Stein, MD,4 and Casey H. Halpern, MD1*

1Department of Neurosurgery, Stanford, California, USA 2Department of Neurology, Stanford, California, USA 3Department of Radiology, Stanford University, Stanford, California, USA 4Department of Neurosurgery, University of Pennsylvania, Philadelphia Pennsylvania, USA

ABSTRACT: Background: Essential tremor equivalent to stereotactic radiosurgery to assess a cost remains a very common yet medically refractory condi- threshold. A decision analysis model was constructed tion. A recent phase 3 study demonstrated that mag- to examine the most cost-effective option for essential netic resonance-guided focused ultrasound tremor, implementing meta-analytic techniques. thalamotomy significantly improved upper limb tremor. Results: Magnetic resonance-guided focused ultra- The objectives of this study were to assess this novel sound thalamotomy resulted in significantly higher utility therapy’s cost-effectiveness compared with existing scores compared with DBS (P < 0.001) or stereotactic procedural options. radiosurgery (P < 0.001). Projected costs of magnetic Methods: Literature searches of magnetic resonance- resonance-guided focused ultrasound thalamotomy guided focused ultrasound thalamotomy, DBS, and ste- were significantly less than DBS (P < 0.001), but not reotactic radiosurgery for essential tremor were per- significantly different from radiosurgery. formed. Pre- and postoperative tremor-related disability Conclusions: Magnetic resonance-guided focused scores were collected from 32 studies involving 83 ultrasound thalamotomy is cost-effective for tremor magnetic resonance-guided focused ultrasound thala- compared with DBS and stereotactic radiosurgery and motomies, 615 DBSs, and 260 stereotactic radiosurgery more effective than both. Even if longer follow-up finds cases. Utility, defined as quality of life and derived from changes in effectiveness or costs, focused ultrasound percent change in functional disability, was calculated; thalamotomy will likely remain competitive with both Medicare reimbursement was employed as a proxy for alternatives. VC 2017 International Parkinson and Move- societal cost. Medicare reimbursement rates are not ment Disorder Society established for magnetic resonance-guided focused ultrasound thalamotomy for essential tremor; therefore, Key Words: essential tremor; focused ultrasound; reimbursements were estimated to be approximately radiosurgery; deep brain stimulation; cost-effectiveness

Essential tremor (ET) affects approximately 15% of ------1 *Correspondence to: Casey H. Halpern, MD, Department of Neurosur- elderly individuals. Nearly 60% of ET patients are gery, Stanford University, 300 Pasteur Drive (A301), Stanford, CA 94305; refractory to pharmacologic therapy and thus suffer [email protected] significant diminution of quality of life.2 It is these Vinod K. Ravikumar and Jonathon J. Parker are co–first authors. patients who require procedural intervention.3,4 Deep Funding agencies: This study received Halpern Laboratory startup fund- brain stimulation (DBS) targeting the ventrointermedi- ing from the Department of Neurosurgery, Stanford University (to C.H.H.). ate nucleus of the thalamus is currently the interven- Relevant conflicts of interest/financial disclosures: The authors have no conflicts of interest or financial disclosures to disclose regarding this tion of choice for stereotactic neurosurgeons because study. of its proven efficacy, reversibility, adjustability, and 5,6 Received: 21 September 2016; Revised: 22 February 2017; Accepted: durability. Surgical thalamotomy may be compara- 5 March 2017 bly efficacious, but it has been reported to have a sig-

Published online 00 Month 2017 in Wiley Online Library niﬁcantly higher complication rate, making DBS a 7-9 (wileyonlinelibrary.com). DOI: 10.1002/mds.26997 superior option in general. Nevertheless, there are

Movement Disorders, Vol. 00, No. 00, 2017 1 The new england journal of medicine

Original Article

A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor

W. Jeffrey Elias, M.D., Nir Lipsman, M.D., Ph.D., William G. Ondo, M.D., Pejman Ghanouni, M.D., Ph.D., Young G. Kim, M.D., Ph.D., Wonhee Lee, M.D., Ph.D., Michael Schwartz, M.D., Kullervo Hynynen, Ph.D., Andres M. Lozano, M.D., Binit B. Shah, M.D., Diane Huss, D.P.T., N.C.S., Robert F. Dallapiazza, M.D., Ph.D., Ryder Gwinn, M.D., Jennifer Witt, M.D., Susie Ro, M.D., Howard M. Eisenberg, M.D., Ph.D., Paul S. Fishman, M.D., Ph.D., Dheeraj Gandhi, M.D., M.B., B.S., Casey H. Halpern, M.D., Rosalind Chuang, M.D., Kim Butts Pauly, Ph.D., Travis S. Tierney, M.D., Ph.D., Michael T. Hayes, M.D., G. Rees Cosgrove, M.D., Toshio Yamaguchi, M.D., Ph.D., Keiichi Abe, M.D., Takaomi Taira, M.D., Ph.D., and Jin W. Chang, M.D., Ph.D.

ABSTRACT

BACKGROUND From the University of Virginia Health Uncontrolled pilot studies have suggested the efficacy of focused ultrasound Sciences Center, Charlottesville (W.J.E., thalamotomy with magnetic resonance imaging (MRI) guidance for the treatment B.B.S., D.H., R.F.D.); Toronto Western Hospital (N.L., A.M.L.) and Sunnybrook of essential tremor. Health Sciences Centre (M.S., K.H.), To- METHODS ronto; Methodist Neurological Institute, Houston (W.G.O.); Stanford University We enrolled patients with moderate-to-severe essential tremor that had not respond- School of Medicine, Stanford, CA (P.G., ed to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio C.H.H., K.B.P.); Yonsei University Col- to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The lege of Medicine, Seoul, South Korea (Y.G.K., W.L., J.W.C.); Swedish Neurosci- Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Ques- ence Institute, Seattle (R.G., J.W., S.R., tionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor as- R.C.); University of Maryland School of sessments were videotaped and rated by an independent group of neurologists who Medicine, Baltimore (H.M.E., P.S.F., D.G.); University of Miami School of were unaware of the treatment assignments. The primary outcome was the between- Medicine, Nicklaus Children’s Hospital, group difference in the change from baseline to 3 months in hand tremor, rated on Miami (T.S.T.); Brigham and Women’s a 32-point scale (with higher scores indicating more severe tremor). After 3 months, Hospital, Boston (M.T.H., G.R.C.); and Shin-yurigaoka General Hospital, Kawa- patients in the sham-procedure group could cross over to active treatment (the open- saki (T.Y.), and Tokyo Women’s Medical label extension cohort). University, Tokyo (K.A., T.T.) — both in RESULTS Japan. Address reprint requests to Dr. Elias at the Department of Neurological Seventy-six patients were included in the analysis. Hand-tremor scores improved Surgery, University of Virginia, Box more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 800212, Charlottesville, VA 22908, or at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between- ksh5m@virginia.edu. group difference in the mean change was 8.3 points (95% confidence interval [CI], N Engl J Med 2016;375:730-9. 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained DOI: 10.1056/NEJMoa1600159 Copyright © 2016 Massachusetts Medical Society. at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively. CONCLUSIONS MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.)

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ssential tremor, the most common acoustic energy was delivered. The primary study movement disorder,1 is characterized by a end point was the change in tremor from baseline Edistinctive postural and intention tremor to 3 months, analyzed on the basis of videotaped typically affecting the hands more than the legs, assessments. After 3 months, patients in the sham- trunk, head, or voice.2,3 Essential tremor does not procedure group could cross over to active treat- shorten life expectancy, but it can affect quality ment (Fig. S2 in the Supplementary Appendix). of life, functional activities, mood, and social- Representatives of the manufacturer of the ization.4-6 focused ultrasound system used in the study A Quick Take Class I evidence exists for propranolol and (InSightec) provided study oversight and techni- is available at primidone as first-line medications that reduce cal support and obtained national regulatory per- NEJM.org tremor by approximately 60% in 50% of patients.7-11 missions. Independent institutional approval of If resistance to medications develops or side ef- the study was obtained by the research team at fects are unacceptable, neurosurgical intervention each participating center, and all patients gave is considered, primarily targeting the nucleus ven- written informed consent. Clinical oversight of the tralis intermedius of the thalamus, a component trial was provided by the principal investigator and of tremor circuitry that connects the cerebellum an independent data and safety monitoring board. with cortical motor pathways. Two surgical thera- The authors vouch for the veracity and complete- pies, radiofrequency thalamotomy and deep-brain ness of the data and data analyses. The first au- stimulation, effectively suppress tremor,2-16 but thor wrote the first draft of the manuscript, and relatively few patients choose surgery because of all authors made the decision to submit the manu- perceived invasiveness from the burr holes and script for publication. The study was conducted intracerebral electrodes. with fidelity to the study protocol, which is avail- The use of ultrasound energy for the creation able at NEJM.org. of discrete intracranial lesions (hereafter referred to as lesioning) has been of interest since the Patients middle of the 20th century.17 Initial procedures Patients with essential tremor, diagnosed by a required craniotomy to establish an acoustic win- neurologist specializing in movement disorders, dow for the treatment of movement disorders were enrolled on the basis of eligibility criteria that and psychiatric conditions.18,19 The subsequent have been described previously.24 Briefly, patients introduction of phased-array transducers20 elim- were eligible if they had a postural or intention inated the need for a craniotomy, and high-res- tremor of the hand that was moderate to severe olution imaging21,22 allows real-time, image-guid- (defined by a score of ≥2 on the Clinical Rating ed lesioning (see Fig. S1 in the Supplementary Scale for Tremor26 [CRST; scores range from 0 to Appendix, available with the full text of this ar- 4 per component assessed and higher scores indi- ticle at NEJM.org). Prospective pilot trials of fo- cate more severe tremor]) and disabling (defined cused ultrasound thalamotomy with magnetic by a score of ≥2 on any of the eight items in the resonance imaging (MRI) guidance in patients disability subsection of the CRST [scores range with essential tremor have shown reductions in from 0 to 4 per item, and higher scores indicate hand tremor, improvements in quality of life, and greater disability]). Additional eligibility criteria minimal procedural morbidity.23-25 Here we describe were tremor that was refractory to at least two the results of a prospective, sham-controlled trial trials of medical therapy, including at least one of MRI-guided focused ultrasound thalamotomy first-line agent (propranolol or primidone). For for the treatment of medication-refractory essen- patients receiving concurrent medical therapy, tial tremor. medication doses had to be stable for 30 days before randomization. Patients were excluded if Methods they had a neurodegenerative condition, unstable cardiac disease, coagulopathy, risk factors for Trial Design and Oversight deep-vein thrombosis, severe depression (defined In this double-blind trial conducted at eight inter- by a score ≥20 on Patient Health Questionnaire national centers, we randomly assigned patients 9 [scores range from 0 to 27, with higher scores in a 3:1 ratio to undergo focused ultrasound indicating more severe depression]), or cognitive thalamotomy or a sham procedure in which no impairment (defined by a score of <24 on the

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Mini–Mental State Examination [scores range from ations were videotaped for primary analysis by 0 to 30, with lower values indicating greater im- an independent core group of neurologists (Trem- pairment]) or if they had undergone a previous or Research Group) at baseline and at 1, 3, 6, and brain procedure (transcranial magnetic stimula- 12 months after treatment. tion, deep-brain stimulation, stereotactic lesioning, The primary efficacy outcome measure was or electroconvulsive therapy). A skull density ratio defined as the change from baseline to 3 months (the ratio of cortical to cancellous bone) of 0.45 in the tremor score for the hand in the thalamot- or more was required from the screening com- omy group as compared with the sham-procedure puted tomographic (CT) scan. group. The tremor score (on a scale ranging from From August 2013 through September 2014, 0 to 32, with higher scores indicating more se- we enrolled 81 patients and randomly assigned vere tremor) was derived from the CRST, Part A them to a study group. Five of these patients were (three items: resting, postural, and action or inten- excluded before undergoing the assigned proce- tion components of hand tremor), and the CRST, dure because they met exclusionary criteria, as Part B (five tasks involving handwriting, drawing, detailed in Figure S2 in the Supplementary Ap- and pouring), in the hand contralateral to the pendix. As predefined in the protocol and statis- thalamotomy. tical analysis plan, only the 76 patients in whom The three prespecified secondary efficacy mea- the study procedure was attempted or completed sures were functional limitations in daily activities, were included in the modified intention-to-treat measured according to eight items in the disabil- analysis. ity subsection of the CRST (maximum overall score, 32; higher scores indicate greater disabil- Focused Ultrasound Thalamotomy ity); quality of life, assessed with the QUEST at The details of focused ultrasound thalamotomy 3 months; and the durability of the reduction in have been described previously.23-25 Briefly, patients hand tremor at 12 months. We also performed a were placed in a stereotactic head frame that was post hoc analysis of total tremor scores (maximum coupled to an MRI-compatible ultrasound trans- overall score for the most severe tremor, 152 points ducer. After stereotactic targeting with the use without supine assessments). Safety was assessed of MRI, acoustic energy was sequentially titrated throughout the study on the basis of reported ad- to temperatures sufficient for tissue ablation (ap- verse events. MRI was performed immediately af- proximately 55 to 60°C). Each brief sonication ter the study procedure and at 12 months. was monitored with magnetic resonance ther- mometry, and the patient was clinically assessed Blinding for tremor reduction and adverse effects (for de- The study participants and the neurologist at each tails, see the description in the Supplementary site were unaware of the treatment assignments Appendix). throughout the first 3 months, and the primary For patients randomly assigned to undergo a assessors of the videotaped tremor evaluations sham procedure, an identical procedure was per- were not involved in the study treatments and formed with a randomized number of sonications were unaware of the treatment assignments and for which the acoustic power was disengaged so the side that was treated (left vs. right). Since the that no acoustic energy was delivered to the brain. patients’ heads were not covered, the assessors Only the treatment team was aware of the group could see whether the videotapes showed preop- assignments; patients and assessors were unaware erative or postoperative tremor evaluations; how- of the assignments. ever, they could not determine whether the videotapes were taken 1, 3, 6, or 12 months after Outcome Assessments treatment. Tremor assessments, based on the CRST,26 were performed at each site by a movement-disorder Statistical Analysis specialist, and functional status was determined We calculated the sample size from pilot-study on the basis of the rating for the disability sub- observations, accounting for a potential dropout section (Part C) of the CRST, as well as the disease- rate of 20%. The null hypothesis was that thala- specific, self-reported Quality of Life in Essential motomy would be either the same as or inferior Tremor Questionnaire (QUEST).27 Tremor evalu- to the sham procedure with respect to the per-

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centage improvement in the primary end point. Table 1. Baseline Demographic and Clinical Characteristics of the Study The alternative hypothesis was that thalamotomy Participants.* would be superior to the sham procedure. Given a sample of at least 60 patients, the study had FUS Thalamotomy Sham Procedure Characteristic (N = 56) (N = 20) almost 100% power to show the primary efficacy of thalamotomy, assuming, on the basis of his- Age — yr 70.8±8.7 71.4±7.3 torical results, average improvements of 78% and BMI† 26.9 27.9 4% in the thalamotomy and sham-procedure Male sex — no. (%) 37 (66) 15 (75) groups, respectively (standard deviation, 25%). Race or ethnic group — no. (%)‡ Power calculations were performed with the use White 41 (73) 16 (80) of an independent-groups t-test, with a random- Black 0 0 ization ratio of 3:1 for assignment to thalamotomy versus the sham procedure. The probability Asian 14 (25) 4 (20) of detecting an adverse event rate of 1% was 0.45, Hispanic 0 0 and the probability of a 5% rate was 0.95. The Other 1 (2) 0 statistical analysis was planned and conducted Disease duration — yr with the assistance of the biostatistics team at From initial symptoms 28.3±16.4 27.9±14.9 TechnoSTAT. The statistical analysis plan (see the From initial diagnosis 16.4±13.1 17.8±10.2 study protocol) was approved by the Food and Drug Administration (FDA). From start of medical therapy 13.9±10.7 14.7±10.5 We used a hierarchical testing design to con- Tremor score§ trol for multiple comparisons across the one Hand 18.1±4.8 16.0±4.4 primary and three prespecified secondary end Overall 50.1±14.0 44.1±12.7 points. The primary efficacy analysis was confirmed at an alpha level of 0.05, and then each * Plus–minus values are means ±SD. There were no significant differences in baseline characteristics between the two study groups. FUS denotes focused of the three secondary efficacy end points was ultrasound. tested at an alpha level of 0.05. No confirmatory † The body-mass index (BMI) is the weight in kilograms divided by the square statements were made about other end points. of the height in meters. ‡ Race or ethnic group was determined by the investigator. Thus, type 1 error was controlled across all end § The tremor score was derived from the Clinical Rating Scale for Tremor, which points tested in this study. ranges from 0 to 32 for tremor in the hand and from 0 to 152 overall. In this A sensitivity analysis with multiple imputation study, the hand tremor was measured in the hand contralateral to the thalamotomy. was planned, but in the primary analysis, only two patients had missing data. Since worst-case and best-case scenarios yielded such similar results, The mean total CRST score for tremor severity additional imputation was not carried out. A sec- was 49.5 (highest possible score, 152). Baseline ond sensitivity analysis, performed because five tremor and demographic characteristics did not patients were found to meet exclusion criteria after differ significantly between the randomized randomization, confirmed that their exclusion groups (Table 1). had no effect on the results of the primary outcome analysis (see the Supplementary Appendix). Tremor The data reported here were locked on Septem- The mean score for hand tremor (highest pos- ber 17, 2015, and the report was finalized on Oc- sible score, 32) improved by 47% at 3 months tober 14, 2015. (from 18.1±4.8 to 9.6±5.1) in the thalamotomy group and by 0.1% in the sham-procedure group Results (from 16.0±4.4 to 15.8±4.9). The between-group difference in the mean change at 3 months, the Study Participants primary efficacy end point, was 8.3 points (95% The 76 patients had a mean (±SD) age of 71.0±8.3 confidence interval [CI], 5.9 to 10.7; P<0.001), years (range, 47 to 89) and a mean disease dura- indicating that there was greater improvement tion of 16.8±12.3 years. Most of the patients were after focused ultrasound thalamotomy than after men (68%), right-handed (83%), and white (75%), the sham procedure. The improvement in hand- and most had a family history of tremor (72%). tremor scores in the patients who underwent fo-

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A total of 21 participants (19 assigned to the A 25 sham procedure group who crossed over to thalamotomy and 2 assigned to thalamotomy in whom the procedure was incomplete) were treated after 20 the 3-month blinded assessment period. In this Sham (N=20) unblinded cohort, the mean score for tremor in 15 the hand contralateral to the thalamotomy, as- FUS thalamotomy (N=56) sessed according to the same videotape proce- 10 dures used for the 3-month assessment period,

Mean Tremor Score improved by 55% at 3 months (from 16.5±4.2 to

5 7.4±3.9, P<0.001) and by 52% at 6 months (from 16.5±4.2 to 8.0±3.9, P<0.001) (Table S1 and Fig. S3

0 in the Supplementary Appendix). Baseline 1 Mo 3 Mo 6 Mo 12 Mo Even with this unilateral procedure, mean total tremor scores on the CRST improved by 41% B at 3 months (from 50.1±14.0 at baseline to 29.6±13) 100 and by 35% at 12 months (from 50.1±14.0 to

80 FUS thalamotomy 32.4±14.5). This improvement was not observed 60 with the sham procedure; the mean total tremor score for patients who underwent the sham pro- 40 cedure was 44.1±12.7 at baseline and 43.1±13.1 Sham 20 at 3 months, representing a 2% change (P<0.001 for the between-group comparison of the change 0 from baseline to 3 months). The improvement in Baseline to 3 Mo (%) –20 total tremor scores in the cohort treated after the Change in Tremor Score from –40 3-month blinded phase was similar to the improvement in the patients who underwent thalamotomy –60 during the blinded phase (Table S2 in the Sup- Figure 1. Tremor Scores. plementary Appendix). Panel A shows tremor scores at baseline and throughout the 12-month study period. The change from baseline to 3 months in the tremor score Functional Improvement and Quality of Life for the hand contralateral to the thalamotomy, the primary outcome mea- Focused ultrasound thalamotomy significantly sure, was derived from eight items on the Clinical Rating Scale for Tremor improved the total disability score from Part C (CRST; scores range from 0 to 32, with higher scores indicating more se- of the CRST at 3 months, as compared with the vere tremor). At 3 months, the mean score was reduced by 47% in the group assigned to unilateral focused ultrasound (FUS) thalamotomy, as sham procedure (a 62% reduction in the score from compared with a reduction of 0.1% in the group assigned to the sham pro- baseline to 3 months [from 16.5±4.6 to 6.2±5.6] cedure (P<0.001). I bars indicate 95% confidence intervals. Panel B shows vs. a 3% reduction [from 16.0±4.3 to 15.6±4.6], individual tremor responses at 3 months in the thalamotomy and sham- P<0.001), and the improvement was sustained at procedure groups. The median improvement was 47% and 7% in the two 12 months (6.3±6.2). The mean disability scores groups, respectively. Negative values indicate worsening tremor. at baseline were highest for drinking and writing. At 12 months, the score for every activity had improved, with a reduction to a score of 0 (normal) cused ultrasound thalamotomy persisted through- or 1 (mild disability) for each item except writing out the 12-month study period (change in the (1.21±1.14) (Fig. 2A and 2B, and Table S3 in the tremor score from baseline to 12 months, 7.2 points; Supplementary Appendix). 95% CI, 6.1 to 8.3; P<0.001), representing a 40% Patients’ ratings of their quality of life, assessed improvement (from a mean score of 18.1±4.8 to on the basis of the QUEST score, also improved 10.9±4.5) (Fig. 1A, and Table S1 in the Supple- significantly at 3 months after focused ultra- mentary Appendix). The tremor score for the sound thalamotomy as compared with the sham hand ipsilateral to the thalamotomy showed no procedure (a 46% reduction in the score from significant change (from 11.8±5.5 at baseline to baseline to 3 months [from 42.6±18.3 to 23.1±16.9] 11.6±5.5 at 3 months, P = 0.50). vs. a 3% reduction [from 42.8±19.5 to 41.4±19.4],

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A B 20 FUS thalamotomy Sham 100

80 15 60

40 10 Score (%) 20 Disability Score

5 Improvement in Disability 0

Eating Hygiene Writing 0 Speaking Drinking Dressing Working

Baseline 3 Mo 12 Mo Social activities Domain

C D 80 60 FUS thalamotomy Sham

50 60

40 40

30 Score (%) 20 QUEST Score

20 Improvement in QUEST

0 10

Physical 0 Speaking leisure Work finance and Baseline 3 Mo 12 Mo Hobbies and Psychosocial Domain

Figure 2. Functional Activities of Daily Living and Quality of Life. Panel A shows total disability scores, which were significantly improved at 3 months (P<0.001 for the between- group difference in the change from baseline) with unilateral FUS thalamotomy but not with the sham procedure. Panel B shows the percent improvement at 3 months after thalamotomy in individual activities typically affected by essential tremor. These eight items represent the disability subsection, or Part C, of the CRST. Panel C shows scores for patient-reported quality of life on the Quality of Life in Essential Tremor Questionnaire (QUEST). Scores were significantly improved at 3 months in the thalamotomy group as compared with the sham-procedure group (P<0.001 for the between-group difference in the change from baseline). Panel D shows the percent improvement at 3 months after thalamotomy in individual domains of the QUEST. The largest improvement in quality of life reported by patients was in the psychosocial domain.

P<0.001) (Fig. 2C and 2D, and Table S4 in the the adjacent ventral posterolateral (sensory) nucle- Supplementary Appendix). The largest improve- us. One patient had dense and permanent hypes- ment was in the psychosocial domain. thesia of the dominant thumb and index finger, categorized as a serious adverse event. Gait dis- Adverse Events turbances also occurred, with ataxia noted on Adverse events associated with focused ultra- postoperative neurologic examination (in 11 pa- sound thalamotomy included gait disturbance in tients [20%]) and at 12 months (in 2 patients [4%]). 36% of patients and paresthesias or numbness in Subjective unsteadiness was reported by 9 patients 38%; these adverse events persisted at 12 months (16%), which persisted at 12 months in 3 patients in 9% and 14% of patients, respectively (Table 2). (5%). Weakness contralateral to the thalamotomy, The sensory side effects of numbness or paresthe- probably resulting from internal-capsule involve- sia involved the face (in 8 patients), hand (in 6), ment, occurred in 2 patients, persisting for 6 or both (in 6), presumably from involvement of months in 1 and 12 months in the other. Intra-

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Table 2. Adverse Events.*

Sham FUS Thalamotomy Procedure Adverse Event (N = 56) (N = 20)

Total 1 Day 7 Days 1 Mo 3 Mo 6 Mo 12 Mo

number of patients (percent) Paresthesia or numbness Any region 21 (38) 18 17 16 14 11 8 (14) 1 (5) Both face and hand 6 (11) 5 5 5 5 5 5 (9) Face, lips, and tongue 8 (14) 7 6 6 6 4 2 (4) Hand and fingers 6 (11) 5 5 4 2 1 1 (2) 1 (5) Leg 1 (2) 1 1 1 1 1 Taste disturbance 3 (5) 3 2 2 2 2 2 (4) Gait disturbance† Any, objective or subjective 20 (36) 19 18 13 9 7 5 (9) 1 (5) Ataxia, noted objectively on examination 11 (20) 11 10 6 2 2 2 (4) “Unsteady” or “unbalanced,” reported subjectively 9 (16) 8 8 7 7 5 3 (5) 1 (5) by examiner or patient Dysmetria, limb 7 (12) 7 7 5 5 4 2 (4) Weakness, contralateral 2 (4) 2 2 2 2 2 1 (2) Dysarthria 1 (2) 1 1 1 1 1 Dysphagia 1 (2) 1 1 1 1 1 Headache lasting >1 day 8 (14) 8 4 4 2 2 4 (20) Fatigue 3 (5) 3 3 2 1 1 (5) Disequilibrium sensation 5 (9) 5 5 5 3 2 1 (2) Tinnitus 3 (5) 3 3 1 Intraprocedural sensations or events‡ Head discomfort: “heat” or “pressure” 17 (30) Vertigo: “dizzy” 12 (21) Nausea 11 (20) 2 (10) Vomiting 2 (4) Scalp tingling 4 (7) 1 (5) Back pain 5 (9) 1 (5) Anxiety 3 (5) 2 (10) Pin-site pain, edema, or bruising attributable to place- 17 (30) 7 (35) ment of the stereotactic frame No adverse events 6 (11) 8 (40)

* Adverse events reported at 12 months are still ongoing. Adverse events in the unblinded cohort (i.e., 21 patients who underwent thalamotomy after the initial 3-month period) and events that were deemed to be unrelated to the study procedures are listed in Tables S5 and S6, respectively, in the Supplementary Appendix. † Five patients with gait disturbances were prescribed physical therapy, and one patient with persistent ataxia required a walker for ambula- tion. ‡ Intraprocedural sensations and events were brief and resolved by the end of the procedure. Five thalamotomy procedures were interrupted or suspended because of pain, nausea, vertigo, or vomiting.

procedural sensations resolved within seconds after sound thalamotomy (Table S5 in the Supplementary the delivery of acoustic energy (Table 2). A similar Appendix). One patient had a transient ischemic profile of side effects was observed in the unblind- attack 6 weeks after undergoing thalamotomy ed cohort of patients undergoing focused ultra- (Table S6 in the Supplementary Appendix).

