Infertility for the Generalist Heather Huddleston, MD Associate - - PowerPoint PPT Presentation

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Infertility for the Generalist Heather Huddleston, MD Associate - - PowerPoint PPT Presentation

Apr 13, 2023 459 likes •611 views

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

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SLIDE 1

Infertility for the Generalist

Heather Huddleston, MD Associate Professor UCSF Center for Reproductive Health

I have nothing to disclose Outline

  • Fecundability and age
  • Advice for the person about to start trying to

conceive

  • Workup of the patient with fertility problems
  • What is new in fertility treatment

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

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SLIDE 2

Fecundability declines with age

Menken, et al., Science 1986, 233:1389-94 Homan, G.F. et al. Hum Reprod Update 2007 13:209-223;

Fecundability and natural fertility in humans

Chance of Natural Conception per Month

24% 22% 20% 16% 13% 10% 7% 5% 3% 2% 25% 18% 24 26 28 30 32 34 36 38 40 42 44 46

Age Percent chance per month

  • 3 mo 6 mo 9 mo 12 mo

Hassan and Killick, Fertility and Sterility 2003

Evaluation of Time to Pregnancy in 2012 women

35-39

Time to Pregnancy and Age

28 % of pregnant women 35-39 will not have conceived in a year

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SLIDE 3

Cumulative pregnancy rate (CPR) according to patient's age (years).

Ferrara I et al. Hum. Reprod. 2002;17:2320-2324

Risk of Fetal Loss According to Maternal Age

Andersen A N et al. BMJ 2000;320:1708-1712

Denmark Registry 1978 to 1992 34 272 women and 1 221 546 pregnancy outcomes.

Abnormalities in the oocyte increase with age

Pellestor et al, Eur J Med Genet 2006

Advice for the person about to start

Timing Lifestyle

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SLIDE 4

Dunson D B et al. Hum. Reprod. 2002;17:1399-1403

Timing of Intercourse

Smoking and Fertility

  • Average age of menopause 3-4

years earlier than non-smokers

  • Nicotine and Cotinine found in

follicular fluid

  • Direct damage to
  • ocytes/follicles suspected

Smoking and Fertility

3.2 3.9 2.6 No Smoking <10/per day >10 per day

Average Time to Conceive by Smoking Status Months

.

Metanalysis: smoking and fertility

Odds Ratio of infertility in smokers: 2.27 (1.34,1.91)

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SLIDE 5

Body Weight and Fertility

Hassan and Killick Fertility and Sterility. VOL. 81, NO. 2, FEBRUARY 2004

6.9 10.9 14 25 <19 19-24 25-39 >39

  • 1,200 consecutive pregnant

women.

  • A questionnaire inquiring

about time to pregnancy

  • Contraceptive use, pregnancy

planning, previous subfertility/pregnancies, age, and lifestyle characteristics examined

Adjusted Months to Conception BMI

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

The Infertility Evaluation

<35 years old: after one year of trying to conceive >35 years old: after six months Patient with irregular cycles, known tubal disease or partner with known subfertility

ASRM Practice Committee 2006

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SLIDE 6

The Basic Infertility Work-up

Ovary Tubes Semen

Other Endocrine

Ovulation And Cycles Ovarian Reserve ???

HSG

Semenanalysis TSH Uterus

Ultrasound

Tubal/Uterine Factor

Normal Filling Defect Blocked Tube Septum

Semen Analysis

  • Volume 1.5-5ml
  • Concentration>20million/ml
  • Motility>50%

WHO,1992

If Abnormal Repeat

Is Ovulation happening?

Regular Cycles with moliminal symptoms Timing of ovulation:

  • Basal body temperature
  • Ovulation predictor kits

Anovulation suggested by cycle length 36 Progesterone <3 seven days after predicted

  • vulation

Inadequate luteal phase <10 days or extended spotting

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SLIDE 7

Endocrine

TSH Prolactin

Ovarian Reserve

Antral Follicle Count AntiMullerian Hormone FSH

Ovarian Reserve

Anti-Mullerian Hormone

Antral Follicle Count (AFC) Inhibin Hypothalamus Pituitary Estradiol FSH FSH and ANTI-MULLERIAN HORMONE are indirect measures of the ANTRAL FOLLICLE COUNT

