Early life programming of neurodevelopment and growth: understanding nutritional, inflammatory, and placental contributions in complex pregnancies

There is substantial evidence to show that inadequate nutrition in the periconceptional, pre- and post-natal periods can profoundly influence developmental and health trajectories of the embryo, fetus, and infant. However, improved knowledge on how nutritional factors may exacerbate, or lessen, suboptimal fetal and infant outcomes in pregnancies complicated by additional adversities is needed. To help address this knowledge gap, two core projects were undertaken to investigate relationships between perinatal nutritional factors (at the molecular, individual, and household levels), the placenta, and fetal or infant neurodevelopment and growth in: 1. pregnancies carrying a fetus with a neural tube defect (NTD), and 2. pregnancies affected by maternal HIV infection. In the first population, we show for the first time that fetal NTDs associate with placental maldevelopment and dysfunction, evidenced by an increased risk of placental pathologies and dysregulation in fundamental placental gene networks, including nutrient transport. Several dysregulated placental gene networks in fetuses with NTDs were sensitive to multiple nutrients, emphasizing the need for research to expand beyond a folic acid-centric view to identify new targets for NTD prevention and improve outcomes in fetuses with NTDs. In the second population, we found that infants who were exposed to maternal HIV infection and antiretroviral therapies in early life are susceptible to the adverse effects of suboptimal nutritional exposures both pre- and postnatally, evidenced by poorer growth outcomes in infants exposed to HIV and household food insecurity. We also found that there is potential for early life nutritional factors to be leveraged to improve outcomes in these infants. An integrated understanding of how nutritional exposures at the molecular, individual, and household/community levels contribute to fetal and infant programming in children exposed to suboptimal prenatal environments is key for developing interventions to improve developmental trajectories and lifecycle health globally.