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Sonications experts who were not involved in the treatments, For the 56 patients undergoing focused ultra- was recruited to objectively evaluate the clinical sound thalamotomy, a mean of 18.5±5.2 sonica- outcomes from videotape analysis. There was high tions were administered. The highest-energy accountability in this trial, with 97% of patients sonication for tissue ablation delivered a mean completing study visits throughout the 3-month acoustic energy of 14,497.0±6695.7 J (range, 3500 primary assessment period, and 91% of the thala- to 34,860), which resulted in a mean peak voxel motomy group assessed through 12 months (Fig. temperature of 55.6±2.3°C (range, 50.0 to 60.7). S2 in the Supplementary Appendix). The sham-procedure cohort received an average Even though the procedure is transcranial and of 15.3±2.3 sonications, with no energy or heat- involves no incision or craniotomy, it does create ing delivered. In 39 active treatments, intraop- a thalamic lesion, which can result in permanent erative clinical or imaging feedback led to a neurologic deficits. There were 74 neurologic ad- mean adjustment in the stereotactic target loca- verse events reported in the 56 patients who under- tion by 1.6±1.1 mm (range, 1.1 to 5.5). In 5 pa- went active treatment. The most common side tients, the full therapeutic temperature could not effect was an alteration in sensation, which was be achieved, despite their receiving similar doses reported by 38% of the patients and persisted at of acoustic energy. 12 months in 14%. Gait disturbance occurred in 36% of patients and persisted at 12 months in Survey of Patients and Assessors about 9%. The incidence of cerebellar deficits such as Randomized Assignments dysmetria, ataxia, and subjective unsteadiness of Special procedures were implemented to ensure gait approached 5% each at 12 months. There were blinding of the treatment assignments. Even so, no infectious or hemorrhagic events, but contra- 95% of patients who underwent active treatment lateral weakness occurred twice. Qualitatively, the and 80% of those who underwent the sham pro- intensity of side effects seemed to peak at ap- cedure correctly guessed their assignment im- proximately 1 week, corresponding to the maximal mediately after the procedure. At the end of the size of the lesion with perilesional edema.28 3-month blinded phase, the correct guesses were Although randomized, controlled studies of 86% and 95%, respectively, with patients accred- medical therapies have shown tremor reductions iting their opinion to the clinical effect of the in roughly 50% of study participants, these stud- treatment or lack thereof. Assessors who re- ies were performed at the early stages of the dis- viewed the videotaped examinations at 3 months ease.9-11 The current trial shows that focused ultra- correctly identified the treatment assignment for sound thalamotomy can further control tremor 70% of the patients in the active-treatment when it has become advanced and resistant to group and 75% of those in the sham-procedure medication. group, most likely on the basis of the presence Deep-brain stimulation is currently the surgi- or absence of a clinical effect. cal standard for medication-refractory essential tremor. Since FDA approval of the procedure in Discussion 1997, numerous studies have confirmed that it is highly effective for tremor suppression, but In this randomized, controlled trial involving 76 guidelines have classified the findings as level C patients with medication-refractory essential trem- evidence in the absence of placebo-controlled or, transcranial focused ultrasound thalamotomy trials.7,8,11 Deep-brain stimulation has been safe- significantly reduced hand tremor at 3 months, ly administered for bilateral and axial symptoms. and the effect persisted during the 12-month study The procedure requires surgical placement of a period. This unilateral procedure reduced disabil- neurostimulator that can be reversed and adjusted ity and improved quality of life as measured by a to minimize side effects. Focused ultrasound patient questionnaire that is specific for essential thalamotomy is also an invasive intervention, tremor. which can result in permanent side effects as a The trial was controlled with a sham procedure, consequence of tissue ablation. A control group of and the results show that tremor reduction was patients undergoing deep-brain stimulation was related to treatment, not a placebo effect. In ad- not included in this trial; the two technologies dition, the Tremor Research Group, a group of were not compared.

n engl j med 375;8 nejm.org August 25, 2016 737 The New England Journal of Medicine Downloaded from nejm.org on September 16, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. The new england journal of medicine

Stereotactic radiofrequency thalamotomy for of the acoustic wave, as well as individual cranial tremor has been available since the 1950s, with characteristics. Additional research is needed to numerous retrospective studies documenting ef- address this issue. ficacy13,16 similar to that of thalamic stimula- In conclusion, our study showed that MRI- tion.29-31 Recently, a prospective, uncontrolled trial guided focused ultrasound thalamotomy reduced of stereotactic radiosurgery showed improve- hand tremor and improved the quality of life in ments in tremor from blinded, videotaped ratings patients with essential tremor. Side effects includ- at 1 year.32 Radiosurgical thalamotomy has not ed sensory and gait disturbances. The benefits and been embraced because intraoperative validation risks of focused ultrasound thalamotomy per- is not possible, the effects are delayed, and there formed in a carefully controlled clinical trial may are theoretical concerns about radiation side ef- differ from the benefits and risks with routine fects, secondary neoplasia, and a less-sharp dose practice in diverse clinical settings. gradient.33,34 Supported by InSightec, the Focused Ultrasound Foundation, and the Binational Industrial Research and Development (BIRD) Our study has several limitations. First, the Foundation. procedures were all performed unilaterally. Al- Dr. Elias reports receiving grant support from InSightec and though unilateral focused ultrasound thalamot- the Focused Ultrasound Foundation; Dr. Lipsman, receiving fees from the Focused Ultrasound Foundation for serving on a steer- omy improved total tremor scores by 47% in the ing committee; Dr. Ghanouni and Dr. Butts Pauly, receiving study cohort, there was no reduction of ipsilat- grant support from InSightec and GE Healthcare; Dr. Hynynen, eral tremor and only minimal improvement in receiving royalties from a patent related to ultrasound therapy (US6770031 B2); Dr. Lozano, receiving grant support from In- axial tremors of the head, neck, and voice. Sec- Sightec; Dr. Gwinn, receiving teaching fees from NeuroPace and ond, some patients may be reluctant or unwill- Boston Scientific; Dr. Cosgrove, receiving consulting fees from ing to undergo MRI studies or it may be unsafe InSightec; and Dr. Taira, receiving lecture fees from Daiichi- Sankyo, Eisai, GlaxoSmithKline, Otsuka, Pfizer, Hisamitsu, for them to do so. Third, lesioning procedures Dainippon-Sumitomo, Takeda, and Kyowa-Hakko, and grant require a balance between the size of the lesion support from St. Jude Medical. No other potential conflict of and the risk of adverse effects, since larger lesions interest relevant to this article was reported. Disclosure forms provided by the authors are available with are expected to have more enduring efficacy but the full text of this article at NEJM.org. a greater incidence of side effects. Finally, tran- We thank Rodger Elble, M.D., Ludy Shih, M.D., Peter Lewitt, scranial delivery of focused ultrasound was diffi- M.D., Raj Pahwa, M.D., Dan Tarsy, M.D., and Theresa Zesiewicz, M.D., of the Tremor Research Group for performing videotape cult to achieve in five of the study patients, prob- tremor ratings, and Vera Hashem, Ph.D., for coordinating the ably because of the frequency and other properties core laboratory.

References 1. Louis ED, Ferreira JJ. How common is 7. Deuschl G, Bain P, Brin M; Ad Hoc ease, essential tremor and extra-pyrami- the most common adult movement disor- Scientific Committee. Consensus state- dal dyskinesias. Acta Neurochir Suppl der? Update on the worldwide prevalence ment of the Movement Disorder Society (Wien) 1993;58: 39-44. of essential tremor. Mov Disord 2010;25: on Tremor. Mov Disord 1998;13:Suppl 3: 13. Goldman MS, Kelly PJ. Stereotactic 534-41. 2-23. thalamotomy for medically intractable es- 2. Ho AL, Erickson-Direnzo E, Pend- 8. Deuschl G, Raethjen J, Hellriegel H, sential tremor. Stereotact Funct Neuro- harkar AV, Sung CK, Halpern CH. Deep Elble R. Treatment of patients with essen- surg 1992;58:22-5. brain stimulation for vocal tremor: a com- tial tremor. Lancet Neurol 2011;10:148-61. 14. Koller W, Pahwa R, Busenbark K, et prehensive, multidisciplinary methodolo- 9. Findley LJ, Calzetti S. Double-blind al. High-frequency unilateral thalamic gy. Neurosurg Focus 2015;38(6):E6. controlled study of primidone in essential stimulation in the treatment of essential 3. Elias WJ, Shah BB. Tremor. JAMA tremor: preliminary results. Br Med J and parkinsonian tremor. Ann Neurol 2014;311: 948-54. (Clin Res Ed) 1982;285:608. 1997;42:292-9. 4. Lorenz D, Schwieger D, Moises H, 10. Winkler GF, Young RR. Efficacy of 15. Kumar K, Kelly M, Toth C. Deep brain Deuschl G. Quality of life and personality chronic propranolol therapy in action stimulation of the ventral intermediate in essential tremor patients. Mov Disord tremors of the familial, senile or essential nucleus of the thalamus for control of 2006;21:1114-8. varieties. N Engl J Med 1974;290:984-8. tremors in Parkinson’s disease and essen- 5. Louis ED, Machado DG. Tremor-relat- 11. Zesiewicz TA, Elble R, Louis ED, et al. tial tremor. Stereotact Funct Neurosurg ed quality of life: a comparison of essen- Practice parameter: therapies for essen- 1999;72: 47-61. tial tremor vs. Parkinson’s disease pa- tial tremor: report of the Quality Stan- 16. Zirh A, Reich SG, Dougherty PM, tients. Parkinsonism Relat Disord 2015; dards Subcommittee of the American Lenz FA. Stereotactic thalamotomy in the 21:729-35. Academy of Neurology. Neurology 2005; treatment of essential tremor of the upper 6. Schneier FR, Barnes LF, Albert SM, 64:2008-20. extremity: reassessment including a blind- Louis ED. Characteristics of social phobia 12. Benabid AL, Pollak P, Seigneuret E, ed measure of outcome. J Neurol Neuro- among persons with essential tremor. Hoffmann D, Gay E, Perret J. Chronic VIM surg Psychiatry 1999;66: 772-5. J Clin Psychiatry 2001;62:367-72. thalamic stimulation in Parkinson’s dis- 17. Fry WJ, Mosberg WH Jr, Barnard JW,

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Fry FJ. Production of focal destructive le- lateral magnetic resonance guided focused Berk C, Lou JS. A randomized comparison sions in the central nervous system with ultrasound thalamotomy for essential of thalamic stimulation and lesion on ultrasound. J Neurosurg 1954;11:471-8. tremor: practices and clinicoradiological self-paced finger movement in essential 18. Meyers R, Fry WJ, Fry FJ, Dreyer LL, outcomes. J Neurol Neurosurg Psychiatry tremor. Neurosci Lett 2009;462:166-70. Schultz DF, Noyes RF. Early experiences 2015;86:257-64. 30. Schuurman PR, Bosch DA, Bossuyt with ultrasonic irradiation of the pallidofu- 24. Elias WJ, Huss D, Voss T, et al. A pilot PMM, et al. A comparison of continuous gal and nigral complexes in hyperkinetic study of focused ultrasound thalamotomy thalamic stimulation and thalamotomy and hypertonic disorders. J Neurosurg for essential tremor. N Engl J Med 2013; for suppression of severe tremor. N Engl J 1959;16: 32-54. 369:640-8. Med 2000;342:461-8. 19. Nelson E, Lindstrom PA, Haymaker 25. Lipsman N, Schwartz ML, Huang Y, et 31. Tasker RR. Deep brain stimulation is W. Pathological effects of ultrasound on al. MR-guided focused ultrasound thala- preferable to thalamotomy for tremor the human brain: a study of 25 cases in motomy for essential tremor: a proof-of- suppression. Surg Neurol 1998;49:145- which ultrasonic irradiation was used as a concept study. Lancet Neurol 2013;12: 53. lobotomy procedure. J Neuropathol Exp 462-8. 32. Witjas T, Carron R, Krack P, et al. Neurol 1959;18: 489-508. 26. Stacy MA, Elble RJ, Ondo WG, Wu SC, A prospective single-blind study of Gamma 20. Clement GT, White J, Hynynen K. In- Hulihan J. Assessment of interrater and Knife thalamotomy for tremor. Neurology vestigation of a large-area phased array intrarater reliability of the Fahn-Tolosa- 2015;85: 1562-8. for focused ultrasound surgery through Marin Tremor Rating Scale in essential 33. Elias WJ, Khaled M, Hilliard JD, et al. the skull. Phys Med Biol 2000;45:1071-83. tremor. Mov Disord 2007;22:833-8. A magnetic resonance imaging, histo- 21. Hynynen K, Vykhodtseva NI, Chung 27. Tröster AI, Pahwa R, Fields JA, Tanner logical, and dose modeling comparison AH, Sorrentino V, Colucci V, Jolesz FA. CM, Lyons KE. Quality of life in Essential of focused ultrasound, radiofrequency, Thermal effects of focused ultrasound on Tremor Questionnaire (QUEST): develop- and Gamma Knife radiosurgery lesions in the brain: determination with MR imag- ment and initial validation. Parkinsonism swine thalamus. J Neurosurg 2013;119: ing. Radiology 1997;204:247-53. Relat Disord 2005;11:367-73. 307-17. 22. McDannold N, Moss M, Killiany R, et 28. Wintermark M, Druzgal J, Huss DS, et 34. Lee MSD, ter Haar G, Sela B, et al. al. MRI-guided focused ultrasound sur- al. Imaging findings in MR imaging- Thermal dose and radiation dose com- gery in the brain: tests in a primate mod- guided focused ultrasound treatment for parison based on cell survival. J Ther Ul- el. Magn Reson Med 2003;49:1188-91. patients with essential tremor. AJNR Am trasound 2015;3:Suppl 1:26.10.1186/2050- 23. Chang WS, Jung HH, Kweon EJ, Zadi- J Neuroradiol 2014;35:891-6. 5736-3-S1-P26 cario E, Rachmilevitch I, Chang JW. Uni- 29. Anderson VC, Burchiel KJ, Hart MJ, Copyright © 2016 Massachusetts Medical Society.

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n engl j med 375;8 nejm.org August 25, 2016 739 The New England Journal of Medicine Downloaded from nejm.org on September 16, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. Sacroiliac Joint Dysfunction Prioritization

Question: Should SI joint dysfunction paired with surgical fusion be moved to a higher priority line?

Question source: Andy Kranenburg, MD orthopedic surgeon from Medford; SI-Bone, manufacturer of SI fusion device

Issue: Andy Kranenburg, MD from Medford, testified at the August 2018 VBBS meeting regarding the treatment of sacroiliac joint pain and dysfunction. Currently, there is a guideline on the Prioritized List regarding when treatment is appropriate, but the diagnosis is on an uncovered line. He requested reconsideration of the prioritization of sacroiliac joint dysfunction to a line above the funding level. He reviewed the HERC prioritization methodology, and SI joint dysfunction ended up with a very high score according to him and his colleagues, higher than many conditions that are currently covered. SI joint pain is a highly burdensome health state.

SI joint dysfunction and SI joint fusion were reviewed in August and November, 2016. ICD-10 M46.1 (Sacroiliitis, not elsewhere classified) and CPT 27279 (Arthrodesis, sacroiliac joint, percutaneous or minimally invasive (indirect visualization), with image guidance, includes obtaining bone graft when performed, and placement of transfixing device) were added to 527 CONDITIONS OF THE BACK AND SPINE WITHOUT URGENT SURGICAL INDICATIONS along with a guideline regarding when fusion should be covered. Sacroiliitis is also on line 401 CONDITIONS OF THE BACK AND SPINE (medical line). The VBBS and HERC felt that surgical treatment of this condition should be low priority. The guideline was adopted as the CCO medical directors thought it would be helpful to have when approving exceptions.

The manufacturer sent updated research synopses; however, the evidence regarding the effectiveness of SI joint fusion was reviewed in 2016. The current question is regarding the prioritization of sacroiliitis paired with surgical fusion.

Current Prioritized List placement: Medical treatment of sacroiliitis is found on line 401 CONDITIONS OF THE BACK AND SPINE

SI joint fusion is found on line 527 CONDITIONS OF THE BACK AND SPINE WITHOUT URGENT SURGICAL INDICATIONS and pairs with sacroiliitis.

Other back surgeries are found on line 346 CONDITIONS OF THE BACK AND SPINE WITH URGENT SURGICAL INDICATIONS.

In order for a condition to be included on line 346, it must meet the criteria outlined in GN37, such as neurogenic claudication or evidence of nerve damage.

GUIDELINE NOTE 37, SURGICAL INTERVENTIONS FOR CONDITIONS OF THE BACK AND SPINE OTHER THAN SCOLIOSIS Lines 346,527 Spine surgery is included on Line 346 only in the following circumstances: A) Decompressive surgery is included on Line 346 to treat debilitating symptoms due to central or foraminal spinal stenosis, and only when the patient meets the following criteria:

Sacroiliac Joint Dysfunction Prioritization

1) Has MRI evidence of moderate or severe central or foraminal spinal stenosis AND 2) Has neurogenic claudication OR 3) Has objective neurologic impairment consistent with the MRI findings. Neurologic impairment is defined as objective evidence of one or more of the following: a) Markedly abnormal reflexes b) Segmental muscle weakness c) Segmental sensory loss d) EMG or NCV evidence of nerve root impingement e) Cauda equina syndrome f) Neurogenic bowel or bladder g) Long tract abnormalities Foraminal or central spinal stenosis causing only radiating pain (e.g. radiculopathic pain) is included only on Line 527.

B) Spinal fusion procedures are included on Line 346 for patients with MRI evidence of moderate or severe central spinal stenosis only when one of the following conditions are met: 1) spinal stenosis in the cervical spine (with or without spondylolisthesis) which results in objective neurologic impairment as defined above OR 2) spinal stenosis in the thoracic or lumbar spine caused by spondylolisthesis resulting in signs and symptoms of neurogenic claudication and which correlate with xray flexion/extension films showing at least a 5 mm translation OR 3) pre-existing or expected post-surgical spinal instability (e.g. degenerative scoliosis >10 deg, >50% of facet joints per level expected to be resected)

For all other indications, spine surgery is included on Line 527.

The following interventions are not included on these lines due to lack of evidence of effectiveness for the treatment of conditions on these lines, including cervical, thoracic, lumbar, and sacral conditions: • prolotherapy • local injections (including ozone therapy injections) • botulinum toxin injection • intradiscal electrothermal therapy • therapeutic medial branch block • coblation nucleoplasty • percutaneous intradiscal radiofrequency thermocoagulation • percutaneous laser disc decompression • radiofrequency denervation • corticosteroid injections for cervical pain

Corticosteroid injections for low back pain with or without radiculopathy are only included on Line 527.

The development of this guideline note was informed by HERC coverage guidances on Percutaneous Interventions for Low Back Pain, Percutaneous Interventions for Cervical Spine Pain, Low Back Pain: Corticosteroid Injections and Low Back Pain: Minimally Invasive and Non-Cordicosteroid Percutaneous Interventions. See https://www.oregon.gov/oha/HPA/CSI-HERC/Pages/Evidence-based-Reports.aspx.

Sacroiliac Joint Dysfunction Prioritization

Current line prioritization scoring

527 CONDITIONS OF THE BACK AND SPINE WITHOUT URGENT SURGICAL INDICATIONS Category: 7 HL: 4 Suffering: 3 Population effects: 0 Vulnerable population: 0 Tertiary prevention: 0 Effectiveness: 1 Need for service: 0.8 Net cost: 2 Score: 112 Approximate line placement: 527

346 CONDITIONS OF THE BACK AND SPINE WITH URGENT SURGICAL INDICATIONS Category: 7 HL: 5 Suffering: 4 Population effects: 0 Vulnerable population: 0 Tertiary prevention: 4 Effectiveness: 3 Need for service: 1 Net cost: 2 Score: 780 Approximate line placement: 346

HERC staff recommendation: 1) Do not rescore line 527 or move surgical treatment of sacroiliitis to line 346 CONDITIONS OF THE BACK AND SPINE WITH URGENT SURGICAL INDICATIONS. a. Sacroiliitis does not meet the criteria of GN47 regarding nerve damage or neurogenic complications

Human Donor Breast Milk

Question: Should human donor breast milk be included on the Prioritized List?

Question source: HSD

Issue: Breast milk is widely considered the healthiest food source for infants, particularly those who are premature. Breastfeeding is associated with multiple health benefits for infants (decreased risk of asthma, obesity, necrotizing enterocolitis, type 2 diabetes, ear infections, respiratory infections, sudden infant death syndrome, and gastrointestinal infections).

Oregon has one of the highest breastfeeding rates in the country, with a >90% initiation rate, 70% breastfeeding at 6 months, and 38% exclusively breastfeeding at 6 months. https://www.oregon.gov/oha/PH/HEALTHYPEOPLEFAMILIES/BABIES/BREASTFEEDING/D ocuments/bf-whitepaper-2017.pdf

Among Medicaid patients discharged from the NICU, 2017 data showed 66.7% were breastfeeding (Dr. Allen Merritt, personal communication).

When breast milk is not available through the mother, whether through medical contraindications or production challenges, donor breast milk is an option. However, it is quite expensive. Donor breast milk is currently paid for through OHP only in rare exceptions.

Clinical background Ip, 2007 https://www.ncbi.nlm.nih.gov/pubmed/17764214 1. AHRQ systematic review of breastfeeding outcomes in developed countries 2. 29 systematic reviews or meta-analyses that covered approximately 400 individual studies were included in this review. 43 primary studies on infant health outcomes. 3. Results: We found that a history of breastfeeding was associated with a reduction in the risk of acute otitis media, non-specific gastroenteritis, severe lower respiratory tract infections, atopic dermatitis, asthma (young children), obesity, type 1 and 2 diabetes, childhood leukemia, sudden infant death syndrome (SIDS), and necrotizing enterocolitis. There was no relationship between breastfeeding in term infants and cognitive performance. The relationship between breastfeeding and cardiovascular diseases was unclear. Similarly, it was also unclear concerning the relationship between breastfeeding and infant mortality in developed countries.

Kramer, 2012 https://www.ncbi.nlm.nih.gov/pubmed/22895934 1. Cochrane systematic review on optimal duration of exclusive breastfeeding 2. 23 studies, 12 from developed countries, all observational studies 3. Results: Infants who are exclusively breastfed for six months experience less morbidity from gastrointestinal infection than those who are partially breastfed

Human Donor Breast Milk, Issue #1447 Page 1

Human Donor Breast Milk

as of three or four months, and no deficits have been demonstrated in growth among infants from either developing or developed countries who are exclusively breastfed for six months or longer.

CDC, 2018 https://www.cdc.gov/breastfeeding/about-breastfeeding/why-it-matters.html Infants who are breastfed have reduced risks of:

• Asthma • Obesity • Type 2 diabetes • Ear and respiratory infections • Sudden infant death syndrome (SIDS) • Gastrointestinal infections (diarrhea/vomiting) • Necrotizing enterocolitis for preterm infants

Breastfeeding can help lower a mother’s risk of:

• High blood pressure • Type 2 diabetes • Ovarian cancer • Breast cancer

Current prioritized list status

Code Description Placement T2102 Human breast milk processing, storage Ancillary and distribution only File

Evidence summary

Quigley, 2018 https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD002971.pub4/full 1. Cochrane systematic review of formula versus donor breast milk in preterm or low birth weight infants 2. Randomized or quasi-randomized controlled trials

Human Donor Breast Milk, Issue #1447 Page 2

Human Donor Breast Milk

3. 11 trials, 1809 infants a. 4 trials compared standard term formula versus donor breast milk b. 7 trials compared nutrient-enriched preterm formula versus donor breast milk 4. Results: a. Formula-fed infants had higher in-hospital rates of weight gain (mean difference (MD) 2.51, 95%confidence interval (CI) 1.93 to 3.08g/kg/day), linear growth (MD 1.21, 95% CI 0.77 to 1.65 mm/week) and head growth (MD 0.85, 95% CI 0.47 to 1.23 mm/week). b. No evidence found of an effect on long-term growth or neurodevelopment. c. Formula feeding increased the risk of necrotizing enterocolitis (typical risk ratio (RR) 1.87, 95% CI 1.23 to 2.85; risk difference (RD) 0.03, 95% CI 0.01 to 0.06). NNH is 33.

5. Limitations - Only the four most recent trials used nutrient-fortified donor breast milk. A number of the trials had limitations in terms of blinding and allocation concealment. 6. Author conclusions: Formula, compared to donor breast milk, results in increased growth parameters and an increased risk of necrotizing enterocolitis.

Human Donor Breast Milk, Issue #1447 Page 3

Human Donor Breast Milk

Villamor-Martinez, 2018 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852814/pdf/nutrients-10-00238.pdf 1. Systematic review and meta-analysis of donor breast milk on bronchopulmonary dysplasia in preterm and very low birthweight infants 2. 18 studies, RCTs and observational studies 3. Results: a. Meta-analysis of RCTs could not demonstrate that supplementation of mothers own milk (MOM) with pasteurized donor human milk reduced bronchopulmonary dysplasia (BPD) when compared to preterm formula (three studies, risk ratio (RR) 0.89, 95% confidence interval (CI) 0.60– 1.32). b. Meta-analysis of observational studies showed that pasteurized donor human milk supplementation reduced bronchopulmonary dysplasia (8 studies, RR 0.78, 95% CI 0.67–0.90). c. An exclusive human milk diet reduced the risk of bronchopulmonary dysplasia, compared to a diet with preterm formula and/or bovine milk- based fortifier (three studies, RR 0.80, 95% CI 0.68–0.95). d. Feeding raw MOM, compared to feeding pasteurized MOM, protected against BPD (two studies, RR 0.77, 95% CI 0.62–0.96). e. Days of mechanical ventilation was less in those receiving pasteurized donor human milk (MD -5.73 days, 95% CI -10.68 to -0.77, p = 0.023) (3 RCTs) a. Days on oxygen was not significantly different (MD -9.11 days, 95% CI -24.82 to 6.60, p = 0.256) (2 RCTs) 4. Authors conclusion: Pasteurized donor human milk protects against BPD in very preterm infants.

Miller, 2018 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024377/pdf/nutrients-10- 00707.pdf 1. Systematic review and meta-analysis look at BW <1500g 2. Experimental and observational studies were pooled separately in meta- analyses. Risk of bias was assessed for each individual study and the GRADE system used to judge the certainty of the findings. 3. Forty-nine studies (with 56 reports) were included, of which 44 could be included in meta-analyses. 4. Results: a. Human milk provided a clear protective effect against necrotizing enterocolitis (NEC), with an approximate 4% reduction in incidence.. Particularly for NEC, any volume of human milk is better than exclusive preterm formula, and the higher the dose the greater the protection. b. Human milk provided a possible reduction in late onset sepsis, severe retinopathy of prematurity and severe NEC

Human Donor Breast Milk, Issue #1447 Page 4

Human Donor Breast Milk

c. Evidence regarding pasteurization is inconclusive, but it appears to have no effect on some outcomes 5. Author conclusions: Improving the intake of mother’s own milk (MOM) and/or donor HM results in small improvements in morbidity in this population.

Abrams, 2014 1. Combination of 2 randomized trials, one including randomization to human milk fortification versus cow milk fortification and the other comparing donor human milk to cow-based formula. 2. Extremely preterm (EP) infants <1,250 g birth weight received a diet consisting of either human milk fortified with a human milk protein-based fortifier (HM) (n = 167) or a diet containing variable amounts of milk containing cow milk-based protein (CM) (n = 93). 3. Results: Mortality (2% versus 8%, p = 0.004) and NEC (5% versus 17%, p = 0.002) differed significantly between the HM and CM groups, respectively. For every 10% increase in the volume of milk containing CM, the risk of sepsis increased by 17.9% (p < 0.001). Growth rates were similar between groups. The duration of parenteral nutrition was 8 days less in the subgroup of infants receiving a diet containing <10% CM versus ≥10% CM (p < 0.02). 4. Author Conclusions: An exclusive human milk diet, devoid of CM-containing products, was associated with lower mortality and morbidity in EP infants without compromising growth and should be considered as an approach to nutritional care of these infants. 5. Note: The human milk based fortifier used in this study, Prolacta, is extremely expensive and this study is funded by Prolacta.

Recommendations from others American Academy of Pediatrics, 2016 1. Policy statement about the use of donor human milk in high risk infants 2. Prioritization of donor human milk is for infants <1,500g 3. There are no clear guidelines for discontinuing the use of donor human milk in an infant <1500 g birth weight when the volume of mother’s milk is not adequate. A range of postmenstrual ages from 32 to 36 weeks is commonly used in the United States, because this range covers the highest risk period for necrotizing enterocolitis. Further research is needed to clarify the optimal timing of discontinuing donor human milk. 4. Intestinal diseases - Fewer data are available regarding the use of donor human milk in other high-risk infants, including infants with abdominal wall defects, such as gastroschisis or omphalocele, and other conditions, such as congenital heart disease. Nonetheless, some infants with these conditions or other neonatal disorders may benefit from donor human milk either because of a direct effect on intestinal growth or improved feeding tolerance. In these cases,

Human Donor Breast Milk, Issue #1447 Page 5

Human Donor Breast Milk

payers may expect documentation of intolerance to specialized infant formulas and the medical necessity for donor human milk before providing payment for human milk at home or in the hospital.

Other payers Medi-Cal http://www.dhcs.ca.gov/formsandpubs/Documents/MMCDAPLsandPolicyLetters/PL199 8/MMCDPL98010.pdf

Medi-Cal benefits include enteral nutritional supplemental or replacement formulas when medically diagnosed conditions preclude the full use of regular food (Title 22, California Code of Regulations, Section 5 13 13.3).

Plans must arrange for the provision of human milk for newborns in the following situation: mother is unable to breastfeed due to medical reasons, and the infant cannot tolerate or has medical contra-indications to the use of any formula, including elemental formulas. Plans must establish policies and procedures for ensuring the timely provision of human milk.

New York Medicaid https://legislation.nysenate.gov/pdf/bills/2017/S4526 New York Medicaid reimburses the cost for inpatient use when: • A licensed medical practitioner has issued an order for an infant who is medically or physically unable to receive maternal breast milk or participate in breast feeding or whose mother is medically or physically unable to produce maternal breast milk or participate in breast feeding despite optimal lactation support. • Such infants must: (I) have a documented birth weight of one thousand five hundred grams or less; or (II) have a congenital or acquired intestinal condition, and is therefore at a high risk for development of necrotizing enterocolitis and/or infection. • Coverage for donor breast milk shall continue until the infant is at an age of medical adjustment of 34 weeks corrected gestational age and such coverage shall be not less than the reasonable cost of such milk procedure from a certified nonprofit milk bank, plus reasonable processing and handling fees.

Missouri https://law.justia.com/codes/missouri/2015/title-xii/chapter-208/section- 208.141/

The department of social services shall reimburse a hospital for prescribed medically necessary donor human breast milk provided to a MO HealthNet participant if:

(1) The participant is an infant under the age of three months;

(2) The participant is critically ill;

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Human Donor Breast Milk

(3) The participant is in the neonatal intensive care unit of the hospital;

(4) A physician orders the milk for the participant;

(5) The department determines that the milk is medically necessary for the participant;

(6) The parent or guardian signs and dates an informed consent form indicating the risks and benefits of using banked donor human milk; and

(7) The milk is obtained from a donor human milk bank that meets the quality guidelines established by the department.

2. An electronic web-based prior authorization system using the best medical evidence and care and treatment guidelines consistent with national standards shall be used to verify medical need.

Texas Medicaid https://hhs.texas.gov/about-hhs/communications-events/news/2017/02/human-donor- milk-new-reimbursement Human donor milk may be reimbursed to hospital providers for services rendered to inpatient clients. Hospital providers may receive reimbursement for the donor human milk service separate from the inpatient Diagnosis-Related Group (DRG) payment.

The Texas Medicaid Provider Procedures Manual does not require prior authorization for this service and HHSC urges MCOs to take this into consideration when developing their own policies around human donor milk. Medicaid clinical policy will require use of revenue code 220 (special charges) with procedure code T2101 as an outpatient hospital service using the Centers for Medicare and Medicaid Services (CMS)-1450 (UB-04) claim form with the most appropriate outpatient type of bill (TOB). Procedure code T2101 may be reimbursed for donor human milk as medically necessary for clients who are 6 months of age and younger.

Hospitals must follow clinical recommendations for administering donor human milk to inpatient clients, and must maintain all applicable and appropriate medical necessity documentation in the client’s medical record. The Texas Medicaid Provider Procedures Manual will be updated to reflect this new policy on April 1, 2017.

Aetna, 2018 http://www.aetna.com/cpb/medical/data/1_99/0061.html Infant formulas are only covered if administered via the tube-feeding route and the criteria for coverage of enteral feedings are met. Infant formulas given orally are not covered. In addition, breast milk additive to prevent necrotizing enterocolitis in premature infants is only covered if administered via the tube-feeding route and the criteria for coverage of enteral feedings are met.

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Human Donor Breast Milk

Cost estimates from Allen Merritt, MD Knowing that donor breast milk costs between $4-$5 per ounce and assuming that it is used at approximately 120 -150 ml/kg/day and taking mean adjusted weights at 3, 6, and 9 months one can estimate cost and compare it to premie formula. Enfamil Enfacare costs $102.86 per can that makes around 24 ounces of formula and one can calculate the price. Similac NeoSure, 3 ounce bottles of 24 bottles cost $182.95 retail. So an ounce for ounce comparison can be made.

Infants who solely receive breast milk (whether donor or from their mother) will also need a daily fortifier that costs approximately $2.40 per day or an additional $1080 for human milk fortifier.

HERC Staff Summary Human breast milk is the best source of nutrition for most infants. Among low birth weight infants, donor breast milk is associated with improved morbidity including lower rates of necrotizing enterocolitis and possibly less bronchopulmonary dysplasia, sepsis and retinopathy of prematurity. Formula increases growth rates compared to human milk. Donor human milk is more expensive than formula, but has many health benefits. There is insufficient evidence to support a specific duration of donor breast milk. There may be significant implementation concerns (coordination with WIC, paying for the milk bank, etc).

