Sex-specific placental adaptations associated with fetal growth restriction: a review

Fetal growth restriction (FGR) is a major obstetric complication linked to placental insufficiency, increasing the risk of perinatal morbidity, mortality, and long-term health issues. The placenta is central to fetal development and maternal-fetal communication; its dysfunction leads to impaired fetal development. Numerous experimental FGR models exist, from rodents to large animals, but most studies, despite changes to some federal funding requirements, have historically overlooked the impact of fetal sex on placental development, function, and adaptation. Recent evidence indicates that male and female placentas employ distinct adaptive strategies in response to adverse intrauterine conditions, potentially contributing to observed sex differences in neonatal outcomes and adult disease risk. Male fetuses often prioritize growth, reducing resilience to environmental stress, while female fetuses exhibit more pronounced growth restriction but greater placental adaptability, such as altered expression of insulin-like growth factors, angiogenic regulators, and nutrient transporters. This review synthesizes data from human studies and animal models to highlight sex-specific placental adaptations to nutrient restriction, hypoxia, maternal hyperthermia, and other stressors. Understanding these differences is critical for both developing future interventions in humans and enhancing livestock productivity/neonatal survival in agriculture.