The French researchers drew fire from a few demographers who, though confirming the trend, dismissed their numbers as too high. Meanwhile, infertility specialists hit upon a new angle from which to examine fecundity. As growing numbers of women underwent treatment with fertility drugs and attempted to conceive through in vitro fertilization, researchers tallied successes and failures according to age group. Almost invariably, older women had a poorer prognosis than younger ones. The test-tube-baby pioneers Patrick Steptoe and Robert Edwards observed this disparity among their patients in a 1983 progress report in The Lancet, and it was seen again and again in programs around the world, with the worst outcome being among women over forty, whose chances of conceiving turned out to be quite slim even if the fertility problem apparently lay with their partners.
Some researchers, puzzling over what could account for the ill fortune of older women, zeroed in on poor egg quality as a possible cause. This "bad eggs" explanation has gained widespread acceptance since the introduction, in 1983, of egg donation, a procedure in which a physician inserts a needle into the ovaries of one woman, sucks mature eggs from her follicles, combines the eggs with sperm, and then transfers the resulting embryos to a second woman, who hopes to carry one or more of them to term. In the bulk of cases, infertility specialists have found, older women who fail to become pregnant using embryos made with their own eggs succeed when the eggs come from a younger donor.
The work of the reproductive endocrinologists Mark Sauer and Richard Paulson and their associates at the University of Southern California School of Medicine has demonstrated in dramatic fashion the difference that young eggs make. From their clinic in downtown Los Angeles, Sauer and Paulson have inadvertently made a name for themselves in the tabloids by helping women old enough to be grandmothers get pregnant. Last year Sauer and Paulson reviewed the results of 300 egg donations carried out at their clinic, 198 of them in women aged forty to fifty-nine, and concluded that the natural aging of eggs accounts for the decline in female fecundity. Sauer and Paulson feel certain of this because even postmenopausal women who received donated eggs were able to undergo successful pregnancies, as long as they were given hormones to plump up the uterine lining.
Embryos from older eggs show no external signs of being flawed. Magnified and floating in culture medium, an eight-cell human embryo produced from a forty-year-old woman's egg cannot be differentiated from that of a teenager. But the eye is no gauge of embryonic fitness. Recently a team of scientists at Cornell University Medical Center, in New York City, provided compelling evidence that abnormalities deep within developing embryos account for failures of in vitro fertilization, and that these abnormalities occur with greater frequency among older women.
We have known since the 1930s that as women age, they are far more likely to produce fetuses and babies with Down syndrome and other "trisomic" anomalies. Embryos that are trisomic contain, instead of matched pairs of chromosomes, one too many of a given chromosome, most commonly chromosome 13, 18, 21 (which is responsible for Down syndrome), X, or Y. Trisomies are the result of a glitch known as nondisjunction, which occurs principally during the creation of egg cells (although sperm cells may also exhibit such errors). Immature human eggs, or oocytes, sit in suspended animation in the ovaries from the time they are formed in the female fetus, and complete the process of meiosis to form mature egg cells only just prior to ovulation. When nondisjunction occurs, the resulting eggs may carry too few or too many chromosomes, a state called aneuploidy.
In a 1983 letter to the journal Nature, British in vitro fertilization researchers conjectured that embryos formed from such botched eggs would be less viable than those with a normal genetic endowment, and either would not implant in the uterine wall or would spontaneously abort shortly after implantation. This, they said, could account for the generally high rate of in vitro failures then being seen—about 80 percent. The further implication, arising out of the well-known correlation between maternal age and chromosomal disorders, was that the longer oocytes sit around in the ovaries, the more likely they are to rub the series of steps vital to dividing up the chromosomes.
This notion has been borne out by the Cornell team, which made its case in one of the main papers presented at last fall's American Fertility Society meeting. Jamie Grifo, a reproductive endocrinologist who also holds a doctorate in biochemistry and is an assistant professor of obstetrics and gynecology at Cornell, read the paper, which had taken top honors from the Society for Assisted Reproductive Technology. Grifo and his colleagues have been fine-tuning an experimental method for diagnosing chromosomal abnormalities in embryos before they are transferred to women undergoing in vitro fertilization (the aim being to help couples at high risk of passing on genetic diseases). The test involves removing one cell, or blastomere, from an eight-cell embryo and exposing the cell to flagged fragments of single-stranded DNA, which bind to the chromosomes and can be viewed, glowing, under a special microscope. If the blastomere is aneuploid, this molecular tool, called "fluorescence in situ hybridization," or FISH, will unmask it. Grifo announced at the meeting that in screening normal-looking pre-implantation embryos from two groups of women, twenty-five to thirty-nine years old, and over thirty-nine, they had found significantly higher proportions of aneuploidy in the second group than in the first—42 percent as against nine percent.
The team has further illuminated the extent to which eggs go bad with age in an unpublished paper written by the geneticist Santiago Munne. Munne reports that FISH screening of 3,594 blastomeres from 514 pre-implantation embryos pinpointed far more aneuploidies among women over forty than should have been expected, given the rates of aneuploidy tallied from amniocentesis tests of fetuses carried by older women and from live births. In other words, more aneuploid embryos are formed than ever show up as pregnancies, and more pregnancies with aneuploid embryos spontaneously terminate at some early stage than ever continue to term. Nature, it appears, has a mechanism for weeding out embryos of inferior quality, whether they're made in a petri dish or in the body.
Grifo and the Cornell team contend that genetically faulty embryos are the main cause of the high failure rate of in vitro fertilization among older women, but other fertility specialists have reservations. Richard Paulson, who was a physics major as an undergraduate, professes to being something of a stickler when it comes to data; he is not entirely persuaded by the Cornell numbers and suggests that flaws in aging eggs other than chromosomal ones might bar their implantation and development. David Meldrum, of the Center for Advanced Reproductive Care, who has made a review of the literature on female reproductive aging, contends that both egg quality and uterine receptivity play a role in the decline of fecundity with age. But whatever the locus of the problem, pregnancies prove harder to establish and maintain in older women—whether in the infertility clinic or in the world at large. Women in their forties are known to have a rate of spontaneous abortion half again as high as those in their twenties. And the older a woman gets, the greater her prospects of bearing a premature or low-birth-weight infant, or of having a stillbirth—and thus the greater her possibilities for heartache.