Reply from L.S. Forbes

Abstract

Some ideas rapidly establish a hegemony over an entire field. Darwin's phyletic gradualism seems more a product of the culture of 19th-Century England than the evidence of the fossil record, yet it became evolutionary orthodoxy. David Lack's brood reduction hypothesis was unchallenged for four decades, yet few if any now hold it as a general explanation for avian hatching asynchrony[1xStenning, M. Trends Ecol. Evol. 1996; 11: 243–246Abstract | Full Text PDF | PubMed | Scopus (111)See all References[1]. And discussions of the rising incidence of birth defects in older human mothers have focussed chiefly on one explanation: defective ova. This idea became entrenched even before any direct evidence was available (studies based on in-vitro techniques now provide such evidence). The logical counterpart—a relaxed maternal screen for defective zygotes— received far less attention. As Krakow notes, the idea is not new, but when proposed received a chilly reception, in part for methodological difficulties, but perhaps also for lack of a suitable conceptual framework.Williams, Nesse, Ewald and Medawar, among others, have performed a great service for the medical sciences by providing a new pair of glasses—evolutionary biology—to look at old problems. Here I used these spectacles to examine spontaneous abortion in humans, especially in the light of Haig's recent and important work[2xHaig, D. Q. Rev. Biol. 1993; 68: 495–532Crossref | PubMedSee all References[2].Part of the problem in the study of pregnancy loss is that we just don't know what is going on in the critical period immediately following conception: the true rates of spontaneous abortion or defective zygotes are largely unknown. By the time pregnancy is clinically recognized, most of the story is already over, and analyses based upon observed rates of pregnancy loss and defective zygotes in spontaneous abortions may well be misleading. I simply aimed to show that relaxed screening can provide another (not the only)explanation for the observed patterns and not erroneously as Krackow claims. Indeed, in-vitro work indeed suggests that the incidence of defective zygotes rises in older mothers[3xPetersen, M.B. et al. Hum. Mol. Genet. 1993; 2: 1691–1695Crossref | PubMed | Scopus (60)See all References, 4xPlachot, M. et al. Hum. Reprod. 1988; 3: 125–127Crossref | PubMedSee all References, 5xPlachot, M. Hum. Reprod. 1989; 4: 425–429Crossref | PubMedSee all References], although the magnitude of the increase seems insufficient to explain the entire pattern. Some of what I presented was conjectural and, as further information comes to light, may be proved wrong.I thank Warburton and Warburton for bringing to my attention recent evidence concerning maternal origin trisomies. There now seems little doubt that the increase in Down's syndrome (DS) with maternal age is at least in part due to more defective ova. However, as I noted originally, the relaxed screening and maternal origin hypotheses are not mutually exclusive. Whether the screen is relaxed in older mothers is, I believe still an open question. The data of Hook et al.[6xHook, E.B. et al. Am. J. Hum. Genet. 1995; 57: 875–881PubMedSee all References[6]are based principally upon cases of Down's Syndrome diagnosed in the second trimester of pregnancy, and thus omit the critical early period. I would suggest that there is both a `hard' and `soft' maternal screen—the soft maternal screen operates passively, and embryos are aborted simply when they prove developmentally incompetent. The hard screen is active as it uses early cues (e.g. early hCG production) to `anticipate' developmental failure, the advantage being that the mother largely avoids the costs of the physiological remodelling required to sustain pregnancy. That older mothers are more prone to aborting DS fetuses may simply reflect a shift from the soft to the hard screen. But maybe not.Recent data on oocyte donation[7xSauer, M., Paulson, R., and Lobo, R. J. Am. Med. Assoc. 1992; 268: 1275–1279Crossref | PubMed | Scopus (134)See all References, 8xSauer, M., Paulson, R., and Lobo, R. Hum. Reprod. 1996; 11: 2540–2543Crossref | PubMedSee all References]are indeed intriguing—there seems to be a suggestion that implantation and pregnancy rates are higher in mothers >40 than mothers <40, consistent with the notion of relaxed screening. The sample sizes are as yet too small, however, to be definitive. As for the adaptive value of meiotic errors—avoiding the costs of pregnancy in older mothers when family size is large—I remain profoundly skeptical. Why then do we see an increase in dizygotic twinning in older mothers if avoiding the burden of pregnancy and infant-care is adaptive? The phenomenon of more defective ova in older mothers probably doesn't require a specific adaptive explanation at all. It may simply arise as an epiphenomena of senescence due to pleiotropy, relaxed selection or an increased exposure to biohazards as Williams, Medawar and others have suggested (see review in Ref. [9xSee all References[9]).