Preimplantation Genetic Screening for Aneuploidy

UPDATE

G. David Adamson, MD Dr. Adamson is Director of Fertility Physicians of Northern California in FERTILITY Palo Alto and San Jose. He is also Adjunct Clinical Professor of Obstetrics and Gynecology at Stanford University Here is new information on reducing adhesions, School of Medicine in Stanford and Associate Clinical Professor of the stress and cost of fertility treatment, unhelpful Obstetrics and Gynecology at the University of California, San Francisco, testing, and “long-shot” oocyte cryopreservation School of Medicine. He is President of the American Society for Reproductive Medicine.

The author receives grant or research he fi eld of reproductive endocri- Highlighted here are notable stud- support from IBSA, Serono, and Viacell. nology and infertility is anything ies and guidelines from the past year, Tbut stagnant. New technolo- including advice on: gies continue to enter the market at a • preventing peritoneal adhesions brisk pace, and a® greaterDowden emphasis Health on • expediting Media in vitro fertilization evidence has produced better-designed (IVF) for unexplained infertility randomized controlled trials, meta- • counseling the patient about the analyses,Copyright andFor practice personal guidelines. Thisuse onlyreal limitations of preimplantation means greater availability of standard- genetic screening for aneuploidy ized protocols that refl ect best practice • informing patients that oocyte and can be tailored to a patient’s condi- cryopreservation is unlikely to IN THIS ARTICLE tion and needs. lead to live birth. ❙ Expedited infertility regimen speeds time to pregnancy Guideline urges good surgical Page 34 technique in battle against adhesions ❙ Preimplantation aneuploidy Practice Committee of the American Society for Repro- their likelihood and extent. These prin- screening ductive Medicine in collaboration with the Society of Re- ciples include the need to: doesn’t help productive Surgeons. Pathogenesis, consequences, and • Perform surgery only when the Page 37 control of peritoneal adhesions in gynecologic surgery. benefi ts of doing so clearly outweigh Fertil Steril. 2007;88:21–26. the risks ❙ Don’t be eager • Handle tissue gently (this is the to recommend This newly released practice guideline most important preventive cryo preservation from the American Society of Repro- technique) ductive Medicine (ASRM) focuses on • Don’t assume laparoscopy is of oocytes adhesions and their impact on fertility. superior to laparotomy—it will be Page 69 The guideline reiterates that peritoneal only if less tissue injury occurs adhesions are a common and serious • Be especially careful when op- complication of gynecologic surgery erating on or near ovaries, and emphasizes key principles to reduce which form adhesions easily.

32 OBG MANAGEMENT • February 2008

For mass reproduction, content licensing and permissions contact Dowden Health Media. Ovarian surgery often necessitates • avoiding the introduction of reactive additional operations foreign bodies Studies have demonstrated that approxi- • reducing the local infl ammatory mately 33% of patients who undergo response open abdominal or pelvic surgery are re- • inhibiting the coagulation cascade admitted, on average, two times over the and promoting fi brinolysis subsequent 10 years for conditions direct- • placing barriers between damaged ly or possibly related to adhesions or for tissues. further surgery that could be complicated Pharmacotherapeutic and ﬂ uid agents. by adhesions. The highest readmission ASRM found no evidence of improved rate directly related to adhesions—7.5 pregnancy outcomes for pharmacologic for every 100 initial operations—was as- and fl uid agents used as an adjunct during sociated with ovarian surgery performed pelvic surgery. For example, anti-infl am- via laparotomy. matory agents that have been evaluated, Adhesion-related complications of both locally and systemically, including gynecologic surgery include small-bowel dexamethasone and promethazine, have obstruction, which occurs in approxi- not reduced postoperative adhesions. mately 1.5% of women who have un- Antibiotic solutions, 32% Dextran 70, dergone abdominal hysterectomy. and crystalloid solutions such as normal The relationship between adhesions saline and Ringer’s lactate with or with- and pelvic pain is unclear, although se- out heparin or corticosteroids have been vere bowel adhesions can cause visceral used to separate adjacent peritoneal sur- pain. The ASRM guideline notes that faces via “hydrofl otation,” but none have “the impact that lysis of bowel or ad- reduced adhesion formation. nexal adhesions may have on abdomi- Surgical barriers may help decrease post- nal and pelvic pain cannot be predicted operative adhesion formation but cannot confi dently.” Postoperative adhesions compensate for poor surgical technique. I increase subsequent operating times rarely use adhesion barriers because I feel and risk of bowel injury. that careful tissue handling, excellent he- FAST TRACK mostasis, avoiding trauma to healthy tis- Careful tissue How adhesions affect fertility sue, and removal of all diseased tissue are Adhesions may impair fertility by distort- the key ways to obtain good postsurgical handling, excellent ing adnexal anatomy and interfering with results and reduce adhesions. hemostasis, avoiding gamete and embryo transport. Among Hyaluronic acid agents may decrease trauma to healthy infertile women who have adnexal ad- the prevalence of adhesions and prevent tissue, and removing hesions, adhesiolysis is associated with the deterioration of preexisting adhe- all diseased tissue pregnancy rates of 32% at 12 months sions, but because of the limited number and 45% at 24 months, compared with of studies available, these data should are the key ways to 11% and 16%, respectively, for untreat- be interpreted with caution.3 However, reduce adhesions ed women.1 Pregnancy rates are inversely ASRM found no substantial evidence correlated with adhesion scores on the that they improve fertility, decrease pain, ASRM classifi cation system for adnexal or reduce the incidence of postoperative adhesions.2 bowel obstruction.