HERC Staff Recommendations: 1. Move T2102 Human breast milk processing, storage and distribution only to: a. Line 2 BIRTH OF INFANT b. Line 11 RESPIRATORY CONDITIONS OF FETUS AND NEWBORN c. Line 16 LOW BIRTH WEIGHT; PREMATURE NEWBORN d. Line 18 FEEDING PROBLEMS IN NEWBORNS e. Line 34 OTHER CONGENITAL ANOMALIES OF MUSCULOSKELETAL SYSTEM i. Modify Line 34 Title to OTHER CONGENITAL ANOMALIES OF MUSCULOSKELETAL SYSTEM ABDOMINAL STRUCTURES f. Line 48 CHRONIC RESPIRATORY DISEASE ARISING IN THE NEONATAL PERIOD g. Line 88 NECROTIZING ENTEROCOLITIS IN FETUS OR NEWBORN

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h. Line 101 CONGENITAL ANOMALIES OF DIGESTIVE SYSTEM AND ABDOMINAL WALL EXCLUDING NECROSIS; CHRONIC INTESTINAL PSEUDO-OBSTRUCTION

2. Adopt a guideline note. Consider one of the options below.

OPTION 1 GUIDELINE NOTE XXX DONOR BREAST MILK FOR HIGH RISK INFANTS Line 2, 11, 16, 18, 34, 48, 88, 101

Donor breast milk is included on these lines for infants up to 6 months of age (adjusted for gestational age) who are low birth weight (<1500g), have underlying gastrointestinal disease (e.g. gastroschisis), are at risk for bronchopulmonary dysplasia, or have intolerance to multiple formulas AND where maternal breast milk is not available or sufficient to meet the infant’s needs, despite lactation support for the mother.

Donor human milk may only be obtained through a milk bank with appropriate quality and infection control standards.

OPTION 2 GUIDELINE NOTE XXX DONOR BREAST MILK FOR VERY LOW BIRTH WEIGHT INFANTS Line 16

Donor breast milk is included on this line for infants up to 3 months of age (adjusted for gestational age) who were low birth weight (<1500g), and where maternal breast milk is not available or sufficient to meet the infants’ needs, despite lactation support for the mother.

Donor human milk may only be obtained through a milk bank with appropriate quality and infection control standards.

Human Donor Breast Milk, Issue #1447 Page 9

BREASTFEEDING MEDICINE Volume 9, Number 6, 2014 Original Articles ª Mary Ann Liebert, Inc. DOI: 10.1089/bfm.2014.0024

Greater Mortality and Morbidity in Extremely Preterm Infants Fed a Diet Containing Cow Milk Protein Products

Steven A. Abrams,1 Richard J. Schanler,2,3 Martin L. Lee,4 David J. Rechtman,4 and the Prolacta Study Group5

Abstract

Background: Provision of human milk has important implications for the health and outcomes of extremely preterm (EP) infants. This study evaluated the effects of an exclusive human milk diet on the health of EP infants during their stay in the neonatal intensive care unit. Subjects and Methods: EP infants <1,250 g birth weight received a diet consisting of either human milk fortified with a human milk protein-based fortifier (HM) (n = 167) or a diet containing variable amounts of milk containing cow milk-based protein (CM) (n = 93). Principal outcomes were mortality, necrotizing enterocolitis (NEC), growth, and duration of parenteral nutrition (PN). Results: Mortality (2% versus 8%, p = 0.004) and NEC (5% versus 17%, p = 0.002) differed significantly between the HM and CM groups, respectively. For every 10% increase in the volume of milk containing CM, the risk of sepsis increased by 17.9% ( p < 0.001). Growth rates were similar between groups. The duration of PN was 8 days less in the subgroup of infants receiving a diet containing <10% CM versus ‡10% CM ( p < 0.02). Conclusions: An exclusive human milk diet, devoid of CM-containing products, was associated with lower mortality and morbidity in EP infants without compromising growth and should be considered as an approach to nutritional care of these infants.

Introduction reported.4,5 The current report combines the original individual subject results from these studies to provide a compre- uman milk provides important advantages to health hensive evaluation of the risk associated with the exposure of outcomes of extremely preterm (EP) infants. The emer- H EP infants to cow milk protein. gence of donor human milk to support policies recommending its use has increased rapidly in the United States and throughout Subjects and Methods the world.1,2 However, the use of human milk as a primary nutrition An exclusively human milk diet was evaluated in two source in EP infants requires that the milk be fortified with clinical trials of EP infants, defined as those born at <1,250 g nutrients, especially protein and micronutrients, to achieve birth weight.4,5 Both trials used the same approach to feeding adequate growth, body composition, and micronutrient status.3 and evaluation of outcomes. The first of these trials,4 con- Currently, most EP infants receive some cow milk-based cluded in 2008, involved infants at 12 centers, all but one of protein (CM), either as their primary diet via infant formula or these in the United States, whose mothers had committed to as a multinutrient fortifier directly added to a human milk- providing them with their milk during the neonatal intensive based diet. A human milk protein-based fortifier (HM) for care unit stay. In brief, infants were randomly assigned to human milk (Prolact+ H2MF; Prolacta Bioscience, City of either an exclusive human milk diet (mother’s own milk or Industry, CA) has been developed. The effect of an exclusive donor human milk) that included a human milk-based human human milk diet on key outcomes in EP infants has been milk fortifier or to a routine approach in which mother’s own

1Children’s Nutrition Research Center, U.S. Department of Agriculture, Agricultural Research Service; and Department of Pediatrics, Baylor College of Medicine, Houston, Texas. 2Neonatal-Perinatal Medicine, Cohen Children’s Medical Center of New York, Manhasset, New York. 3Hofstra North Shore–LIJ School of Medicine, Hempstead, New York. 4Prolacta Bioscience, City of Industry, California. 5The H2MF Study Group is listed in the Appendix. This study is registered at ClinicalTrials.gov with clinical trial registration number NCT00506584.

281 282 ABRAMS ET AL. milk was fortified with a cow milk-based fortifier containing assigned to only human milk protein are designated as Group cow milk protein. In that group, if mother’s own milk was not HM (human milk fortified with a human milk protein-based available, a cow milk-based infant formula product was used fortifier), and those who were assigned to receive any cow to supplement the mother’s own milk, but donor human milk milk protein, either as human milk fortifier or infant formula, was not provided. are designated as Group CM. The second trial5 was completed in 2010 and included Descriptive statistics for quantitative data were used to infants whose mothers, for any reason, were unable or un- summarize the characteristics of the two groups on a uni- willing to provide their milk during the neonatal intensive variate basis. These included mean – SD for nonskewed data care unit stay. In that trial, infants were assigned randomly to and median – interquartile range for skewed data (e.g., milk receive either an all human milk-based diet using donor intake). The groups were compared using the nonparametric human milk and human milk-based human milk fortifier Wilcoxon rank-sum test. The chi-squared test for homoge- (Prolact + ) or cow milk-based formula products. The proto- neity or Fisher’s exact test (if the expected frequencies in any col, other than feeding assignments and blinding, and study given cell were less than 5) was used to compare the pro- end points were the same as for the first trial. portions in the two groups from a univariate perspective. Taken together, these two trials provided a cohort of 260 EP Ninety-five percent confidence intervals were calculated us- infants who received a diet that ranged from 100% cow milk to ing large sample (normal distribution) methods for the dif- 100% human milk. The preceding articles4,5 reported the results ference in outcomes between the CM and HM groups, of each of the trials as analyzed by treatment group assignment. including necrotizing enterocolitis (NEC)/surgical NEC and The results being reported here represent the post hoc analysis sepsis risk, and growth velocities. For mortality, an exact of these two randomized clinical trials and are, in a sense, a calculation of the 95% confidence interval for the difference meta-analysis of those sets of data. Of course, the individual in risk was based on the Blythe–Still–Casella method.6 For data points are available, making this a more detailed evalua- parenteral nutrition (PN) days, because of the censoring in tion than in the typical meta-analysis. Here, the complete cohort this variable, the method of Kaplan and Meier7 was used to data were combined and analyzed in two ways. First, the results estimate the distribution of these events, and the formula of of the two studies were combined to investigate differences Greenwood8 was used to help in the determination of the 95% between infants receiving any cow milk-based nutrition in their confidence interval for the difference in medians. diet and infants receiving only a 100% human milk diet (no Multivariate binary logistic regression was used to evalu- cow milk-based nutrition). Second, taking advantage of the ate key end points, such as the occurrence of NEC, NEC larger number of patients and broader range of exposures to surgery, and sepsis. These models were used to evaluate the cow milk-based products, the combined results were analyzed effect of the amount of the diet from cow milk sources using to determine if any of the observed differences in outcome was odds ratios and 95% confidence intervals. The significance of attributed to the proportion of human milk or cow milk-based the regression coefficients was assessed by the usual Wald’s product received during the study period. Z-statistic. In addition, adjustments for key covariates were All analyses were based on the intent-to-treat designation, incorporated into the models. For NEC and surgical NEC, we except as specifically noted. Infants in the two trials who were used Apgar scores, gestational age, use of antenatal steroids,

Table 1. Patient Characteristics Parameter Group CM (n = 93) Group HM (n = 167) p value Gender (male) 47 (51%) 69 (41%) 0.15a Completed study 70 (75%) 134 (80%) 0.35a Transferred to another hospital 16 (17%) 21 (13%) 0.10a Withdrew consent 0 2 (1%) 0.54b Race (black) 21 (23%) 50 (30%) 0.22a BPD 28 (30%) 50 (30%) 0.98a SGA 10 (11%) 15 (9%) 0.36a Prenatal steroids 71 (82%) 128 (81%) 0.83a Postnatal steroids 23 (30%) 39 (28%) 0.71a Apgar score < 6 11 (12%) 13 (8%) 0.28a Mechanical ventilation at study entry 53 (76%) 105 (76%) 0.95a Birth weight (mean – SD) 938 – 200 939 – 192 0.97c GA (mean – SD) 27 – 227– 2 0.85c Volume (mL) [median (25th, 75th percentile)] Mother’s milk 2,102 (1, 7,174) 1943 (127, 6,960) 0.96c Donor human milk 0 883 (0, 4,581) Formula 2,109 (54, 5,764) Total milk intake 7,190 (4,402, 10,008) 8,169 (5,331, 11,016) 0.13c

aBy chi-squared test. bBy Fisher’s exact test. cBy Wilcoxon rank-sum test. BPD, bronchopulmonary dysplasia; CM, milk containing cow milk-based protein; GA, gestational age; HM, human milk fortiﬁed with a human milk protein-based fortiﬁer; SGA, small for gestational age. COW MILK PROTEIN AFFECTS OUTCOMES IN EP INFANTS 283

Table 2. Outcome of Study Infants Group CM (n = 93) Group HM (n = 167) p value 95% CI (difference) Mortality 7/93 (8%) 3/167 (2%) 0.04 0.3% to 13% NEC 16/93 (17%) 9/167 (5%) 0.002 2.4% to 21.3% Surgical NEC 11/93 (12%) 2/167 (1%) 0.0003 4.4% to 18.9% Sepsis 32/93 (34%) 50/167 (30%) 0.46 - 7.1% to 16.6% TPN (median days)a 25 23 0.26 - 2to5 Weight (g/kg/day) 13.6 – 4.1 14.9 – 7.2 0.11 - 0.1 to 2.7 Length (cm/week) 0.89 – 0.45 0.97 – 0.35 0.12 - 0.02 to 0.19 FOC (cm/week) 0.73 – 0.23 0.77 – 0.22 0.10 - 0.01 to 0.11

aFrom the Kaplan and Meier7 estimate. CI, confidence interval; CM, milk containing cow milk-based protein; FOC, fronto-occipital circumference; NEC, necrotizing enterocolitis; HM, human milk fortified with a human milk protein-based fortifier; TPN, total parenteral nutrition.

African American race, and presence of bronchopulmonary clinical outcomes. However, most importantly, significantly dysplasia because each of these has been previously identi- lower mortality ( p = 0.04), risk of NEC ( p = 0.002), and NEC fied as potential risk factors for NEC.9–11 For sepsis, the requiring surgery within 2 weeks of diagnosis ( p = 0.0003) were adjustment covariates were birth weight, days of PN, days on seen in Group HM versus Group CM. a central line, days on a ventilator, and Apgar score. Again, The incidence of NEC, NEC requiring surgery, and sepsis these are known risk factors for the development of sepsis in were evaluated using a multivariate logistic model to evalu- this population.12–14 In all cases a p value of 5% or less was ate whether the percentage of the diet containing cow milk set as the definition of statistical significance. protein had an impact on those outcomes. Potentially miti- Informed written consent was obtained from parents sep- gating covariates were included in the model. For the two arately for each trial after review and approval of the In- NEC models these included Apgar score, gestational age, stitutional Review Board for Human Subject Research at receipt of antenatal steroids, black race, and presence of each site. bronchopulmonary dysplasia. The results of these models are given in Table 3. The percentage of diet containing cow Results milk was a significant predictor of NEC ( p = 0.047) and NEC surgery ( p = 0.01). The other covariates, although Characteristics of the study subjects and study outcomes are considered to be risk factors for NEC and NEC surgery, did given in Tables 1 and 2. The patient populations were not sig- not mitigate this effect. The odds ratios for cow milk per- nificantly different with respect to characteristics and various centage can be interpreted as follows: for each 10% (an incremental value selected to allow ease of interpretation of Table 3. Multivariate Logistic Models the odds ratios from the regression models) increase in the for Necrotizing Enterocolitis (NEC) and Surgical intake of other than an exclusive human milk diet, the risk of NEC as a Function of the Percentage NEC increases by 11.8% (95% confidence interval, 0.2– of the Diet Containing Cow Milk Protein 24.8%), and the risk of surgical NEC increases by 21% (95% confidence interval, 4.2–39.6%). The multivariate Odds ratio (95% model for sepsis risk as a function of the percentage of diet Parameter confidence interval) p value from cow milk is given in Table 4. The key potentially All NECa mitigating covariates in this model included Apgar score, % dietary volume from 1.01 (1.00, 1.02) 0.047 birth weight, PN duration, central line days, and ventilation cow milk Apgar score 1.12 (0.82, 1.52) 0.48 GA 0.86 (0.68, 1.10) 0.22 Table 4. Multivariate Logistic Models Antenatal steroids 1.10 (0.34, 3.55) 0.87 for Sepsis as a Function of the Percentage Black race 0.76 (0.29, 2.03) 0.59 of the Diet Containing Cow Milk Protein BPD 0.84 (0.30, 2.33) 0.74 Surgical NECb Odds ratio (95% % dietary volume from 1.02 (1.004, 1.03) 0.01 Parameter confidence interval) p value cow milk Apgar score 1.29 (0.80, 2.09) 0.30 % dietary volume 1.02 (1.01, 1.025) 0.00006 GA 0.79 (0.56, 1.12) 0.19 from cow’s milk Antenatal steroids 0.82 (0.16, 4.28) 0.81 Birth weight 0.999 (0.997, 1.001) 0.21 Black race 1.20 (0.27, 5.31) 0.81 TPN days 1.04 (1.01, 1.06) 0.009 BPD 0.98 (0.24, 3.92) 0.97 Central line days 1.02 (0.996, 1.04) 0.10 Ventilation days 0.99 (0.98, 1.005) 0.19 aFit of the regression model: pseudo-R2 = 0.039, area under the Apgar score 1.03 (0.85, 1.24) 0.80 receiver operator characteristic curve = 0.65. bFit of the regression model: pseudo-R2 = 0.087, area under the Fit of the regression model: pseudo-R2 = 0.15, area under the receiver operator characteristic curve = 0.70. receiver operator characteristic curve = 0.77. BPD, bronchopulmonary dysplasia; GA, gestational age. TPN, total parenteral nutrition. 284 ABRAMS ET AL.

FIG. 1. Inverse empirical cumulative distribution of sepsis as a function of the amount of nonhuman milk in the diet. days. The percentage of diet from cow milk was signifi- The results of this analysis indicate a significant effect on cantly associated with the risk of sepsis ( p = 0.00006). For overall mortality as well as sepsis that was not identified in each 10% increase in the intake of other than an exclusive the individual studies previously reported.4,5 The combined human milk diet, there was a 17.9% increase in risk in sepsis studies demonstrate a dose-related effect of nonhuman milk (95% confidence interval, 8.8–27.8%). The overall rela- intake in increasing negative patient outcomes. Furthermore, tionship between the risk of sepsis and amount of nonhuman by including infants with a range of cow milk protein intake, milk is shown in Figure 1 as an inverse empirical cumulative we have shown a significant benefit to using very minimal distribution function. cow milk protein on the duration of PN, a measure of overall We did not find any overall effect on length of time for PN. morbidity in EP infants. However, in a subgroup analysis of infants receiving <10% (a In interpreting these findings, clinicians should recognize reasonably small number) of their diet as formula (n = 182), that there is firm support to the American Academy of Pe- the number of PN days was lower than in the subgroup diatrics and other statements regarding the importance of receiving ‡10% of the diet as formula (n = 78): 21 versus 29 human milk for preterm infants. Efforts should be developed days ( p = 0.02). The incidence of sepsis also was signifi- to provide adequate donor milk to supplement mother’s own cantly lower in the <10% formula group (24% versus 49% milk so that these goals can be achieved. [p < 0.0001]), as was the percentage of NEC (6% versus 18% [p < 0.001]) and NEC surgery (3% versus 10% [p = 0.01]). Conclusions The implications of these data are that efforts should be Discussion extended to provide as much human milk as possible to high- We have shown that provision of an exclusively human milk risk EP infants. The Surgeon General has advocated for ex- diet during the early postnatal period, a diet devoid of cow milk panding the use of donor milk that is pasteurized and safely protein, is associated with lower risks of death, NEC, NEC providedtosuchinfants.1 Efforts to enhance the availability requiring surgery, and sepsis in EP infants. This information is and affordability of pasteurized donor human milk should be necessary to calculate a cost:benefit ratio so that healthcare increased. Our data suggest that the use of an exclusively hu- teams can support the optimization of nutritional outcomes in man milk-based diet, using a nutritionally appropriate human EP infants. The cost of major complications of extreme pre- milk-based fortifier, should be considered for all EP infants. maturity, such as sepsis and NEC, is high, typically more than $250,000 for each case of NEC that requires surgery.15 Life- Acknowledgments time costs are likely much higher because of the increased risk Prolacta Bioscience paid for the clinical studies discussed of long-term neurodevelopmental problems in infants who in this article. have had NEC requiring surgery.16 These outcomes are the major drivers of costs and long-term morbidity in this popu- Disclosure Statement lation, and their avoidance is a principal goal of contemporary neonatal care. A recent analysis confirmed that human milk D.L.R. and M.J.L. are employees of Prolacta Bioscience. costs are minimal compared with the costs of the major mor- S.A.A. and R.J.S. declare no competing financial interests bidities in very low birth weight infants.17 exist. COW MILK PROTEIN AFFECTS OUTCOMES IN EP INFANTS 285

References 12. Ozkan H, Cetinkaya M, Koksal N, et al. Culture-proven neonatal sepsis in preterm infants in a neonatal intensive care 1. U.S. Department of Health and Human Services. The Sur- unit over a 7 year period: Coagulase-negative Staphylo- geon General’s Call to Action to Support Breastfeeding. coccus as the predominant pathogen. Pediatr Int 2014;56: Washington, DC: Office of the Surgeon General, U.S. 60–66. Department of Health and Human Services, 2011. 13. Leal YA, Alvarez-Nemegyei J, Vela´zquez JR, et al. Risk 2. Section on Breastfeeding. Breastfeeding and the use of factors and prognosis for neonatal sepsis in southeastern human milk. Pediatrics 2012;129:e827–e841. Mexico: Analysis of a four-year historic cohort follow-up. 3. Schanler RJ. Evaluation of the evidence to support current BMC Pregnancy Childbirth 2012;12:48. recommendations to meet the needs of premature infants: The 14. Troger B, Gopel W, Faust K, et al. Risk for late-onset role of human milk. Am J Clin Nutr 2007;85:625S–628S. blood-culture proven sepsis in very-low-birth weight in- 4. Sullivan S, Schanler RJ, Kim JH, et al. An exclusively fants born small for gestational age: A large multicenter human milk-based diet is associated with a lower rate of study from the German Neonatal Network. Pediatr Infect necrotizing enterocolitis than a diet of human milk and Dis J 2014;33:238–243. bovine milk-based products. J Pediatr 2010;156:562–567. 15. Ganapathy V, Hay JW, Kim JH. Costs of necrotizing en- 5. Cristofalo EA, Schanler RJ, Blanco CL. Randomized trial of terocolitis and cost-effectiveness of exclusively human exclusive human milk versus preterm formula diets in ex- milk-based products in feeding extremely premature in- tremely premature infants. J Pediatr 2013;163:1592–1595. fants. Breastfeed Med 2012;7:29–37. 6. Blyth CR, Still HA. Binomial confidence intervals. JAm 16. Ganapathy V, Hay JW, Kim JH, et al. Long term healthcare Stat Assoc 1983;78:108–116. costs of infants who survived neonatal necrotizing entero- 7. Kaplan EL, Meier P. Nonparametric estimation from in- colitis: A retrospective longitudinal study among infants complete observations. J Am Stat Assoc 1958;53:457–481. enrolled in Texas Medicaid. BMC Pediatr 2013;13:127. 8. Greenwood M. The Natural Duration of Cancer. Reports 17. Johnson TJ, Patel AL, Bigger HR, et al. Economic benefits on Public Health and Medical Subjects. Vol. 33. London: and costs of human milk feedingss: A strategy to reduce the Her Majesty’s Stationery Office, 1926:1–26. risk of prematurity-related morbidities in very-low-birth- 9. Wo´jkowska-Mach J, Ro´zan_ ´ska A, Borszewska-Kornacka weight infants. Adv Nutr 2014;5:207–212. M, et al. Necrotising enterocolitis in preterm infants: Epi- demiology and antibiotic consumption in the Polish neo- natology network neonatal intensive care units in 2009. Address correspondence to: PLoS One 2014;9:e92865. Steven A. Abrams, MD 10. Carter BM, Holditch-Davis D. Risk factors for necrotizing Department of Pediatrics enterocolitis in preterm infants: How race, gender, and health Baylor College of Medicine status contribute. Adv Neonatal Care 2008;8:285–290. 1100 Bates Street 11. Guthrie SO, Gordon PV, Thomas V, et al. Necrotizing Houston, TX 77030 enterocolitis among neonates in the United States. J Peri- natol 2003;23:278–285. E-mail: [email protected]

Appendix The H2MF Study Group is composed of the following Ursula Kiechl Kohlendofer, MD, Pediatrics, Innsbruck investigtors (listed alphabetically): Cynthia L. Blanco, MD, Medical University, Innsbruck, Austria; Jae H. Kim, MD, Pediatrics, University of Texas Health Science Center, San PhD, Pediatrics, University of California, San Diego Medical Antonio, TX; Gary M. Chan, MD, Pediatrics, University of Center, San Diego, CA; Nirupama Laroia, MD, Pediatrics, Utah Medical Center, Salt Lake City, UT; C. Michael Cotten, University of Rochester, Rochester General Hospital, Ro- MD, MHS, Pediatrics, Duke University Medical Center, chester, NY; Alan Lucas, MD, MRC Child Nutrition Re- Durham, NC; Elizabeth A. Cristofalo, MD, MPH, Pediatrics, search Center, Institute of Child Health, London, United Johns Hopkins School of Medicine, Baltimore, MD; Golde Kingdom; Aloka L. Patel, MD, Pediatrics, Rush University Dudell, MD, Pediatrics, Children’s Hospital and Research Medical Center, Chicago, IL; Sandra Sullivan, MD, Pedia- Center, Oakland, CA; Richard A. Ehrenkranz, MD, Pedia- trics, University of Florida, Gainesville, FL; and Rudolph trics, Yale University School of Medicine, New Haven, CT; Trawoeger, MD, Pediatrics, Innsbruck Medical University. POLICY STATEMENT Organizational Principles to Guide and Define the Child Health Care System and/or Improve the Health of all Children

Donor Human Milk for the High- Risk Infant: Preparation, Safety, and Usage Options in the United States COMMITTEE ON NUTRITION, SECTION ON BREASTFEEDING, COMMITTEE ON FETUS AND NEWBORN

The use of donor human milk is increasing for high-risk infants, primarily abstract for infants born weighing <1500 g or those who have severe intestinal disorders. Pasteurized donor milk may be considered in situations in which the supply of maternal milk is insuffi cient. The use of pasteurized donor milk This document is copyrighted and is property of the American is safe when appropriate measures are used to screen donors and collect, Academy of Pediatrics and its Board of Directors. All authors have store, and pasteurize the milk and then distribute it through established fi led confl ict of interest statements with the American Academy of Pediatrics. Any confl icts have been resolved through a process human milk banks. The use of nonpasteurized donor milk and other forms approved by the Board of Directors. The American Academy of of direct, Internet-based, or informal human milk sharing does not involve Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication. this level of safety and is not recommended. It is important that health Policy statements from the American Academy of Pediatrics benefi t care providers counsel families considering milk sharing about the risks of from expertise and resources of liaisons and internal (AAP) and bacterial or viral contamination of nonpasteurized human milk and about external reviewers. However, policy statements from the American Academy of Pediatrics may not refl ect the views of the liaisons or the the possibilities of exposure to medications, drugs, or herbs in human milk. organizations or government agencies that they represent.

Currently, the use of pasteurized donor milk is limited by its availability The guidance in this statement does not indicate an exclusive course and affordability. The development of public policy to improve and expand of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. access to pasteurized donor milk, including policies that support improved All policy statements from the American Academy of Pediatrics governmental and private ﬁ nancial support for donor milk banks and the automatically expire 5 years after publication unless reafﬁ rmed, use of donor milk, is important. revised, or retired at or before that time. DOI: 10.1542/peds.2016-3440

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). INTRODUCTION Copyright © 2017 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they do not have Human milk provides health benefits for all newborn infants but is of a ﬁ nancial relationship relevant to this article to disclose. particular importance for high-risk infants, especially those born with FUNDING: No external funding. very low birth weight (<1500 g). Donor human milk also can be beneficial POTENTIAL CONFLICT OF INTEREST: The authors have indicated they to supplement the mother’s own milk when necessary. The evidence to have no potential conﬂ icts of interest to disclose. support the use of donor human milk has been reviewed, 1 – 6 and recent studies 7 – 9 support health benefits for its use in infants with a birth weight <1500 g, especially in decreasing rates of necrotizing enterocolitis. To cite: AAP COMMITTEE ON NUTRITION, AAP SECTION ON BREASTFEEDING, AAP COMMITTEE ON FETUS AND NEWBORN. Donor milk banks represent a safe and effective approach to obtaining, Donor Human Milk for the High-Risk Infant: Preparation, pasteurizing, and dispensing human milk for use in NICUs and other Safety, and Usage Options in the United States. Pediatrics. 2017;139(1):e20163440 settings. However, accessibility to donor milk in the United States

Downloaded from www.aappublications.org/news by guest on September 2, 2018 PEDIATRICS Volume 139 , number 1 , January 2017 :e 20163440 FROM THE AMERICAN ACADEMY OF PEDIATRICS continues to be substantially and these have been reviewed this statement, the processes used in limited in terms of supply, cost, extensively. 1, 3, 11 The Holder pasteurization of donor human milk and distribution. Because of these pasteurization method uses heating are highly effective in removing viral limitations, some parents have at 62.5°C for 30 minutes and is the infectious contaminants. 10 –14 Human chosen to exchange human milk that primary method used by HMBANA milk banks vary in their approach to is not pasteurized or handled by milk banks. One commercial milk bacterial screening of incoming milk, an established milk bank with each bank, Medolac Laboratories (Lake but postpasteurization bacteriologic other (milk sharing). This report Oswego, OR), uses a different thermal cultures are performed routinely. reviews the preparation, safety, and pasteurization system. Published data 10, 11 have revealed a usage options for donor human milk very low or unmeasurable level of in the United States. Distribution infectious contaminants. Families In the United States and Canada, and caregivers may be reassured most donor milk is distributed by that, at the time of this publication, PREPARATION OF DONOR HUMAN MILK, established milk banks to NICUs. there are no reported cases of PASTEURIZATION, AND DISTRIBUTION Each milk bank and/or processing pasteurized donor human milk The number of human milk banks center has policies, including causing an infection with hepatitis in the United States is increasing. cost-related guidelines, for this viruses or HIV and that the likelihood Currently, there are 20 donor milk distribution. The distribution of of this type of infection occurring in banks in the United States and 4 in donor milk may be subject to federal a neonate given donor human milk is Canada that pasteurize milk as part or state guidelines in some situations, extremely small. of a professional organization for but at the time of this publication, With regard to noninfectious supporters of nonprofit human milk there are no restrictions on the use of contaminants, although these can banking, the Human Milk Banking pasteurized donor human milk in any be difficult to completely eliminate, Association of North America state in the United States. the pooling process with donor milk (HMBANA); 7 others are in various Frozen donor human milk is makes it very unlikely that these stages of planning and development distributed by using shipping will represent a significant exposure (www. hmbana. org). In addition, guidelines established by the risk. An exception to this is cow milk several commercial (for-profit) milk banks. Receiving hospitals protein, which is present in the milk human milk banks collect, pasteurize, are provided guidance related to of mothers who include dairy in their and distribute donor human milk but temperature and other storage diet. The contamination of human are not part of HMBANA. conditions for the milk, and these milk purchased via the Internet with may be subject to state and local cow milk (up to a 10% dilution of Donor Human Milk Collection regulations. Hospitals that use the human milk) has recently been 15 HMBANA has established policies frozen donor human milk must have reported. for donor human milk collection, as properly regulated freezers and other In contrast, informal direct milk do commercial human milk banks. 10 methods for handling and tracking sharing without pasteurization These have been described in the donor milk. exposes infants to a range literature 1, 2 and in the policies of possible risks, including usually found on the Web sites of the bacterial contamination 16 and individual milk banks. Guidelines for SAFETY viral transmission, including donors include completion of a health Human milk is a biological product; cytomegalovirus, hepatitis viruses, screen, blood serologic testing, and therefore, whether from an infant’s and HIV. 17 Individual screening detailed instructions on collecting, own mother or a donor mother, is performed by some Internet- storing, and shipping milk. 10 In there will always be concerns based groups that organize contrast, direct milk sharing or about contamination. Possible direct milk sharing, but these are other forms of milk collection and contaminants are infectious agents, neither consistently applied nor distribution are extremely variable including both bacteria and viruses, documented. Furthermore, even with in the screening of donors and and contamination with other serologic blood testing, infectious the methods of milk storage and substances, most notably toxic complications remain a significant transportation. components in the environment (eg, risk in unpasteurized milk. pesticides, mercury, medications, Because direct milk sharing is often Pasteurization drugs, or herbs). arranged by using milk from a single Several methods may be used to Although a detailed description of donor mother, other contaminants, pasteurize donor human milk, each of these is beyond the scope of such as medications or drugs, may be

