Sex differences in innate and adaptive immunity impact fetal, placental, and maternal health†

Abstract

The differences between males and females begin shortly after birth, continue throughout prenatal development, and eventually extend into childhood and adult life. Male embryos and fetuses prioritize proliferation and growth, often at the expense of the fetoplacental energy reserves. This singular focus on growth over adaptability leaves male fetuses and neonates vulnerable to adverse outcomes during pregnancy and birth and can have lasting impacts throughout life. Beyond this prioritization of growth, male placentas and fetuses also respond to infection and inflammation differently than female counterparts. Pregnancies carrying female fetuses have a more regulatory immune response, whereas pregnancies carrying male fetuses have a stronger inflammatory response. These differences can be seen as early as the innate immune response with differences in cytokine and chemokine signaling. The sexual dimorphism in immunity then continues into the adaptive immune response with differences in T-cell biology and antibody production and transfer. As it appears that these sex-specific differences are amplified in pathologic pregnancies, it stands to reason that differences in the placental, fetal, and maternal immune responses in pregnancy contribute to increased male perinatal morbidity and mortality. In this review, we will describe the genetic and hormonal contributions to the sexual dimorphism of fetal and placental immunity. We will also discuss current research efforts to describe the sex-specific differences of the maternal–fetal interface and how it impacts fetal and maternal health.