3/5/2020

INFERTILITY WORKUP FOR BASIS OF TODAY’S TALK THE WOMEN’S HEALTH SPECIALIST SUKHKAMAL B. CAMPBELL, MD FELLOW, REPRODUCTIVE ENDOCRINOLOGY AND FAMILY FERTILITY CENTER, BAYLOR COLLEGE OF MEDICINE

02/21/2020

OUTLINE BACKGROUND AND PREVALENCE • BACKGROUND • PRE- COUNSELING AND EVALUATION • INFERTILITY: FAILURE TO ACHIEVE PREGNANCY WITHIN • 12 MONTHS OF UNPROTECTED INTERCOURSE/DONOR INSEMINATION < 35 YEARS OLD • FEMALE FACTOR INFERTILITY • WITHIN 6 MONTHS IN > 35 YEARS OLD • MALE FACTOR INFERTILITY • > 40 YEARS OLD WARRANT IMMEDIATE EVALUATION

• • PREVALENCE: AFFECTS UP TO 15% OF COUPLES • FAMILY BUILDING FOR LGBTQIA POPULATIONS • EVALUATION: OFFER TO ANY WHO BY DEFINITION INFERTILE OR AT HIGH RISK OF INFERTILITY • CONCLUSIONS

CAUSES WARRANTING IMMEDIATE EVALUATION PRE-PREGNANCY COUNSELING AND EVALUATION • OLIGOMENORRHEA OR • GOAL: TO OPTIMIZE HEALTH AND ADDRESS MODIFIABLE RISK FACTORS

• KNOWN / SUSPECTED UTERINE, TUBAL, PERITONEAL DISEASE • THUS REDUCE RISK OF ADVERSE HEALTH EFFECTS WOMAN + FETUS • MULLERIAN ANOMALIES, TUBAL OCCLUSION, ADHESIVE DISEASE • WHO: ALL THOSE PLANNING TO INITIATE PREGNANCY • STAGE III OR STAGE IV ENDOMETRIOSIS • “WOULD YOU LIKE TO BECOME PREGNANT IN THE NEXT YEAR?” • CAN OCCUR SEVERAL TIMES DURING A WOMAN’S LIFESPAN • RISK FACTORS/HEALTH CHANGES • KNOWN OR SUSPECTED

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RECOMMENDATIONS AND CONCLUSIONS

• ANY PATIENT ENCOUNTER = OPPORTUNITY TO COUNSEL ABOUT WELLNESS AND HEALTH HABITS • IN TURN IMPROVE REPRODUCTIVE AND OBSTETRIC OUTCOMES

• COUNSEL TO SEEK MEDICAL CARE BEFORE ATTEMPTING TO BECOME PREGNANT • DATING; MONITORING FOR CONDITIONS IN WHICH TREATMENT SHOULD BE MODIFIED • HTN, DM II, PSYCH, THYROID DISEASE

• REVIEW ALL PRESCRIPTION + NON-PRESCRIPTION MEDS (HERBALS, VITAMINS)

• WOMEN PRESENTING FOR PRE-PREGNANCY COUNSELING SHOULD BE OFFERED GENETIC SCREENING

• ASSESS IMMUNIZATION STATUS ANNUALLY FOR WOMEN OF REPRODUCTIVE AGE, INCLUDING: • TDAP, MMR, HEPATITIS B, VARICELLA, INFLUENZA

• STI SCREENING SHOULD BE OFFERED; INTIMATE PARTNER VIOLENCE VACCINATIONS AND GENETICS • ROUTINELY ASK ABOUT ALCOHOL, NICOTINE PRODUCTS, AND DRUGS • (PRESCRIPTION OPIOIDS)

• PRE-PREGNANCY FOLIC ACID SUPPLEMENTATION TO REDUCE NEURAL TUBE DEFECTS

• ENCOURAGE TO ATTAIN A BMI IN THE NORMAL RANGE BEFORE ATTEMPTING PREGNANCY

VACCINATIONS GENETICS

• GENETIC/FAMILY HX OF PATIENT AND PARTNER ARE NEEDED • INFLUENZA: ANNUAL VACCINE; WOMEN PREGNANT IN FLU SEASON REAP ADDITIONAL BENEFIT • HX OF GENETIC DISEASES, BIRTH DEFECTS, MENTAL DISORDERS, HERITABLE CANCERS

