Let's Talk about Placental Sex, Baby: Understanding Mechanisms That Drive Female- and Male-Specific Fetal Growth and Developmental Outcomes.

Ashley S Meakin,Janna L Morrison,Jack R T Darby,James S M Cuffe,Vicki L Clifton

doi:10.3390/ijms22126386

Abstract

It is well understood that sex differences exist between females and males even before they are born. These sex-dependent differences may contribute to altered growth and developmental outcomes for the fetus. Based on our initial observations in the human placenta, we hypothesised that the male prioritises growth pathways in order to maximise growth through to adulthood, thereby ensuring the greatest chance of reproductive success. However, this male-specific “evolutionary advantage” likely contributes to males being less adaptable to shifts in the in-utero environment, which then places them at a greater risk for intrauterine morbidities or mortality. Comparatively, females are more adaptable to changes in the in-utero environment at the cost of growth, which may reduce their risk of poor perinatal outcomes. The mechanisms that drive these sex-specific adaptations to a change in the in-utero environment remain unclear, but an increasing body of evidence within the field of developmental biology would suggest that alterations to placental function, as well as the feto-placental hormonal milieu, is an important contributing factor. Herein, we have addressed the current knowledge regarding sex-specific intrauterine growth differences and have examined how certain pregnancy complications may alter these female- and male-specific adaptations.

Highlights

Evidence of sex-specific intrauterine growth rates and outcomes have been observed throughout gestation with males, on average, having accelerated growth rates and increased growth outcomes relative to females [1,2,3,4,5,6,7,8,9,10,11,12,13]
In the presence of a maternal complication, the increased adaptability of a female feto-placental unit may reduce intrauterine morbidity and mortality rates when compared to males exposed to a comparable in utero environment
The mechanisms by which these sex differences in feto-placental function are regulated may, in part, be due to alterations in the unit’s responsivity to specific hormones: in general, females appear to increase glucocorticoid sensitivity, whereas males favour signalling pathways mediated by androgens (Figure 3)

Summary

Introduction

Evidence of sex-specific intrauterine growth rates and outcomes have been observed throughout gestation with males, on average, having accelerated growth rates and increased growth outcomes relative to females [1,2,3,4,5,6,7,8,9,10,11,12,13]. The work of Dr Clarke noted an increase in the rates of mortality of male fetuses and neonates, an observation that has since been consistently reported in several human pregnancy cohorts. Our group and others have reported sex-specific rates in small for gestational age (SGA), preterm delivery, and additional intrauterine and neonatal morbidities and mortality in the presence of pregnancy complications—including maternal asthma, preeclampsia (PE), and gestational diabetes mellitus (GDM)—whereby males are at a greater risk of adverse outcomes [16,17,18,19,20,21]. The mechanisms that drive these sex-specific risks remain largely unknown, but alterations to physiological processes that are both dependent and independent on placental function and structure are thought to be critical, determining factors

From Blastocyst to Neonate

Findings

Conclusions