Pregnancy and motherhood: The biological clock

Tests to determine ovarian reserve 

It is not surprising that many tests have been developed to determine the ovarian reserve of women who are interested in fertility and fertility treatment or those who are concerned about the impending cessation of menstrual function. It is also not surprising that the perfect test has yet to be developed. While some tests focus on ovarian reserve (the total number of eggs left in the ovaries) others seek to predict the woman's response to fertility treatments. It can sometimes be confusing to patients when the same tests are used to predict natural fertility, ovarian response to gonadotropins, and the likelihood of pregnancy in IVF. Some tests are widely available, while others are in the developmental stages and limited to specific laboratories (see “Tests to determine ovarian reserve” on this page).

Until recently, all of these tests as well as semen analysis involved medical supervision with follow-up with a health professional. This is being changed by new tests. Companies that market near-patient (at home) testing claim their products allow a woman to screen for ovarian reserve with a mail-order fertility test (for follicle-stimulating hormone [FSH], inhibin B, and anti-mullerian hormone [AMH]), test for ovulation at home (LH), and allow her partner to determine the normality of his ejaculate with a home test—all without follow-up advice. It remains to be seen if the privacy that these tests afford will encourage the public to pursue therapies in a more timely manner.

Fertility demographics 

We are now seeing that the average age that women deliver a first child has risen from 24.6 years in 1970 to 29.1 years in 1999 in Canada and Western Europe. Most women in Canada will deliver their first child above the age of 30 with the proportions of first births after age 34 increasing from 6% (1975) to 18% (1995) to 25% in 2005 (see Table 1). We are seeing the age-specific fertility rates shifting to the over-30 woman in Canada, but less so in the United States. 8

TABLE 1. Age-specific fertility rates in Canada

		Fertility rate per 1000 women
	Age group	1986	1991	1995	1996	1997
	15–19 years	23.01	25.98	24.49	22.34	20.19
	20–24 years	78.74	77.50	70.53	67.28	64.07
	25–29 years	119.01	120.33	109.69	105.82	103.88
	30–34 years	72.52	83.63	86.77	85.51	84.44
	35–39 years	22.30	28.27	31.26	32.22	32.52
	40–44 years	3.15	3.88	4.83	5.06	5.19
	45–49 years	0.13	0.17	0.19	0.20	0.20

1.Age-specific fertility rates are calculated by dividing the number of live births in each age group by the total female population (in thousands) in each age group. 2.Births to women aged 14 and under are included in the 15–19 age groups. 3.Births to women aged 50 and over are included in the 45–49 age groups. Source: Births 2003, Statistics Canada, Administration of Industry, July 2005: Catalogue no.82F0075XCB.

Regrettably, most women seek assisted reproduction (AR) when they and their partners are 35 years of age or older. At this time, the pool of useable eggs appears to be declining, and sperm counts and semen quality are also deteriorating while the rates of spontaneous losses are increasing. Assisted reproduction only partially corrects for the age-related decline in fertility and success rates for all forms of AR are less. For those fortunate to become pregnant, spontaneous losses increase with age, and the risk for adverse perinatal outcomes increases.

It has been estimated that AR, such as IVF, would make up 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. 9 Studies in the literature conclude that women aged 35–40 years should turn to ART sooner. When pregnant, both women and men contribute to the 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 caesarean section (increases by 77%) and stillbirth (increases by 41%).

The traditional infertility evaluation 

Delayed parenting has created a new sense of urgency in undertaking that assessment. New data allow 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 have supported early intervention for women in their mid-thirties.

In anovulatory women who conceive after clomiphene citrate (CC) ovulation induction, studies suggest that age does not influence ovulation rates, but an age of over 30 years negatively affects risk of conception and a live birth in women. 10 In summary:

Pregnancy rates in nonovulating women after CC 

The same pregnancy and delivery rates are seen regardless of whether donor or partner semen is used in each age group but are significantly less for those 35 years or older10, 11, 12 (see Figure 1).

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FIGURE 1. Clomiphene citrate + hMG and IUI: Pregnancy rates and age 2 hMG = human menopausal gondaotropin; IUI = intrauterine insemination.

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 are seeking IVF at a later age each year over the past decade—independent of whether the treatment is fully insured or not. These databases confirm the findings seen in donor insemination and super ovulation with intrauterine insemination: pregnancy rates decrease and miscarriage rates increase with age (see Table 2).11

TABLE 2. Age and delivery rates after stimulated or natural donor insemination *

	Age (years)	Pregnancies/cycle (%)	Pregnancies/patient (%)	Delivery rate (%)
	<35	39/211 (18.5)	39/67 (58.2)	18.8
	35–40	60/506 (11.9)	60/133 (45.1)	5.8 †
	>40	13/339 (5.4) †	13/61 (21.3) †	3.0 †

* Table printed with permission from the publisher and the authors, reference 11 † Statistically significant differences.

The causes for the decline in live birth rates after assisted human reproduction 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 due to changes of sperm chromosomal anomalies and disomies, reduced male hormone (testosterone) levels; or a life-time accumulation of environmental toxicants that mimic female hormones and block male hormone action (such as phthalates found in plastics).

The therapeutic challenge 

Women over 35 years of age are more likely to have a repeatedly poor response 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 need to understand the potential responsiveness of our patient. This is based either on recent past responses, careful attention to the mother's date of birth and a careful assessment of ovarian reserve. If the woman's partner is more than five years her senior, then any estimation of success needs to be adjusted downwards.

Where an inadequate response has occurred previously, then we may have to invoke strategies that may enhance oocyte production or help our patients to consider adoption, egg donation, or child-free living.

It is not proven that the use of pre-implantation aneuploidy screening of day-three embryos either significantly reduces the risk of spontaneous abortion or increases the probability of a healthy newborn in older women. The impact of blastomere biopsy on either the pregnancy or the newborn has yet to be determined.

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. Women 35 years or older married to men their age or older are at the greatest risk of remaining childless without treatment. If treatment is contemplated in these couples, ART can only partially compensate for their age-related infertility.