UPDATE CONTINUES ON PAGE 34 Some, but not all, adhesion- reducing measures work More For more on the prevention of adhesions, According to the ASRM guideline, adhe- ONLINE see our May 2007 issue sions may be prevented, at least theoreti- cally, by: Averting adhesions: Surgical techniques and tools By Togas Tulandi, MD, MHCM, and Mohammed Al-Sunaidi, MD • minimizing peritoneal injury It’s available in our archive at www.obgmanagement.com during surgery

www.obgmanagement.com February 2008 • OBG MANAGEMENT 33

333_OBGM0208_r13_OBGM0208_r1 33 1/22/08 1:49:28 PM UPDATE FERTILITY CONTINUED A move from clomiphene directly to IVF may cut time to pregnancy

Reindollar RH, Regan MM, Neumann PJ, Thornton KL, • three cycles of clomiphene citrate Alper MM, Goldman MB. A randomized controlled tri- with IUI and then as many as six al of 503 couples assigned to conventional infertility cycles of IVF. treatment or an accelerated track to IVF: Preliminary Time to pregnancy was defi ned as results of the fast track and standard treatment the time from randomization to confi r- (FASTT) trial. Fertil Steril. 2007;88(Suppl 1):S41. mation of a fetal heart beat for a deliv- This very important abstract, presented ery resulting in a live birth. The trial was at the annual meeting of ASRM, has the stratifi ed by age (younger than 35 years potential to dramatically change fertil- versus 35 or older), recent laparoscopy ity treatment. The multicenter random- (yes/no), and study site. ized controlled clinical trial measured the effi cacy and time to pregnancy of an Regimen likely reduces cost, stress accelerated treatment strategy for wom- Major issues affecting the eventual suc- en 21 to 39 years old who had unex- cess rate for infertile couples are cost and plained infertility. A similar percentage psychological stress, which can cause of patients—approximately 75%—be- even patients who have a good prognosis came pregnant in each arm (traditional to drop out of treatment. The major com- versus accelerated), with a shorter time plication of fertility treatment is multiple to pregnancy in the accelerated arm. pregnancy. By avoiding the use of go- The new paradigm for management of nadotropins in couples with unexplained unexplained infertility includes: infertility and accelerating the transition • comprehensive fertility history to IVF, physicians can lower the cost and and physical examination psychological stress of treatment. They FAST TRACK • targeted laboratory testing and can also reduce the likelihood of multiple Avoiding the use other investigation, as needed pregnancy because it is easier to control • counseling and psychological the number of embryos transferred in IVF of gonadotropins support for the patient once than the number of follicles that develop and moving straight the diagnosis is made with gonadotropins. to IVF reduces the • empiric treatment with clomiphene In women younger than 35 years on risk of multiple citrate plus intrauterine insemination the fi rst IVF cycle who have a good prog- pregnancy (IUI) for as many as three cycles nosis, ASRM now recommends that only • immediate IVF for as many as one or two day-3 embryos be transferred, six cycles. and not more than one day-5 blastocyst.4 The multiple-birth rate has declined in Details of the trial recent years, as more and more IVF clin- Women in the trial had attempted to ics place fewer embryos; the rate should conceive for 12 months and had normal continue to fall with wider application of ovarian reserve (and semen analysis) and elective single-embryo transfer.5,6 no pelvic pathology. Couples already Because this accelerated protocol treated for infertility were excluded. produces a similar number of births over Participants were randomized to: a shorter period and has the potential to • a conventional treatment regimen lower cost, psychological stress, and the of three cycles of clomiphene citrate multiple-birth rate, it deserves implemen- with IUI, three cycles of follicle- tation for many patients and warrants stimulating hormone (FSH) and IUI, further evaluation for potential benefi ts and as many as six cycles of IVF or in other populations. CONTINUED