• TDAP: UNKNOWN OR NO PRIOR • CARRIER STATUS DIAGNOSED (IN ONE OR BOTH PARTNERS): • EACH PREGNANCY BETWEEN 27-36 WEEKS REGARDLESS OF PRE-PREGNANCY HISTORY • FULL REVIEW OF MEDICAL RECORDS + RECOMMENDED

• PRE-PREGNANCY COUNSELING = SAME SCREENING AS PREGNANT WOMEN • HPV: VACCINATION NOT RECOMMENDED DURING PREGNANCY, EVEN IF STARTED PRE-PREGNANCY • INSURANCE COVERAGE (BARRIER)

• VARICELLA AND RUBELLA: • COUPLES AT RISK OF HERITABLE DISEASES CAN BE OFFERED PREIMPLANTATION GENETIC • GIVE AT LEAST 28 DAYS PRE-PREGNANCY OR IN PP PERIOD TESTING FOR ANEUPLOIDY OR MONOGENIC DISORDERS (PGT-A/M) • 2 DOSES VARICELLA RECOMMENDED  NO PREGNANCY X 1 MONTH POST VACCINE (CDC)

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FEMALE FACTOR INFERTILITY

HISTORY BASIC INFERTILITY EVALUATION • DURATION; RESULTS OF PREVIOUS EVALUATION AND TREATMENT

• MENSTRUAL HISTORY • MENARCHE, CYCLE LENGTH/INTERVAL, +/- MOLIMINA, +/- DYSMENORRHEA • SIGNS OF : BBT, CERVICAL MUCUS CHANGE, + OPKS

• PREGNANCY HISTORY • G/P, TIME TO PREGNANCY, FERTILITY TREATMENT, OUTCOME, DELIVERY ROUTE, PP COMPLICATIONS

• CONTRACEPTION, COITAL FREQUENCY AND TIMING /

• SURGICAL HISTORY • INDICATIONS, OUTCOMES, COMPLICATIONS  FOCUS ON ABDOMINAL AND PELVIC PROCEDURES

• GYN HISTORY & SEXUAL HISTORY • PID, SEXUALLY TRANSMITTED INFECTIONS, ENDOMETRIOSIS, FIBROIDS, AUB PHYSICAL EXAMINATION

• VITAL SIGNS • REVIEW OF SYSTEMS

• THYROID, GALACTORRHEA, HIRSUTISM, PELVIC PAIN, DYSPAREUNIA • THYROID, BREAST, PELVIC • THYROID ENLARGEMENT, NODULES OR TENDERNESS • MEDICATIONS AND SUPPLEMENTS • BREAST SECRETIONS • ALLERGIES AND TERATOGENS • SIGNS OF ANDROGEN EXCESS (FERRIMAN-GALLWEY)

• FAMILY HISTORY • DEVELOPMENTAL DELAY, EARLY MENOPAUSE, REPRODUCTIVE PROBLEMS (RPL) • SIGNS OF INSULIN RESISTANCE (ACANTHOSIS)

• TANNER STAGING • OCCUPATION / EXPOSURE TO ENVIRONMENTAL TOXINS • SOCIAL HISTORY: ALCOHOL, RECREATIONAL / ILLICIT DRUGS, SMOKING

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OVARIAN RESERVE OVARIAN RESERVE TESTING

• MEASURE SERUM AND FSH • THE REPRODUCTIVE POTENTIAL OF THE OVARIES • BETWEEN CYCLE DAYS 2-5 *WHY* • ESTRADIOL: AID FOR INTERPRETATION • REPRESENTS THE NUMBER OF OOCYTES AVAILABLE FOR POTENTIAL FERTILIZATION • BASAL E2 < 60-80 PG/ML • ELEVATED E2 MAY SUPPRESS FSH