Downloaded from www.aappublications.org/news by guest on September 2, 2018 2 FROM THE AMERICAN ACADEMY OF PEDIATRICS a higher risk than with pooled milk its pasteurization before use. Donor There are no clear guidelines for products. It is unknown what effects human milk may have a lower discontinuing the use of donor paying women for milk might have protein and energy content than the human milk in an infant <1500 g on these risks. milk of mothers of preterm infants, in birth weight when the volume of addition to lost bile salt–dependent mother’s milk is not adequate. A Growth Issues lipase activity, which may affect range of postmenstrual ages from Early studies in the use of donor fortification strategies and growth. 32 to 36 weeks is commonly used human milk for small preterm infants Alternative sterilization methods to in the United States, because this showed relatively slow growth. preserve innate bioactive properties range covers the highest risk period More recent studies 18 – 20 showed and to decrease the cost of preparing for necrotizing enterocolitis. Further improved growth outcomes, which donor milk need investigation. research is needed to clarify the may be attributable both to a greater optimal timing of discontinuing availability of donor milk with higher The principal goal for infants with donor human milk. Breastfeeding nutrient content and to widely used very low birth weight is the provision should be encouraged during strategies for fortifying donor milk. of the mother’s own milk, with donor hospitalization for these infants to However, these are retrospective human milk as a bridge or support enhance the likelihood of successful cohort studies, and further studies while the mother’s milk is made breastfeeding after hospital are needed. Strategies for fortifying available or increasing in volume. It discharge.28 donor human milk include both is important to encourage and assist commercial human milk–based and mothers to pump or express and Other Intestinal Diseases cow milk protein–based fortifiers. provide their own milk whenever Fewer data are available regarding Both types of fortifiers have been possible and at the maximum volume the use of donor human milk in other shown to lead to appropriate growth, possible. Although the use of donor high-risk infants, including infants and the use of donor human milk human milk has not been shown to with abdominal wall defects, such does not need to be limited on the decrease the frequency or volume as gastroschisis or omphalocele, and basis of growth concerns in most of mother’s own milk to NICU other conditions, such as congenital high-risk infants. Growth monitoring patients, 9, 23, 26, 27 vigilance and heart disease. Nonetheless, some is always paramount for infants, and education are needed regarding the infants with these conditions or other human milk fortification is needed superiority of mother’s own milk neonatal disorders may benefit from for all infants with very low birth relative to donor human milk. donor human milk either because of weight. a direct effect on intestinal growth or improved feeding tolerance. 29 Loss of Nutrients and USAGE In these cases, payers may expect Antiinﬂ ammatory Properties documentation of intolerance to The process of pasteurization Infants <1500 g Birth Weight specialized infant formulas and the destroys cells, such neutrophils and medical necessity for donor human stem cells, and affects macronutrients The supply of donor human milk milk before providing payment and antiinflammatory factors. currently available in the United for human milk at home or in the In addition, pasteurization can States and Canada is less than hospital. eliminate bacterial strains with optimal. Although a goal of providing probiotic properties. Substantial donor milk to supplement the Outpatient (Home) Versus Hospital evidence describing these losses mother’s milk for all preterm infants Distribution is available. 21 –25 Bioactive has been described, 5 this goal may The vast majority of donor human components of human milk, including not be achievable for a period of time; milk distributed from HMBANA milk lactoferrin and immunoglobulins, thus, prioritization may be needed banks is distributed to hospitals are substantially decreased by for infants weighing <1500 g. for internal use in NICU patients. pasteurization, but there is much less Relatively few data are available on However, in some cases, donor effect on macro- or micronutrients, whether this would include small human milk may be provided for including vitamins. 22, 23 Overall, for gestational age infants, such as home use from HMBANA milk banks. 1 the benefits of improved feeding those who are >32 to 33 weeks’ In cases of limited supply, health tolerance and clinical outcomes postmenstrual age at birth who also care providers, such as community support the concept that some weigh <1500 g; but, in general, the pediatricians and neonatologists, nutrient losses of bioactive primary guide for use is birth weight, can work together to establish components should not limit the use not gestational age, in prioritizing priority for such use relative to of donor human milk or preclude donor milk use. local NICU needs. A pediatrician/

Downloaded from www.aappublications.org/news by guest on September 2, 2018 PEDIATRICS Volume 139 , number 1 , January 2017 3 neonatal clinician generally will state of research regarding the substances, including cow milk need to be involved in ordering benefits of using human milk to protein. and supervising the use of donor decrease the risks of complications 5. The use of donor human milk milk in any outpatient setting. Clear such as necrotizing enterocolitis. This in appropriate high-risk infants documentation as to the reason for discussion may include appropriate should not be limited by an the use of donor human milk at home warnings about risks related to individual’s ability to pay. Policies is recommended. infectious complications when are needed to provide high-risk human milk is shared or distributed infants access to donor human outside of established milk banks. milk on the basis of documented OTHER POLICY ISSUES Neonatologists and other health medical necessity, not financial care providers should advocate Cost Reimbursement status. for policies of full disclosure of A major limitation in the use of donor the risks and benefits related to LEAD AUTHORS human milk is the cost of providing direct or informal milk sharing Steven A. Abrams, MD, FAAP this milk to hospitals or to families. without pasteurization. Hospitals Susan Landers, MD, FAAP Reimbursement for donor milk is should develop standards such Lawrence M. Noble, MD, FAAP inconsistent between states and that all human milk given to infants Brenda B. Poindexter, MD, FAAP often between sources of payment. meets appropriate standards for Health care providers can advocate preparation and distribution and that COMMITTEE ON NUTRITION, 2015–2016 for the development of public and pasteurization of all donor human Stephen Daniels, MD, PhD, FAAP, Chairperson local hospital policies to enhance milk occurs. Mark Corkins, MD, FAAP Sarah de Ferranti, MD, FAAP the availability and affordability Neville H. Golden, MD, FAAP of donor human milk on the basis Jae H. Kim, MD, PhD, FAAP of evidence. Resources from the SUMMARY OF KEY POINTS Sheela N. Magge, MD, MSCE, FAAP American Academy of Pediatrics and Sarah Jane Schwarzenberg, MD, FAAP 1. Although a mother’s own milk is other groups can also assist those always preferred, donor human LIAISONS involved in the care of neonates in milk may be used for high-risk this discussion. Carrie L. Assar, PharmD, MS – Food and Drug infants when the mother’s milk is Administration The use of donor human milk in not available or the mother cannot Jeff Critch, MD – Canadian Pediatric Society appropriate high-risk infants is provide milk. Priority should be Van Hubbard, MD, PhD – National Institutes of consistent with good health care for given to providing donor human Health 30,31 Kelley Scanlon, PhD – Centers for Disease Control these infants. Policies are needed milk to infants <1500 g birth and Prevention to provide high-risk infants access weight. Valery Soto, MS, RD, LD – US Department of to donor human milk on the basis of Agriculture 2. Human milk donors should be documented medical necessity, not identified and screened by using financial status. STAFF methods such as those currently Debra Burrowes, MHA Federal and State Regulation of Milk used by HMBANA milk banks or Banks and Donor Milk Sharing other established commercial milk SECTION ON BREASTFEEDING EXECUTIVE banks. COMMITTEE, 2015–2016 Legal issues exist regarding the Joan Younger Meek, MD, MS, RD, FAAP, regulation of donor human milk 3. Donor milk should be pasteurized Chairperson banks on both a state and national according to accepted standards. Margreete G. Johnston, MD, MPH, FAAP level. Federal or state guidelines are Postpasteurization testing should Mary Ellen O’Connor, MD, MPH, FAAP needed regarding the preparation, be performed according to Lisa M. Stellwagen, MD, FAAP Jennifer Peelen Thomas, MD, MPH, FAAP handling, and transfer of human internal quality-control guidelines. Julie L. Ware, MD, FAAP milk as well as the operation of 4. Health care providers should Richard J. Schanler, MD, FAAP, Immediate Past donor human milk banks and would discourage families from direct Chair be best accomplished via formal human milk sharing or purchasing regulation by the US Food and Drug STAFF human milk from the Internet Administration with oversight by Ngozi Onyema-Melton, MPH because of the increased risks of the Centers for Disease Control and bacterial or viral contamination COMMITTEE ON FETUS AND NEWBORN, Prevention. of nonpasteurized milk and 2015–2016 Families of high-risk infants should the possibility of exposure to Kristi L. Watterberg, MD, FAAP, Chairperson be fully informed about the current medications, drugs, or other Susan Wright Aucott, MD, FAAP

Downloaded from www.aappublications.org/news by guest on September 2, 2018 4 FROM THE AMERICAN ACADEMY OF PEDIATRICS William E. Benitz, MD, FAAP at: www.pediatrics. org/ cgi/ content/ human milk purchased via the James J. Cummings, MD, FAAP full/ 129/ 3/ e827 Internet. Pediatrics. 2013;132(5). Eric C. Eichenwald, MD, FAAP 7. Sullivan S, Schanler RJ, Kim JH, Available at: www.pediatrics. org/ cgi/ Jay P. Goldsmith, MD, FAAP content/ full/ 132/ 5/ e1227 Brenda B. Poindexter, MD, MS, FAAP et al. An exclusively human milk-based Karen M. Puopolo, MD, PhD, FAAP diet is associated with a lower rate of 17. Lindemann PC, Foshaugen I, Dan L. Stewart, MD, FAAP necrotizing enterocolitis than a diet Lindemann R. Characteristics of of human milk and bovine milk-based breast milk and serology of women LIAISONS products. J Pediatr. 2010;156(4): donating breast milk to a milk bank. 562–7.e1 Arch Dis Child Fetal Neonatal Ed. Erin L. Keels, APRN, MS, NNP – National 2004;89(5):F440–F441 Association of Neonatal Nurses 8. Cristofalo EA, Schanler RJ, Blanco CL, Thierry Lacaze, MD – Canadian Pediatric Society et al. Randomized trial of exclusive 18. Colaizy TT, Carlson S, Saftlas AF, Maria A. Mascola – American College of human milk versus preterm formula Morriss FH Jr. Growth in VLBW infants Obstetricians and Gynecologists diets in extremely premature infants. fed predominantly fortifi ed maternal Tonse N.K. Raju, MD, FAAP – National Institutes of J Pediatr. 2013;163(6):1592–1595, e1 and donor human milk diets: a Health 9. Kantorowska A, Wei JC, Cohen RS, retrospective cohort study. BMC Pediatr. 2012;12:124–133 STAFF Lawrence RA, Gould JB, Lee HC. Impact of donor milk availability 19. Rochow N, Fusch G, Choi A, et al. Jim R. Couto, MA on breast milk use and necrotizing Target fortifi cation of breast milk enterocolitis rates. Pediatrics. with fat, protein, and carbohydrates 2016;137(3):e20153123 for preterm infants. J Pediatr. ABBREVIATION 10. Human Milk Banking Association 2013;163(4):1001–1007 HMBANA: Human Milk Banking of North America. Guidelines for 20. Hair AB, Hawthorne KM, Chetta KE, Association of North Establishment and Operation of a Abrams SA. Human milk feeding America Donor Human Milk Bank. 16th ed. supports adequate growth in infants Fort Worth, TX: Human Milk Banking ≤ 1250 grams birth weight. BMC Res Association of North America; 2011 Notes. 2013;6:459–467 11. Czank C, Prime DK, Hartmann B, 21. Garc ía-Lara NR, Vieco DE, De la Cruz- REFERENCES Simmer K, Hartmann PE. Retention B értolo J, Lora-Pablos D, Velasco NU, 1. Landers S, Hartmann BT. Donor human of the immunological proteins of Pallás-Alonso CR. Effect of Holder milk banking and the emergence of pasteurized human milk in relation pasteurization and frozen storage on milk sharing. Pediatr Clin North Am. to pasteurizer design and practice. macronutrients and energy content of 2013;60(1):247–260 Pediatr Res. 2009;66(4):374–379 breast milk. J Pediatr Gastroenterol 2. Arslanoglu S, Ziegler EE, Moro GE; 12. Landers S, Updegrove K. Nutr. 2013;57(3):377–382 World Association of Perinatal Bacteriological screening of donor 22. Garc ía-Lara NR, Escuder-Vieco D, Medicine Working Group on human milk before and after Holder García-Algar O, De la Cruz J, Lora D, Nutrition. Donor human milk in pasteurization. Breastfeed Med. Pallás-Alonso C. Effect of freezing preterm infant feeding: evidence and 2010;5(3):117–121 time on macronutrients and energy recommendations. J Perinat Med. 13. Terpstra FG, Rechtman DJ, Lee ML, content of breastmilk. Breastfeed Med. 2010;38(4):347–351 et al. Antimicrobial and antiviral effect 2012;7(4):295–301 3. Arslanoglu S, Corpeleijn W, Moro G, of high-temperature short-time (HTST) 23. Silvestre D, Miranda M, Muriach et al; ESPGHAN Committee on Nutrition. pasteurization applied to human milk. M, Almansa I, Jareño E, Romero FJ. Donor human milk for preterm infants: Breastfeed Med. 2007;2(1):27–33 Antioxidant capacity of human milk: current evidence and research 14. de Segura AG, Escuder D, Montilla A, effect of thermal conditions for directions. J Pediatr Gastroenterol et al. Heating-induced bacteriological the pasteurization. Acta Paediatr. Nutr. 2013;57(4):535–542 and biochemical modifi cations in 2008;97(8):1070–1074 4. Bertino E, Giuliani F, Baricco M, et al. human donor milk after holder 24. Wada Y, Lönnerdal B. Bioactive Benefi ts of donor milk in the feeding pasteurisation. J Pediatr Gastroenterol peptides released from in vitro of preterm infants. Early Hum Dev. Nutr. 2012;54(2):197–203 digestion of human milk with or 2013;89(suppl 2):S3–S6 15. Keim SA, Kulkarni MM, McNamara K, without pasteurization. Pediatr Res. 5. Quigley M, McGuire W. Formula versus et al. Cow’s milk contamination 2015;77(4):546–553 donor breast milk for feeding preterm of human milk purchased via the 25. Coscia A, Peila C, Bertino E, et al. Effect or low birth weight infants. Cochrane Internet. Pediatrics. 2015;135(5). of Holder pasteurisation on human Database Syst Rev. 2014;4:CD002971 Available at: www.pediatrics. org/ cgi/ milk glycosaminoglycans. J Pediatr 6. Section on Breastfeeding. content/ full/ 135/ 5/ e1157 Gastroenterol Nutr. 2015;60(1):127–130 Breastfeeding and the use of human 16. Keim SA, Hogan JS, McNamara KA, 26. Delfosse NM, Ward L, Lagomarcino milk. Pediatrics. 2012;129(3). Available et al. Microbial contamination of AJ, et al. Donor human milk largely

Downloaded from www.aappublications.org/news by guest on September 2, 2018 PEDIATRICS Volume 139 , number 1 , January 2017 5 replaces formula-feeding of preterm 28. Meier PP, Engstrom JL, Patel AL, Jegier 30. Parker MG, Barrero-Castillero A, Corwin infants in two urban hospitals. BJ, Bruns NE. Improving the use of BK, Kavanagh PL, Belfort MB, Wang CJ. J Perinatol. 2013;33(6):446–451 human milk during and after the NICU Pasteurized human donor milk use 27. Arslanoglu S, Moro GE, Bellù R, stay. Clin Perinatol. 2010;37(1):217–245 among US level 3 neonatal intensive care et al. Presence of human milk 29. Kohler JA Sr, Perkins AM, Bass WT. units. J Hum Lact. 2013;29(3):381–389 bank is associated with elevated Human milk versus formula after 31. Perrine CG, Scanlon KS. Prevalence rate of exclusive breastfeeding gastroschisis repair: effects on time of use of human milk in US advanced in VLBW infants. J Perinat Med. to full feeds and time to discharge. care neonatal units. Pediatrics. 2013;41(2):129–131 J Perinatol. 2013;33(8):627–630 2013;131(6):1066–1071

Downloaded from www.aappublications.org/news by guest on September 2, 2018 6 FROM THE AMERICAN ACADEMY OF PEDIATRICS Donor Human Milk for the High-Risk Infant: Preparation, Safety, and Usage Options in the United States COMMITTEE ON NUTRITION, SECTION ON BREASTFEEDING and COMMITTEE ON FETUS AND NEWBORN Pediatrics originally published online December 19, 2016;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2016/12/15/peds.2 016-3440 References This article cites 30 articles, 6 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2016/12/15/peds.2 016-3440#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Nutrition http://www.aappublications.org/cgi/collection/nutrition_sub Breastfeeding http://www.aappublications.org/cgi/collection/breastfeeding_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

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The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2016/12/15/peds.2016-3440

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2016 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on September 2, 2018 Testicular Hypofunction/Low Testosterone

Question: Should physiologic testicular hypofunction be moved to a lower priority position on the Prioritized List?

Question source: Walter Hardin, Medical Director Tuality Health Alliance

Issue: As many men age, their testosterone levels decrease. Many of these men receive treatment with exogenous testosterone, but there is controversy about the safety and efficacy of testosterone supplementation in men without profoundly low testosterone levels. Men with profoundly low testosterone levels have some type of diagnosis such as hypopituitarism, men who are status post orchiectomy, etc. The FDA recently added wording to the drug label requiring men get information on increased risk of cardiovascular events. Many men have vague complaints as they age, such as fatigue or lower muscle strength, or experience erectile dysfunction, all of which are at times treated with testosterone therapy. The presence of low serum testosterone is 9.0% in men aged 45 to 54 years, 16.5% in men aged 55 to 64 years, and 18.3% in men aged 65 to 74 years. Age related hypogonadism (e.g. lower testosterone in the older male population) is not necessarily a disease and may be asymptomatic and / or may be related or associated with many chronic illnesses.

From the American Urological Association: Hypogonadism is defined as biochemically low testosterone levels in the setting of a cluster of symptoms, which may include reduced sexual desire (libido) and activity, decreased spontaneous erections, decreased energy and depressed mood. Men with hypogonadism may also experience reduced muscle mass and strength and increased body fat. Hypogonadism may also contribute to reduced bone mineral density and anemia.

Currently, FFS P&T PA criteria have no limits on testosterone therapy. Review of private payer and other Medicaid programs find most limit testosterone to men with profoundly low levels or special cases such as treatment of gender dysphoria.

Current Prioritized List status Testicular hypofunction (ICD-10 E29.1) and related diagnoses such as other testicular dysfunction (ICD- 10 E29.8) and testicular dysfunction, unspecified (ICD-10 E29.9) are on line 467 GONADAL DYSFUNCTION, MENOPAUSAL MANAGEMENT

Evidence 1) Xu 2013, Systematic review and meta-analysis of testosterone therapy https://bmcmedicine.biomedcentral.com/track/pdf/10.1186/1741-7015-11-108 a. N=27 trials (2,994 men) i. Only trials last 12+ weeks reporting cardiovascular related events were included b. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). c. The cardiovascular-related event rate was lower in trials funded by the pharmaceutical industry (4% (66/1,651)) than in other trials (8% (114/1,343)). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone

Testicular Hypofunction/Low Testosterone

therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). a. Conclusions: The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular- related events, with corresponding implications for the use of testosterone therapy. 2) Elliott 2017, Systematic review and meta-analysis of testosterone therapy https://bmjopen.bmj.com/content/bmjopen/7/11/e015284.full.pdf a. N=87 RCTs and 51 non randomized studies i. Most were at high or unclear risk of bias, with short duration of treatment and follow b. When compared as a class against placebo, testosterone replacement therapy (TRT) improved quality of life (standardized mean difference (SMD) −0.26, 95% CI −0.41 to – 0.11), libido (SMD 0.33, 95% CI 0.16 to 0.50), depression (SMD −0.23, 95% CI −0.44 to – 0.01) and erectile function (SMD 0.25, 95% CI 0.10 to 0.41). Most individual TRTs were significantly better than placebo at improving libido (6/10). Only one TRT was better than placebo at improving quality of life, and no individual TRTs improved depression or erectile function. There was no increased risk of adverse events, with the exception of withdrawals due to adverse events with the use of some TRTs. c. Conclusion Despite a class effect of improving quality of life, depression, erectile function and libido, major improvements were not observed with the use of any individual product. We observed no statistically significant increase in the risk of adverse events; however, longer term high- quality trials are needed to fully assess the risk of harm. 3) Alexander 2017, Systematic review and meta-analysis of risks of testosterone therapy https://www.amjmed.com/article/S0002-9343(16)31024-5/pdf a. N=39 RCTs, 10 observational studies b. In meta-analysis of data from 30 RCTs, compared with placebo, exogenous testosterone treatment did not show any significant increase in risk of myocardial infarction (odds ratio [OR] 0.87; 95% CI, 0.39-1.93; 16 RCTs), stroke (OR 2.17; 95% CI, 0.63-7.54; 9 RCTs), or mortality (OR 0.88; 95% CI, 0.55-1.41; 20 RCTs). c. CONCLUSIONS: We did not find any significant association between exogenous testosterone treatment and myocardial infarction, stroke, or mortality in randomized controlled trials. The very low quality of the evidence precludes definitive conclusion on the cardiovascular effects of testosterone. 4) Fernandez-Balsells 2010, Systematic review and meta-analysis of risks of testosterone therapy https://academic.oup.com/jcem/article/95/6/2560/2597959 d. N=51 studies i. Low to medium methodological quality ii. Follow up 3 months to 3 years. e. Testosterone treatment was associated with a significant increase in hemoglobin [weighted mean difference (WMD), 0.80 g/dl;95%confidence interval (CI), 0.45 to 1.14] and hematocrit (WMD, 3.18%; 95% CI, 1.35 to 5.01), and a decrease in high-density lipoprotein cholesterol (WMD, -0.49 mg/dl; 95% CI, -0.85 to -0.13). There was no significant effect on mortality, prostate, or cardiovascular outcomes. f. Conclusions: The adverse effects of testosterone therapy include an increase in hemoglobin and hematocrit and a small decrease in high-density lipoprotein cholesterol. These findings are of unknown clinical significance. Current evidence about the safety of

Testicular Hypofunction/Low Testosterone

testosterone treatment in men in terms of patient-important outcomes is of low quality and is hampered by the brief study follow-up.

Expert groups 1) American Urological Association 2015: a. The American Urological Association (AUA) concludes that there is conflicting evidence about the impact of testosterone therapy on cardiovascular risks. Definitive studies have not been performed. The FDA drug safety communication cautions that benefits and risks of testosterone products for low testosterone due to aging are not clearly established. The potential adverse effects of testosterone therapy should be discussed prior to treatment. These include acne, breast swelling or tenderness, increased red blood cell count, swelling of the feet or ankles, reduced testicular size and infertility. Current evidence does not provide any definitive answers regarding the risks of testosterone therapy on prostate cancer and cardiovascular disease, and patients should be so informed. 2) Endocrine Society (Bhasin 2018) https://academic.oup.com/jcem/article/103/5/1715/4939465 a. We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) deficiency and unequivocally and consistently low serum T concentrations. We recommend measuring fasting morning total T concentrations using an accurate and reliable assay as the initial diagnostic test. We recommend confirming the diagnosis by repeating the measurement of morning fasting total T concentrations. b. We recommend T therapy for men with symptomatic T deficiency to induce and maintain secondary sex characteristics and correct symptoms of hypogonadism after discussing the potential benefits and risks of therapy and of monitoring therapy and involving the patient in decision making. c. We recommend against starting T therapy in patients who are planning fertility in the near term or have any of the following conditions: breast or prostate cancer, a palpable prostate nodule or induration, prostate-specific antigen level >4 ng/mL, prostate- specific antigen >3 ng/mL in men at increased risk of prostate cancer (e.g., African Americans and men with a first-degree relative with diagnosed prostate cancer) without further urological evaluation, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia.

Other policies 1) CVS Caremark, depo-testosterone a. Depo-Testosterone (testosterone cypionate injection) will be covered with prior authorization when the following criteria are met: i. The drug is being prescribed for a male patient with congenital or acquired primary hypogonadism (i.e., testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, or orchidectomy) OR ii. The drug is being prescribed for a male patient with congenital or acquired hypogonadotropic hypogonadism (i.e., gonadotropin or luteinizing hormone- releasing hormone [LHRH] deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation) AND

Testicular Hypofunction/Low Testosterone

i. The patient has NOT received testosterone medication in the last 12 months AND ii. The patient had or currently has at least TWO confirmed low testosterone levels according to current practice guidelines or your standard lab reference values OR i. The drug is being prescribed for a male patient with congenital or acquired primary hypogonadism (i.e., testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, or orchidectomy) OR ii. The drug is being prescribed for a male patient with congenital or acquired hypogonadotropic hypogonadism (i.e., gonadotropin or luteinizing hormone- releasing hormone [LHRH] deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation) AND i. The patient has received testosterone medication in the last 12 months AND ii. The patient had or currently has at least ONE confirmed low testosterone level according to current practice guidelines or your standard lab reference values

Other Medicaid policies 1) Washington Medicaid a. Testosterone replacement therapy (TRT) may be considered medically necessary when used for the following conditions: i. Primary Hypogonadism (congenital or acquired) ii. Hypogonadotropic Hypogonadism (congenital or acquired) iii. HIV-associated weight loss iv. Chronic, high-dose glucocorticoid-therapy v. Men with osteoporosis or young men with low trauma fractures vi. Delayed Puberty vii. Metastatic Breast Cancer viii. Transgender Health b. Testosterone Replacement Therapy (TRT) may be considered medically necessary for the treatment of hypogonadism when the patient meets criteria 1–3 of the INCLUSION CRITERIA and none of the EXCLUSION CRITERIA i. Inclusion criteria: 1. Patient is male, 18 years of age or older; AND 2. Patient has had TWO morning (between 8 a.m. to 10 a.m.) tests (at least 1 week apart) at baseline demonstrating low testosterone levels as defined by the following criteria: a. Total serum testosterone level less than 300ng/dL (10.4nmol/L); OR b. Total serum testosterone level less than 350ng/dL (12.1nmol/L) AND free serum testosterone level less than 50pg/mL (or 0.174nmol/L) c. Second morning test should follow excluding reversible illnesses, drugs, and nutritional deficiencies. Providers should also include LH and FSH draws to guide diagnosis as primary or secondary hypogonadism; AND 3. Patient has received ONE of the following diagnoses:

Testicular Hypofunction/Low Testosterone

a. Primary Hypogonadism (congenital or acquired): as defined as testicular failure due to such conditions as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchidectomy, Klinefelter’s syndrome, chemotherapy, trauma, or toxic damage from alcohol or heavy metals; OR b. Hypogonadotropic Hypogonadism (congenital or acquired): as defined by idiopathic gonadotropin or luteinizing hormone- releasing hormone (LHRH) deficiency, or pituitary-hypothalamic injury from tumors, trauma or radiation; OR c. HIV-associated weight loss (defined as <90% of ideal body weight or weight loss of >10% in the last 6 months); OR d. Chronic, high-dose glucocorticoid-therapy (defined as more than 5mg/day of prednisone or equivalent daily for greater than two (2) weeks; OR e. Men with osteoporosis or young men with low trauma fractures c. Exclusion criteria: i. Patient has ANY of the following contraindications: 1. Breast cancer or known or suspected prostate cancer 2. Elevated hematocrit (>50%) 3. Untreated severe obstructive sleep apnea 4. Severe lower urinary tract symptoms 5. Uncontrolled or poorly-controlled heart failure ii. Patient has experienced a major cardiovascular event (such as a myocardial infraction, stroke, acute coronary syndrome) in the past six months iii. Patient has uncontrolled or poorly-controlled benign prostate hyperplasia or is at a higher risk of prostate cancer, such as elevation of PSA after initiating TRT iv. Patient is intending on using testosterone for the indications of delayed puberty, metastatic breast cancer, or for transgender health care (such as hormone replacement therapy) 2) Indiana Medicaid a. Covers testosterone for most cases of low testosterone levels 3) Iowa Medicaid a. Patient is male and 18 years of age or older (or 12 years of age and older for testosterone cypionate); and b. Patient has two (2) morning pre-treatment testosterone levels below the lower limit of the normal testosterone reference range of the individual laboratory used (attach results); and Patient has primary hypogonadism or hypogonadotropic hypogonadism (further defined below) i. Primary hypogonadism (congenital or acquired) caused by testicular failure due to one of the following: cryptorchidism, bilateral torsion, orchitis, vanishing testes syndrome, orchiectomy, Klinefelter’s syndrome, chemotherapy, toxic damage from alcohol or heavy metals Hypogonadotropic hypogonadism: idiopathic gonadotropin or luteinizing hormone-releasing (LHRH) deficiency, pituitary-hypothalamic injury from tumors, trauma, or radiation c. Patient does not have: i. Breast or prostate cancer ii. Palpable prostate nodule or prostate-specific antigen (PSA) > 4ng/mL

Testicular Hypofunction/Low Testosterone

iii. Hematocrit > 50% iv. Untreated severe obstructive sleep apnea v. Severe lower urinary tract symptoms vi. Uncontrolled or poorly controlled heart failure

P&T feedback: Testosterone medications are low cost and are therefore low priority for PA controls.

COO feedback: Some CCOs indicated they would PA testosterone medications, other indicated that when they had PA’s in the past, they approved most and it was not worth the pharmacy team time/effort.

Testicular Hypofunction/Low Testosterone

HERC staff summary: Testosterone therapy for physiologic low testosterone levels have equivocal evidence of effectiveness and evidence of cardiovascular harms, particularly in non-industry sponsored studies. These medications are of low cost. Many private insurers and other state Medicaid programs have restrictions on testosterone therapy for physiologic low testosterone levels.

HERC staff recommendations 1) Add a new guideline to line 467 GONADAL DYSFUNCTION, MENOPAUSAL MANAGEMENT as shown below

GUIDELINE NOTE XXX TESTOSTERONE REPLACEMENT FOR TESTICULAR HYPOFUNCTION Line 467 Testosterone replacement therapy is included on this line for testicular hypofunction or dysfunction only when all of the following inclusion criteria are met and none of the exclusion criteria apply: Inclusion criteria: 1) The patient is a male 18 years of age or older; AND 2) The patient has had TWO morning (between 8 a.m. to 10 a.m.) tests (at least 1 week apart) at baseline demonstrating low testosterone levels as defined by the following criteria: a. Total serum testosterone level less than 300ng/dL (10.4nmol/L); OR b. Total serum testosterone level less than 350ng/dL (12.1nmol/L) AND free serum testosterone level less than 50pg/mL (or 0.174nmol/L); AND 3) Patient has received ONE of the following diagnoses: a. Primary Hypogonadism (congenital or acquired): as defined as testicular failure due to such conditions as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchidectomy, Klinefelter’s syndrome, chemotherapy, trauma, or toxic damage from alcohol or heavy metals; OR b. Hypogonadotropic Hypogonadism (congenital or acquired): as defined by idiopathic gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary-hypothalamic injury from tumors, trauma or radiation Exclusion criteria: 1) Patient has ANY of the following contraindications: a. Breast cancer or known or suspected prostate cancer b. Elevated hematocrit (>50%) c. Untreated severe obstructive sleep apnea d. Severe lower urinary tract symptoms e. Uncontrolled or poorly-controlled heart failure 2) Patient has experienced a major cardiovascular event (such as a myocardial infraction, stroke, acute coronary syndrome) in the past six months 3) Patient has uncontrolled or poorly-controlled benign prostate hyperplasia or is at a higher risk of prostate cancer, such as elevation of PSA after initiating testosterone replacement therapy

This guideline does not apply to testosterone replacement therapy for HIV-associated weight loss, delayed puberty, treatment of metastatic breast cancer, or transgender health.

