The Unifying Effects of Maternal-Placental-Fetal Axis Dysregulation on Neurodevelopment Following Infectious and Toxic In Utero Insults

Homeostasis during pregnancy and in the in utero environment is essential for prenatal development. Prenatal maturation is hallmarked by an orchestrated and rigorous developmental program characterized by critical cascades in multiple organ systems.  During these critical periods of development, however, potential vulnerability to injury exists throughout pregnancy. Indeed, the developing central nervous system (CNS) is extremely vulnerable to environmental insults throughout the entirety of gestation.  These insults can adversely affect the developing brain and spinal cord, and permanently alter the neurodevelopmental trajectory. Specifically, in utero insults and dysregulation of the maternal-placental-fetal axis can change molecular, cellular, structural, and functional development of the CNS, culminating in adverse outcomes and neurological disorders throughout postnatal life. In this review, we will discuss common infectious and toxin-induced in utero insults that have recently garnered attention, including Zika virus, prenatal opioid and alcohol exposure, and chorioamnionitis.  The goals are to identify common pathophysiological mechanisms, to emphasize the urgent need for new diagnostic tools, and to promote a broader understanding of the diverse array of neurological outcomes presenting in these children throughout their lifespan. With an increasing number of infants exposed to in utero infections and toxins, and the expanding public health awareness of the consequences of Zika infection, the opioid crisis, alcohol consumption during pregnancy, and the frequency of preterm birth in the United States, familiarity with the underlying mechanisms of each of these insults is paramount to improve the diagnosis and treatment for this exceedingly vulnerable patient population.