Review: Sex and the Human Placenta: Mediating Differential Strategies of Fetal Growth and Survival

Abstract

There are known sex specific differences in fetal and neonatal morbidity and mortality. There are also known differences in birthweight centile with males generally being larger than females at birth. These differences are generally ignored when studying obstetric complications of pregnancy and the mechanisms that confer these differences between the sexes are unknown. Current evidence suggests sex specific adaptation of the placenta may be central to the differences in fetal growth and survival. Our research examining pregnancies complicated by asthma has reported sexually dimorphic differences in fetal growth and survival with males adapting placental function to allow for continued growth in an adverse maternal environment while females reduce growth in an attempt to survive further maternal insults. We have reported sex differences in placental cytokine expression, insulin-like growth factor pathways and the placental response to cortisol in relation to the complication of asthma during pregnancy. More recently we have identified sex specific alterations in placental function in pregnancies complicated by preterm delivery which were associated with neonatal outcome and survival. We propose the sexually dimorphic differences in growth and survival of the fetus are mediated by the sex specific function of the human placenta. This review will present evidence supporting this hypothesis and will argue that to ignore the sex of the placenta is no longer sound scientific practice.

Introduction

There are known sex specific differences in fetal growth and fetal and neonatal morbidity and mortality [1], [2], [3]. The earliest known English report of sex specific differences in fetal and neonatal outcomes was given by Josef Clarke in 1786 [4]. Dr Clarke examined birth outcomes at the Lying-in Hospital in Dublin from 1757 to 1784 recording the outcomes of more than 20,000 deliveries [4]. He observed greater mortality of males than females in both the number of stillbirths and neonatal deaths. The birthweight range of males and females was also different in that males were generally larger than females and females were more likely to be growth reduced. He also reported that the sex ratio was different in that more males were delivered than females rather than an expected 1:1 ratio [4]. These findings have been reported consistently in the literature to the present day [1], [2], [5], [6]. Even so, we still consider the fetus to be asexual in its response to a pathological condition of pregnancy. If that were the case, however, then males would not be 20% more likely to experience a poorer outcome in pregnancies complicated by pre-eclampsia, preterm delivery and intrauterine growth restriction (IUGR) [1]. To extend this concept further, the placenta, an important part of the fetus, which plays a central role in mediating growth and development, is also viewed as an asexual organ with most placental studies consistently pooling data derived from male and female placentae into one group. Sex differences in fetal growth are likely to be mediated by sex specific placental function. It is likely that not all mechanistic adjustments to a pathophysiology of pregnancy are sex specifically different [7] but in studying the placenta it is essential to at least consider the possibility that there may be a sex difference and to design experiments accordingly.