• ASSESS BY SERUM TESTS AND/OR ULTRASOUND • FSH > 10 IU/L • LESS ROBUST RESPONSE TO STIMULATION

• PRESENCE OF DIMINISHED RESERVE  PREDICTS FUTURE STIMULATION RESPONSE

ANTRAL FOLLICLE COUNT (AFC) ANTI-MULLERIAN HORMONE

• NUMBER OF FOLLICLES MEASURING 2-10 MM IN BOTH OVARIES • PRODUCED BY THE GRANULOSA CELLS OF THE ANTRAL FOLLICLES • THUS A BIOMARKER OF SERUM OVARIAN RESERVE • LOW AFC = 5-7 FOLLICLES • POOR RESPONSE TO OVARIAN STIMULATION • RELATIVELY STABLE THROUGHOUT • HYPOTHALAMIC AMENORRHEA; POI; OCPS (LOW) • ELEVATED IN PCOS • SIMILAR TO AFC IN ABILITY TO PREDICT RESPONSE TO STIMULATION IN INFERTILE WOMEN

• RELATIVELY POOR PREDICTOR OF FUTURE ABILITY TO BECOME PREGNANT

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AGE – RELATED DISTRIBUTION CHART OF SERUM AMH TAKE HOME POINT ON OVARIAN RESERVE TESTING

GOOD PREDICTORS OF RESPONSE TO OVARIAN STIMULATION

BUT

POOR RESULTS DO NOT NECESSARILY PREDICT INABILITY TO ACHIEVE A LIVE BIRTH

**AKA DO NOT PREDICT ABILITY TO CONCEIVE NATURALLY OR WITH OVULATION INDUCTION**

PREMATURE OVARIAN INSUFFICIENCY DIMINISHED OVARIAN RESERVE (DOR)

• NO DEFINITIVE CRITERIA

• FOLLOWING VALUES MAY BE CONSISTENT WITH DOR • UNEXPLAINED ELEVATED FSH < 40 YEARS OLD • ANTI MULLERIAN HORMONE (AMH) < 1 NG/ML • ANTRAL FOLLICLE COUNT < 5-7 • FRAGILE X CARRIER SCREENING • FOLLICLE STIMULATING HORMONE (FSH) > 10 IU/L • FMR1 PREMUTATION (55 TO 200 REPEATS) • HISTORY OF POOR RESPONSE TO IVF (< 4 OOCYTES AT EGG RETRIEVAL) • EXPOSURE TO GONADOTOXIC THERAPIES

CAUSES OF OVULATORY DYSFUNCTION

• HISTORY OF OLIGOMENORRHEA OR AMENORRHEA AND/OR • 1. OVULATORY DYSFUNCTION • LUTEAL PROGESTERONE LEVELS REPEATEDLY LESS THAN 3 NG/ML • 2. TUBAL DISEASE • SIGNIFICANT PROPORTION OF FEMALE INFERTILITY • 3. UTERINE FACTOR • 4. UNEXPLAINED • CLINICAL HISTORY CAN BE USED TO ASSESS OVULATORY CYCLES • MOST OVULATORY WOMEN HAVE MENSES Q25-35 DAYS + MOLIMINA • CONFIRMATION OF OVULATION SHOULD BE PERFORMED (1/3 ARE ANOVULATORY)

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CAUSES OF

OBJECTIVE QUANTIFICATION OF OVULATION • OBESITY

• MID-LUTEAL PROGESTERONE MEASUREMENT • HYPOTHALAMIC AND PITUITARY DYSFUNCTION • P4 > 3 NG / ML

• MID-CYCLE LH SURGE MEASUREMENT • PCOS • 9-77 IU / L • MOST COMMON CAUSE OF OVULATORY INFERTILITY

• POSITIVE LH OVULATION KIT TEST • THYROID DISEASE • BIPHASIC BASAL BODY TEMPERATURE / CERVICAL MUCUS CHANGES (STRIKE)

• HYPERPROLACTINEMIA

DIAGNOSIS OF PCOS PCOS SEQUELAE

• BE AWARE OF ASSOCIATED HEALTH RISKS • METABOLIC SYNDROME • CV DISEASE • POOR PREGNANCY OUTCOMES

• METABOLIC SYNDROME SCREENING: • WAIST CIRCUMFERENCE • BLOOD PRESSURE • FASTING LIPIDS • GTT (TESTING FOR INSULIN RESISTANCE)

