I have nothing to disclose Infertility for the Generalist Heather Huddleston, MD Associate Professor UCSF Center for Reproductive Health Knowledge Gap: Age and Fertility Outline Survey by American Fertility Association 2001 • Fecundability and age • 12,382 women responded to 15 questions • Advice for the person about to start trying to conceive • 1 responded correctly to all • More than ½ of all questions answered • Workup of the patient with fertility problems incorrectly • 85% overestimated by 5-10 years the point at • What is new in fertility treatment which fertility declines
Fecundability and natural fertility in humans Fecundability declines with age Homan, G.F. et al. Hum Reprod Update 2007 13:209-223; Menken, et al., Science 1986, 233:1389-94 Time to Pregnancy and Age Chance of Natural Conception per Month Evaluation of Time to Pregnancy in 2012 women 28 % of pregnant women 35-39 will not 25% Percent chance 24% 22% 20% have conceived in a year per month 18% 35-39 16% • 13% 10% 7% 5% 3% 2% 3 mo 6 mo 9 mo 12 mo 24 26 28 30 32 34 36 38 40 42 44 46 Age Hassan and Killick, Fertility and Sterility 2003
Risk of Fetal Loss According to Maternal Cumulative pregnancy rate (CPR) according to patient's age (years). Age � Denmark Registry � 1978 to 1992 � 34 272 women and � 1 221 546 pregnancy outcomes. Ferrara I et al. Hum. Reprod. 2002;17:2320-2324 Andersen A N et al. BMJ 2000;320:1708-1712 Abnormalities in the oocyte increase Advice for the person about to start with age � Timing � Lifestyle Pellestor et al, Eur J Med Genet 2006
Smoking and Fertility Timing of Intercourse • Average age of menopause 3-4 years earlier than non-smokers • Nicotine and Cotinine found in follicular fluid • Direct damage to oocytes/follicles suspected Dunson D B et al. Hum. Reprod. 2002;17:1399-1403 Smoking and Fertility Metanalysis: smoking and fertility Average Time to Conceive by Smoking Status 3.9 3.2 2.6 Months No Smoking <10/per day >10 per day Odds Ratio of infertility in smokers: 2.27 (1.34,1.91) .
Body Weight and Fertility Body Weight and Fertility Adjusted Months to Conception • 1,200 consecutive pregnant BMI Adj RR Infertility p women. 25 • A questionnaire inquiring <19 4.8 (1.2 - 19.7) .03 about time to pregnancy 14 10.9 19-25 1.0 •Contraceptive use, pregnancy 6.9 planning, previous 25 – 39 2.2 (1.6-3.2) <0.001 subfertility/pregnancies, age, >39 6.9 (2.9-16.8) <0.001 and lifestyle characteristics <19 19-24 25-39 >39 examined BMI Hassan and Killick Fertility and Sterility. VOL. 81, NO. 2, FEBRUARY 2004 Hassan and Killick Fertility and Sterility. VOL. 81, NO. 2, FEBRUARY 2004 The Infertility Evaluation Lifestyle Factors � Alcohol: Evidence that >7 drinks � <35 years old: after one year of trying to conceive per week is deleterious to fertility � >35 years old: after six months � Exercise: No evidence that moderate amounts are deleterious � Patient with irregular cycles, known tubal disease or partner with known subfertility ASRM Practice Committee 2006
The Basic Infertility Work-up Tubal/Uterine Factor Ovary Tubes Uterus Other Endocrine Semen Normal Filling Defect HSG Ultrasound Ovulation Semenanalysis And Cycles Ovarian Reserve ??? TSH Septum Blocked Tube Semen Analysis Is Ovulation happening? � Regular Cycles with moliminal symptoms • Volume 1.5-5ml � Timing of ovulation: • Concentration>20million/ml Basal body temperature � • Motility>50% Ovulation predictor kits � � Anovulation suggested by cycle length 36 If Abnormal Repeat � Progesterone <3 seven days after predicted ovulation � Inadequate luteal phase <10 days or extended spotting WHO,1992
Ovarian Reserve Endocrine � TSH � Prolactin � Antral Follicle Count � AntiMullerian Hormone � FSH FSH and Response to Gonadotropin Treatment Ovarian Reserve Hypothalamus Highly FSH useful in Predictive predicting poor Pituitary Estradiol response FSH Not Antral Follicle predictive Count (AFC) Anti-Mullerian Hormone Inhibin FSH and ANTI-MULLERIAN HORMONE are indirect measures of the ANTRAL FOLLICLE COUNT Broekmans F et al. Hum. Reprod. Update 2006;12:685-718
