Reproductive Aging - by Dr. Arthur Leader (Fall 2010)

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REPRODUCTIVE AGING

by Arthur Leader, BA, MD, FRCSC
Fall 2010

Women who put off trying to have children until their mid-thirties worsen their chances for pregnancy and motherhood.

Reproductive aging in women is a continuous process that begins prior to birth and ends with menopause. Recent studies have suggested that by age 25 women lose about 80% of the eggs they were born with. The average woman will have lost 95% of her eggs by age 35. Only 5% of this loss is due to smoking, stress or body mass. [Human Reproduction 2008, 23(3), 699-708]

In a recent Canadian survey of 360 undergraduate university women, most were aware that fertility declines with age, but they significantly overestimated the chance of pregnancy at all ages and were not conscious of the steep rate of fertility decline. Surprisingly, women overestimated the chance of pregnancy loss at all ages, but did not generally identify a woman’s age as the strongest risk factor for miscarriage [Fertil Steril 93(7)2010; 2162-2168]. As a result, women put off child-bearing without fully understanding the possible consequences. As well, men have bought into the myth, inspired by Trudeau, Picasso, Larry King and other 60-plus fathers, that their reproductive potential is unchanged by age.

Among women of child-bearing age today, having children is no longer an unavoidable biological destiny. As men and women pursue careers, many have doubts as to when or whether they want children. Key to this doubt is the difficulty people have in combining child rearing with educational/professional development and in accepting the loss of personal freedom that comes with building a family. These same men and women are falsely reassured by the media that steroid contraception delays reproductive aging and that advances in new reproductive technologies can compensate for the age-related decline in fertility.

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Source: Statistics Canada, CANSIM table 102-4505.


In Canada and Western Europe, the average age of women delivering a first child has risen from 24.6 years in 1970 to 29.1 years in 1999 and to 30.1 years in 2007. Most women in Canada will deliver their first child after the age of 30, with the proportions of first births after age 34 increasing from 6% (1975) to 18% (1995) to 25% in 2005. As women and men age, the per cent of couples who fail to deliver increases from 9% at ages 25-29 to 30% at ages 35-39. Consequently, our fertility rate has plummeted.

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Source: Statistics Canada, unpublished data.

Regrettably, most women come to assisted reproduction when they and their partners are 35 years of age or older. By this time the pool of usable eggs is severely reduced, sperm counts and semen quality are also deteriorating, and the rates of miscarriage are increasing. Assisted Reproductive Technology (ART) can only partially correct the age-related decline in fertility, and success rates for all forms of ART are less. For those fortunate enough to become pregnant, spontaneous losses increase with age and the risk of adverse perinatal outcomes increases.

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2007: ASSISTED REPRODUCTIVE TECHNOLOGY SUCCESS RATES NATIONAL SUMMARY AND FERTILITY CLINIC REPORTS
Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Division of Reproductive Health, Atlanta, Georgia (2009)


It has been estimated that ART, such as in vitro fertilization (IVF), would compensate for only half of the births lost by postponing pregnancy from age 30 to 35 and less than 30% of the births lost by postponing pregnancy from age 35 to 40. Studies in the literature conclude that women aged 35-40 years should turn to ART sooner. Both women and men contribute to age-related increased risks of pregnancy, such as diabetes in pregnancy (increases by 263%); congenital abnormalities (male age over 40 doubles the risk of nervous system abnormalities, independent of the woman’s age); placenta previa (increases by 94%); elective cesarean section (increases by 77%) and stillbirth (increases by 41%).  


The traditional evaluation of infertility includes:
Confirmation of ovulation and ovarian reserve (FSH, antral follicle count and anti-mullerian hormone)
Semen assessment (semen analysis)
Sexual history
Assessment of tubal patency, the endometrial lining and pelvic structures

Delayed parenting has created a new sense of urgency in undertaking this assessment. New data provides a better understanding of the effects of age, duration of infertility and lifestyle, on fertility. Emerging data on effectiveness and cost-effectiveness of different interventions recommends early intervention for women in their mid-thirties.

In non-ovulating women who conceive after taking clomiphene citrate (CC), ovulation induction studies suggest that while ovulation rates are not tied to age, women over age 30 who receive CC are less likely to conceive and carry a child to full term. Women at age 30 have only an 18% delivery rate which by age 35, drops to 10%.

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Pregnancy rates in non-ovulating women after CC


A similar picture is seen whether donor or partner sperm is used.

Age and delivery rates after stimulated or natural Donor Sperm Insemination

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* Statistically significant differences
Hum Reprod 17:2320-2324, 2002

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Clomiphene citrate + IUI pregnancies and age
Fertil Steril 78(5):1088-95, 2002

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Controlled ovarian stimulation and IUI: Cumulative pregnancy rates and age
Gynecological Endocrinology, 2010: 26(7):500-504

For those who pursue IVF, the news is not much better. National databases (registries) from France, Australia, the United States and Canada show that women came to IVF at a later age each year over the past decade - independent of whether the treatment was fully insured or not. These databases confirm the findings seen in donor insemination and controlled ovarian stimulation with intrauterine insemination (IUI) – pregnancy rates decrease and miscarriage rates increase with age.

The causes for the decline in live birth rates after ART are directly related to the increased miscarriage rates in older women who produce fewer eggs when stimulated with gonadotropins. Altered egg quality may be due to the increasing rate of egg chromosome abnormalities, to the increased rate of genetic abnormalities in the cytoplasm (the fluid surrounding the nucleus of the egg), or the reduced influence of hormones in stimulating egg production. Age-related alterations in sperm quality may be caused by changes in sperm genetic material, reduced male hormone (testosterone) levels, or an accumulation of environmental toxicants that mimic female hormones and block male hormone action (such as BPA or phthalates that are found in plastics).

The Therapeutic Challenge

Women over 35 are more likely to respond poorly to gonadotropin stimulation and as clinicians we have little, if any, influence over the number of follicles that are available to be stimulated in a given treatment cycle. Prior to initiating therapy, we try to understand the potential responsiveness of our patient. This is based either on recent responses or on a careful assessment of ovarian reserve. If the woman’s partner is more than 5 years her senior, then any estimation of success needs to be adjusted downward.

Where an inadequate response has occurred previously, various strategies to enhance oocyte production can be pursued. Unfortunately, as a result of the Assisted Human Reproduction Act, egg donation in IVF has become unavailable in Canada, unless donated altruistically. It remains commercially available, though costly, in the United States and Europe.

Conclusions

Female fertility has a “best before date” of 35 and for men it is probably before age 40. We should expedite therapy when a decision to treat has been made. When women are 35 years or older, and married to men their age or older, they are at the greatest risk of remaining childless without treatment. If treatment is contemplated in these couples, ART can only partially compensate for age-related infertility.

ABOUT THE AUTHOR:  Dr. Arthur Leader is Professor of Obstetrics, Gynecology and Medicine (Endocrinology) at the University of Ottawa and former Chief, Division of Reproductive Medicine at the Ottawa Hospital. He is one of the founding physicians of the Ottawa Fertility Centre. Dr. Leader has cared for infertile patients over the last 30 years. His other professional interests include clinical trials of new pharmaceuticals, reproductive toxicants, quality assurance in ART and public policy around the regulation of ART. He is a past president of the Canadian Fertility and Andrology Society. He was a member of Ontario’s Expert Panel on Infertility and Adoption.