EVALUATION OF TUBAL PATENCY

• HYSTEROSALPINGOGRAM (HSG): TUBAL FACTOR • RADIOLOGIC PROCEDURE UNDER FLUOROSCOPY, INJECT RADIOPAQUE CONTRAST VIA • VIEWS SHAPE/CONTOUR OF UTERUS AND FALLOPIAN TUBES, AS WELL AS TUBAL PATENCY

• WHAT CAN YOU SEE? • PROXIMAL AND DISTAL TUBAL OCCLUSION • PERITUBAL ADHESIONS • SALPINGITIS ISTHMICA NODOSA • UTERINE CONTOUR

• LOW POSITIVE PREDICTIVE VALUE (38%) MAY REQUIRE FURTHER EVALUATION TO CONFIRM TUBAL OCCLUSION • TUBAL SPASM

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UTERINE CAUSES OF INFERTILITY • ENDOMETRIAL POLYPS, ADHESIONS

• MULLERIAN ANOMALIES UTERINE FACTOR • LEIOMYOMAS • SUBMUCOUS OR ENDOMETRIAL CAVITY-DISTORTING COMPONENT • SOME DATA> 4 CM ANYWHERE IN UTERUS

• SONOHYSTEROGRAPHY (SALINE INFUSED SONOGRAM (SIS)): • > 16% OF INFERTILE WOMEN + 40% OF WOMEN WITH AUB  ABNORMALITY ON SIS • VISUALIZATION OF UTERINE CAVITY WITH INFUSION OF SALINE THROUGH TRANSCERVICAL CATHETER • CHALLENGING TO VISUALIZE TUBAL PATENCY • SENSITIVITY 91%, SPECIFICITY 84% FOR DETECTING POLYPS OR LEIOMYOMAS

• SOME CASES CONSIDER TUBAL PATENCY BASED ON HISTORY + FREE FLUID IN PELVIS • TVUS ALSO CAN DETECT FIBROIDS THAT AFFECT THE UTERINE CAVITY • SIZE, NUMBER, LOCATION

• 3D US IMPROVES DETECTION OF MULLERIAN ANOMALIES • COMPARABLE TO MRI FOR DIAGNOSTIC ACCURACY HYSTEROSCOPIC EVALUATION OF THE UTERUS

• HSG IS LIMITED IN ABILITY TO IDENTIFY UTERINE CAVITY • DIRECT VISUALIZATION OF THE UTERINE CAVITY VIA HYSTEROSCOPY MASSES OR ADHESIONS (NON RADIOPAQUE)

• RELIES OF VISUALIZATION OF MASS EFFECT • INDICATED TO CONFIRM AND TREAT INTRACAVITARY LESION DETECTED BY OTHER MODALITIES

• SENSITIVITY FOR UTERINE POLYP ONLY 50% • MOST DEFINITIVE METHOD FOR DIAGNOSIS + TREATMENT • ENDOMETRIAL POLYPS • MULLERIAN ANOMALIES CAN BE DETECTED – OTHER • UTERINE SYNECHIAE IMAGING (3D US OR MRI) NEEDED TO DIFFERENTIATE AND CONFIRM DIAGNOSIS • SUB-MUCOSAL FIBROIDS

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• CAUSE OF INFERTILITY IN 40-50% OF COUPLES • BASIC MEDICAL HISTORY AND EVALUATION IS THUS, WARRANTED FROM OUTSET MALE FACTOR INFERTILITY • MINIMAL EVALUATION OF MALE PARTNER INCLUDES • REPRODUCTIVE HISTORY • SEMEN ANALYSIS

• *WOMEN’S HEALTH SPECIALIST MAY REASONABLY OBTAIN MALE HISTORY AND SA; ALSO REASONABLE TO REFER TO REPRODUCTIVE UROLOGIST OR ENDOCRINOLOGIST *

• ANY ABNORMALITY NOTED IN HISTORY OF SA WARRANTS REFERRAL TO SPECIALTY

MALE PARTNER HISTORY SEMEN ANALYSIS

• COITAL FREQUENCY AND TIMING

• PREVIOUS SURGERY • QUANTITATIVE MICROSCOPIC EVALUATION OF PARAMETERS • EVIDENCE OF SEXUAL DYSFUNCTION (ERECTILE OR • CRYPTORCHIDISM WITH / WITHOUT SURGERY EJACULATORY DYSFUNCTION)

