Reproductive suppression, birth defects, and periviable birth

Abstract

We argue that reproductive suppression has clinical implications beyond its contribution to the burden of spontaneous abortion. We theorize that the incidence of births before the 28th week of gestation, which contribute disproportionately to infant morbidity and mortality, varies over time in part due to reproductive suppression in the form of selection in utero. We further theorize that the prevalence of structural birth defects among survivors to birth from conception cohorts gauges selection in utero. We based these theories on literature positing that natural selection conserved mechanisms that spontaneously abort “risky” pregnancies including those otherwise likely to yield infants with structural birth defects or small‐for‐gestational age males. We test our theory using high‐quality birth defect surveillance data. We identify 479,885 male infants exposed to strong selection defined as membership in conception cohorts ranked in the lowest quartile of odds of a birth defect among live‐born females. We estimate the risk of periviable birth among these infants as a function of selective pressure as well as of mother's race/ethnicity and age. We find that male infants from exposed conception cohorts exhibited 10% lower odds of periviable birth than males from other conception cohorts. Our findings support the argument that selection in utero has implications beyond its contribution to the burden of spontaneous abortion.

Cohort Selection In Utero against Male Twins and Childhood Cancers: A Population-Based Register Study

“…Live births that ultimately are diagnosed with cancer before age 15 may disproportionately occupy this left tail. This work, if replicated, coheres with the “reproductive suppression” ( 39 , 58 ) argument of the conservation of maternal mechanisms that spontaneously abort gestations unlikely to thrive if born. Scholars from a range of disciplines contend that, over much of human history, the subset of childhood cancers arising from chromosomal translocations, mutations in oncogenes and/or mutations in tumor suppressor genes during fetal development would have undergone strong selection in utero ( 11 , 12 , 59 ).…”

“…The autoregressive parameter at t − 12 (0.343, SE = 0.080, P < 0.05) months gauges the known seasonality in fertility in general and in twinning in particular ( 39 , 40 ). Figure 2 shows the fitted (i.e., expected) and observed values of this variable over the test period.…”

“…Our findings align with previous research on cohort variation in selection in utero against other conditions that impose severe morbidity (e.g., birth defects). 21,22,39 However, the mechanism, or set of mechanisms, by which relatively frail fetuses may "signal" their hardiness to the mother remains unknown. Data limitations precluded examination of the relation between other candidate measures of cohort selection and male childhood cancers.…”

“…Our findings align with previous research on cohort variation in selection in utero against other conditions that impose severe morbidity (e.g., birth defects; refs. 21 , 22 , 39 ). However, the mechanism, or set of mechanisms, by which relatively frail fetuses may “signal” their hardiness to the mother remains unknown.…”

Stillbirth as left truncation for early neonatal death in California, 1989–2015: a time-series study

“…The annual resolution of our cohorts, moreover, indicates that we cannot align pregnancies by estimated month of conception to establish clear temporal order between stillbirth and early neonatal death. Our work, rather, complements other research examining the potential role of selection in utero in shaping the survival characteristics of live-born cohorts [ 2 , 11 , 23 , 53 ]. We encourage subsequent analyses of cohorts using larger datasets with sufficient counts of fetal and early neonatal death per month to establish such temporal order between loss in utero and the risk of death among extremely preterm live births.…”