Nelson: Primary Care Work Up for the Infertile Couple

Transcription

1 Primary Care Work Up for the Infertile Couple Conflict of Interest Disclosure Anita L. Nelson, MD Anita L. Nelson, MD Professor OB-GYN David Geffen School of Medicine at UCLA 38 th Annual CAPA Conference Palm Springs, CA October 09, 2014 Grants/ Research Honoraria/ Speakers Bureau Consultant/ Advisory Board Bayer, Merck, Pfizer, Teva Actavis, Bayer Merck, Pfizer, Teva Actavis, Agile, Bayer, ContraMed, Merck, Teva, MicroCHIPS, Pharmanest Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 2 Learning Objectives At the end of this presentation, the participant will be able to: List the elements needed for fertility. Describe the history needed to help establish etiology(ies) for infertility. List tests recommended in evaluation of infertile couple. Outline therapies primary care clinicians can offer without referring to OB-GYN. Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 3 Infertility Definitions Inability to establish a pregnancy within one year of unprotected intercourse. In women > 35 years, 6 month trial period used 1 Primary infertility: the couple has never experienced pregnancy Secondary infertility: the couple has previously experienced pregnancy, but now cannot. ASRM. Fertil Steril. 2008;90(5 Suppl):S60. Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 4 Normal Fecundity Pregnancy occurs in 85% of couples having unprotected intercourse for one year. Chance of pregnancy per month 20-25% for first 4-5 months Rate decreases thereafter Most conceptions occur in the first 6 months Fecundity drops to 3% by 13 th cycle 1 Zinaman MJ. Fertil Steril. 1996;65(3): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 5 Subgroups Within Infertility Couples unable to establish pregnancy within 12 months are in 1 of 3 categories: Infertile Unable to establish pregnancy without intervention Subfertile Couples with lower per-cycle fecundity rate 5% of couples unable to become pregnant in 12 months will do so by 24 months 52.6% of subfertile couples at 12 months have live birth by 36 months 1 Unlucky Snick HK. Hum Reprod. 1997;12(7): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 6 1

2 It Gets Complicated But... Overview of Infertility Etiologies No. Months Without Conception Proportion (%) CouplesNot Yet Having Conceived Mean Fecundability of CouplesNot Yet Having Conceived Proportion (%) Couples Who Will Conceive Within 12 Months Among CouplesNot Yet Having Conceived Trussell J, et al. Contraceptive Technology. NY, NY. ArdentMedia, Inc. 2007; Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 7 % of Cases * Sperm dysfunction and other male problems Ovarian dysfunction Tubal and pelvic pathology Unexplained infertility 10 Unusual problems 5 * Varies in different populations. Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 8 Overview of Infertility Etiologies Infertility by Partner % of Cases Female partner only 40 Male partner only 40 Some combination from each 20 Objectives in Treating Couples with Fertility Challenges Determine the cause(s) of those challenges Counsel couple on Fertility potential Therapeutic options Estimates of success, side effects, costs, etc. Maximize health outcome of woman and newborn Preconception care Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 9 Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 10 What Does It Take to Make a Baby? Eggs Sperm A place to get them together Uterus able to grow pregnancy Woman s healthy body to support the pregnancy Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 11 In More Detail: Requirements for Female Fertility Health and nutrition to permit ovulatory cycling and support of a pregnancy Functioning reproductive anatomy and physiology An introitus and vagina that permit penile entry A vagina capable of capturing sperm A patent cervix with cervical mucus that periodically permits passage of sperm into the upper genital tract Ovulatory cycling with extrusion of the ovum Fallopian tubes that permit the sperm to fertilize the ovum and that facilitate migration of the conceptus into the uterus A uterus capable of permitting implantation and developing and sustaining the conceptus to term Adequate hormonal status to maintain pregnancy Normal immunology to accommodate sperm, fertilization, and fetal health Absence of genetic causes of recurrent losses (e.g., balanced translocations, etc) Trussell J, et al. Contraceptive Technology. NY, NY. ArdentMedia, Inc. 2007; Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 12 2