• MEDICATION USE (ANABOLIC STEROIDS, SUPPLEMENTS • RECOMMEND 2-5 DAYS, NO MORE THAN 7 DAYS ABSTINENCE PRIOR TO SAMPLE (TESTOSTERONE), ALLERGIES) • DURATION OF INFERTILITY

• IDEALLY OBTAINED IN LAB COLLECTION ROOM • SEXUAL HISTORY / STI HISTORY • PRIOR FERTILITY • HOME COLLECT ACCEPTABLE IF TRANSPORTED WITHIN 1 HOUR AT ROOM OR BODY TEMPERATURE • EXPOSURE TO GONADAL TRAUMA / TOXINS • CHILDHOOD ILLNESS / DEVELOPMENTAL HISTORY

• SYSTEMIC MEDICAL ILLNESS • SPERMATOGENESIS TAKES ~74 DAYS (ILLNESS)

• TOTAL MOTILE COUNT (VOL X CONCENTRATION X MOTILITY) • OLIGOSPERMIA • AZOOSPERMIA

• MOTILITY • ASTHENOSPERMIA

• MORPHOLOGY SPERM PARAMETERS • TERATOSPERMIA

• FORWARD PROGRESSION

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TESTOSTERONE SUPPLEMENTATION AND SPERM

• TESTICULAR TESTOSTERONE AND OVERALL TESTOSTERONE PRODUCTION DECREASES (< 20 NG/ML) --> IMPAIRS SPERMATOGENESIS AND CAN CAUSE AZOOSPERMIA • RECOVERY: 6 MONTHS

• ALTERNATIVE THERAPIES (REPRODUCTIVE UROLOGIST) UNEXPLAINED INFERTILITY • CLOMIPHENE CITRATE (SERM) • HCG (LH ANALOG)

UNEXPLAINED INFERTILITY PERCENTAGES OF SUCCESS PER CYCLE

• DIAGNOSED IN AS MANY AS 30% OF INFERTILE COUPLES • NATURAL FECUNDITY ~18%

• DEFINITION OF INFERTILITY IS MET, EVALUATION PERFORMED, ALL TESTS ARE NORMAL • CC / LTZ (OVULATION INDUCTION) ~6%

• TREATMENT BENEFIT OF OVULATION INDUCTION WITH CLOMIPHENE CITRATE + IUI (CUMULATIVE) • OVULATION INDUCTION + IUI ~12-15% • 35% WITH CC / IUI; 23% LIVE BIRTH (1% MULTIPLES) • 28% PREGNANCY RATE WITH LTZ/IUI; 19% LIVE BIRTH (3% MULTIPLES) • 47% PREGNANCY RATE WITH GND/IUI; 32% LIVE BIRTH (13% MULTIPLES) • IVF ~60 – 70% PER EUPLOID EMBRYO

RECOMMENDATIONS

• UNDERSTAND FAMILY BUILDING DESIRES

• RECOGNIZE PREPONDERANCE OF RESEARCH SUPPORTING HEALTHY OUTCOMES FOR CHILDREN

• INCLUDE LGBTQIA AND GENDER NON-CONFORMING HEALTH AND ADVOCACY IN MEDICAL EDUCATION

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FINAL CONCLUSIONS

• ENSURE CLINICAL SPACES ARE OPEN TO ALL PATIENTS • EVALUATE ANY PATIENT WITH INFERTILITY OR AT HIGH RISK OF INFERTILITY

• EQUITABLE, COMPREHENSIVE REPRO HEALTH CARE NEEDS ARE MET • WOMEN > 35 YEARS: EXPEDITED EVALUATION • TREATMENT: 6 MONTHS • UNDERSTAND, RECOGNIZE, & ADDRESS CHALLENGES IN ACCESSING CARE • WOMEN > 40 YEARS OLD: MORE IMMEDIATE EVALUATION

• ELIMINATE OVERT/COVERT DISCRIMINATORY PROCEDURES & PRACTICES • CONDITIONS KNOWN TO CAUSE INFERTILITY = IMMEDIATE EVALUATION

• THOROUGH PATIENT AND PARTNER (IF EXISTS) MEDICAL HISTORY REFERENCES

• TARGETED PHYSICAL EXAMINATION OF FEMALE PARTNER INCLUDING: • ACOG COMMITTEE OPINION NO 781. INFERTILITY WORKUP FOR THE WOMEN’S HEALTH SPECIALIST. JUNE 2019

• ACOG COMMITTEE OPINION NO 762. PREPREGNANCY COUNSELING. DECEMBER 2018.