34 OBG MANAGEMENT • February 2008 UPDATE FERTILITY CONTINUED It’s no help, after all: Preimplantation genetic screening for aneuploidy

Practice Committee of the Society for Assisted benefi cial—or, at least, harmless. Some Reproductive Technology and Practice Committee of now argue that the benefi ts of PGS, if the American Society for Reproductive Medicine. any, cannot be intuitively assumed and Preimplantation genetic testing: A Practice Committee assert that the burden of proof of those report. Fertil Steril. 2007;88:1497–1504. benefi ts rests with proponents of PGS. Mastenbroek S, Twisk M, van Echten-Arends J, et al. The practice committees of the Soci- In vitro fertilization with preimplantation genetic ety for Assisted Reproductive Technolo- screening. N Engl J Med. 2007;357:9–17. gy (SART) and ASRM found insuffi cient evidence to support the use of PGS to Preimplantation genetic diagnosis of improve the live birth rate in women of known single-gene defects, structural advanced age or in those who have had chromosomal rearrangements, X-linked implantation failure or recurrent preg- disorders, and human leukocyte anti- nancy loss (TABLE). Many physicians be- gen typing is a major benefi t to couples lieve, however, that technologies under known to be at risk of passing on a heri- development will soon bring verifi able table and debilitating genetic disease. An- benefi ts of PGS to patients. euploidy is the most common cause of UPDATE CONTINUES ON PAGE 69 early pregnancy loss, and its prevalence increases with maternal age and may increase in chromosomally normal couples SART and ASRM weigh in on use who experience recurrent early pregnan- of preimplantation genetic testing cy loss or repeated failure of IVF cycles. TEST RECOMMENDATION Preimplantation genetic screening (PGS) Pre- • Provide genetic counseling to help the patient has been advocated to identify and trans- implantation understand: fer only euploid embryos and increase genetic - risk of having an affected child the chance of successful pregnancy. diagnosis - impact of the disease New data from Mastenbroek and - limitations of options that may help prevent the birth of an affected child colleagues indicate that PGS for aneuploidy does not increase the rate of • If one or both parents carry a genetic abnormality, the risk of conceiving a child with the same abnormality can pregnancy or live birth. After several be identifi ed with tests performed on a single cell years of increasing utilization and stud- • Prenatal diagnostic testing to confi rm the results of ies suggesting that PGS has benefi t, the preimplantation genetic diagnosis is strongly encouraged fi rst multicenter, randomized, double- because of the possibility of a false-negative result blind, controlled study that compared Pre- • Provide thorough education and counseling to the three cycles of IVF with and without implantation patient before preimplantation genetic screening is PGS in women 35 to 41 years old con- genetic performed, including explanation of: cluded that PGS does not increase but, screening - its limitations in fact, signifi cantly reduces the rate of - risk of error - lack of evidence that it improves pregnancy rates pregnancy and live birth in this group. • Evidence does not support the use of preimplantation genetic screening as currently performed to improve live Findings sparked controversy birth rates in patients with: This trial generated controversy within - advanced maternal age the genetics and reproductive endocrinol- - previous implantation failure ogy specialties because it challenged the - recurrent pregnancy loss intuitive view that screening of embryos SOURCE: Society for Assisted Reproductive Technology and American Society before transfer into the uterus should be for Reproductive Medicine

www.obgmanagement.com February 2008 • OBG MANAGEMENT 37 UPDATE FERTILITY CONTINUED FROM PAGE 37 Advise your patients that oocyte cryopreservation is “a long shot”