3 In More Detail: Requirements for Male Fertility Normal spermatogenesis of functional sperm Functioning ductal system Ability to transmit the sperm into the woman s vagina Ability to maintain an erection until coital ejaculation Ability to achieve a normal ejaculation within the vaginal vault Absences of genetic causes of recurrent losses (e.g., balanced translocations, etc.) Trussell J, et al. Contraceptive Technology. NY, NY. ArdentMedia, Inc. 2007; Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 13 In More Detail: Requirements for Couple s Fertility Ability and desire for intravaginal, penile coital activity Correct timing of intercourse within a woman s cycle Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 14 First Visit and Before Obtain full history both patients for Preconception care Infertility work up Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 15 Preconception History Elements Reproductive histories Prior fertility challenges, treatments, outcomes Obstetrical outcomes: Infant death, fetal loss, birth defects, low birthweight, prematurity Previous maternal pregnancy complications: diabetes, hypertension Contraceptive history Medical history: Heart disease, VTE, autoimmune disease, diabetes, hypertension, seizure disorders Lu MC. Am Fam Physician. 2007;76(3): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 16 Preconception History Elements Surgical history Medication use Old category X and most old category D drugs Over-the-counter drugs, herbal Immunization history History Continued Review of systems (thyroid, galactorrhea, recent weight changes, pain) Genetic screening and family history Substance abuse (tobacco, alcohol, recreational/illicit drugs) CAGE or T-ACE Toxin and teratogen exposure (home and workplace) Material safety data sheets Exposure to cats, small children during pregnancy (TORCH) Depression, anxiety, violence, major psychosocial stressors Lu MC. Am Fam Physician. 2007;76(3): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 17 Lu MC. Am Fam Physician. 2007;76(3): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 18 3

4 Preconception Screening Examination of periodontal conditions, thyroid, heart, breast and pelvic examination Laboratory tests: All prenatal labs CBC, UA, type, Rh and antibody screening, rubella, syphilis, hepatitis B, HIV, GC, CT, diabetes screening Cervical cytology if time for testing Consider PPD, if risk factors present Lu MC. Am Fam Physician. 2007;76(3): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 19 Genetic Screening Assess risk of chromosomal or genetic disorders Family history Ethnic group Age Note: balanced translocations may be more challenging to detect Ethic group issues Sickle cell disease, Tay Sacs, cystic fibrosis, thalassemia Lu MC. Am Fam Physician. 2007;76(3): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 20 Lifestyle Recommendations Daily aerobic exercise minutes Prepares for challenges of pregnancy Helps reduce stress Dietary recommendations: Prevent overweight or achieve normal weight Take multivitamin with folic acid 400 mcg daily for routine patient, 4-5 mg daily for previous NTDs, DM, smokers, noncompliant Avoid high levels vitamin A Vegetarians need adequate vitamin B12 Chandranipapongese W, et al. Can Fam Physician. 2013;59(7): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 21 Immunization Updates Hepatitis B Rubella, measles, mumps Varicella Tdap HPV Influenza Chandranipapongese W, et al. Can Fam Physician. 2013;59(7): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 22 Tobacco Environmental Toxins Decreases fertility Increases spontaneous abortion, premature deliver, low birth weight Increases risk of oral cleft Increases sudden infant death Dose-responses impacts Greatest risk with > 10 cigarettes a day Air pollutants Heavy metals Organic solvents Pesticides Fish methylmercury levels Chandranipapongese W, et al. Can Fam Physician. 2013;59(7): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 23 Chandranipapongese W, et al. Can Fam Physician. 2013;59(7): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 24 4

5 Additional History Needed to Evaluate Woman: Infertility Menstrual history Age of menarche, cycle length, duration, flow Mittelschmerz, moliminal symptoms, dysmenorrhea Changes in menses over time Correlate menses with weight changes over time Sexual history number of partners, problems Current coital activity How often? When in cycle? Duration of this episode of infertility Current and past contraceptives used Sexually transmitted infections and treatments Jensen JR, July Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 25 History Needed to Evaluate Man: Infertility Age of onset of puberty Reproductive tract infection, surgery or injury Fertility history Sexual practices and/or dysfunction Medical and surgical history Current medications and social history (habits + hot tubs) Toxin exposures Family history ethnicity, birth defects, mental retardation, infertility Review of systems (thyroid, diabetes, HIV) Jensen JR, July Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 26 Male Exam Arm span vs. height, lower body vs upper body Cranial nerves for pituitary tumor Midline facial defects congenital secondary hypogonadism Thyroid, R/O dysfunction with reflexes Liver hepatomegaly Gynecomastia Genital hair distribution, hypospadias, penile curve, phimosis, testicular exam, epididymidis Differential Diagnosis Male Infertility Hypothalamic disease Gonadotropin deficiency Congenital: Kallmann, Prader-Willis, etc. Acquired: Trauma, tumor, renal/liver failure, malnutrition, infiltrative diseases Hyperprolactinemia: drug induced, tumor Pituitary disease: tumor, hemochromatosis Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 27 Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 28 Differential Diagnosis Male Infertility Gonadal defects: Genetic syndromes: Klinefelter, XYY, Down, muscular dystrophy Orchitis: Mumps, viral, autoimmune Enzyme defects: Androgen Paraplegia Hormone resistance Normal Values for Semen Analysis WHO, th Percentile 95 th Percentile Semen volume 1.5 ml ( ) Total sperm count 39 million (33-46) Sperm concentration 15 million/ml (12-16) Vitality 58% live (55-63) Progressive motility 32% (31-34) Total motility 40% (38-42) Morphologically normal forms 4.0% ( ) Note: Varicocele repair now discouraged Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 29 Cooper TC, et al. Hum Reprod. 2010;16(3): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 30 5

