The gestational foundation of sex differences in development and vulnerability

Abstract

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.

Keywords: fetal development; male vulnerability; perinatal risk; pregnancy; prenatal exposures; sex differences.

Figure 1

Conceptual model of fetal neurobehavioral development within the maternal context (DiPietro et al, 2015.

Figure 2

Fetal heart rate by fetal sex. Female fetuses had significantly faster heart rates at the second and third gestational periods and Lowess curve estimates depict significantly greater decline in fetal heart rate from the second to third periods in male fetuses. Scatter points represent data from individual fetuses at each gestational age and illustrate inter-individual variation and distributional overlap between sexes.

Figure 3

Fetal heart rate variability by fetal sex. Male fetuses had significantly greater variability in fetal heart rate at the second and third gestational periods and Lowess curve estimates depict a steeper developmental trajectory between the first and second periods in male fetuses. Scatter points represent data from individual fetuses at each gestational age and illustrate inter-individual variation and distributional overlap between sexes.

Figure 4

Schematic representation of early sex differences, distributed over gestation. Depicted are the most well-supported and documented sex differences in pregnant women, fetuses and neonates. Although some differences may not be expressed until later in development, such as heightened vulnerability of the male central nervous system to environmental exposures or preterm birth, their origins are in the prenatal or perinatal period. Placement within columns is somewhat arbitrary as a number of these observations affect both the mother and fetus, or span the prenatal and perinatal domains, depending on when either the exposure or delivery occurs. Maternal microchimerism (first column) typically refers to that observed as the result of vestiges of the Y chromosome, its implications for long term maternal well-being remains uncertain. Variation in fetal neurobehavioral indicators (second column) has primarily been observed in the 3^rd trimester. Morbidity and mortality (final column) spans the gestational age and birth weight continuum.