FSH and Response to Gonadotropin Treatment

Broekmans F et al. Hum. Reprod. Update 2006;12:685-718

Not predictive Highly Predictive FSH useful in predicting poor response

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SLIDE 8

Basal FSH and Pregnancy During Treatment

Broekmans F et al. Hum. Reprod. Update 2006;12:685-718

Day 3 FSH not predictive of pregnancy during treatment

Age specific nomogram of AFC in infertile women Antral Follicle Count in the Community

Rosen et al F and S 2010

AMH: conception to menopause

Kelsey TW: PLoS ONE 2011

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SLIDE 9

Ovarian Reserve Testing: Summary

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

What is new for Treatment? Optimal Treatment of Anovulatory Infertility

Clomiphene Citrate (Clomid)

  • Synthetic Anti-estrogen
  • Convenient
  • Inexpensive
  • Long-standing first choice for
  • vulation induction in women

with PCOS

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SLIDE 10

Imani, B. et al. J Clin Endocrinol Metab 1998;83:2361-2365

How Many Women Will Ovulate With Clomid?

About ¾ of women with PCOS will

  • vulated

with clomid

Imani, B. et al. J Clin Endocrinol Metab 1999;84:1617-1622

160 patients Normogonadotropi c anovulation Successful response to clomid Normal SA BMI >18.5

Clomid: Chances for conception?

Metformin For Ovulation

  • Biguanide Insulin Sensitizer
  • Category B
  • Not FDA approved

Results of RMN PPCOS Trial

P<.001 P<.001

Legro et al. NEJM 2007; 35:551-66

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SLIDE 11

Aromatase Inhibitors Letrozole versus Clomiphene for Infertility

  • RCT of 750 women

comparing letrozole of cloniphene for five treatments

  • Cumulative Ovulation

Rate higher in Letrozole (61.7% vs. 48.3%)

  • No differences in

pregnancy loss rate or twin pregnancy rate.

28% 19% 0% 5% 10% 15% 20% 25% 30% Letrozole Clomid

Live Birth Rate

Legro et al NEJM 2014

The Withdrawal Bleed Could Be a Hindrance

  • Secondary analysis of RMN PCOS trial
  • Use of withdrawal bleed prior to cycle start was up to

discretion of site investigators

0% 10% 20% 30%

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%

*

*

* * * P<.001

Diamond et al Obset Gyncol 2012 119: 902-905

Treatment of Unexplained

Expectant 4%

Clomid

4%

IUI

5%

Clomid and IUI 8% Gonadotropin IUI 15%

IVF 25% Guzick Fertility and Sterility 1998

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SLIDE 12

Clomid for Unexplained Infertility

  • 100 mg for five days (typical: 3-7)
  • Acts as estrogen antagonist
  • Assist in production >1 oocyte

Practice committee ASRM, Fertil Steril, 2004

Risks/Side Effects:

  • Headache
  • Hot Flash
  • Mood Changes
  • Ovarian Cysts
  • Twins

Clomid alone vs. IUI

Battacharya BMJ 2008

580 women randomized (avg age 32) Clomid alone IUI alone Expectant 14% 23% 17%

Not statistically different

6 months

Unexplained Infertility: Clomid & IUI

Deaton et al, Fertil Sterility 54:1083 1990

3.3% 9.5%

Clomid and IUI Timed Intercourse

  • Number of cycles to achieve one pregnancy: 16

Pregnancy rate per Cycle

  • Randomized

Controlled Trial

  • 298 cycles
  • 67 patients with

unexplained Infertility

Treatment of Unexplained Infertility

  • Treatment effect of clomid without IUI is

quite modest compared to timed intercourse

  • Recommend for patients if:

No time constraints (ie young) Patients who wish to avoid additional intervention

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SLIDE 13

Amigos Trial FORT-T Trial

  • 154 women randomized to Clomid/IUI, FSH/IUI or IVF

10 20 30 40 50 60 Clomid IUI FSH IUI IVF First Clinical Pregnancy Live Birth

Results after first two treatment cycles

FORT-T Trial

10 20 30 40 50 60 70 80 Clomid IUI FSH IUI IVF First Clinical Pregnancy Live Birth

Results by the End of the Study

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SLIDE 14

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: Patient Care

  • 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:

  • Semenanalysis and HSG most high yield

Summary: Treatment

  • Clomid alone not more effective than no

treatment

  • 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

Thank you