AUA Position Statement on Testosterone Therapy In a recent drug safety communication the FDA requires manufacturers of approved testosterone products to add labeling information about possible increased risk of heart attack and stroke. The American Urological Association (AUA) concludes that there is conflicting evidence about the impact of testosterone therapy on cardiovascular risks. Definitive studies have not been performed. The FDA drug safety communication cautions that benefits and risks of testosterone products for low testosterone due to aging are not clearly established. Hypogonadism is defined as biochemically low testosterone levels in the setting of a cluster of symptoms, which may include reduced sexual desire (libido) and activity, decreased spontaneous erections, decreased energy and depressed mood. Men with hypogonadism may also experience reduced muscle mass and strength and increased body fat. Hypogonadism may also contribute to reduced bone mineral density and anemia. Testosterone therapy is appropriate treatment for patients with clinically significant hypogonadism, including those with idiopathic clinical hypogonadism that may or may not be age-related, after full discussion of potential adverse effects. Patients should understand that treatment requires follow-up and medical monitoring. Testosterone therapy in the absence of hypogonadism is inappropriate. Increased public awareness about hypogonadism has been stimulated by recent increases in availability and diversity of patient-acceptable forms of testosterone replacement options. Only FDA-approved medications should be used; over-the-counter preparations generally should be avoided based on lack of efficacy and safety data. The management of hypogonadism should start with careful evaluation by a physician experienced in diagnosing and managing patients with hypogonadism. Many of the symptoms are non-specific and may be multifactorial in origin. Hence, symptoms may not be necessarily linked to hypogonadism alone. This fact needs to be considered in the overall evaluation. The diagnosis should be made only after taking detailed medical history, physical examination, and obtaining appropriate blood tests. Testosterone therapy should not be offered to men with normal testosterone levels. Testosterone therapy is never a treatment for infertility, and may cause infertility. The AUA is also concerned about the risks associated with misuse of testosterone for non-medical indications, such as body building or performance enhancement. The potential adverse effects of testosterone therapy should be discussed prior to treatment. These include acne, breast swelling or tenderness, increased red blood cell count, swelling of the feet or ankles, reduced testicular size and infertility. Current evidence does not provide any definitive answers regarding the risks of testosterone therapy on prostate cancer and cardiovascular disease, and patients should be so informed. The optimal follow-up of men on testosterone therapy has not been defined, but should include measurement of testosterone level, PSA (for men of appropriate age) and hematocrit. Other patient- specific measures may be appropriate. There is a critical need for more federal and industry funding of research to better understand indications, long term benefits and risks of current treatments of hypogonadism, as well as to develop new and improved treatment options. AUA recognizes and encourages the increased educational awareness of the benefits and risks of testosterone therapy among both patients and healthcare providers. This statement has been endorsed by the American Society for Men's Health, the Sexual Medicine Society of North America and the Society for the Study of Male Reproduction. Board of Directors, February 2014 Board of Directors, August 2015 (Revised) PRIOR AUTHORIZATION CRITERIA DRUG CLASS TESTOSTERONE PRODUCTS - INJECTABLE

BRAND NAME DEPO-TESTOSTERONE (generic) (testosterone cypionate injection)

Status: CVS Caremark Criteria Type: Initial Prior Authorization

POLICY

COVERAGE CRITERIA  Depo-Testosterone (testosterone cypionate injection) will be covered with prior authorization when the following criteria are met: o The drug is being prescribed for a male patient with congenital or acquired primary hypogonadism (i.e., testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, or orchidectomy) OR o The drug is being prescribed for a male patient with congenital or acquired hypogonadotropic hypogonadism (i.e., gonadotropin or luteinizing hormone-releasing hormone [LHRH] deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation) AND o The patient has NOT received testosterone medication in the last 12 months AND o The patient had or currently has at least TWO confirmed low testosterone levels according to current practice guidelines or your standard lab reference values OR o The drug is being prescribed for a male patient with congenital or acquired primary hypogonadism (i.e., testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, or orchidectomy) OR o The drug is being prescribed for a male patient with congenital or acquired hypogonadotropic hypogonadism (i.e., gonadotropin or luteinizing hormone-releasing hormone [LHRH] deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation) AND o The patient has received testosterone medication in the last 12 months AND o The patient had or currently has at least ONE confirmed low testosterone level according to current practice guidelines or your standard lab reference values

REFERENCES 1. Assurant Health Prior Authorization Approval Policy.

Testosterone - Depo-Testosterone Policy Assurant Health C6858-A 04-2016.doc © 2016 Caremark. All rights reserved. This document contains confidential and proprietary information of CVS/caremark and cannot be reproduced, distributed or printed without written permission from CVS/caremark. This page contains prescription brand name drugs that are trademarks or registered trademarks of pharmaceutical manufacturers that are not affiliated with CVS/caremark. 1

Androgenic Agents – Testosterone Replacement Therapy (TRT) Medical policy no. 23.10.00-1 Effective: July 1, 2018 Background: The Food and Drug Administration (FDA) approved testosterone products for testosterone replacement therapy in males with primary hypogonadism (congenital or acquired) or hypogonadrotropic hypogonadism (congenital or acquired). Primary hypogonadism originates from a deficiency or disorder in the testicles. Secondary hypogonadism indicates a problem in the hypothalamus or the pituitary gland. Medical necessity Drug Medical Necessity Testosterone Testosterone replacement therapy (TRT) may be considered medically  Androderm (Transdermal patch, ER) necessary when used for the following conditions:  AndroGel (Topical gel)  Primary Hypogonadism (congenital or acquired)  Axiron (Topical solution)  Hypogonadotropic Hypogonadism (congenital or acquired)  Fortesta (Topical gel)  HIV-associated weight loss  Nastesto (Nasal gel)  Chronic, high-dose glucocorticoid-therapy  Striant (Buccal patch, ER)  Men with osteoporosis or young men with low trauma fractures  Testim (Topical gel)  Delayed Puberty  Vogelxo (Topical gel)  Metastatic Breast Cancer  Transgender Health Methyltestosterone  Android (Oral capsule)  Methitest (Oral tablet)  Testred (Oral capsule)  generic (Oral capsule)

Testosterone Enanthate  Delatestryl (IM Injection)  generic (IM injection)

Testosterone Cypionate  Depo-Testosterone (IM Injection)  generic (IM injection) Clinical policy: Clinical Criteria Testosterone Replacement Therapy Testosterone Replacement Therapy (TRT) may be considered medically for Adult Males necessary for the treatment of hypogonadism when the patient meets criteria 1–3 of the INCLUSION CRITERIA and none of the EXCLUSION

Policy: Testosterone Replacement Therapy Medical Policy No. 23.10.00-1 Last Updated 04/20/2016 1

CRITERIA. Quantity and dispensing limits are listed in Table 1. (Documentation from the patient’s chart is REQUIRED):

INCLUSION CRITERIA 1. Patient is male, 18 years of age or older; AND 2. Patient has had TWO morning (between 8 a.m. to 10 a.m.) tests (at least 1 week apart) at baseline demonstrating low testosterone levels as defined by the following criteria: a. Total serum testosterone level less than 300ng/dL (10.4nmol/L); OR b. Total serum testosterone level less than 350ng/dL (12.1nmol/L) AND free serum testosterone level less than 50pg/mL (or 0.174nmol/L) c. Second morning test should follow excluding reversible illnesses, drugs, and nutritional deficiencies. Providers should also include LH and FSH draws to guide diagnosis as primary or secondary hypogonadism; AND 3. Patient has received ONE of the following diagnoses: a. Primary Hypogonadism (congenital or acquired): as defined as testicular failure due to such conditions as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchidectomy, Klinefelter’s syndrome, chemotherapy, trauma, or toxic damage from alcohol or heavy metals; OR b. Hypogonadotropic Hypogonadism (congenital or acquired): as defined by idiopathic gonadotropin or luteinizing hormone- releasing hormone (LHRH) deficiency, or pituitary- hypothalamic injury from tumors, trauma or radiation; OR c. HIV-associated weight loss; OR i. HIV-associated weight loss is defined as <90% of ideal body weight or weight loss of >10% in the last 6 months d. Chronic, high-dose glucocorticoid-therapy; OR i. Defined as more than 5mg/day of prednisone or equivalent daily for greater than two (2) weeks e. Men with osteoporosis or young men with low trauma fractures

Policy: Testosterone Replacement Therapy Medical Policy No. 23.10.00-1 Last Updated 04/20/2016 2

3. Patient has uncontrolled or poorly-controlled benign prostate hyperplasia or is at a higher risk of prostate cancer, such as elevation of PSA after initiating TRT 4. Patient is intending on using testosterone for the indications of delayed puberty, metastatic breast cancer, or for transgender health care (such as hormone replacement therapy).

PRIOR AUTHORIZATION APPROVAL DURATION AND LIMITS  Patients meeting the criteria above may receive TRT. Approved medications are listed in Table 1. Quantity level limits are listed along with each product.  Approval is for one (1) year except for patients who met the diagnosis criteria for (c) HIV-associated weight loss or (d) men receiving chronic, high-dose glucocorticoid-therapy.  For men who meet criterion (c) HIV-associated weight loss, the approval is set for 6 months.  For men who meet criterion (d) men receiving chronic, high-dose glucocorticoid-therapy, the approval is set upon the expected regimen of chronic, high-dose glucocorticoid-therapy with a maximum of one (1) year.

Criteria (Reauthorization) Testosterone may be continued when ALL of the following are met:

1. Patient continues to meets criteria 1 and 3 of the INCLUSION CRITERIA and none of the EXCLUSION CRITERIA. 2. Patient has documentation of positive clinical response for one of the diagnosis listed above

Testosterone for use in Delayed Testosterone Therapy may be considered medically necessary for treatment Puberty of delayed puberty when the patient meets criteria 1–3 of the INCLUSION CRITERIA and none of the EXCLUSION CRITERIA. The treatment recommendations follow this policy. (Documentation from the patient’s chart is REQUIRED):

INCLUSION CRITERIA 1. Patient is male, 14 years of age or older; AND a. Under very severe and unusual circumstances, the patient may be under 14 years of age with documentation on why the patient cannot wait until 14 years of age for the treatment of delayed puberty 2. Patient has received the diagnosis of delayed puberty that is NOT secondary to a pathological cause; AND a. Diagnosis should include family history to demonstrate familial delayed puberty b. Provider should obtain random measurements of serum LH, FSH, and testosterone to

Policy: Testosterone Replacement Therapy Medical Policy No. 23.10.00-1 Last Updated 04/20/2016 3

c. support diagnosis 3. Patient must try and fail “watchful waiting” with reassurance and psychological support a. Failure of “watchful waiting” may be demonstrated by psychological concerns about b. delayed puberty and cannot be addressed by reassurance and psychological support alone

EXCLUSION CRITERIA 1. Patient has ANY of the following contraindications: a. Breast cancer or known or suspected prostate cancer b. Elevated hematocrit (>50%) c. Untreated severe obstructive sleep apnea d. Severe lower urinary tract symptoms e. Uncontrolled or poorly-controlled heart failure 2. Patient has experienced a major cardiovascular event (such as a myocardial infarction, stroke, acute coronary syndrome) in the past six months 3. Patient has uncontrolled or poorly-controlled benign prostate hyperplasia or are at higher risk of prostate cancer, such as elevation of PSA after initiating TRT 4. Is intending on using testosterone therapy for the indications of testosterone replacement therapy, metastatic breast cancer, or for transgender health care (such as hormone replacement therapy).

Criteria (Reauthorization) Testosterone may be continued when ALL of the following are met:

1. Patient continues to meet criteria 1–3 of the INCLUSION CRITERIA and none of the EXCLUSION CRITERIA. 2. Patient has documentation of positive clinical response

Testosterone for use in Metastatic Testosterone therapy may be considered medically necessary for treatment Breast Cancer of metastatic breast cancer when the patient meets criteria 1–4 of the INCLUSION CRITERIA and none of the EXCLUSION CRITERIA. The treatment recommendations follow this policy. (Documentation from the patient’s chart is REQUIRED):

INCLUSION CRITERIA 1. Patient is female, 18 years of age or older; AND 2. Patient has received a diagnosis of advancing, inoperable metastatic breast cancer; AND 3. Patient is 1 to 5 years postmenopausal OR is premenopausal and has demonstrated benefit from oophorectomy and has a hormone- responsive tumor; AND

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4. Testosterone treatment is considered secondarily to failure of first-line therapies and is being prescribed by oncologist with expertise in the field

EXCLUSION CRITERIA 1. Patient has ANY of the following contraindications: a. Elevated hematocrit (>50%) b. Untreated severe obstructive sleep apnea c. Severe lower urinary tract symptoms d. Uncontrolled or poorly-controlled heart failure 2. Patient has experienced a major cardiovascular event (such as a myocardial infarction, stroke, acute coronary syndrome) in the past six months 3. Patient is intending on using testosterone therapy for the indications of testosterone replacement therapy, delayed puberty, or for transgender health care (such as hormone replacement therapy).

Criteria (Reauthorization) Testosterone may be continued when ALL of the following are met:

1. Patient meets criteria 1–4 of the INCLUSION CRITERIA and none of the EXCLUSION CRITERIA. 2. Patient has documentation of positive clinical response

Testosterone Hormone The intent of this section is to describe an existing medical benefit where Replacement Therapy [Transgender testosterone is used as hormone replacement therapy (HRT) as covered Health] under Transgender Health. Pharmacists may process claims for testosterone therapy as an expedited authorization (EA) during the following circumstances when:

INCLUSION CRITERIA 1. Patient identifies as a female-to-male (FTM); AND 2. Patient has received the diagnosis of gender dysphoria as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria by a licensed behavioral health practitioner, OR a licensed physician, advanced registered nurse practitioner (ARNP), physician’s assistant (PA), or psychologist who is treating the patient for primary care or transgender services who is continuing to treat the patient with a comprehensive patient-centered treatment plan AND demonstrates that gender dysphoria is not due to another mental or physical health conditions

Testosterone for HRT should be prescribed under the following guidelines for provider to follow as part of standard of practice:

Policy: Testosterone Replacement Therapy Medical Policy No. 23.10.00-1 Last Updated 04/20/2016 5

1. Provider has documentation that the patient has the capacity to make fully informed decisions and consents for the treatment of gender dysphoria; AND 2. Provider prescribing hormone replacement therapy must meet the following criteria; AND a. Meet the requirements of professional licensure and practice according to the scope of practice for their license; AND b. Demonstrate specialized competencies in managing hormone therapies for gender dysphoria (including documentation of supervised training or mentoring by a more experienced physician); AND c. Follow the standards of care for the health of transgender, transsexual and gender-nonconforming people outlined by the World Professional Association for Transgender Health (WPATH) 3. Patient does not have any of the following contraindications or other precautions: a. Breast cancer b. Elevated hematocrit (>50%) c. Untreated severe obstructive sleep apnea d. Severe lower urinary tract symptoms e. Uncontrolled or poorly-controlled heart failure f. Experienced a major cardiovascular event (such as an MI, stroke, acute coronary syndrome) in the past six months g. Is intending on using testosterone therapy for the indications of testosterone replacement therapy, delayed puberty, or for metastatic breast cancer.

Criteria (Reauthorization) Documentation of positive clinical response

Approval for 12 months Table 1 Dosage and quantity limits Name Dosage Form Strength Quantity Level Limit 2mg 60 patches per 30 days 2.5mg 60 patches per 30 days Androderm transdermal patch 4mg 30 patches per 30 days 5mg 30 patches per 30 days gel packet (2.5g) 1% 300g (4x75g) per 30 days AndroGel gel packet (5g) 1% 150g (2x75g) per 30 days gel pump 1% 300g (4x75g) per 30 days gel packet (1.25g) 1.62% 37.5 (30 packets) per 30 days AndroGel gel packet (2.5g) 1.62% 150g (60 packets) per 30 days gel pump 1.62% 150g (2x75g) per 30 days Policy: Testosterone Replacement Therapy Medical Policy No. 23.10.00-1 Last Updated 04/20/2016 6

Axiron topical solution 30mg 180mL (2x90mL) per 30 days Fortesta gel 2% 120g (2x60g) per 30 days Striant buccal system 30mg 60 systems per 30 days Testim gel 1% 300g (2x5g tubes/day) for 30 days gel packet 1% 300g (4x75g) per 30 days Vogelxo gel pump 1% 300g (60x5g tubes) per 30 days Depo-Testosterone 100mg/mL 400mg per 28 days injectable solution (cypionate) 200mg/mL 400mg per 28 days Delatestryl injectable solution 200mg/mL 400mg per 28 days (enanthate) Methitest oral 10mg 150 tablets per 30 days (methyltestosterone) Android oral 10mg 150 tablets per 30 days (methyltestosterone) Testred oral 10mg 150 tablets per 30 days (methyltestosterone) Note: Testopel (implanted pellets) is excluded from this policy and is covered under medical benefit

Coding: HCPCS Code Description J3130 Injection, testosterone enanthate, up to 200 mg J1071 Injection, testosterone cypionate, 1 mg

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References 1. AACE Hypogonadism Task Force. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult Male Patients – 2002 Update. Endocr Pract. 2002; 8(No. 6): 439-456. 2. The World Professional Association for Transgender Health (WPATH), Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People, 7th Version. 3. Cook, David M, et al. "American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients - 2009 update: executive summary of recommendations." Endocrine practice 15.6 (2009):580-586. 4. Gibney, James, et al. "Growth hormone and testosterone interact positively to enhance protein and energy metabolism in hypopituitary men." American journal of physiology: endocrinology and metabolism 289.2 (2005):E266-E271 5. Bhasin, S, et al. "Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels." JAMA. 2000. 283.(6) 763-770. 6. Isidori, Andrea M, et al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clinical endocrinology. 2005 63(4):381-394. 7. Kenny, A M, et al. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. The journals of gerontology. 2001. 56(5) M266-M272. 8. Tracz, Michal J, et al. Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials. The Journal of clinical endocrinology and metabolism. 2006. 91(6):2011-2016. 9. Bolona, Enrique R, et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clinic proceedings.2007. 82(1):20-28. 10. The Endocrine Society. Testosterone therapy in Adult Men with Androgen Deficiency Syndromes. J Clini Endocrinol Metab. 2010; 95(6): 2546-59. 11. Androderm® (testosterone) transdermal system. Prescribing information. Parsippany, NJ: Watson Laboratories, Inc., July 2015. 12. Androgel® (testosterone) 1.62% gel. Prescribing information. Abbvie Inc. Chicago, IL. May 2015. 13. Androgel® (testosterone) 1% gel. Prescribing information. Abbvie Inc. Chicago, IL. October 2016. 14. Axiron® (testosterone) topical solution. Prescribing Information. Indianapolis, IN: Lilly USA, LLC. October 2016. 15. Fortesta® (testosterone) 2% gel. Prescribing Information. Malvern, PA: Endo Pharmaceuticals. October 2016. 16. Testim® (testosterone) 1% gel. Prescribing information. Malvern, PA: Endo Pharmaceuticals, Inc., October 2016. 17. Striant® (testosterone) buccal system. Prescribing information. Endo Pharmaceuticals. Malvern, PA. October 2016. 18. Natesto® (testosterone) nasal gel. Prescribing information. Endo Pharmaceuticals. Malvern, PA. May 2015. 19. Vogelxo® (testosterone) gel. Prescribing information. Maple Grove, MN: Upsher-Smith Laboratories, September 2016. 20. Hembree, Wylie C, et al. "Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline." The Journal of clinical endocrinology and metabolism 94.9 (2009):3132-3154.

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Criteria for Indiana Medicaid Testosterones PA

Prepared for State of Indiana by OptumRx

EXECUTIVE SUMMARY

Purpose: Promote prudent prescribing of Testosterones

Setting & Population: All members

Type of Criteria: Increased Risk of ADE Non-Preferred Agent Appropriate Indications Other:

Data Sources: Only administrative databases Databases + Prescriber-supplied

Drug Name Topicals Androderm (testosterone patches) Androgel (testosterone gel) Axiron (testosterone solution) Fortesta (testosterone gel) Natesto (testosterone nasal gel) Striant Buccal System (testosterone buccal) Testim (testosterone gel) Vogelxo (testosterone gel) Orals Anadrol-50 Androxy Danazol Methitest Methyltestosterone Oxandrolone Injectable Aveed Testopel Pellet Testosterone cypionate Testosterone enanthate

Page 1

APPROVAL DURATION

 Up to 1 year

APPROVAL CRITERIA

Prior authorization for the prescribed drug will be granted when the following approval criteria has been met:

Injectable Testosterone Agents  Diagnosis of delayed puberty or palliative treatment of breast cancer (excluding Aveed and Testopel) in the past 2 years OR  Diagnosis of hypogonadism in the past 2 years AND  Total testosterone level <=350ng/dL at initiation and <=1000ng/dL at renewal

Topical Testosterone Agents  Must be 18 years of age or older  Criteria for exceeding quantity limit: o Diagnosis of hypogonadism in the past 2 years AND o Total testosterone level <=400ng/dL after at least 14 days of topical testosterone therapy

Oral Testosterone Agents

Anadrol-50

 Diagnosis of anemia, myelofibrosis, or AIDS wasting syndrome in the last 2 years AND  None of the following contraindications to therapy: o Pregnancy o Prostate cancer o Breast cancer in men o Severe hepatic disease o Nephrosis o Hypercalcemia due to breast cancer women

Methitest; Methyltestosterone

 Diagnosis of hypogonadism (total testosterone <=350ng/dL at initiation or <=1000ng/dL at renewal), delayed puberty, palliative treatment of breast cancer, or cryptorchidism in the last 2 years AND  None of the following contraindications to therapy: o Pregnancy o Prostate cancer

Page 2

o Breast cancer in men

Androxy

 Diagnosis of hypogonadism (total testosterone <=350ng/dL at initiation or <=1000ng/dL at renewal), delayed puberty, or palliative treatment of breast cancer in the last 2 years AND  None of the following contraindications to therapy: o Pregnancy o Prostate cancer

Danazol

 Diagnosis of endometriosis, fibrocystic breast disease, or hereditary angioedema in the last 2 years AND  None of the following contraindications to therapy: o Pregnancy or breast-feeding o Severe renal disease o Severe hepatic disease o Cardiac disease o Porphyria o Undiagnosed genital bleeding o Androgen-dependent tumor o Active or history of thrombosis or thromboembolic disease

Oxandrolone

 Diagnosis of cachexia or AIDS wasting syndrome in the last 2 years  None of the following contraindications to therapy: o Pregnancy o Prostate cancer o Breast cancer in men o Hypercalcemia o Severe renal disease

Existing Criteria Revision of Existing Criteria New Criteria

Page 3

Iowa Department of Human Services FAX Completed Form To 1 (800) 574-2515 Request for Prior Authorization TESTOSTERONE PRODUCTS Provider Help Desk 1 (877) 776-1567 (PLEASE PRINT – ACCURACY IS IMPORTANT) IA Medicaid Member ID # Patient name DOB

Patient address

Provider NPI Prescriber name Phone

Prescriber address Fax

Pharmacy name Address Phone

Prescriber must complete all information above. It must be legible, correct, and complete or form will be returned. Pharmacy NPI Pharmacy fax NDC

Prior authorization is required for testosterone products. Payment will be considered with documentation of a specific testicular or hypothalamic/pituitary disease (primary hypogonadism or hypogonadotropic hypogonadism) that results in classic hypogonadism. Requests for FDA approved indications other than hypogonadism will not be subject to prior authorization criteria with adequate documentation of diagnosis. Payment for non-preferred testosterone products will be authorized only for cases in which there is documentation of previous trials and therapy failures with two preferred agents. Requests for erectile dysfunction, infertility, and age-related hypogonadism will not be considered. Payment will be considered under the following conditions: 1) Patient is male and 18 years of age or older (or 12 years of age and older for testosterone cypionate); and 2) Patient has two (2) morning pre-treatment testosterone levels below the lower limit of the normal testosterone reference range of the individual laboratory used (attach results); and 3) Patient has primary hypogonadism or hypogonadotropic hypogonadism (further defined below) • Primary hypogonadism (congenital or acquired) caused by testicular failure due to one of the following: cryptorchidism, bilateral torsion, orchitis, vanishing testes syndrome, orchiectomy, Klinefelter’s syndrome, chemotherapy, toxic damage from alcohol or heavy metals • Hypogonadotropic hypogonadism: idiopathic gonadotropin or luteinizing hormone-releasing (LHRH) deficiency, pituitary-hypothalamic injury from tumors, trauma, or radiation 4) Patient does not have: • Breast or prostate cancer • Palpable prostate nodule or prostate-specific antigen (PSA) > 4ng/mL • Hematocrit > 50% • Untreated severe obstructive sleep apnea • Severe lower urinary tract symptoms • Uncontrolled or poorly controlled heart failure If criteria for coverage are met, initial authorizations will be given for 3 months. Requests for continuation of therapy will require the following: • An updated testosterone level (attach result); and • Documentation the patient has not experienced a hematocrit > 54% or an increase in PSA > 1.4ng/mL in the past 12 months. The required trials may be overridden when documented evidence is provided that use of these agents would be medically contraindicated.

470-5188 (Rev. 1/18) Page 1 of 2 Iowa Department of Human Services

Request for Prior Authorization TESTOSTERONE PRODUCTS (PLEASE PRINT – ACCURACY IS IMPORTANT)

Preferred Non-Preferred F Androderm F Androgel F Depo-Testosterone F Striant F Testred F Methitest F Android F Fortesta F Testim F Vogelxo F Testosterone Cypionate F Aveed F Methyltestosterone F Testosterone Gel Pump F Testosterone Enanthate F Axiron F Natesto F Testosterone Topical Solution F Testosterone Gel 1% Packets

Strength Dosage Instructions Quantity Days Supply

Complete for diagnosis of hypogonadism:

F Primary Hypogonadism (congenital or acquired) caused by testicular failure due to one of the following: F Cryptorchidism F Bilateral torsion F Orchitis F Vanishing testes syndrome F Orchiectomy F Klinefelter’s syndrome F Chemotherapy F Toxic damage from alcohol or heavy metals F Other: ______

F Hypogonadotropic Hypogonadism: F Idiopathic gonadotropin or luteinizing hormone-releasing (LHRH) deficiency F Pituitary-hypothalamic injury from tumors, trauma, or radiation

List & attach results of two (2) morning pre-treatment testosterone levels below the lower limit of the normal testosterone reference range of the individual laboratory used: Level 1: Date: Level 2: Date:

Does patient have any of the following: Breast or prostate cancer: F Yes F No Palpable prostate nodule or prostate-specific antigen (PSA) > 4ng/mL: F Yes F No Hematocrit > 50%: F Yes F No Untreated severe obstructive sleep apnea: F Yes F No Severe lower urinary tract symptoms: F Yes F No Uncontrolled or poorly controlled heart failure: F Yes F No

Renewal Requests:

List & attach updated testosterone level: Level: Date:

Has patient experienced the following in the past 12 months: Hematocrit > 54%: F Yes F No Most recent lab date: Increase in PSA > 1.4ng/mL: F Yes F No Most recent lab date:

Other medical conditions to consider: Attach lab results and other documentation as necessary. Prescriber signature (Must match prescriber listed above.) Date of submission

IMPORTANT NOTE: In evaluating requests for prior authorization the consultant will consider the treatment from the standpoint of medical necessity only. If approval of this request is granted, this does not indicate that the member continues to be eligible for Medicaid. It is the responsibility of the provider who initiates the request for prior authorization to establish by inspection of the member’s Medicaid eligibility card and, if necessary by contact with the county Department of Human Services, that the member continues to be eligible for Medicaid. 470-5188 (Rev. 1/18) Page 2 of 2 iStent for Glaucoma with Cataract Removal

Question: Should iStent® (CPT 0191T) be added to the Prioritized List for treatment of glaucoma?

Question source: Holly Jo Hodges, CCO medical director

Issue: The CPT code used for the iStent is current not on the Prioritized List or any other list of codes at HSD. This type of CPT code is normally temporary, but 0191T has been in use for over 5 years. Dr. Hodges has seen requests for this procedure, and would like to have it reviewed for efficacy. CPT 0191T description is “Insertion of anterior segment aqueous drainage device, without extraocular reservoir; internal approach, into the trabecular meshwork.”

Open-angle glaucoma is a chronic condition associated with elevated intraocular pressure and leads to progressive damage to the optic nerve. Treatment is usually eye drops containing drugs that either reduce the production of aqueous humor or increase its drainage. Surgical procedures such as trabeculectomy, drainage tubes, deep sclerectomy, viscocanalostomy or laser trabeculoplasty may also be used. iStent is a small device designed to fit into Schlemm’s canal to facilitate aqueous drainage from the anterior chamber. It Is considered a type of trabecular stent bypass surgery. As approved by the FDA on June 25, 2012, the iStent “…is indicated for use in conjunction with cataract surgery for the reduction of intraocular pressure (IOP) in adult patients with mild or moderate open-angle glaucoma currently treated with ocular hypotensive medication.” iStent is not FDA approved for use outside of cataract surgery.