Basal FSH and Pregnancy During Treatment Age specific nomogram of AFC in infertile women Day 3 FSH not predictive of pregnancy during treatment Broekmans F et al. Hum. Reprod. Update 2006;12:685-718 Antral Follicle Count in the AMH: conception to menopause Community Kelsey TW: PLoS ONE 2011 Rosen et al F and S 2010
Ovarian Reserve Testing: Summary What is new for Treatment? � FSH, Antral Follicle Count, etc – arose as a predictive tool during infertility treatment � Unclear and likely small relationship to possibility of natural pregnancy � Strong relationship with degree of ovarian response during treatment � Minimal relationship to live birth rate in IVF in women under 40 Optimal Treatment of Clomiphene Citrate (Clomid) Anovulatory Infertility • Synthetic Anti-estrogen • Convenient • Inexpensive • Long-standing first choice for ovulation induction in women with PCOS
Clomid: Chances for conception? How Many Women Will Ovulate With Clomid? About ¾ of � 160 patients women � Normogonadotropi c anovulation with PCOS will � Successful response to clomid ovulated � Normal SA with clomid � BMI >18.5 Imani, B. et al. J Clin Endocrinol Metab 1998;83:2361-2365 Imani, B. et al. J Clin Endocrinol Metab 1999;84:1617-1622 Metformin For Ovulation Results of RMN PPCOS Trial P<.001 • Biguanide Insulin Sensitizer • Category B P<.001 • Not FDA approved Legro et al. NEJM 2007; 35:551-66
Letrozole versus Clomiphene for Aromatase Inhibitors Infertility Live Birth Rate 30% • RCT of 750 women 25% comparing letrozole of cloniphene for five 20% treatments 15% • Cumulative Ovulation 28% Rate higher in Letrozole 10% 19% (61.7% vs. 48.3%) 5% • No differences in pregnancy loss rate or 0% Letrozole Clomid twin pregnancy rate. Legro et al NEJM 2014 The Withdrawal Bleed Could Be a Hindrance Treatment of Unexplained • Secondary analysis of RMN PCOS trial • Use of withdrawal bleed prior to cycle start was up to discretion of site investigators * P<.001 IVF * Gonadotropin 25% 30% * Clomid IUI and IUI * Clomid 15% 20% Expectant IUI * 8% 4% 4% 5% 10% 0% Preg/cycle Preg/Ov LB/cycle LB/Ov Spont menses 3% 5% 2% 3% Withdraw 2% 7% 2% 5% No Withdraw 8% 27% 5% 20% Guzick Fertility and Sterility 1998 Diamond et al Obset Gyncol 2012 119: 902-905
Clomid alone vs. IUI Clomid for Unexplained Infertility • 100 mg for five days (typical: 3-7) 580 women randomized • Acts as estrogen antagonist (avg age 32) • Assist in production >1 oocyte Risks/Side Effects: Clomid 6 months IUI alone Expectant alone •Headache •Hot Flash 17% 14% 23% •Mood Changes •Ovarian Cysts •Twins Not statistically different Battacharya BMJ 2008 Practice committee ASRM, Fertil Steril, 2004 Unexplained Infertility: Clomid & IUI Treatment of Unexplained Infertility Pregnancy rate per Cycle •Randomized 9.5% o Treatment effect of clomid without IUI is Controlled Trial quite modest compared to timed •298 cycles intercourse 3.3% •67 patients with o Recommend for patients if: unexplained Infertility � No time constraints (ie young) Clomid and IUI Timed Intercourse � Patients who wish to avoid additional intervention • Number of cycles to achieve one pregnancy: 16 Deaton et al, Fertil Sterility 54:1083 1990
Amigos Trial FORT-T Trial FORT-T Trial • 154 women randomized to Clomid/IUI, FSH/IUI or IVF Results by the End of the Study 80 Results after first two treatment 70 cycles 60 60 50 50 Clinical Pregnancy 40 40 Live Birth 30 Clinical Pregnancy 30 Live Birth 20 20 10 10 0 0 Clomid IUI FSH IUI IVF First Clomid IUI FSH IUI IVF First
Summary: Patient Care Summary • Fertility Declines with Age • Counseling regarding implications of age Natural Fecundity by age of 35 is almost ½ • Counseling regarding other factors associated that of a 22 year old woman with fertility: smoking and BMI • Miscarraige Rates increase • Basic fertility workup at age 35 recommended after six months: A pregnancy conceived by a 35 yo is twice as likely to miscarry as a woman age 22. • Semenanalysis and HSG most high yield • These changes are thought to be due to a decrease oocyte quality Summary: Treatment • Clomid alone not more effective than no treatment Thank you • Clomid and IUI reasonable first step • IVF is the more cost effective than Gonadotropin IUI as next step after Clomid IUI • Preimplantation Genetic Screening not recommended on basis of maternal age
Recommend
More recommend