Practice Committee of the Society for Assisted Counseling is crucial Reproductive Technology and Practice Committee of According to the SART and ASRM guide- the American Society for Reproductive Medicine. line, pretreatment counseling should in- Essential elements of informed consent for elective clude comprehensive information on oocyte cryopreservation: a practice committee opinion. Fertil Steril. 2007;88:1495–1496. a range of topics (see the box below). In addition, women considering oocyte Oocyte cryopreservation is an experimen- cryopreservation should be counseled tal procedure that should not be offered thoroughly about reproductive aging or marketed as a means to defer repro- and life planning.7,8 ductive aging, primarily because data on clinical outcomes are limited. That is the Few alternatives for some women conclusion of this guideline from SART Women who have cancer should receive and ASRM. Consequently, women who the same counseling. Unlike healthy may be considering the procedure should women, however, they may have no be fully informed about the process and other options, and cryopreservation likely outcomes and counseled by a qual- may be more appropriate for them de- ifi ed mental health professional. spite experimental status. ■

Be forthright about oocyte cryopreservation Patients considering this procedure need comprehensive information about: • Ovarian stimulation and oocyte age-related probabilities of • Potential risks of basing important retrieval success per IVF cycle using fresh life decisions and expectations on • Methods of oocyte cryopreservation nondonor oocytes a limited number of cryopreserved • Storage fees • The relatively low likelihood that oocytes • The expected thaw survival rate a woman who cryopreserves her • The possibility that the facility • The requirement for intracytoplas- eggs before age 35 will ever need may cease operation, necessitating mic sperm injection or use them transfer of cryopreserved oocytes • Clinic-specifi c data and outcomes • Disposition of any cryo- to another facility or, in their absence, literature preserved eggs not used by a • The possibility that estimates of a 2% overall live birth predetermined age cryopreserved oocytes might be rate per oocyte thawed using • State and federal screening lost or damaged as a result of slow-freeze methods and 4% for laws for potential donation of laboratory error or other events vitrifi cation, compared with cryopreserved oocytes beyond control.

References 1. Tulandi T, Collins JA, Burrows E, et al. Treat- adhesions after fertility-preserving gynecologi- 6. Stern JE, Cedars MI, Jain T, et al, for the So- ment-dependent and treatment-independent cal surgery: a metaanalysis of randomized con- ciety for Assisted Reproductive Technology pregnancy among women with periadnexal ad- trolled trials. Fertil Steril. 2007;87:1139–1146. Writing Group. Assisted reproductive technol- hesions. Am J Obstet Gynecol. 1990;162:354– 4. Practice Committee of the Society for Assisted ogy practice patterns and the impact of em- 357. Reproductive Technology and the Practice bryo transfer guidelines in the United States. 2. Marana R, Rizzi M, Muzii L, Catalano GF, Ca- Committee of the American Society for Repro- Fertil Steril. 2007;88:275–282. ruana P, Mancuso S. Correlation between the ductive Medicine. Guidelines on number of em- 7. Menken J, Trussell J, Larsen U. Age and infer- American Fertility Society classifi cation of ad- bryos transferred. Fertil Steril. 2006;86(Suppl nexal adhesions and distal tubal occlusion, sal- 4):S51–S52. tility. Science. 1986;233:1389–1394. pingoscopy, and reproductive outcome in tubal 5. Adamson GD, Baker VL. Multiple births 8. Leridon H. Can assisted reproduction tech- surgery. Fertil Steril. 1995;64:924–929. from assisted reproductive technologies: nology compensate for the natural decline in 3. Metwally M, Gorvy D, Watson A, Li TC. Hyal- a challenge that must be met. Fertil Steril. fertility with age? A model assessment. Hum uronic acid fl uid agents for the prevention of 2004;81:517–522. Reprod. 2004;19:1548–1553.