Infertility in Women over 35 Alison Jacoby, MD Dept. of Ob/Gyn UCSF
Learning Objectives Review the effect of age on fertility Fertility counseling for the patient >35 - timing - lifestyle - workup Fertility treatment of the patient >35 - which steps Options for fertility preservation
Case 35 yo G0 recently married with questions about fertility
Knowledge Gap: Age and Fertility Survey by American Fertility Association 2001 12,382 women responded to 15 questions 1 responded correctly to all More than ½ of all questions answered incorrectly 85% overestimated by 5-10 years the point at which fertility declines
Celebrities/Media perpetuate the myth of limitless fecundity
Definitions Fecundability- probability of becoming pregnant in a single menstrual cycle Fecundity- probability of achieving a live birth within a single menstrual cycle Fertility- actual reproductive rate of an individual or population
Fecundability declines with age Menken, et al., Science 1986, 233:1389-94
Fecundability and natural fertility in humans Homan, G.F. et al. Hum Reprod Update 2007 13:209-223;
Chance of Natural Conception per Month Percent chance per month 25% 24% 22% 20% 18% 16% 13% 10% 7% 5% 3% 2% 24 26 28 30 32 34 36 38 40 42 44 46 Age
Oocyte Depletion
Risk of Fetal Loss According to Maternal Age Denmark Registry 1978 to 1992 34 272 women and 1 221 546 pregnancy outcomes. Andersen A N et al. BMJ 2000;320:1708-1712
Miscarriage Rate by Age Dutch Health Registry: 1978-1992 634,272 women 1,221,546 pregnancy outcomes 51% 75% 9% 11% 15% 25% 20-24 25-29 30-34 35-39 40-44 >45 Nyabo Anderson BMJ 2000
Abnormalities in the oocyte increase with age Pellestor et al, Eur J Med Genet 2006
Case 35 yo ready to start trying
Learning Objectives Review the effect of age on fertility Fertility counseling for the patient >35 Fertility treatment of the patient > 35 Options for fertility preservation
Smoking and Fertility Average age of menopause 3-4 years earlier than non-smokers Nicotine and Cotinine found in follicular fluid Direct damage to oocytes/follicles suspected
Smoking and Fertility Average Time to Conceive by Smoking Status 2.6 3.2 3.9 Months No Smoking <10/per day >10 per day
Metanalysis: smoking and fertility Odds Ratio of infertility in smokers: 2.27 (1.34,1.91).
Body Weight and Fertility 1,200 consecutive pregnant women. 25 Adjusted Months to Conception A questionnaire inquiring about time to pregnancy Contraceptive use, pregnancy planning, previous subfertility/pregnancies, age, and lifestyle characteristics examined 14 10.9 6.9 <19 19-24 25-39 >39 BMI Hassan and Killick Fertility and Sterility. VOL. 81, NO. 2, FEBRUARY 2004
Body Weight and Fertility BMI Adj RR Infertility p <19 4.8 (1.2-19.7).03 19-25 1.0 25 39 2.2 (1.6-3.2) <0.001 >39 6.9 (2.9-16.8) <0.001 Hassan and Killick Fertility and Sterility. VOL. 81, NO. 2, FEBRUARY 2004
Lifestyle Factors Alcohol: Evidence that >7 drinks per week is deleterious to fertility Exercise: No evidence that moderate amounts are deleterious
Case 35 yo recently married reports trying to conceive for the past six months without success
When should an infertility evaluation begin? 1. After attempting conception x 12 months 2. Now, only if she has irregular cycles 3. Now, even if her cycles suggest monthly ovulation 4. It will depend on her FSH and estradiol levels 50% 18% 18% 15% After attempti... Now, only if s... Now, even if h... It will depend...
Initiation of the Infertility Evaluation ASRM Practice Committee 2006
Causes of Infertility Unexplained- 28% Male factors- 24% Ovulatory dysfunction- 21% Tubal damage- 14% Endometiosis- 6% Coital problems- 6% Cervical factor- 3%
The Basic Infertility Work-up Ovary Tubes Semen Lifestyle Ovulation HSG Ovarian Reserve??? Semen Analysis Counseling
Ovarian Reserve FSH/Estradiol Antral Follicle Count Clomid Challenge Test AntiMullerian Hormone
Ovarian Reserve FSH Hypothalamus Pituitary Estradiol Antral Follicle Count (AFC) Anti-Mullerian Hormone Inhibin FSH and ANTI-MULLERIAN HORMONE are indirect measures of the ANTRAL FOLLICLE COUNT
Testing Ovarian Reserve: What does it tell you? A. It is a predictor of whether a person will achieve pregnancy with treatment B. It is predicator of how well a person will respond to gonadotropin stimulation 69% C. It is an indicator of whether a person will conceive spontaneously 24% D. All of the above 2% 6% It is a predic... It is predicat... It is an indic... All of the abo...