Evidence 1) Zhang 2016, Cochrane review of combined surgery for cataracts and glaucoma vs cataract surgery along https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD008671.pub3/epdf/full a. N=9 RCTs (655 patients, 657 eyes) i. 3 studies used iStent implants ii. Follow up 12-30 months iii. Overall quality of evidence was low b. All of these studies found a statistically significant greater decrease in mean IOP postoperatively in the combined surgery group compared with cataract surgery alone; the mean difference (MD) was -1.62 mmHg (95% confidence interval (CI) -2.61 to -0.64; 489 eyes) among six studies with data at one year follow-up c. two studies found the mean number of medications used postoperatively at one year was about one less in the combined surgery group than the cataract surgery alone group (MD -0.69, 95% CI -1.28 to -0.10; 301 eyes) d. participants in the combined surgery group were about 50% less likely compared with the cataract surgery alone group to use one or more IOP-lowering medications one year postoperatively (risk ratio (RR) 0.47, 95% CI 0.28 to 0.80; 453 eyes). e. six studies reported no significant differences in visual acuity and two studies reported no significant differences in visual fields between the two intervention groups postoperatively (data not analyzable). f. The effect of combined surgery versus cataract surgery alone on the need for reoperation to control IOP at one year was uncertain (RR 1.13, 95% CI 0.15 to 8.25; 382

iStent for Glaucoma with Cataract Removal

eyes). Also uncertain was whether eyes in the combined surgery group required more interventions for surgical complications than those in the cataract surgery alone group (RR 1.06, 95% CI 0.34 to 3.35; 382 eyes). No study reported any vision-related quality of life data or cost outcome. g. Complications were reported at 12 months (two studies), 12 to 18 months (one study), and two years (four studies) after surgery. Due to the small number of events reported across studies and treatment groups, the difference between groups was uncertain for all reported adverse events. h. Authors' conclusions—There is low quality evidence that combined cataract and glaucoma surgery may result in better IOP control at one year compared with cataract surgery alone. The evidence was uncertain in terms of complications from the surgeries. Additional high-quality RCTs measuring clinically meaningful and patient-important outcomes are required to provide evidence to support treatment recommendations. 2) NICE 2017, Trabecular stent bypass microsurgery for open angle glaucoma a. Current evidence on the safety of trabecular stent bypass microsurgery for open-angle glaucoma raises no major safety concerns. Evidence on efficacy is adequate in quality and quantity. b. N=1 systematic review and meta-analysis of 2,143 patients from 32 studies comparing stent insertion combined with phacoemulsification against phacoemulsification alone in patients with glaucoma and cataract, there was a statistically significant decrease in intraocular pressure (IOP) from baseline in the combined group compared against the phacoemulsification-only group at a follow-up of 12 to 58 months (standardised mean deviation [SMD] −0.46, 95% confidence interval [CI] −0.87 to −0.06, 4 randomised controlled trials [RCTs], I2=47%, p=0.128). There was also a statistically significant reduction in the number of topical glaucoma medications used after the procedure in the combined group compared against the phacoemulsification-only group (SMD −0.65, 95% CI −1.18 to −0.12, 3 studies; I2=58%, p=0.092). a. In a systematic review and meta-analysis of 248 patients (5 studies) with mild to moderate glaucoma treated by stent insertion alone, there was a statistically significant reduction in IOP from baseline after implantation of 1 stent at a follow-up of 6 to 18 months (SMD −1.95, 95% CI −3.41 to −0.49, 3 studies; I2=96%, p=0.000 (sic)) and of 3 stents at 6-month follow-up (SMD −4.26, 95% CI −5.18 to −3.33, 1 study). But there was not a statistically significant reduction in IOP from baseline after implantation of 2 stents at 6 to 12 months (SMD −3.08, 95% CI −6.90 to 0.74, 2 studies; I2=98%, p=0.000 (sic)). a. Safety a. No differences were seen between groups (combined procedures vs phacoemulsification-only group) in severe loss of corrected distance visual acuity, macular edema, vitreomacular traction, or need for secondary procedures b. Studies reported small numbers of patients with optic disc hemorrhage, hyphema, subconjunctival hemorrhage, hypotony, intraocular inflammation, cataract progression, iris synechiae, posterior capsule opacification, iris atrophy, uveitis, dry eye with combined procedures c. In the systematic review and meta-analysis of 2,143 patients, stent malposition was reported in 2 to 18% of patients in 6 studies, stent occlusion was reported in 4 to 15% of patients in 4 studies and blockage of the opening of the stent lumen was reported in 15% of patients in 1 study.

iStent for Glaucoma with Cataract Removal

d. In the systematic review and meta-analysis of 248 patients, a need to reposition the stent was reported in 2% of patients in 1 study, stent not visible upon gonioscopy was reported in 13% of patients in 1 study, and stent replacement was reported in 5% of patients in 1 study.

HERC staff summary: iStent appears to be effective at reducing intraocular pressure and reducing glaucoma medication amount. It appears to be a safe procedure. Trusted sources such as NICE recommend utilization. This procedure is only FDA approved when done in conjunction with cataract surgery, and CMS rules require that these services be bundled together; therefore, there should be minimal cost increase with coverage.

HERC staff recommendation: 1) Add CPT 0191T (Insertion of anterior segment aqueous drainage device, without extraocular reservoir; internal approach, into the trabecular meshwork) to line 139 GLAUCOMA, OTHER THAN PRIMARY ANGLE-CLOSURE

Trabecular stent bypass microsurgery for open- angle glaucoma

Interventional procedures guidance Published: 22 February 2017 nice.org.uk/guidance/ipg575

Your responsibility

This guidance replaces IPG396.

© NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- Page 1 of conditions#notice-of-rights). 9 Trabecular stent bypass microsurgery for open-angle glaucoma (IPG575)

1 Recommendations

1.1 Current evidence on the safety of trabecular stent bypass microsurgery for open-angle glaucoma raises no major safety concerns. Evidence on efficacy is adequate in quality and quantity. Therefore, this procedure may be used provided that standard arrangements are in place for clinical governance, consent and audit.

1.2 Trabecular stent bypass microsurgery for open-angle glaucoma should only be done by clinicians with specific training in the procedure.

2 Indications and current treatments

2.1 Open-angle glaucoma is a chronic condition associated with elevated intraocular pressure and leads to progressive damage to the optic nerve. Early stages are usually asymptomatic but as the condition progresses it causes visual impairment and, if untreated, blindness.

2.2 Treatment is usually eye drops containing drugs that either reduce the production of aqueous humor or increase its drainage. Surgical procedures such as trabeculectomy, drainage tubes, deep sclerectomy, viscocanalostomy or laser trabeculoplasty may also be used.

3 The procedure

3.1 Trabecular stent bypass microsurgery aims to reduce intraocular pressure by creating a bypass channel between the anterior chamber and Schlemm's canal to improve drainage of aqueous humor.

3.2 This procedure is often combined with phacoemulsification and intraocular lens insertion for the concomitant treatment of cataracts. Using local anaesthesia, a small corneal incision is made and viscoelastic is inserted into the anterior chamber. Under gonioscopic guidance and using a special applicator, a stent is slid through the trabecular meshwork (a small slit may be necessary) and into Schlemm's canal. The position of the stent is verified, then the applicator and viscoelastic are removed.

3.3 Either 1 or multiple stents may be inserted during the same procedure.

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4 Efficacy

This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.

4.1 In a systematic review and meta-analysis of 2,143 patients from 32 studies, comparing stent insertion combined with phacoemulsification against phacoemulsification alone in patients with glaucoma and cataract, there was a statistically significant decrease in intraocular pressure (IOP) from baseline in the combined group compared against the phacoemulsification-only group at a follow-up of 12 to 58 months (standardised mean deviation [SMD] −0.46, 95% confidence interval CI][ −0.87 to −0.06, 4 randomised controlled trials [RCTs], I2=47%, p=0.128). In a systematic review and meta-analysis of 248 patients (5 studies) with mild to moderate glaucoma treated by stent insertion alone, there was a statistically significant reduction in IOP from baseline after implantation of 1 stent at a follow-up of 6 to 18 months (SMD −1.95, 95% CI −3.41 to −0.49, 3 studies; I2=96%, p=0.000) and of 3 stents at 6-month follow-up (SMD −4.26, 95% CI −5.18 to −3.33, 1 study). But there was not a statistically significant reduction in IOP from baseline after implantation of 2 stents at 6 to 12 months (SMD −3.08, 95% CI −6.90 to 0.74, 2 studies; I2=98%, p=0.000). In the same study there was a 22% reduction in IOP from baseline after 1-stent insertion at 18-month follow-up (1 study), and at 6-month follow-up there was a 30% reduction in IOP after 2-stent implantation (2 studies) and a 41% reduction after 3-stent insertion (1 study).

4.2 In the systematic review and meta-analysis of 2,143 patients there was a statistically significant reduction in the number of topical glaucoma medications used after the procedure in the combined group compared against the phacoemulsification-only group (SMD −0.65, 95% CI −1.18 to −0.12, 3 studies; I2=58%, p=0.092). There was a weighted mean reduction in topical glaucoma medications per patient of 1.33 from baseline after insertion of 1 stent combined with phacoemulsification (3 RCTs), of 1.1 from baseline after insertion of 2 stents combined with phacoemulsification (1 RCT) and of 1.01 after phacoemulsification alone (3 RCTs).

4.3 In an RCT of 239 patients comparing stent insertion combined with phacoemulsification (n=116) against phacoemulsification alone (n=123) in

© NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- Page 3 of conditions#notice-of-rights). 9 Trabecular stent bypass microsurgery for open-angle glaucoma (IPG575)

patients with open-angle glaucoma not controlled on 1 medication, the proportions of eyes with corrected distance visual acuity of 20/40 or better in the combined group were 45% (49 eyes) before the procedure and 94% (99 eyes) at 12-month follow-up. In the phacoemulsification-only group, the proportions were 44% (53 eyes) before the procedure and 90% (101 eyes) 12 months after the procedure. In an RCT of 192 patients comparing implantation of 2 stents (n=94) against medical therapy (n=98), the proportions of eyes with best corrected visual acuity (BCVA) of 20/40 or better in the stent group were 84% before the procedure and 79% at 12-month follow-up. In the medical therapy group, the proportions were 87% before the procedure and 84% at 12-month follow-up.

4.4 In the RCT of 192 patients, the vertical cup-to-disc ratio had not changed from baseline (change within ±0.2) in 97% (90/93) of patients in the stent group at 1-year follow-up, and was worse than baseline (increase of more than 0.2) in 1 patient (n=93). In the medication group, the vertical cup-to-disc ratio had not changed from baseline in 99% (88/89) of patients in the stent group at 1-year follow-up and was better than baseline (decrease of more than 0.2) in 1 patient (n=89). In an RCT of 119 patients comparing implantation of 1 stent (n=38) against implantation of 2 stents (n=41) or 3 stents (n=40), the mean cup-to-disc ratios at 18-month follow-up were the same as preoperative values.

4.5 In an RCT of 100 patients comparing stent insertion combined with phacoemulsification (n=50) against phacoemulsification alone (n=50) in patients with open-angle glaucoma and cataract, the successful stent implantation rate was 96% (48/50). In a prospective case series of 19 patients treated by stent implantation and phacoemulsification, the stent was successfully implanted in all eyes (19/19).

4.6 The specialist advisers listed the following key efficacy outcomes: IOP reduction, glaucoma medication use and quality of life.

5 Safety

This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.

© NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- Page 4 of conditions#notice-of-rights). 9 Trabecular stent bypass microsurgery for open-angle glaucoma (IPG575)

5.1 Severe loss of corrected distance visual acuity (CDVA) was reported in 1 patient each in the combined group and in the phacoemulsification-only group in a randomised controlled trial (RCT) of 239 patients with open-angle glaucoma not controlled on 1 medication comparing stent insertion combined with phacoemulsification (n=116) against phacoemulsification alone (n=123). In the combined group, the loss of CDVA occurred after a stroke; in the phacoemulsification-only group, it occurred after macular traction, macular hole and macular oedema treated with vitrectomy. In the same study, CDVA worse than 20/40 was reported in 7 eyes in the combined group and in 9 eyes in the phacoemulsification group at 24-month follow-up. The causes reported were onset or progression of macular disease (n=6), posterior capsule opacification (n=2) and dry eye (n=2). Blurry vision or visual disturbance were also reported in 3% (4/116) of eyes in the combined group and in 7% (8/117) of eyes in the phacoemulsification-only group.

5.2 Increase in intraocular pressure (IOP) above 10 mmHg after the procedure was reported in 48% of patients in the combined group of 1 of the 32 studies included in a systematic review and meta-analysis of 2,143 patients with glaucoma and cataract comparing stent insertion combined with phacoemulsification against phacoemulsification alone. In the same systematic review, rise in IOP above 30 mmHg after the procedure was reported in 15% of patients in the combined group in 1 of the studies. Elevated IOP was reported in 10% of patients in 1 of the 5 studies included in a systematic review and meta- analysis of 248 patients treated by stent insertion alone.

5.3 Cystoid macular oedema was reported in 1% of patients in the combined group of 1 of the studies included in the systematic review and meta-analysis of 2,143 patients. Macular oedema was reported in 2% (1/50) of patients in the combined group and in 4% (2/50) of patients in the phacoemulsification-only group in an RCT of 100 patients comparing stent insertion combined with phacoemulsification (n=50) against phacoemulsification alone (n=50), during the first eary of follow-up.

5.4 Optic disc haemorrhage was reported in 1 patient in each of the combined groups in the RCTs of 239 patients and 100 patients, within 24 months and 1 year of follow-up respectively.

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5.5 Hyphema was reported in 2 to 4% of patients in 3 of the studies included in the systematic review and meta-analysis of 2,143 patients, and in 3% of patients in 1 of the studies included in the systematic review and meta-analysis of 248 patients.

5.6 Subconjunctival haemorrhage was reported in 2% of patients in the combined group in 1 of the studies included in the systematic review and meta-analysis of 2,143 patients, and in 1% of patients in 1 of the studies included in the systematic review and meta-analysis of 248 patients.

5.7 Anterior chamber collapse was reported in 2% of patients in the combined group in 1 of the studies included in the systematic review and meta-analysis of 2,143 patients. Hypotony was reported in 3% of patients in 1 of the studies included in the systematic review and meta-analysis of 248 patients.

5.8 Intraocular inflammation was reported in 1% of patients in 1 of the studies included in the systematic review and meta-analysis of 248 patients.

5.9 Cataract progression was reported in 3% (4/119) of patients (2 in the 1-stent group and 2 in the 3-stent group) in an RCT comparing implantation of 1 stent (n=38) against implantation of 2 stents (n=41) or 3 stents (n=40) in patients with primary open-angle glaucoma not controlled on ocular hypotensive medication; the patients were treated by cataract surgery.

5.10 Goniosynechiae or iris synechiae each were reported in 1% of patients in 1 of the studies included in the systematic review and meta-analysis of 248 patients. Focal peripheral anterior synechiae were reported in 30% (15/50) of patients in the combined group and in 4% (2/50) of patients in the phacoemulsification- only group in the RCT of 100 patients within 2 years of follow-up.

5.11 Vitreous wick incarcerated in paracentesis was reported in 2% of patients in the combined group in 1 of the studies included in the systematic review and meta- analysis of 2,143 patients.

5.12 Vitreomacular traction was reported in 2% (1/50) of patients in each group in the RCT of 100 patients within 2 years of the procedure.

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5.13 Posterior capsule opacification was reported in 3% and 1% of patients and in 6% (7/116) of eyes in the combined group in 1 of the studies included in the systematic review and meta-analysis of 2,143 patients, in the systematic review and meta-analysis of 248 patients and in the RCT of 239 patients respectively, within 24 months of the procedure.

5.14 Epiretinal membrane was reported in 2% of patients in the combined group in 1 of the studies included in the systematic review and meta-analysis of 2,143 patients.

5.15 Iris atrophy was reported in 2% of patients in the combined group in 1 of the studies included in the systematic review and meta-analysis of 2,143 patients.

5.16 Uveitis (iritis) was reported in 2% of patients and in 1 (n=116) eye treated by stent insertion and phacoemulsification in the systematic review and meta- analysis of 2,143 patients and in the RCT of 239 patients respectively.

5.17 Dry eye was reported in 2% of patients in the combined group in 1 of the studies included in the systematic review and meta-analysis of 2,143 patients. Soreness or discomfort was reported in 1 patient in an RCT of 192 patients comparing implantation of 2 stents (n=94) against medical therapy (n=98); this was treated with non-steroidal anti-inflammatory medications.

5.18 Descemet folds were reported in 1 patient in each group at 1-month follow-up in the RCT of 100 patients; they resolved before the 3-month follow-up visit.

5.19 In the systematic review and meta-analysis of 2,143 patients, stent malposition was reported in 2 to 18% of patients in 6 studies, stent occlusion was reported in 4 to 15% of patients in 4 studies and blockage of the opening of the stent lumen was reported in 15% of patients in 1 study.

5.20 In the systematic review and meta-analysis of 248 patients, a need to reposition the stent was reported in 2% of patients in 1 study, stent not visible upon gonioscopy was reported in 13% of patients in 1 study, and stent replacement was reported in 5% of patients in 1 study.

5.21 Secondary surgical interventions were needed in 4% (5/116) of eyes in the combined group and in 5% (6/117) of eyes in the phacoemulsification-only

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group in the RCT of 239 patients, within 24 months of follow-up (including patients who had more than 1 surgical re-intervention). In the combined group of 116 patients, the secondary surgical interventions were stent repositioning (3% [3/116]), stent removal and replacement (1 patient), Nd:YAG laser for stent obstruction (1 patient), trabeculoplasty (1 patient) and focal argon laser photocoagulation (1 patient). Secondary glaucoma surgery was reported in 1 patient in the combined group and in 2 patients in the phacoemulsification- only group in the RCT of 100 patients during the second year of follow-up.

5.22 In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse event: stent dislocation. They considered that the following was a theoretical adverse event: stent movement during MRI scan.

6 Committee comments

6.1 The committee noted that more than 1 device is available for this procedure and that the evidence on the safety and efficacy of the procedure is predominantly from 1 device.

7 Further information

7.1 For related NICE guidance, see the NICE website.

7.2 Patient commentary was sought but none was received.

Information for patients

NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.

ISBN: 978-1-4731-2344-1

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Endorsing organisation

This guidance has been endorsed by Healthcare Improvement Scotland.

Accreditation

Question: should procedure codes for proximal humeral osteotomy be paired with recurrent shoulder dislocation?

Question source: HSD claims reconsideration

Issue: When recurrent shoulder dislocation results in proximal humeral bone loss, humeral osteotomy is one procedure which is standard to minimize risk of future dislocation and best restore function to the shoulder. These procedures can be rotational osteotomy of the proximal humerus or partial or total humeral head arthroplasty, depending on the clinical situation.

Rotational osteotomy of the proximal humerus is also an option that has been described to deal with large humeral head defects in younger patients to delay the need for prosthetic replacement. A standard deltopectoral approach is utilized to expose the proximal humerus and an oscillating saw is then used to complete a transverse osteotomy through the surgical neck. The humeral shaft is rotated externally to 5–10 degrees more than the position of instability measured on physical exam and the osteotomy is then secured using a rigid fixation implant such as a blade plate. Imbrication of the anterior capsule and subscapularis tendon is then done in conjunction with the bony procedure.

The review by Mascarenhas et al (2014) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124833/pdf/AORTH2014-640952.pdf) includes summary of a review by Weber et al. of 180 rotational subcapital humeral osteotomies with shortening of the subscapularis tendon and capsule for recurrent shoulder instability. The overall redislocation rate was 5.7% and the rate of nontraumatic redislocation was 1.1%. Limitation of motion of more than 10 degrees was present in only 3.9% of patients. The average loss of external rotation was less than 5 degrees without noticeable diminution of power or function in most patients. The results were good to excellent in 90% of cases as determined by the Rowe score.

Similar procedures are paired with other joint recurrent dislocations on the List.

Current Prioritized List status ICD10 M24.41 (Recurrent dislocation, shoulder) is on line 359 DEFORMITY/CLOSED DISLOCATION OF JOINT AND RECURRENT JOINT DISLOCATIONS CPT 24400 (Osteotomy, humerus, with or without internal fixation) is on lines 441 MALUNION AND NONUNION OF FRACTURE CPT 22420 (Osteoplasty, humerus (eg, shortening or lengthening) (excluding 64876)) is on lines 184,255,400,556

HERC staff recommendation: 1) Add CPT 24400 (Osteotomy, humerus, with or without internal fixation) and 22420 (Osteoplasty, humerus (eg, shortening or lengthening) to line 359 DEFORMITY/CLOSED DISLOCATION OF JOINT AND RECURRENT JOINT DISLOCATIONS

Section 7.0 Coverage Guidances CardioMEMS™ for Heart Failure Monitoring Draft Coverage Guidance for VbBS Consideration October 4, 2018

Center For Evidence-based Policy Background

• Heart failure occurs when the heart muscle is damaged and cannot meet the body's needs for blood and oxygen • Nearly 6 million adults in the U.S. have heart failure • Heart failure is a contributing cause to 1 in 9 deaths • About 50% of people who develop heart failure die within 5 years of diagnosis • Annual economic costs of heart failure in the U.S. are estimated at $30.7 billion

2 Center For Evidence-based Policy Background

• Risk factors for heart failure: – Coronary heart disease – Hypertension – Diabetes • Behavioral risk factors: – Cigarette smoking – Diet high in fat, cholesterol, and sodium – Physical inactivity – Obesity

3 Center For Evidence-based Policy Background

• Early diagnosis and treatment can improve outcomes for patients with heart failure • Treatment usually involves medications, behavioral interventions focusing on diet and physical activity, and daily monitoring of symptoms • Heart failure can be difficult to monitor – Subtle onset of decompensation

4 Center For Evidence-based Policy Background

• Interventions to monitor ambulatory heart failure patients: – Increased self-care and self-management – Home visitations by providers – Structured telephone support – Telemonitoring – Remote monitoring through the use of implantable devices, such as CardioMEMS™

5 Center For Evidence-based Policy Background

• CardioMEMS™ measures pulmonary artery hemodynamic data to inform decisions to initiate or modify treatments for heart failure – Implantable wireless sensor with delivery catheter, permanently implanted into the distal pulmonary artery • Data are transmitted to the patient database on a secure website

6 Center For Evidence-based Policy Background

• CardioMEMS™ is indicated for New York Heart Association (NYHA) Class III heart failure patients who have been hospitalized for heart failure in previous year – Contraindicated for patients who cannot take dual antiplatelet or anticoagulant medication for 1 month after implant of the device • Manufacturer lists the potential adverse events: – Infection, arrhythmias, bleeding, hematoma, thrombus, myocardial infarction, transient ischemic attack, stroke, device embolization, and death • Received FDA premarket approval in 2014

7 Center For Evidence-based Policy Scope Statement

• Populations – Adults with chronic heart failure • Interventions – CardioMEMS™ heart failure monitoring system • Comparators – Usual care (e.g., daily weight measurements, symptom reporting, frequent encounters), heart rate variability monitors, intrathoracic impedance monitors

8 Center For Evidence-based Policy Scope Statement

• Critical Outcomes – All-cause mortality – Cardiovascular mortality – Heart failure-related hospitalizations • Important Outcomes – Quality of life – Harms

9 Center For Evidence-based Policy Scope Statement Key Questions 1. What is the comparative effectiveness of CardioMEMS™ for the management of patients with chronic systolic heart failure? 2. How does the comparative effectiveness of CardioMEMS™ vary by: a. Age b. Gender c. Race/ethnicity d. Comorbid medical conditions e. Prior and current treatments f. Previous hospitalization for acute decompensated heart failure g. Heart failure etiology h. Preserved vs. reduced ejection fraction i. Treatment setting (inpatient/outpatient) j. Patient adherence to prior treatment and monitoring plans k. New York Heart Association class/American College of Cardiology stage 3. What are the harms of CardioMEMS™?

10 Center For Evidence-based Policy Evidence Sources

• Pivotal trial is known as the CardioMEMS™ Heart Sensor Allows Monitoring of Pressures to Improve Outcomes in NYHA III Heart Failure Patients (CHAMPION) trial – Enrolled adults with a diagnosis of heart failure for at least three months with NYHA functional Class III symptoms and at least one heart failure-related hospitalization in the preceding 12 months – Patients must have been on optimal or best-tolerated guideline- directed heart failure therapies – Major exclusion criteria were a history of recurrent pulmonary embolism or deep venous thrombosis, Stage IV or V chronic kidney disease, implantation of cardiac resynchronization device in the three months prior to enrollment, recent major adverse cardiovascular events, and hypersensitivity to aspirin or clopidogrel

11 Center For Evidence-based Policy Evidence Sources

• CHAMPION trial – Randomized, single-blind, multicenter trial conducted at 64 sites in the U.S. – Study enrolled 550 patients who all underwent implantation of the CardioMEMS™ device – Prior to discharge from the hospital, patients were randomized • Experimental arm: treating clinicians could access readings from the device • Control arm: treating clinicians could not access readings from the device – Patients in both groups were seen by their treating clinician at 1, 3, and 6 months, then every 6 months – In the experimental group, CardioMEMS™ data were reviewed at least weekly, and more often if changes were made in the treatments

12 Center For Evidence-based Policy Evidence Sources

• CHAMPION trial – Primary outcomes: • Rate of heart failure-related hospitalizations • Freedom from device-related complications • Freedom from pressure sensor failure – Secondary outcome measures: • Change in mean pulmonary artery pressure • Proportion of patients with heart failure-related hospitalization • Days alive outside the hospital • Quality of life as measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ)

13 Center For Evidence-based Policy Evidence Sources

• Abraham et al., 2011 – First publication of CHAMPION results • Adamson et al., 2014 – Reported the effectiveness of CardioMEMS™ in patients with preserved left ventricular function from the CHAMPION trial • Adamson et al., 2016 – Reported the effectiveness of CardioMEMS™ in reducing the risk of 30-day readmissions among a subgroup of Medicare-eligible participants in the CHAMPION trial

14 Center For Evidence-based Policy Evidence Sources

• Abraham et al., 2016 – Reported complete results of the CHAMPION trial after the open access period • Givertz et al., 2017 – Reported the effectiveness of CardioMEMS™ in reducing the risk of hospitalization for heart failure or death among patients with reduced ejection fraction who were on at least one guideline-directed medical therapy at baseline

15 Center For Evidence-based Policy Evidence Summary

• There is low-quality evidence from a single, seriously flawed RCT that CardioMEMS™ reduces the risk of heart failure-related hospitalization in patients with NYHA Class III heart failure who have had a previous admission for heart failure • This finding was consistent for patients with preserved LV function and patients with reduced function, but in the initial trial, this result was not significant among women • The trial was mainly limited by its single-blind design, manufacturer funding and involvement, and concerns (raised by an FDA advisory panel) related to the statistical analysis plan and improper communications between the sponsor and study investigators in the experimental group • The evidence for a reduction in all-cause mortality, improved quality of life, and harms is very low because it is further limited by imprecision in the estimates

16 Center For Evidence-based Policy GRADE Table

Estimate of Effect for Outcome/ Outcomes Confidence in Estimate All-cause mortality 19% for CardioMEMS™ vs. (Critical outcome) 23% for control HR 0.80 (95% CI 0.55 to 1.15, p = 0.23) ●◌◌◌ (Very low confidence, based on 1 RCT, n = 550) Cardiovascular mortality Not reported (Critical outcome) Heart failure-related 0.46 events per patient-year for CardioMEMS™ vs. hospitalization 0.68 events per patient year for control (Critical outcome) HR 0.67 (95% CI 0.55 to 0.80, p < 0.001) Approximate NNT = 5 ●●◌◌ (Low confidence, based on 1 RCT, n = 550)

17 Center For Evidence-based Policy GRADE Table

Estimate of Effect for Outcome/ Outcomes Confidence in Estimate Quality of life Improved Minnesota Living with Heart Failure (Important outcome) Questionnaire score in the CardioMEMS™ group (45) vs. the control group (51), (105 point scale, p = 0.02) ●◌◌◌ (Very low confidence, based on 1 RCT, n = 550) Harms 15 serious procedure-related or device-related adverse (Important outcome) events were reported (4 bleeding events, 3 events related to interruption of anticoagulation, 2 exacerbations of atrial arrhythmias, 2 febrile illnesses, 1 in-situ pulmonary thrombus, 1 episode of cardiogenic shock, 1 episode of atypical chest pain, and 1 delivery-system failure that required snare retrieval) Approximate NNH = 37 ●◌◌◌ (Very low confidence, based on 1 RCT, n = 550)

18 Center For Evidence-based Policy Payer Policies

• Washington State Medicaid Program: – No coverage policy was identified for CardioMEMS™ • Medicare: – No Medicare National Coverage Determination was found for CardioMEMS™ – One Local Coverage Determination was found for CardioMEMS™, which considers the device investigational and non-covered unless in an approved clinical trial • Private Payers: – Cigna policy and Regence do not cover CardioMEMS™ – No coverage policies for CardioMEMS™ found for Aetna or Moda

19 Center For Evidence-based Policy Guidelines

• American College of Cardiology’s 2017 Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment summarized the evidence on CardioMEMS™ and concluded: – “This suggests that in well-selected patients with recurrent congestion, this highly specialized monitoring strategy may guide therapeutic decision making. The impact on mortality is unknown.” • European Society of Cardiology poor-quality 2016 guidelines on diagnosis and treatment of acute and chronic heart failure: – CardioMEMS™ could be considered in symptomatic heart failure patients who have had a previous hospitalization for heart failure (Class IIb: conflicting evidence or a divergence of opinion about the usefulness or efficacy)

20 Center For Evidence-based Policy Discussion

Values and Preferences We would assume that patients would strongly prefer to avoid heart failure exacerbations and repeated heart failure hospitalizations. However, this preference would be tempered by the serious adverse event rate of 15/550 that includes events such as arrhythmias, bleeding, and shock. More rare but plausible concerns include infection, thrombosis, and device migration; the study might have been underpowered to detect these events. Given the noninvasiveness of alternatives (e.g., using a scale and communication with clinic staff), we would expect high variability in preferences.

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Resource Allocation The cost of the CardioMEMS™ device is substantial. The cost of the device, implantation, and complications in 2016 dollars is reportedly close to $19,000. Ongoing monitoring is necessary and would increase costs associated with the device. If this device were effective at reducing hospitalizations and morbidity and mortality, it has the potential to be cost-effective.

22 Center For Evidence-based Policy Discussion

Other Considerations All of the reports are derived from a single trial (CHAMPION) for which there are concerns about bias. There are concerns about external validity given that the monitoring and recommendations of the data obtained through CardioMEMS™ was interpreted by specialty heart failure centers (with assistance of device manufacturer consultation). It is unclear how adoption of this technology within non-specialty centers could modify its potential effectiveness.

23 Center For Evidence-based Policy Discussion

Balance of Benefits and Harms We have low confidence that CardioMEMS™ decreases the rate of heart failure-related hospitalization, very low confidence that it improves quality of life, and very low confidence that there is a mortality benefit. We have very low confidence that it is associated with serious adverse events. While the balance of benefits and harms weighs in favor of the intervention, based on the limited evidence, it is unclear that the benefit outweighs the risk.

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Rationale The balance of benefits and harms weighs in favor of the intervention, but it is very expensive and invasive, and preferences would likely be highly variable. Given that the evidence is derived from only one trial that has concern of bias, a confirmatory trial is necessary to improve the confidence regarding the potential benefit of this intervention.

CardioMEMS™ is not recommended for coverage for heart failure monitoring (weak recommendation).

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Health Evidence Review Commission (HERC) Coverage Guidance: CardioMEMS™ for Heart Failure Monitoring DRAFT for VbBS/HERC meeting materials 10/4/2018

HERC Coverage Guidance CardioMEMS™ is not recommended for coverage for heart failure monitoring (weak recommendation).