• THYROID, BREAST, AND PELVIC EXAMINATION • ACOG COMMITTEE OPINION SUMMARY NO 749. MARRIAGE AND FAMILY BUILDING EQUALITY FOR LESBIAN, GAY, BISEXUAL, TRANSGENDER, QUEER, INTERSEX, ASEXUAL, AND GENDER NONCONFORMING INDIVIDUALS. SEPTEMBER 2013.

• FERRIMAN-GALLWEY HIRSUTISM SCORING SYSTEM. ENDOCRINE SOCIETY CENTER FOR LEARNING.

• BASAL BODY TEMPERATURE FOR NATURAL . MAYO CLINIC RESOURCES.

• , , OR CLOMIPHENE FOR UNEXPLAINED INFERTILITY. DIAMOND MP, LEGRO RS, COUTIFARIS C, ALVERO R, ROBINSON RD, CASSON P, CHRISTMAN GM, AGER J, HUANG H, HANSEN KR, BAKER V, USADI R, SEUNGDAMRONG A, BATES GW, ROSEN RM, HAISENLEDER D, KRAWETZ SA, BARNHART K, TRUSSELL JC, OHL D, JIN Y, SANTORO N, EISENBERG E, ZHANG H; NICHD NETWORK. N ENGL J MED. 2015 SEP • 24;373(13):1230-40. DOI: 10.1056/NEJMOA1414827. PMID: 26398071. IMAGING IS VALUABLE: • WADHWA L, ET AL. AN INTRAUTERINE INSEMINATION AUDIT AT TERTIARY CARE HOSPITAL: A RETROSPECTIVE ANALYSIS OF 800 INTRAUTERINE INSEMINATION CYCLES. J HUM REPRODUCTIVE SCIENCES. JULY 2018.

• ASRM; FERTILITY AND STERILITY. THE USE OF PREIMPLANTATION GENETIC TESTING FOR ANEUPLOIDY (PGT-A) A COMMITTEE OPINION. MARCH 2018. • TUBAL PATENCY, PELVIC PATHOLOGY, OVARIAN RESERVE • FECUNDITY AND NATURAL FERTILITY IN HUMANS. OXFORD REV REPRODUCTIVE BIOLOGY. 1989. • SCOVELL JM ET AL. TESTOSTERONE REPLACEMENT THERAPY VS CLOMIPHENE CITRATE IN THE YOUNG HYPOGONADAL MALE. EUROPEAN UROLOGY FOCUS. APRIL 2018.

• WILLIAMS T ET AL. DIAGNOSIS AND TREATMENT OF POLYCYSTIC OVARY SYNDROME. AMERICAN FAMILY PHYSICIAN. JULY 2016.

• MORANTZ C ET AL. DEFINITION OF METABOLIC SYNDROME – PRACTICE GUIDELINES. AAFP. JANUARY 2005.

• LEE R ET AL. THE PREDICTABILITY OF SERUM ANTI-MÜLLERIAN LEVEL IN IVF/ICSI OUTCOMES FOR PATIENTS OF ADVANCED REPRODUCTIVE AGE. REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY. AUGUST 2011.

• FEMALE SPECIALISTS CAN OBTAIN MALE PARTNER’S INITIAL WORKUP (HX & SA) • RODRIGUEZ-REVENGA L, ET AL. PENETRANCE OF FMR1 PREMUTATION ASSOCIATED PATHOLOGIES IN FRAGILE X SYNDROME FAMILIES. EUROPEAN JOURNAL OF HUMAN GENETICS. APRIL 2009.

QUESTIONS?

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