The gestational foundation of sex differences in development and vulnerability

- Fetal sex confers effects on pregnancy, the intrauterine milieu and early development.
- Prenatal and perinatal adversity affects male fetuses and neonates more negatively.
- Fetal sex has been under-recognized as physiologically consequential for pregnant women.
- Mechanisms by which biological sex imparts vulnerability or protection are largely unknown.

Despite long-standing interest in the role of sex on human development, the functional consequences of fetal sex on early development are not well-understood. Here we explore the gestational origins of sex as a moderator of development. In accordance with the focus of this special issue, we examine evidence for a sex differential in vulnerability to prenatal and perinatal risks. Exposures evaluated include those present in the external environment (e.g., lead, pesticides), those introduced by maternal behaviors (e.g., alcohol, opioid use), and those resulting from an adverse intrauterine environment (e.g., preterm birth). We also provide current knowledge on the degree to which sex differences in fetal neurobehavioral development (i.e., cardiac and motor patterns) are present prior to birth. Also considered are contemporaneous and persistent sex of fetus effects on the pregnant woman. Converging evidence confirms that infant and early childhood developmental outcomes of male fetuses exposed to prenatal and perinatal adversities are more highly impaired than those of female fetuses. In certain circumstances, male fetuses are both more frequently exposed to early adversities and more affected by them when exposed than are female fetuses. The mechanisms through which biological sex imparts vulnerability or protection on the developing nervous system are largely unknown. We consider models that implicate variation in maturation, placental functioning, and the neuroendocrine milieu as potential contributors. Many studies use sex as a control variable, some analyze and report main effects for sex, but those that report interaction terms for sex are scarce. As a result, the true scope of sex differences in vulnerability is unknown.