6 Semen Analysis Caveats Values derived from men who recently fathered children Values of normal are excellent predictors for populations, but are less predictive in individual cases Significant variation specimen to specimen from same man Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 31 Infertility: First Line Approaches Timed intercourse No more often than every other day Start idealized CD 11 for conception Extend to idealized CD 15 Make specific recommendations based on woman s own cycle length. For example: 30 day cycle Every other day, CD 13 -CD day cycle Recommend every other day, CD 9-13 Ovulation detection kits can be very helpful Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 32 Probability of Pregnancy by Cycle Day (CD) 3 days before ovulation 15% 1-2 days before ovulation 30% Day of ovulation 12% 1-2 days after ovulation ~ 0% Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 33 Myths About Conception Online survey of 1,000 women years 80% attended college 13% of smokers had discussed effects of smoking on reproductive health 1/3 unaware fertility compromised by STDs Obesity Irregular menses 20% did not know fertility diminished with age Lundsberg LS, et al. Fertil Steril. 2014;764. Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 34 Myths About Conception 40% did not know ovulation occurs 14 days before menses. To maximize chance of pregnancy 60% believed should have sex after ovulation 40% believed woman should stay lying down with pelvis elevated after sex A 24 year old nulliparous woman with proven partner presents for infertility work up. No pregnancy despite 5 months of unprotected intercourse What else do you want to know? Should your front office book her an appointment? Lundsberg LS, et al. Fertil Steril. 2014;764. Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 35 Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 36 6

7 Menses: 1-2 times a year No moliminal symptoms Flow variable: light to very heavy Duration: 2-15 days LMP 6 months ago BMI: 43 No obvious hirsutism Acne mild Waist circumference is > 80 cm What labs do you want to draw? What other questions do you have? Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 37 Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 38 Menstrual Disorder Evaluation of Infrequent Menses Clinical Presentation Acne, hirsutism Increased BMI, low BMI Galactorrhea Suggested Work-up Total testosterone TSH Prolactin Hot flashes, amenorrhea FSH, LH, E 2 Age > 35 Cycle day 3 FSH, +/- E 2 +/- AMH Tests that are of limited or no value: Progesterone, LH/FSH Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 39 Revised 2003 PCOS Criteria (2 out of 3 Criteria) 1. Oligo-ovulation or anovulation 2. Clinical and/or biochemical signs of hyperandrogenism 3. Polycystic ovaries with Exclusion of other etiologies: congenital adrenal hyperplasia, androgen-secreting tumors, Cushing syndrome Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Fertil Steril. 2004;81: Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 40 PCOS: Poster Child for Anovulatory Cycling Promote lifestyle changes Weight loss with exercise (if overweight) 5-10% loss in weight can restore ovulation Beware if patient still obese! Be cognizant of nutritional defects induced by diet If no spontaneous ovulation occurs, induce ovulation using standard approaches ACOG Practice Bulletin No Obstet Gynecol. 2009;114(4): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 41 Therapies for Ovulatory Disfunction First Line Medical Treatment Clomiphene citrate: Initial dose 50 mg daily, cycle days 4-9 Test progesterone levels CD 21 Increase doses by 50 mg a cycle until ovulation detected or reach maximal dose ( mg) Pretreatment: Progestin withdrawal COCs Aromatase inhibitor Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 42 7