Note: Definitions for strength of recommendation are in Appendix A. GRADE Table Element Descriptions. Rationales for each recommendation appear below in the GRADE table.

Table of Contents

Coverage Guidance: CardioMEMS™ for Heart Failure Monitoring ...... 1 Table of Contents ...... 2 Rationale for development of coverage guidances and multisector intervention reports ...... 3 GRADE Table ...... 3 GRADE Table ...... 5 Should CardioMEMS™ be recommended for coverage for heart failure monitoring? ...... 5 Background ...... 8 Indications ...... 8 Technology Description ...... 8 Evidence Review ...... 9 Abraham et al., 2011 ...... 9 Adamson et al., 2014 ...... 11 Adamson et al., 2016 ...... 12 Abraham et al., 2016 ...... 13 Givertz et al., 2017 ...... 15 Evidence Summary ...... 16 Policy Landscape ...... 16 Payer Coverage Policies ...... 16 Recommendations from Others ...... 16 Quality Measures ...... 17 References ...... 17 Evidence Sources ...... 17 Other Citations ...... 18 Appendix A. GRADE Table Element Descriptions ...... 20 Appendix B. GRADE Evidence Profile ...... 22 Appendix C. Methods ...... 23 Scope Statement ...... 23 Search Strategy ...... 24 Appendix D. Applicable Codes ...... 25

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Rationale for development of coverage guidances and multisector intervention reports

Coverage guidances are developed to inform coverage recommendations for public and private health plans in Oregon as plan administrators seek to improve patients’ experience of care, population health, and the cost-effectiveness of health care. In the era of public and private sector health system transformation, reaching these goals requires a focus on maximizing the benefits and minimizing the harms and costs of health interventions. HERC uses the following principles in selecting topics for its reports to guide public and private payers:

• Represents a significant burden of disease or health problem • Represents important uncertainty with regard to effectiveness or harms • Represents important variation or controversy in implementation or practice • Represents high costs or significant economic impact • Topic is of high public interest HERC bases its reports on a review of the best available research applicable to the intervention(s) in question. For coverage guidances, which focus on diagnostic and clinical interventions, evidence is evaluated using an adaptation of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. For more information on coverage guidance methodology, see Appendix A. Multisector interventions can be effective ways to prevent, treat, or manage disease at a population level. In some cases, HERC has reviewed evidence and identified effective interventions, but has not made formal coverage recommendations when these policies are implemented in settings other than traditional health care delivery systems because effectiveness could depend on the environment in which the intervention is implemented. GRADE Table

HERC develops recommendations by using the concepts of the GRADE system. GRADE is a transparent and structured process for developing and presenting evidence and for performing the steps involved in developing recommendations. The table below lists the elements that determine the strength of a recommendation. HERC reviews the evidence and assesses each element, which in turn is used to develop the recommendations presented in the coverage guidance box. Estimates of effect are derived from the evidence presented in this document. Assessments of confidence are from the published systematic reviews and meta-analyses, where available and judged to be reliable. In some cases, no systematic reviews or meta-analyses encompass the most current literature. In those cases, HERC may describe the additional evidence or alter the assessments of confidence in light of all available information. Such assessments are informed by clinical epidemiologists from the Center for Evidence-based Policy. Unless otherwise noted, statements regarding resource allocation, values and preferences, and other considerations are the assessments of HERC, as informed by the evidence reviewed, public testimony, and subcommittee discussion.

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Recommendations for coverage are based on the balance of benefit and harms, resource allocation, values and preferences, and other considerations. See Appendix A for more details about the factors that constitute the GRADE table.

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GRADE Table Should CardioMEMS™ be recommended for coverage for heart failure monitoring?

Estimate of Effect for Outcome/ Outcomes Resource Allocation Values and Preferences Other Considerations Confidence in Estimate All-cause 19% for CardioMEMS™ vs. The cost of the We would assume that All of the reports are mortality 23% for control CardioMEMS™ device is patients would strongly derived from a single (Critical outcome) HR 0.80 (95% CI 0.55 to 1.15, p = substantial. The cost of prefer to avoid heart failure trial (CHAMPION) for 0.23) the device, exacerbations and repeated which there are ●◌◌◌ (Very low confidence, based on implantation, and heart failure hospitalizations. concerns about bias. 1 RCT, n = 550) complications in 2016 However, this preference There are concerns dollars is reportedly would be tempered by the about external validity close to $19,000. serious adverse event rate of given that the Ongoing monitoring is 15/550 that includes events monitoring and necessary and would such as arrhythmias, recommendations of increase costs bleeding, and shock. More the data obtained associated with the rare but plausible concerns through CardioMEMS™ device. If this device include infection, thrombosis, was interpreted by were effective at and device migration; the specialty heart failure reducing study might have been centers (with hospitalizations and underpowered to detect assistance of device further morbidity and these events. manufacturer mortality, it has the Given the noninvasiveness of consultation). It is potential to be cost- alternatives (e.g., using a unclear how adoption effective. scale and communication of this technology with clinic staff), we would within non-specialty expect high variability in centers may modify its preferences. potential effectiveness.

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GRADE Table Should CardioMEMS™ be recommended for coverage for heart failure monitoring?

Estimate of Effect for Outcome/ Outcomes Resource Allocation Values and Preferences Other Considerations Confidence in Estimate Cardiovascular Not reported mortality (Critical outcome) Heart failure- 0.46 events per patient-year for related CardioMEMS™ vs. hospitalization 0.68 events per patient year for (Critical outcome) control HR 0.67 (95% CI 0.55 to 0.80, p < 0.001) Approximate NNT = 5 ●●◌◌ (Low confidence, based on 1 RCT, n = 550) Quality of life Improved Minnesota Living with (Important Heart Failure Questionnaire score in outcome) the CardioMEMS™ group (45) vs. the control group (51), (105 point scale, p = 0.02) ●◌◌◌ (Very low confidence, based on 1 RCT, n = 550)

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GRADE Table Should CardioMEMS™ be recommended for coverage for heart failure monitoring?

Estimate of Effect for Outcome/ Outcomes Resource Allocation Values and Preferences Other Considerations Confidence in Estimate Harms 15 serious procedure-related or (Important device-related adverse events were outcome) reported (4 bleeding events, 3 events related to interruption of anticoagulation, 2 exacerbations of atrial arrhythmias, 2 febrile illnesses, 1 in-situ pulmonary thrombus, 1 episode of cardiogenic shock, 1 episode of atypical chest pain, and 1 delivery-system failure that required snare retrieval) Approximate NNH = 37 ●◌◌◌ (Very low confidence, based on 1 RCT, n = 550)

Balance of benefits and harms: We have low confidence that CardioMEMS™ decreases the rate of heart failure-related hospitalization, very low confidence that it improves quality of life, and very low confidence that there is a mortality benefit. We have very low confidence that it is associated with serious adverse events. While the balance of benefits and harms weighs in favor of the intervention, based on the limited evidence it is unclear that the benefit outweighs the risk. Rationale: The balance of benefits and harms weighs in favor of the intervention, but it is very expensive and invasive, and preferences would likely be highly variable. Given that the evidence is derived from only one trial that has concern of bias, a confirmatory trial is necessary to improve the confidence regarding the potential benefit of this intervention. Recommendation: CardioMEMS™ is not recommended for coverage for heart failure monitoring (weak recommendation).

Note: GRADE table elements are described in Appendix A. A GRADE Evidence Profile is in Appendix B.

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Background

Heart failure occurs when the heart muscle is damaged to the extent that it cannot meet the body's needs for blood and oxygen (American Health Association, 2018). About 5.7 million adults in the U.S. have heart failure, and heart failure is a contributing cause to one in nine deaths (Heidenreich et al., 2013). About half of people who develop heart failure die within five years of diagnosis (Heidenreich et al., 2013). The annual economic costs of heart failure in the U.S. are estimated at $30.7 billion, including the costs of health care services, medications, and missed days of work (Mozaffarian et al., 2016). Risk factors for heart failure include coronary heart disease, myocardial infarction, hypertension, and diabetes. Behavioral risk factors include cigarette smoking; a diet high in fat, cholesterol, and sodium; physical inactivity; and being obese (Centers for Disease Control and Prevention [CDC], 2016). Early diagnosis and treatment can improve outcomes for patients with heart failure, and treatment usually involves medications, behavioral interventions focusing on diet and physical activity, and daily monitoring of symptoms (CDC, 2016). Heart failure symptoms and disease progression can be difficult to monitor because of subtle onset of decompensation, medication regimens, the complexities of lifestyle changes, and interactions with comorbid conditions (Bui & Fonarow 2012). Interventions to monitor ambulatory heart failure patients include increased self-care and self-management; home visitations by providers; structured telephone support; telemonitoring; and remote monitoring through the use of implantable devices, such as CardioMEMS™ (Bui & Fonarow 2012). Because of penalties imposed by the Centers for Medicare and Medicaid Services (CMS) for heart failure readmissions, preventing rehospitalization has become a major focus of health insurers and hospital systems (Boccuti & Casillas, 2017). Indications

CardioMEMS™ is indicated for wirelessly measuring and monitoring pulmonary artery pressure and heart rate in New York Heart Association (NYHA) Class III heart failure patients who have been hospitalized for heart failure in the previous year. CardioMEMS™ is contraindicated for patients who are unable to take dual antiplatelet or anticoagulants for one month after implant of the device (Abbott, 2018). Technology Description

CardioMEMS™ measures pulmonary artery hemodynamic data that physicians can use to initiate or modify treatments for heart failure. The CardioMEMS™ heart failure monitoring system includes the implantable wireless sensor with delivery catheter, a patient-based or clinic-based electronics system, and a patient database. The wireless sensor is permanently implanted into the distal pulmonary artery (CardioMEMS, 2014). The manufacturer lists the potential adverse events from implanting CardioMEMS™ as infection, arrhythmias, bleeding, hematoma, thrombus, myocardial infarction, transient ischemic attack, stroke, device embolization, and death (Abbott 2018). The data provided by CardioMEMS™ are heart rate; pulmonary artery waveform; and systolic, diastolic, and mean pulmonary artery pressure. These data are transmitted to the patient database on a secure website (CardioMEMS, 2014). CardioMEMS™ received premarket approval from the U.S. Food and Drug Administration (FDA) in May 2014 (FDA, 2014a).

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Evidence Review Abraham et al., 2011

The pivotal trial examining the effectiveness of the implantable hemodynamic monitoring system (IHMS) is known as the CardioMEMS™ Heart Sensor Allows Monitoring of Pressures to Improve Outcomes in NYHA III Heart Failure Patients (CHAMPION) trial. Its initial results were published in February 2011. The CHAMPION trial enrolled adults with a diagnosis of heart failure for at least three months with NYHA functional Class III symptoms and at least one heart failure-related hospitalization in the preceding 12 months. Patients were eligible without respect to the left ventricular ejection fraction. To be eligible, patients must have been on optimal or best-tolerated guideline-directed heart failure therapies. Major exclusion criteria were a history of recurrent pulmonary embolism or deep venous thrombosis, Stage IV or V chronic kidney disease, implantation of cardiac resynchronization device in the three months prior to enrollments, recent major adverse cardiovascular events, and hypersensitivity to aspirin or clopidogrel. CHAMPION was designed as a randomized, single-blind, multicenter trial and was conducted at 64 sites in the United States. The study enrolled 550 patients who all underwent implantation of the CardioMEMS™ device and were admitted to the hospital overnight for observation. Prior to discharge from the hospital, patients were randomized (1:1) to an experimental arm (in which treating clinicians could access readings from the device) and to a control arm (in which treating clinicians could not access readings from the device). All patients were instructed to take pressure readings every day to ensure that patients were blinded to their treatment allocation. In the experimental group, invasive hemodynamic data were reviewed at least weekly, and more often if changes were made in the treatments. Patients in both groups were seen by their treating clinician at one, three, and six months, then every six months. Each study site was required to balance the number of patient contacts between the experimental and control groups. The primary outcomes were the rate of heart failure-related hospitalizations, freedom from device-related complications, and freedom from pressure sensor failure, all measured at six months. The secondary outcome measures were change in mean pulmonary artery pressure, proportion of patients with heart failure-related hospitalization, days alive outside the hospital, and quality of life as measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ), all measured at six months. Outcomes assessment and adjudication were performed by an independent, blinded committee. The trial was conducted between September 2007 and October 2009. Overall, 550 patients were enrolled and had the device implanted. There were 270 patients randomized to the experimental arm and 280 patients randomized to the control arm. The mean age of patients was 61 years, roughly 72% of patients were men, and roughly 80% had a left ventricle (LV) ejection fraction of < 40%. Approximately 75% of patients were on ACE inhibitors, 90% were on beta blockers, and 40% were on aldosterone antagonists at baseline. The two groups were generally comparable with respect to baseline characteristics, but there were small differences with respect to the following: • Proportion of patients with LV ejection fraction > 40% (62 [23%] in the experimental group vs. 57 [20%] in the control group) • Proportion of patients with coronary artery disease (182 [67%] in the experimental group vs. 202 [72%] in the control group)

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• Proportion of patients with atrial flutter or atrial fibrillation (120 [44%] in the experimental group vs. 135 [48%] in the control group) • Proportion of patients on nitrates (64 [24%] in the experimental group vs. 56 [20%] in the control group). All patients remained in their assigned treatment group until the six month follow-up period was completed for every enrollee; the mean follow-up duration during the randomized portion of the trial was 15 months. Six month follow-up was available for 244 patients in the experimental arm and 254 patients in the control arm. The overall rate of attrition was approximately 10% and was non- differential. The study authors used intention-to-treat analysis. For the primary efficacy outcome of heart failure-related hospitalizations at up to six months, there were fewer events in the experimental arm (84 events, 0.32 events per patient per six months) compared with the control arm (120 events, 0.44 events per patient per six months); this equated to a statistically significant reduction of 28% (HR 0.72, 95% CI 0.60 to 0.85, p = 0.0002, number needed to treat [NNT] 8). The authors found a statistically significant reduction in events in the experimental arm (HR 0.63, 95% CI 0.52 to 0.77, p < 0.0001, NNT 4) for the pre-specified supplemental efficacy endpoint of heart failure-related hospitalizations during the complete randomized follow-up period. For the safety- related primary endpoints, there were no pressure sensor failures, and there were 15 serious procedure-related or device-related adverse events (four bleeding events, three events related to interruption of anticoagulation, two exacerbations of atrial arrhythmias, two febrile illnesses, one in-situ pulmonary thrombus, one episode of cardiogenic shock, one episode of atypical chest pain, and one delivery-system failure that required snare retrieval). Relevant secondary outcomes were a lower proportion of patients admitted to the hospital at six months in the experimental group (20% vs. 29% in the control group, RR 0.71, 95% CI 0.53 to 0.96, p = 0.03), small but statistically significant improvements in days alive outside the hospital at six months (174.4 vs. 172.1, p = 0.02), and MLHFQ score at six months (45 vs. 51, p = 0.02). There was no statistically significant difference in survival at six months (HR 0.77, 95% CI 0.40 to 1.51, p = 0.45). In a pre-specified subgroup analysis by LV systolic function, the rate of heart failure-related hospitalizations was lower in the experimental arm in both subgroups (0.16 per patient per six months vs. 0.33 per patient per six months for patients with preserved ejection fraction; 0.36 per patient per six months vs. 0.47 per patient per six months for patients with reduced ejection fraction). The authors also conducted an incompletely reported cost-effectiveness analysis. Using a hypothetical cohort of patients with a five-year time horizon, the authors estimated that the treatment group gained 0.306 quality-adjusted life years (QALY) at an incremental cost of $4,282, leading to an incremental cost- effectiveness ratio of $13,979 per QALY gained. The authors did not specify the perspective, clearly outline all assumptions or report sensitivity analyses, and did not state whether a customary discounting rate was applied. Potential sources of bias in the initial report of the CHAMPION trial were that study clinicians (who were ultimately responsible for decisions regarding hospitalization) were not blinded to the treatment group (performance bias), that the device manufacturer sponsored the trial and was involved in data collection and management, and that all authors disclosed conflicts of interest (including consultancies, research grants, or employment).

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At the initial FDA Circulatory System Devices Panel meeting at which CardioMEMS™ was discussed in 2011, several criticisms of the design, conduct, and reporting of the CHAMPION trial were leveled (Loh, Barbash, & Waksman, 2013). Three major concerns were outlined. First, FDA statisticians questioned the robustness of the statistical models used in the analysis of heart failure admissions. As an example, if an alternative bootstrap model was applied, as few as two additional hospitalizations in the experimental arm would have increased the likelihood of a type I error to greater than 10% (i.e., p value in excess of 0.1). Second, an FDA Division of Bioresearch Monitoring audit found evidence that unblinded representatives of the sponsor or principal investigators communicated with study sites to make specific treatment recommendations for some patients in the experimental group. Third, in a post-hoc subgroup analysis by gender, the putative efficacy of the device was not observed in women for whom the hazard ratio for heart failure-related hospitalization was 1.15 (95% CI 0.83 to 1.59, p = 0.3953). Partly on the basis of these concerns, the advisory panel voted (7 to 3) that there was not reasonable assurance that the device was effective. The manufacturer and principal investigators responded to these criticisms at a subsequent FDA advisory panel meeting. They provided additional analyses emphasizing that the number of communications with specific recommendations to treating clinicians was small and that a propensity score analysis comparing experimental group patients whose clinicians did not receive investigator communications to a matched group of controls found a similar reduction in heart failure-related hospitalizations. They also contended that the absence of efficacy in women stemmed from a small number of women in the trial and an excess number of deaths in the control group (which reduced their time in the study); using a combined endpoint of mortality or heart failure-related hospitalization, there was not a treatment-by-gender interaction at a p value of 0.05 (although the FDA pointed out that under a more customary p value cutoff of 0.15 for tests of interaction, the observed subgroup difference remained). Despite the additional information and analyses, the advisory panel again voted (7 to 4) that there was not “reasonable assurance” that the device was effective. The FDA disagreed with the advisory panel’s determination, noting that: When considering the totality of effectiveness data, the consistency of the results indicate a positive treatment effect in reducing HFR hospitalizations. This positive treatment effect seen in the Open Access (Part 2) of the study also agrees with the positive treatment effect seen in the Randomized Access (Part 1). However, because of the confounding effect of the nurse communications from Part 1 and the limitations of the ancillary analyses from Part 2, there remains some uncertainty regarding the magnitude of that positive effect. (FDA, 2014b, p. 89) Adamson et al., 2014

This study, derived from the previously described CHAMPION trial, reported the effectiveness of CardioMEMS™ in patients with preserved left ventricular function. Of the 550 patients enrolled in the CHAMPION trial, 119 had a left ventricular ejection fraction (EF) > 40% (mean EF 50.6%). Because the American Heart Association and American College of Cardiology consensus definition for heart failure with preserved ejection fraction changed in 2013, the authors also provided a subgroup analysis based on the newer EF cutoff of 50% (n = 66 patients). In general, within the subgroup of patients with preserved ejection fraction, the baseline patient characteristics were similar between the experimental and control groups. Compared to those with reduced EF, patients with preserved EF were more likely to

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have comorbid diabetes and cerebrovascular disease and less likely to have a history of myocardial infarction or hypotension. In the preserved EF group (> 40%), for the primary efficacy endpoint of heart failure-related hospitalization at six months, there were 11 hospitalizations in the experimental arm (0.18 events per patient per six months) and 19 hospitalizations in the control arm (0.33 events per patient per six months) (incidence rate ratio [IRR] 0.54, 95% CI 0.38 to 0.70, p < 0.0001). Among the group of patients with EF > 50%, for the primary efficacy endpoint of heart failure-related hospitalization at six months, there were nine hospitalizations in the experimental arm (0.18 events per patient per six months) and 10 hospitalizations in the control arm (0.35 events per patient per six months) (IRR 0.50, 95% CI 0.29 to 0.86, p = 0.0129). The authors stated that the greater event rate in the control group, despite a numerically similar number of events, derived from a shorter combined follow-up period in the control group. During the complete randomized follow-up period (mean 17.6 months), for patients with preserved EF (> 40%) there were 29 hospitalizations in the experimental arm (0.43 events per patient per year) and 59 hospitalizations in the control arm (0.86 events per patient per year) (IRR 0.50, 95% CI 0.35 to 0.70, p < 0.0001). Among the group of patients with EF > 50%, there were 13 hospitalizations in the experimental arm (0.41 events per patient per year) and 31 hospitalizations in the control arm (1.39 events per patient per year) (IRR 0.30, 95% CI 0.18 to 0.48, p < 0.0001). At the six-month follow-up, the proportion of patients with preserved EF (> 40%) who were hospitalized was 12.9% in the experimental arm and 22.8% in the control arm. During the complete randomized follow-up period, the proportion of patients with preserved EF (> 40%) who were hospitalized was 29% in the experimental arm and 38.6% in the control arm. The authors did not report the proportion of patients with EF > 50% who were hospitalized during either timeframe. Adamson et al., 2016

This study, derived from the previously described CHAMPION trial, reported the effectiveness of CardioMEMS™ in reducing the risk of 30-day readmissions among a subgroup of Medicare-eligible participants. Of the 550 patients enrolled in the trial, 245 were older than 65 at the time of device implantation. Compared to the overall study population, this group was largely composed of white men with ischemic cardiomyopathy and reduced LV ejection fraction. Within the subgroup, the mean LV ejection fraction was lower in the control group (30.4% vs. 34.6%), and the baseline pulmonary artery pressures were slightly higher in the control group. The reason for hospitalization was prospectively adjudicated by an independent group of cardiologists, although the authors did not state that these adjudicators were blinded to the treatment group. The mean follow-up time in the subgroup was 515 days. During this follow-up period, there were 175 total heart failure-related hospitalizations, of which 155 were considered index admissions that contributed to the analysis. Overall, there were 44 all-cause readmissions, of which 21 were heart failure-related. The overall rate of heart failure-related hospitalizations was 0.34 events per patient per year in the experimental group, compared to 0.67 events per patient per year in the control group (HR 0.51, 95% CI 0.37 to 0.70, p < 0.0001). The rate of 30-day all-cause readmission was 0.07 events per patient per year in the experimental group, compared to 0.18 events per patient per year in the control group (HR 0.42, 95% CI 0.22 to 0.80, p = 0.008). The rate of 30-day heart failure readmission was 0.02

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events per patient per year in the experimental group, compared to 0.10 events per patient per year in the control group (HR 0.23, 95% CI 0.08 to 0.68, p = 0.008). During the open access period, 63 control arm patients were followed for a mean of 13 months. After these patients had entered the open access period (and clinicians had access to hemodynamic measurements), the heart failure-related hospitalization rate was 0.35 events per patient per year compared to a rate of 0.67 events per person per year during the randomized phase of the trial. More than half (n = 135) of the originally randomized patients in this subgroup completed the full randomized portion of the trial. Abraham et al., 2016

This report, derived from the previously described CHAMPION trial, reported complete results of the trial after the open access period. As patients enrolled in the trial, they remained in their randomly allocated treatment group until the last patient completed six months of follow-up. At that point, pressure measurements for patients in the control arm during the randomized portion of the trial were made available to the treating clinicians. Patients were followed for an average of 13 months in the open access period. No communications between the sponsor and study clinicians occurred during the open access period. The statistical analysis plan was developed in conjunction with the FDA. Of the original 550 patients enrolled in the trial, 347 patients completed the full randomized access period (177 in the experimental group and 170 in the control group). The study withdrawals that occurred during the randomized access portion of the trial were most commonly due to death. During the open access period, an additional 43 patients in the former control group and 58 patients in the former experimental group withdrew. Complete outcomes from the randomized access portion of the trial at a mean follow-up duration of 18 months were reported as follows: Randomized access Randomized access Statistical analysis experimental group control group Heart failure n = 182 n = 279 HR 0.67 (0.55 to 0.80) admissions 0.46 events per 0.68 events per p < 0.0001 patient-year patient-year Deaths and heart n = 232 n = 343 HR 0.69 (0.59 to 0.82) failure admissions 0.58 events per 0.84 events per p < 0.0001 patient-year patient-year Death n = 50 (19%) n = 64 (23%) HR 0.80 (0.55 to 1.15) p = 0.23 Death or first n = 121 (45%) n = 145 (52%) HR 0.77 (0.60 to 0.98) admission for heart p = 0.033 failure All-cause admissions n = 554 n = 672 HR 0.84 (0.75 to 0.95) p = 0.0032

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Randomized access Randomized access Statistical analysis experimental group control group 1.38 events per 1.65 events per patient-year patient-year

Deaths and all-cause n = 604 n = 736 HR 0.84 (0.76 to 0.94) admissions 1.51 events per 1.80 events per p = 0.0017 patient-year patient-year

Outcomes comparing the randomized access control group to the open-access former control group were reported as follows: Randomized access Open-access former Statistical analysis control group control group Heart failure n = 279 n = 64 HR 0.52 (0.40 to 0.69) admissions 0.68 events per 0.36 events per p < 0.0001 patient-year patient-year Deaths and heart n = 343 n = 85 HR 0.61 (0.48 to 0.78) failure admissions 0.84 events per 0.51 events per p < 0.0001 patient-year patient-year Death n = 64 (23%) n = 21 (12%) HR 0.71 (0.43 to 1.17) p = 0.17 Death or first n = 145 (52%) n = 49 (29%) HR 0.53 (0.38 to 0.73) admission for heart p < 0.0001 failure All-cause admissions n = 672 n = 230 HR 0.35 (0.67 to 0.92) 1.65 events per 1.30 events per p = 0.0034 patient-year patient-year Deaths and all-cause n = 736 n = 251 HR 0.85 (0.72 to 0.99) admissions 1.80 events per 1.52 events per p = 0.0351 patient-year patient-year

Outcomes comparing the randomized access experimental group to the open-access former experimental group were reported as follows: Randomized access Open-access former Statistical analysis experimental group experimental group Heart failure n = 182 n = 78 HR 0.93 (0.70 to 1.22) admissions p = 0.58

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Randomized access Open-access former Statistical analysis experimental group experimental group 0.48 events per 0.45 events per patient-year patient-year Deaths and heart n = 232 n = 109 HR 1.09 (0.86 to 1.39) failure admissions 0.61 events per 0.67 events per p = 0.46 patient-year patient-year Death n = 50 (19%) n = 31 (18%) HR 1.40 (0.89 to 2.23) p = 0.15 Death or first n = 121 (45%) n = 55 (31%) HR 0.85 (0.61 to 1.17) admission for heart p = 0.32 failure All-cause admissions n = 554 n = 218 HR 0.87 (0.74 to 1.03) 1.51 events per 1.32 events per p = 0.10 patient-year patient-year Deaths and all-cause n = 604 n = 249 HR 0.97 (0.83 to 1.14) admissions 1.65 events per 1.61 events per p = 0.75 patient-year patient-year

Givertz et al., 2017

This study, derived from the previously described CHAMPION trial, reported the effectiveness of CardioMEMS™ in reducing the risk of hospitalization for heart failure or death among patients with reduced ejection fraction who were on at least one guideline-directed medical therapy at baseline. This analysis by baseline tolerance of angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) and β-Blockers (BB) was not pre-specified. Of the 550 trial participants, 456 had a reduced LV ejection fraction (< 40%). Among patients with reduced EF, 445 patients were on either an ACEi/ARB or a BB at baseline (Group 1), and 337 patients were on ACEi/ARB and BB at baseline. In the overall group of patients with reduced EF at mean follow-up of 18 months, the rate of hospitalization for heart failure was 0.49 events per patient-year in the experimental group and 0.69 events per patient-year in the control group (HR 0.72, 95% CI 0.59 to 0.88, p = 0.013), and death occurred in 17.6% of experimental group patients compared to 24.4% of the control group patients (HR 0.68, 95% CI 0.45 to 1.02, p = 0.06). Using a Cox proportional hazards model that accounted for changes in the doses of ACEi/ARB and BB, or nitrates and hydralazine, the hazard ratios for mortality were similar and remained statistically nonsignificant. Among Group 1 patients (those on at least one ACEi/ARB or BB at baseline), the rate of hospitalization for heart failure was 0.45 per patient-year in the experimental group and 0.68 per patient-year in the control group (HR 0.67, 95% CI 0.54 to 0.82, p = 0.0002), and the all-cause mortality rate was 0.171 per patient-year in the control group and 0.107 per patient-year in the experimental group (HR 0.63, 95% CI 0.41 to 0.96, p = 0.0293). Among Group 2 patients (those on both an ACEi/ARB or BB at baseline), the

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rate of hospitalization for heart failure was 0.69 per patient-year in the control group and 0.39 per patient-year in the experimental group (HR 0.57, 95% CI 0.45 to 0.73, p = 0.0002), and the all-cause mortality rate was 0.155 per patient-year in the control group and 0.067 per patient-year in the experimental group (HR 0.43, 95% CI 0.24 to 0.76, p = 0.0052). Using a Cox proportional hazards model that accounted for changes in the doses of ACEi/ARB and BB, or nitrates and hydralazine, the hazard ratios for mortality were similar and remained statistically significant. Evidence Summary

There is low-quality evidence from a single, seriously flawed randomized controlled trial (RCT) that CardioMEMS™ reduces the risk of heart failure-related hospitalization in patients with NYHA Class III heart failure who have had a previous admission for heart failure. This finding was consistent in patients with both preserved and reduced LV function, but in the initial trial, this result was not significant among women. The evidence for a reduction in all-cause mortality, improved quality of life, and harms is very low because it is further limited by imprecision in the estimates. The trial was mainly limited by its single-blind design, manufacturer funding and involvement, and concerns (raised by an FDA advisory panel) related to the statistical analysis plan and improper communications between the sponsor and study investigators in the experimental group. Policy Landscape Payer Coverage Policies Medicaid

No coverage policy for was identified for CardioMEMS™ for the Washington State Medicaid Program. Medicare

No Medicare National Coverage Determinations were found for CardioMEMS™. One Local Coverage Determination (L36419) was found for CardioMEMS™, which considers this device investigational and non-covered unless in an approved clinical trial. Private Payers

Coverage policies were searched for four private payers: Aetna, Cigna, Moda, and Regence. The Cigna policy (effective 10/15/2017) and the Regence policy (effective: 1/1/2018) do not cover CardioMEMS™. No coverage policies for CardioMEMS™ were found for Aetna or Moda. Recommendations from Others

The 2017 Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment published by the American College of Cardiology summarized the evidence on CardioMEMS™ and then concluded: “This suggests that in well-selected patients with recurrent congestion, this highly specialized monitoring strategy may guide therapeutic decision making. The impact on mortality is unknown. A team-based approach may be necessary to best deploy this monitoring strategy” (Yancy et al., 2017, p. 215).

