Infertility in Women over 35. Alison Jacoby, MD Dept. of Ob/Gyn UCSF

Transcription

1 Infertility in Women over 35 Alison Jacoby, MD Dept. of Ob/Gyn UCSF

2 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

3 Case 35 yo G0 recently married with questions about fertility

4 Knowledge Gap: Age and Fertility Survey by American Fertility Association ,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

5 Celebrities/Media perpetuate the myth of limitless fecundity

6 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

7 Fecundability declines with age Menken, et al., Science 1986, 233:

8 Fecundability and natural fertility in humans Homan, G.F. et al. Hum Reprod Update : ;

9 Chance of Natural Conception per Month Percent chance per month 25% 24% 22% 20% 18% 16% 13% 10% 7% 5% 3% 2% Age

10 Oocyte Depletion

11 Risk of Fetal Loss According to Maternal Age Denmark Registry 1978 to women and pregnancy outcomes. Andersen A N et al. BMJ 2000;320:

12 Miscarriage Rate by Age Dutch Health Registry: ,272 women 1,221,546 pregnancy outcomes 51% 75% 9% 11% 15% 25% >45 Nyabo Anderson BMJ 2000

13 Abnormalities in the oocyte increase with age Pellestor et al, Eur J Med Genet 2006

14 Case 35 yo ready to start trying

15 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

16 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

17 Smoking and Fertility Average Time to Conceive by Smoking Status Months No Smoking <10/per day >10 per day

18 Metanalysis: smoking and fertility Odds Ratio of infertility in smokers: 2.27 (1.34,1.91).

19 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 < >39 BMI Hassan and Killick Fertility and Sterility. VOL. 81, NO. 2, FEBRUARY 2004

20 Body Weight and Fertility BMI Adj RR Infertility p < ( ) ( ) <0.001 > ( ) <0.001 Hassan and Killick Fertility and Sterility. VOL. 81, NO. 2, FEBRUARY 2004

21 Lifestyle Factors Alcohol: Evidence that >7 drinks per week is deleterious to fertility Exercise: No evidence that moderate amounts are deleterious

22 Case 35 yo recently married reports trying to conceive for the past six months without success

23 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...

24 Initiation of the Infertility Evaluation ASRM Practice Committee 2006

25 Causes of Infertility Unexplained- 28% Male factors- 24% Ovulatory dysfunction- 21% Tubal damage- 14% Endometiosis- 6% Coital problems- 6% Cervical factor- 3%

26 The Basic Infertility Work-up Ovary Tubes Semen Lifestyle Ovulation HSG Ovarian Reserve??? Semen Analysis Counseling

27 Ovarian Reserve FSH/Estradiol Antral Follicle Count Clomid Challenge Test AntiMullerian Hormone

28 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

29 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...

30 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:

31 Basal FSH and Pregnancy During Treatment Day 3 FSH not predictive of pregnancy during treatment Broekmans F et al. Hum. Reprod. Update 2006;12:

32 FSH and Natural Fertility Unexplained subfertility for one year 3270 patients Followed prospectively

33 Antral Follicle Count varies by age Rosen et al F and S 2010

34 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:

35 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

36 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

37 Case 35 yo wants treatment after 12 months of trying

38 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

39 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

40 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

41 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:

42 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

43 What treatment is next if Clomiphene-IUI is unsuccessful?

44 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

45 After Clomid and IUI: Faster Trial 503 couples with unexplained infertility Clomiphene IUI -> Gonadotropin IUI -> IVF Clomiphene IUI -> IVF Reindollar F &S 2010

46 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

47 IVF outcomes

48 Cumulative Live-Birth Rates Stratified According to Maternal Age at the Start of Cycle 1. Cumulative IVF Success Rates 6164 women completing cycles yo TAKE HOME: First 3 cycles highest yield with diminishing returns after three Malizia BA et al. NEJM 2009.

49 Live birth from IVF by age 44% 45% 44% 42% 41% 35% 30% 23% 14% 7% National Clinic Data for

50 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

51 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

52 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

53 Doctor, I m single and focusing on my career, how can I preserve my fertility?

54 Options for Fertility Preservation Embryo cryopreservation Mature oocyte cryopreservation Immature oocyte cryopreservation

55 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

56 Mature Oocyte Preservation More challenging than freezing sperm or embryos Low success rates May need oocytes to achieve 1 live birth High cost Ethical implications Complications of pregnancy in older women

57 Immature Oocyte Cryopreservation Ovarian tissue freezing Investigational Allotopic vs heterotopic transplantation

58 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

59 Thank you