8 Clomiphene, Metformin or Both for Infertility in PCOS Clomiphene Metformin* Both N % Ovulation % Pregnancy % Live birth * Extended release metformin Legro RS, et al. N Engl J Med. 2007;356(6): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 43 Therapies for Ovulatory Disfunction Second Line Treatment Option If PCOS, consider adding metformin 500 mg to clomiphene citrate Insulin sensitizing agents no longer used as single agent therapy for infertility Other approaches in 2 nd level Low dose gonadotropin Ovarian drilling Aromatase inhibitors ACOG Practice Bulletin No Obstet Gynecol. 2009;114(4): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 44 Aromatase Inhibitors Progestin-induced withdrawal bleed Agents used cycle days 3-7 Letrozole 2.5 mg daily Anastrozole 1 mg daily Exemestane 2.5 mg daily Letrozole vs anastrozole Ovulation rates: 84% vs 60% Pregnancy rates: 27% vs 17% Multiple gestation rates lower than with clomiphene Barbieri RL. OBG Management. 2005;17(10): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 45 Endocrine Society: PCOS 2013 Hormonal contraceptives: first line management Menstrual disorder Hirsutism/acne Clomiphene: first line management Infertility Metformin: beneficial for metabolic/glycemic abnormalities Limited or no value treating androgen excess, infertility, obesity or prevention of pregnancy complications Lifestyle intervention: beneficial Overweight/obese women Other health benefits Legro RS et al. J Clin Endocrinol Metab. 2013;98(12): Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 46 Infrequent Menses: Take Two Ovarian Reserve Tests What if your patient with infrequent menses were 41 years old? Cycle day 2-3 FSH +/- E 2 Cycle day 10 FSH +/- E 2 after stimulation with clomiphene citrate Serum antimüllerian hormone (AMH) Ultrasound imaging with direct count of follicles Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 47 Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 48 8

9 Rationale Ovarian Reserve Testing Cycle Day 3 If few follicles present, levels of E 2 and inhibin B will be low to provide negative feedback and suppress FSH It takes much higher levels of FSH to stimulate remaining follicles Low ovarian reserve if FSH on cycle day 2-3 > 10 IU/L If FSH > 25, no cases of successful IVF Confirmed if E 2 levels low (normal < 50 pg/ml) Note: One elevated FSH trumps other normal FSH results Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 49 Cycle Day 3 FSH Abnormal Variant FSH low or normal, but E 2 elevated (> 75 pg/ml) Interpretation: Pool of oocytes small, one follicle able to gain dominance early Jensen JR, July Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 50 A 32 year old nulliparous woman presents for evaluation. She and her husband have been trying for pregnancy for 1 year without success. Where do you start? Menstrual history Menarche age 12 Monthly menses lasting 9 days with heavy flow Denies any STDs Would you get an chlamydia antibody test? What if she said she had 6 lifetime partners? Husband has 2 children by previous marriages How old is he? Coital issues? What tests do you want to order? Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 51 Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 52 Ovulatory Dysfunction Evaluation Regular Cycling Woman LH surge: urinary ovulation detection kits Also helpful to time coitus Serum progesterone on cycle day 21 Must count back from first day of next menses to verify correct timing of test Progesterone > 3 indicates ovulation Progesterone > 10 is better Case Continued Laboratory values: all normal Lifestyle issues optimized Ovulation documented by LH kits Timed coitus recorded What troubles you about her history? What additional tests do you want now? Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 53 Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 54 9

10 Tubal Factor or Intrauterine Defects High suspicion in face of history of STDs, especially GC/CT/PID Also suspect if monthly menses, especially if ovulation documented Cycle day 21 progesterone > 3 LH surge noted on ovulation detection kits Tubal Factor or Intrauterine Defects Order hysterosalpingogram with water-based contrast Looking for: Endometrial filling defect Spillage of dye into peritoneal cavity Character of tubal lumen Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 55 Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 56 Menstrual Disorder Evaluation of Heavy, Prolonged Bleeding Saline Infusion Sonography Polyps Pelvic ultrasound +/- saline infusion sonography Leiomyoma-submucosal vs. myometrial Endometrial polyps Consider hematologic evaluation, especially if anemic Von Willebrand Platelet function disorder Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 57 Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 58 Tests to Avoid Post-coital testing to detect cervical factors Except to do semen analysis if masturbation forbidden or documentation of ejaculation needed Endometrial biopsy to detect luteal phase defects FSH/LH ratios to diagnose PCOS Infertility Evaluations and Treatments by Primary Care Clinicians Optimize outcome by preparing women for pregnancies Preconceptional care Primary care clinicians can easily determine if woman is ovulatory or nonovulatory and fertility potential of man Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 59 Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 60 10

11 Infertility Evaluations and Treatments by Primary Care Clinicians Partner with others on team (OB/GYN, urologist, geneticist) Familial disorders Common genetic disorders Tubal factors Male factors Counsel on ovulation detection, timed coitus Promote lifestyle changes, first line Anita L. Nelson,MD - 9/29/2014 2:43 PM Infertility Palm Springs CAPA 61 11