FSH and Response to Gonadotropin Treatment Highly Predictive FSH useful in predicting poor response Not predictive Broekmans F et al. Hum. Reprod. Update 2006;12:685-718
Basal FSH and Pregnancy During Treatment Day 3 FSH not predictive of pregnancy during treatment Broekmans F et al. Hum. Reprod. Update 2006;12:685-718
FSH and Natural Fertility Unexplained subfertility for one year 3270 patients Followed prospectively
Antral Follicle Count varies by age Rosen et al F and S 2010
Antral Follicle Count in Treatment ROC curves Antral Follicle Count -> Good at predicting poor response Ability to predict lack of conception is less clear Broekmans F et al. Hum. Reprod. Update 2006;12:685-718
Ovarian Reserve Testing: Summary FSH, Antral Follicle Count, etc arose as a predictive tool during infertility treatment Weak relationship to possibility of spontaneous pregnancy Strong relationship with degree of ovarian response during treatment Minimal relationship to live birth rate in IVF in women under 40
Learning Objectives Review the effect of age on fertility Fertility counseling for the patient >35 Fertility treatment of the patient >35 Options for fertility preservation
Case 35 yo wants treatment after 12 months of trying
Treatment Expectant 1-4% IUI 3.8% Clomiphene 5.6% Clomiphene + IUI 8.3% Gonadotropin IUI 17.1% IVF 20.7% Guzick Fertility and Sterility 1998
Clomid for Unexplained Infertility 50 mg for five days (typical: 3-7) Increase to 100 mg if no ovulation Acts as estrogen antagonist Assist in production >1 oocyte Risks/Side Effects: Headache Hot Flash Mood Changes Ovarian Cysts Twins-7-9% Practice committee ASRM, Fertil Steril, 2004
Clomid alone vs. IUI 580 women randomized (avg age 32) Clomiphene alone IUI alone Expectant 14% 23% 17% 6 months Not statistically different Battacharya BMJ 2008
Unexplained Infertility: Clomid & IUI Randomized Controlled Trial 298 cycles 67 patients with unexplained Infertility Pregnancy rate per Cycle 9.5% 3.3% Clomiphene+ IUI Timed Intercourse Deaton et al, Fertil Sterility 54:1083 1990
Treatment of Unexplained Infertility o Treatment effect of Clomiphene without IUI is quite modest compared to timed intercourse o Recommend for patients if: No time constraints (ie young) Patients who wish to avoid additional intervention
What treatment is next if Clomiphene-IUI is unsuccessful?
Treatment Expectant 1-4% IUI 3.8% Clomiphene 5.6% Clomiphene and IUI 8.3% Gonadotropin IUI 17.1% IVF 20.7% Guzick Fertility and Sterility 1998
After Clomid and IUI: Faster Trial 503 couples with unexplained infertility Clomiphene IUI -> Gonadotropin IUI -> IVF Clomiphene IUI -> IVF Reindollar F &S 2010
Infertility Cost/ Delivery Total Cost / Delivery Conventional 4,594 38,806 Accelerated 4,524 29,003 Role for gonadotropin/iui called into question Reindollar F &S 2010
IVF outcomes www.cdc.gov
Cumulative Live-Birth Rates Stratified According to Maternal Age at the Start of Cycle 1. Cumulative IVF Success Rates 6164 women completing 14248 cycles 35-38 yo TAKE HOME: First 3 cycles highest yield with diminishing returns after three Malizia BA et al. NEJM 2009.
Live birth from IVF by age 44% 45% 44% 42% 41% 35% 30% 23% 14% 7% 26 28 30 32 34 36 38 40 42 44 National Clinic Data for 2005 www.cdc.gov
Summary Fertility Declines with Age Natural Fecundity by age of 35 is almost ½ that of a 22 year old woman Miscarraige Rates increase A pregnancy conceived by a 35 yo is twice as likely to miscarry as a woman age 22. These changes are thought to be due to a decrease oocyte quality
Summary: Treatment Clomiphene alone not more effective than no treatment Clomiphene and IUI reasonable first step IVF is the more cost effective than Gonadotropin IUI as next step after Clomiphene IUI
Learning Objectives Review the effect of age on fertility Fertility counseling for the patient >35 Fertility treatment of the patient > 35 Options for fertility preservation
Doctor, I m single and focusing on my career, how can I preserve my fertility?
Options for Fertility Preservation Embryo cryopreservation Mature oocyte cryopreservation Immature oocyte cryopreservation
Embryo Cryopreservation Proven method of fertility preservation Live birth rates from frozen/thawed embryos depends on age of woman at time of egg retrieval Donor sperm
Mature Oocyte Preservation More challenging than freezing sperm or embryos Low success rates May need 20-25 oocytes to achieve 1 live birth High cost Ethical implications Complications of pregnancy in older women
Immature Oocyte Cryopreservation Ovarian tissue freezing Investigational Allotopic vs heterotopic transplantation
Conclusions Counseling regarding implications of age Counseling regarding other factors associated with fertility: smoking and BMI Basic fertility workup at age 35 recommended after six months. Semen analysis and HSG most high yield
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