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The poor-quality 2016 guidelines from the European Society of Cardiology on diagnosis and treatment of acute and chronic heart failure state that CardioMEMS™ could be considered in symptomatic heart failure patients who have had a previous hospitalization for heart failure (Ponikowski et al., 2016). The guidelines rate this recommendation as Class IIb, meaning that there is conflicting evidence or a divergence of opinion about the usefulness or efficacy of CardioMEMS™. Quality Measures

No quality measures were identified when searching the National Quality Measures Clearinghouse for CardioMEMS or heart failure monitoring. The Clearinghouse lists a number of quality measures related to hospital admissions and health outcomes for patients with heart failure. One example of a measure, developed by CMS, is the 30-day risk-standardized mortality rate for patients discharged from the hospital with a principal diagnosis of heart failure (mortality defined as death from any cause within 30 days of the start of the index admission). Another measure developed by CMS is the 30-day risk- standardized hospital readmission rate for patients with heart failure. This measures unplanned hospital readmissions within 30 days of the original discharge date. References Evidence Sources

Abraham, W. T., Adamson, P. B., Bourge, R. C., Aaron, M. F., Costanzo, M. R., Stevenson, L. W., . . . Yadav, J. S. (2011). Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: A randomised controlled trial. Lancet, 377(9766), 658-666. doi: 10.1016/s0140- 6736(11)60101-3

Abraham, W. T., Stevenson, L. W., Bourge, R. C., Lindenfeld, J. A., Bauman, J. G., & Adamson, P. B. (2016). Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: Complete follow-up results from the CHAMPION randomised trial. Lancet, 387(10017), 453-461. doi: 10.1016/s0140-6736(15)00723-0

Adamson, P. B., Abraham, W. T., Bourge, R. C., Costanzo, M. R., Hasan, A., Yadav, C., . . . Stevenson, L. W. (2014). Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction. Circulation: Heart Failure, 7(6), 935-944. doi: 10.1161/circheartfailure.113.001229

Adamson, P. B., Abraham, W. T., Stevenson, L. W., Desai, A. S., Lindenfeld, J. A., Bourge, R. C., & Bauman, J. (2016). Pulmonary artery pressure-guided heart failure management reduces 30-day readmissions. Circulation: Heart Failure, 9(6), e002600. doi: 10.1161/ circheartfailure.115.002600

Givertz, M. M., Stevenson, L. W., Costanzo, M. R., Bourge, R. C., Bauman, J. G., Ginn, G., & Abraham, W. T. (2017). Pulmonary artery pressure-guided management of patients with heart failure and reduced ejection fraction. Journal of the American College of Cardiology, 70(15), 1875-1886. doi: 10.1016/j.jacc.2017.08.010

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Other Citations

Abbott. (2018). CardioMEMS™ HF System. Retrieved from https://www.sjm.com/en/patients/heartfailure/our-solutions/pulmonary-artery-pressure-monitoring/cardiomems-hf-system/important- safety-information

American Heart Association. High blood pressure guidelines. Retrieved from http://www.heart.org/HEARTORG/Conditions/HeartFailure/Heart- Failure_UCM_002019_SubHomePage.jsp

Boccuti, C., & Casillas, G. Aiming for fewer hospital u-turns: The Medicare hospital readmission reduction program. Retrieved from https://www.kff.org/medicare/issue-brief/aiming-for-fewer- hospital-u-turns-the-medicare-hospital-readmission-reduction-program/

Bui, A. L., & Fonarow, G. C. (2012). Home monitoring of heart failure management. Journal of the American College of Cardiology, 59(2), 97-104. doi: 10.1016/j.jacc.2011.09.044

CardioMEMS, Inc. (2014). CardioMEMS™ HF System: User's Manual. Retrieved from: https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100045d.pdf

Centers for Disease Control and Prevention. (2016). Heart failure fact sheet. Retrieved from https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm

Heidenreich, P. A., Albert, N. M., Allen, L. A., Bluemke, D. A., Butler, J., Fonarow, G. C., . . . Trogdon, J. G. (2013). Forecasting the impact of heart failure in the United States: A policy statement from the American Heart Association. Circulation: Heart Failure, 6(3), 606-619. doi: 10.1161/HHF.0b013e318291329a

Loh, J. P., Barbash, I. M., & Waksman, R. (2013). Overview of the 2011 Food and Drug Administration Circulatory System Devices Panel of the Medical Devices Advisory Committee Meeting on the CardioMEMS Champion Heart Failure Monitoring System. Journal of the American College of Cardiology, 61(15), 1571-1576. doi: 10.1016/j.jacc.2012.08.1035

Mozaffarian, D., Benjamin, E. J., Go, A. S., Arnett, D. K., Blaha, M. J., Cushman, M., . . . Turner, M. B. (2016). Heart disease and stroke statistics--2016 update: A report from the American Heart Association. Circulation, 133(4), e38-360. doi: 10.1161/cir.0000000000000350

Ponikowski, P., Voors, A. A., Anker, S. D., Bueno, H., Cleland, J. G., Coats, A. J., . . . van der Meer, P. (2016). 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). European Journal of Heart Failure, 18(8), 891-975. doi: 10.1002/ejhf.592

U.S. Food and Drug Administration. (2014a). Premarket approval (PMA). Retrieved from https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm?id=P100045

U.S. Food and Drug Administration. (2014b). Summary of safety and effectiveness data (SSED). Retrieved from https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100045b.pdf

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Yancy, C. W., Januzzi, J. L., Jr., Allen, L. A., Butler, J., Davis, L. L., Fonarow, G. C., . . . Wasserman, A. (2018). 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: Answers to 10 pivotal issues about heart failure with reduced ejection fraction. Journal of the American College of Cardiology, 71(2), 201-30. doi: 10.1016/j.jacc.2017.11.025

Coverage guidance is prepared by the Health Evidence Review Commission (HERC), HERC staff, and subcommittee members. The evidence summary is prepared by the Center for Evidence-based Policy at Oregon Health & Science University (the Center). This document is intended to guide public and private purchasers in Oregon in making informed decisions about health care services. The Center is not engaged in rendering any clinical, legal, business or other professional advice. The statements in this document do not represent official policy positions of the Center. Researchers involved in preparing this document have no affiliations or financial involvement that conflict with material presented in this document.

Suggested citation: Obley, A., Mosbaek, C., King, V., & Livingston, C. (2018). Coverage guidance: CardioMEMS™ for heart failure monitoring. Portland, OR: Center for Evidence-based Policy, Oregon Health & Science University

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Appendix A. GRADE Table Element Descriptions

Element Description Balance of benefits The larger the difference between the desirable and undesirable effects, the higher the and harms likelihood that a strong recommendation is warranted. An estimate that is not statistically significant or has a confidence interval crossing a predetermined clinical decision threshold will be downgraded. Quality of evidence The higher the quality of evidence, the higher the likelihood that a strong recommendation is warranted Resource allocation The higher the costs of an intervention—that is, the greater the resources consumed in the absence of likely cost offsets—the lower the likelihood that a strong recommendation is warranted Values and The more values and preferences vary, or the greater the uncertainty in values and preferences preferences, the higher the likelihood that a weak recommendation is warranted Other considerations Other considerations include issues about the implementation and operationalization of the technology or intervention in health systems and practices within Oregon.

Strong recommendation

In Favor: The subcommittee concludes that the desirable effects of adherence to a recommendation outweigh the undesirable effects, considering the balance of benefits and harms, resource allocation, values and preferences and other factors. Against: The subcommittee concludes that the undesirable effects of adherence to a recommendation outweigh the desirable effects, considering the balance of benefits and harms, resource allocation, values and preferences and other factors. Weak recommendation

In Favor: The subcommittee concludes that the desirable effects of adherence to a recommendation probably outweigh the undesirable effects, considering the balance of benefits and harms, resource allocation, values and preferences and other factors., but further research or additional information could lead to a different conclusion. Against: The subcommittee concludes that the undesirable effects of adherence to a recommendation probably outweigh the desirable effects, considering the balance of benefits and harms, cost and resource allocation, and values and preferences, but further research or additional information could lead to a different conclusion. Confidence in estimate rating across studies for the intervention/outcome

Assessment of confidence in estimate includes factors such as risk of bias, precision, directness, consistency and publication bias. High: The subcommittee is very confident that the true effect lies close to that of the estimate of the effect. Typical sets of studies are RCTs with few or no limitations and the estimate of effect is likely stable.

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Moderate: The subcommittee is moderately confident in the estimate of effect: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Typical sets of studies are RCTs with some limitations or well-performed nonrandomized studies with additional strengths that guard against potential bias and have large estimates of effects. Low: The subcommittee’s confidence in the estimate of effect is limited: The true effect may be substantially different from the estimate of the effect. Typical sets of studies are RCTs with serious limitations or nonrandomized studies without special strengths. Very low: The subcommittee has very little confidence in the estimate of effect: The true effect is likely to be substantially different from the estimate of effect. Typical sets of studies are nonrandomized studies with serious limitations or inconsistent results across studies.

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Appendix B. GRADE Evidence Profile

Quality Assessment (Confidence in Estimate of Effect) No. of Study Risk of Other Studies Design(s) Bias Inconsistency Indirectness Imprecision Factors Quality All-cause mortality 1 RCT High N/A None Serious Very low ●◌◌◌ Cardiovascular mortality 0 RCT High N/A N/A N/A Insufficient evidence Heart failure-related hospitalization 1 RCT High N/A None Not serious Low ●●◌◌ Quality of life 1 RCT High N/A None Serious Very low ●◌◌◌ Harms 1 RCT High N/A None Serious Very low ●◌◌◌

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Appendix C. Methods Scope Statement Populations Adults with chronic heart failure Population scoping notes: None Interventions CardioMEMS™ heart failure monitoring system Intervention exclusions: None Comparators Usual care (e.g., daily weight measurements, symptom reporting, frequent encounters), heart rate variability monitors, intrathoracic impedance monitors Outcomes Critical: All-cause mortality, cardiovascular mortality, heart failure-related hospitalizations Important: Quality of life, harms Considered but not selected for the GRADE table: None Key Questions KQ1: What is the comparative effectiveness of CardioMEMS™ for the management of patients with chronic systolic heart failure?

KQ2: How does the comparative effectiveness of CardioMEMS™ vary by: a. Age b. Gender c. Race/ethnicity d. Comorbid medical conditions e. Prior and current treatments f. Previous hospitalization for acute decompensated heart failure g. Heart failure etiology h. Preserved vs. reduced ejection fraction. i. Treatment setting (inpatient/outpatient) j. Patient adherence to prior treatment and monitoring plans k. New York Heart Association class/American College of Cardiology stage

KQ3: What are the harms of CardioMEMS™?

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Search Strategy

A full search of the core sources was conducted to identify systematic reviews, meta-analyses, and technology assessments that meet the criteria for the scope described above. Searches of core sources were limited to citations published after 2010. The following core sources were searched: Agency for Healthcare Research and Quality (AHRQ) Canadian Agency for Drugs and Technologies in Health (CADTH) Cochrane Library (Wiley Online Library) Institute for Clinical and Economic Review (ICER) Medicaid Evidence-based Decisions Project (MED) National Institute for Health and Care Excellence (NICE) Tufts Cost-effectiveness Analysis Registry Veterans Administration Evidence-based Synthesis Program (ESP) Washington State Health Technology Assessment Program

A MEDLINE® search was also conducted to identify systematic reviews, meta-analyses, and technology assessments, using the search terms for CardioMEMS. The search was limited to publications in English published since 2010. In addition, a MEDLINE® search was conducted for randomized controlled trials published since 2010. Searches for clinical practice guidelines were limited to those published since 2010. A search for relevant clinical practice guidelines was also conducted using MEDLINE® and the following sources: Australian Government National Health and Medical Research Council (NHMRC) Canadian Agency for Drugs and Technologies in Health (CADTH) Centers for Disease Control and Prevention (CDC), Community Preventive Services National Guidelines Clearinghouse National Institute for Health and Care Excellence (NICE) Scottish Intercollegiate Guidelines Network (SIGN) United States Preventive Services Task Force (USPSTF) Veterans Administration/Department of Defense (VA/DoD) Clinical Practice Guidelines Inclusion/Exclusion Criteria

Studies were excluded if they were not published in English, did not address the scope statement, or were study designs other than systematic reviews, meta-analyses, technology assessments, randomized controlled trials, or clinical practice guidelines.

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Appendix D. Applicable Codes

CODES DESCRIPTION CPT Codes Right heart catheterization including measurement(s) of oxygen saturation and cardiac output, 93451 when performed Injection procedure during cardiac catheterization including imaging supervision, interpretation, 93568 and report; for pulmonary angiography (List separately in addition to code for primary procedure) 93799 Unlisted cardiovascular service or procedure Interrogation device evaluation(s), (remote) up to 30 days; implantable cardiovascular monitor system, including analysis of 1 or more recorded physiologic cardiovascular data elements from all 93297 internal and external sensors, analysis, review(s) and report(s) by a physician or other qualified health care professional Interrogation device evaluation(s), (remote) up to 30 days; implantable loop recorder system, 93299 including analysis of recorded heart rhythm data, analysis, review(s) and report(s) by a physician or other qualified health care professional HCPCS Level II Codes Right heart catheterization with implantation of wireless pressure sensor in the pulmonary artery, C9741 including any type of measurement, angiography, imaging supervision, interpretation, and report Implantable wireless pulmonary artery pressure sensor with delivery catheter, including all system C2624 components Note: Inclusion on this list does not guarantee coverage.

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Question: How should the Coverage Guidance on CardioMEMS™ For Heart Failure be applied to the Prioritized List?

Question source: Evidence-based Guideline Subcommittee

Issue: Should CardioMEMS be recommended for coverage?

HERC Coverage Guidance CardioMEMS™ is not recommended for coverage for heart failure monitoring (weak recommendation).

Current Prioritized CODES DESCRIPTION List Placement CPT Codes Diagnostic Right heart catheterization including measurement(s) of oxygen saturation 93451 Procedures and cardiac output, when performed File Injection procedure during cardiac catheterization including imaging Diagnostic 93568 supervision, interpretation, and report; for pulmonary angiography (List Procedures separately in addition to code for primary procedure) File Ancillary 93799 Unlisted cardiovascular service or procedure Procedures File Interrogation device evaluation(s), (remote) up to 30 days; implantable Diagnostic cardiovascular monitor system, including analysis of 1 or more recorded Procedures 93297 physiologic cardiovascular data elements from all internal and external File sensors, analysis, review(s) and report(s) by a physician or other qualified health care professional Interrogation device evaluation(s), (remote) up to 30 days; implantable loop Diagnostic recorder system, including analysis of recorded heart rhythm data, analysis, Procedures 93299 review(s) and report(s) by a physician or other qualified health care File professional HCPCS Level II Codes Right heart catheterization with implantation of wireless pressure sensor in Diagnostic C9741 the pulmonary artery, including any type of measurement, angiography, Procedures imaging supervision, interpretation, and report File Implantable wireless pulmonary artery pressure sensor with delivery Not on List C2624 catheter, including all system components

HERC Staff Recommendations:

1) Place C2624 on Line 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS 2) Place C9741 on Line 660, remove from the Diagnostic Procedures File

CG - Cardiomems For Heart Failure, Issue #1371 Page 1

CG - CardioMEMS™ For Heart Failure

Procedure Intervention Description Rationale Last Review Code C2624, CardioMEMS™ – Implantable Insufficient evidence of October, 2018 C9741 wireless pulmonary artery effectiveness Coverage pressure monitor for heart guidance failure monitoring

CG - Cardiomems For Heart Failure, Issue #1371 Page 2

HERC Coverage Guidance: CardioMEMS™ for Heart Failure Monitoring Disposition of Public Comments

Table of Contents Discussion Table ...... 1 Commenters...... 2 Public Comments ...... 2 References Provided by Commenters ...... 7

Discussion Table IDs/#s Summary of Issue Subcommittee Response A1, B4 Additional observational trials and a conference abstract Observational studies are generally not considered when higher-level were submitted supporting the efficacy of CardioMEMS studies are available (e.g., RCTs). Conference abstracts are not considered by the HERC. Given the potential harms and high costs associated with CardioMEMS™, higher confidence in the efficacy of CardioMEMS™ and lack of harms would be required for EbGS to recommend coverage.

B3, B4 CardioMEMS is associated with significant improvements The point estimate is encouraging that CardioMEMS™ could have a in heart failure hospitalizations. significant impact on health outcomes, however, we have low confidence in this estimate because it is based on a single RCT with concern for bias. B3 Elements of standard of care for preventing heart failure The diagnostic accuracy of the current standard of care was outside exacerbations have limitations. the scope of the coverage guidance. Significant changes to the standard of care have developed in the last few years to try to decrease heart failure readmissions, which might have affected secular trends.

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HERC Coverage Guidance: CardioMEMS™ for Heart Failure Monitoring Disposition of Public Comments

Commenters Identification Stakeholder A Jacob Abraham, MD [Submitted April 13, 2018] B Wendy Chan, Global Director, Health Economics and Reimbursement, Reimbursement (HE&R), Heart Failure Therapies, Abbott [Submitted May 10, 2018]

Public Comments ID/# Comment Disposition A1 Three citations and a PowerPoint file were submitted. The study by Heywood et al. was observational and only reported on changes in hemodynamic parameters (not on clinical endpoints), and therefore is out of scope. The study by Desai et al. is essentially a before-and-after study using Medicare claims data for heart failure hospitalizations six months before CardioMEMS™ implantation and six months after implantation. In general, when higher-quality data from RCTs are available, HERC and its subcommittees do not consider the findings of observational studies. B1 Abbott requests reconsideration of the draft Coverage Guidance in revising the Thank you for your comments. designation of the CardioMEMS™ Heart Failure (HF) System as “not recommended for coverage for heart failure monitoring (weak recommendation)” to medically appropriate based on the FDA indication. We believe the CardioMEMS’ technology holds promise and that the totality of the evidence supports HERC’s coverage consideration. Our rationale is summarized below.

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HERC Coverage Guidance: CardioMEMS™ for Heart Failure Monitoring Disposition of Public Comments ID/# Comment Disposition B2 1. CHAMPION Trial: Trial Validity and Applicability The coverage guidance outlines the concerns raised by the FDA Circulatory System Devices Panel (and others) The FDA approved the CHAMPION trial based on successfully achieving the primary and the manufacturer’s response to those concerns. The safety and efficacy endpoints. As with most pivotal trials, manufacturers work closely ultimate conclusions of the advisory panel and the FDA with the FDA to ensure completeness of trial design, trial integrity and limitation of are noted in the coverage guidance. confounding issues. The concerns about bias referenced by HERC were evaluated by the FDA with the completion of a clinical and propensity analysis of the CHAMPION The coverage guidance acknowledged that the available trial to determine the influence and impact of nurse communications in terms of trial data have demonstrated that CardioMEMS™ results characterizing and quantifying the results observed in the trial’s treatment group.1 in fewer heart failure hospitalizations. However, the These analyses supported that there was no apparent bias associated with the GRADE rating for that outcome was assessed as low conduct of the trial. Both independent findings by the FDA supported their confidence because of concerns for a high risk of bias in recommendation for approval of the CardioMEMS HF System based on the totality of the design and conduct of the one available RCT. the effectiveness data and the consistency of the results indicate a positive treatment It should be noted that a wide range of cost-effectiveness effect in reducing HF rehospitalizations for both the Randomized Access (Part 1) and estimates have been reported in the peer-reviewed in the Open Access (Part 2) of the CHAMPION study.2 literature. The low confidence in the estimate of effect for HERC indicated in the values and preferences section that “…patients would prefer to reducing heart failure admission raises questions about avoid heart failure exacerbations and repeated hospitalizations.” The benefit of the accuracy of these analyses. CardioMEMS for indicated patients shows reductions in repeat hospitalizations with low adverse event rates of <5% which is well within reason and lower than most implantable cardiac devices. Unlike some implantable cardiac devices, there is no battery replacement associated with the CardioMEMS’ sensor after initial implant. The cost savings from preventing decompensation and repeat hospitalizations is significant and translates to $5,296/patient/year (comprehensive patient management cost reduction, inclusive of HF hospitalizations) from the payer’s perspective.3 We continue to validate the applicability of the CHAMPION results with real-world publications presented in section 3. B3 2. Limitations of Current Standard of Care The background section of the coverage guidance acknowledged the difficulty in monitoring heart failure

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HERC Coverage Guidance: CardioMEMS™ for Heart Failure Monitoring Disposition of Public Comments ID/# Comment Disposition Studies have demonstrated that weight change cannot reliably be used as an symptoms and progression. Since the CHAMPION trial indicator of rising pressures. Lewin et al. showed that an absolute weight gain of 2 KG was conducted, health insurers and health systems have (or relative weight gain of 2%) over 48-72 hours had poor sensitivity (only 9% and increased their focus on preventing heart failure 17%) for acute decompensation.4 Data from the FAST trial showed that at the readmissions using a variety of interventions. nominal weight gain threshold of 3lbs in 1 day or 5 lbs. within 3 days, sensitivity for The data presented here relating to heart failure decompensation was 22.5% (ranging from 12.5% to 37.1%).5 These data demonstrate hospitalizations were included in the coverage guidance. that increases in body weight in isolation are not sensitive in assessing clinical We have added the approximate number needed to treat deterioration in established heart failure. and an approximate number needed to harm to the Multiple trials and studies with enrollment upwards of 8,500 patients have GRADE table for subcommittee consideration. demonstrated that current markers do not lead to improvement on HF hospitalizations.6-14 These studies examined signs/symptoms, daily weights, blood pressure, intrathoracic impedance, and remote monitoring via ICD, CRT-D, and CRT-P devices to gauge their impact on HF hospitalization. The results from these studies showed that monitoring these parameters have no impact on lowering HF hospitalizations. In fact, van Veldhuisen et al. showed that intrathoracic impedance increased HF hospitalizations. CardioMEMS’ intervention provides reliable prediction via pulmonary artery (PA) pressures to prevent clinical deterioration and rehospitalization. In CHAMPION, patients managed with PA pressure information had significantly less HF-related hospitalizations (28% reduction at 6 months, 33% annualized reduction over 18 months p=0.017), when compared to the control group.15 During the Open Access Period of CHAMPION (patients in the former control group where physicians had access to their PA pressures), a longitudinal analysis showed PA pressure in the Former Control group resulted in a 48% reduction in HF hospitalization rates (0.36 vs. 0.68, HR 0.52, 95% CI 0.40-0.69, p<0.0001).16

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HERC Coverage Guidance: CardioMEMS™ for Heart Failure Monitoring Disposition of Public Comments ID/# Comment Disposition B4 3. Real World Evidence The study by Heywood et al. was observational and only reported on changes in hemodynamic parameters (not on Regarding the HERC statement about the adoption of this technology within the non- clinical endpoints), and therefore is out of scope. specialty settings, real-world post-market data continues to support the efficacy and safety of this therapy. Randomized clinical trials provide one perspective in validating The study by Desai et al. is also observational (essentially the science in a limited setting; whereas, real-world evidence provides insight to the a before-and-after study) using Medicare claims data for applicability in translating how the technology performs outside the confines of a heart failure hospitalizations six months before trial. The real-world evidence supporting CardioMEMS complements the CHAMPION CardioMEMS™ implantation and six months after results and provides compelling argument for coverage. These key publications are implantation. summarized below: In general, when higher-quality data from RCTs are • Heywood et al. demonstrated that general-use of implantable hemodynamic available, HERC and its subcommittees do not consider technology in a non-trial setting (first consecutive 2,000 patients implanted with the findings of observational studies. 17 CardioMEMS sensor) led to significant lowering of PA pressures. Conference abstracts are not considered by HERC or its • Desai et al. demonstrated a 45% reduction in HF hospitalizations at 5 months and subcommittees. significant cost reductions associated with HF care at $7,433/patient-6months and $11,260/patient-year with data from Medicare claims.18 Data from the GUIDE-HF randomized trial would likely • At the 2018 ACC scientific session, Abraham et al., presented a propensity increase the subcommittee’s confidence in the estimate matched cohort of those patients with identical characteristics as those of effect on heart failure hospitalization and mortality. appropriate to receive CardioMEMS but did not receive the implant compared to those that received the CardioMEMS Sensor. This retrospective study from the Medicare claims database showed a 30% reduction in all-cause mortality and a 24% reduction in HF hospitalizations.19 CardioMEMS continues to perform well outside the clinical trial setting in addressing clinicians’ challenges to manage chronic HF patients proactively. Abbott’s investment in CardioMEMS continues with the GUIDE-HF IDE trial (NCT 03387813) to specifically evaluate the technology in relation to a composite primary endpoint that focuses on

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HERC Coverage Guidance: CardioMEMS™ for Heart Failure Monitoring Disposition of Public Comments ID/# Comment Disposition the reduction of HF hospitalizations and mortality and secondary endpoints on improved quality of life and functional assessment. B5 CardioMEMS would benefit appropriate patients under Oregon HERC because of the Thank you for your comments. value it provides patients and clinicians in addressing the challenges associated with managing chronic HF. It is our strong desire that HERC consider the latest evidence to support reconsideration and appropriate coverage of hemodynamic monitoring with the CardioMEMS HF System.

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HERC Coverage Guidance: CardioMEMS™ for Heart Failure Monitoring Disposition of Public Comments

References Provided by Commenters ID References A Desai, A. S., Bhimaraj, A., Bharmi, R., Jermyn, R., Bhatt, K., Shavelle, D., . . . Heywood, J. T. (2017). Ambulatory Hemodynamic Monitoring Reduces Heart Failure Hospitalizations in "Real-World" Clinical Practice. Journal of the American College of Cardiology, 69(19), 2357-2365. doi: 10.1016/j.jacc.2017.03.009 Givertz, M. M., Stevenson, L. W., Costanzo, M. R., Bourge, R. C., Bauman, J. G., Ginn, G., & Abraham, W. T. (2017). Pulmonary Artery Pressure-Guided Management of Patients With Heart Failure and Reduced Ejection Fraction. Journal of the American College of Cardiology, 70(15), 1875-1886. doi: 10.1016/j.jacc.2017.08.010 Heywood, J. T., Jermyn, R., Shavelle, D., Abraham, W. T., Bhimaraj, A., Bhatt, K., . . . Stevenson, L. W. (2017). Impact of Practice-Based Management of Pulmonary Artery Pressures in 2000 Patients Implanted With the CardioMEMS Sensor. Circulation, 135(16), 1509-1517. doi: 10.1161/circulationaha.116.026184 B 1. FDA Summary of Safety and Effectiveness Data (SSED): PMA P100045 CardioMEMS HF System, 2014. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm?id=P100045 2. FDA Summary of Safety and Effectiveness Data (SSED): PMA P100045 CardioMEMS HF System, 2014. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm?id=P100045 3. Martinson M, Bharmi R, Dalal N, Abraham WT, Adamson PB. Pulmonary artery pressure‐guided heart failure management: US cost‐effectiveness analyses using the results of the CHAMPION clinical trial. Eur J Heart Fail 2017;19:652–660. 4. Lewin J, et al. Clinical deterioration in established heart failure: what is the value of BNP and weight gain in aiding diagnosis? Eur J Heart Fail. 2005 Oct;7(6):953-7. 5. Abraham WT, Compton S, Haas G et al. Intrathoracic Impedance vs. Daily Weight Monitoring for Predicting Worsening Heart Failure Events: Results of the Fluid Accumulation Status Trial (FAST). Congest Heart Fail 2011 March;17(2):51-5. 6. Chaudhry, S. I. et al. (2010). Telemonitoring in patients with heart failure. The New England Journal of Medicine, 363, 2301-2309. 7. Koehler, F., et al. Telemedical Interventional Monitoring in Heart Failure Investigators. (2011). Impact of remote telemedical management on mortality and hospitalizations in ambulatory patients with chronic heart failure: The Telemedical Interventional Monitoring in Heart Failure study. Circulation, 123, 1873-1880. 8. Cleland, J.G et al. TENS-HMS Investigators. (2005) Noninvasive Home Telemonitoring for Patients with Heart Failure at High Risk of Recurrent Admission and Death: The Trans-European Network-Home-Care Management System (TEN-HMS) study. JACC, 45, 1654-1664. 9. Ong, M.K., et al. BEAT-HF Research Group. The Better Effectiveness After Transition – Heart Failure Study - Remote Patient Management After Discharge of Hospitalized Heart Failure Patients. AHA 2015 LBCT. 10. Angermann, C.E., et al. (2012). Mode of Action and Effects of Standardized Collaborative Disease Management on Mortality and Morbidity in Patients with Systolic Heart Failure: The Interdisciplinary Network for Heart Failure (INH) Study. Circ Heart Failure 2012;5;25-35. 11. van Veldhuisen DJ, et al. DOT-HF Investigators. Intrathoracic Impedance Monitoring, Audible Patient Alerts, and Outcome in Patients with Heart Failure. Circulation. 2011 Oct 18;124(16):1719-1726.

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HERC Coverage Guidance: CardioMEMS™ for Heart Failure Monitoring Disposition of Public Comments ID References 12. Bohm, M., et al. Effect of implanted device-based impedance monitoring with telemedicine alerts on mortality and morbidity in heart failure (OptiLinkHF). European Journal of Heart Failure. 2011;13:796-804. 13. Cowie MR. REM-HF: Remote monitoring: an evaluation of implantable devices for management of heart failure patients. European Society of Cardiology 2016 Congress; August 28, 2016; Rome, Italy. Abstract 1223. 14. Boriani G, et al. Effects of remote monitoring on clinical outcomes and use of healthcare resources in heart failure patients with biventricular defibrillators; results of the MORE CARE multicentre randomized controlled trial. Eur J Heart Fail 2016; DOI:10.1002/ejhf.626. 15. Abraham WT, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. The Lancet. 2011;377(9766):658-66. 16. Abraham, W. T., Stevenson, L. W., Bourge, R. C., Lindenfeld, J. A., Bauman, J. G., & Adamson, P. B. (2016). Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: Complete follow-up results from the CHAMPION randomised trial. The Lancet, 387(10017), 453-461. 17. Heywood JT, Jermyn R, Shavelle D, Abraham WT, Bhimaraj A, Bhatt K, Sheikh F, Eichorn E, Lamba S, Rharmi B, Agarwal R, Kumar C, Stevenson LW. Impact of practice based management of PA pressures in 2000 patients implanted with the CardioMEMS sensor. 2017. https://doi.org/10.1161/CIRCULATIONAHA.116.026184 Circulation. 2017;CIRCULATIONAHA.116.026184. 18. Desai et al. Ambulatory Hemodynamic Monitoring Reduces Heart Failure Hospitalizations in "Real-World" Clinical Practice. J Am Coll Cardiol. 2017 May 16;69(19):2357-2365. 19. ACC 2018 67th Annual Scientific Session & Expo. 412-16-Lower mortality and heart failure hospitalization rates in patients implanted with pulmonary artery pressure sensor- a real-world comparative effectiveness study. Presented on March 12, 2018 by Jacob Abraham, MD. Publication pending. Note that CardioMEMS HF System is not indicated for a reduction in mortality and no claims are being made as such.

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