Neurodevelopmental Outcomes of Prenatal Preeclampsia Exposure

Abstract

Preeclampsia is a dangerous hypertensive disorder of pregnancy with known links to negative child health outcomes. Here, we review epidemiological and basic neuroscience work from the past several decades linking prenatal preeclampsia to altered neurodevelopment. This work demonstrates increased rates of neuropsychiatric disorders [e.g., increased autism spectrum disorder, attention deficit hyperactivity disorder (ADHD)] in children of preeclamptic pregnancies, as well as increased rates of cognitive impairments [e.g., decreased intelligence quotient (IQ), academic performance] and neurological disease (e.g., stroke and epilepsy). We also review findings from multiple animal models of preeclampsia. Manipulation of key clinical preeclampsia processes in these models (e.g., placental hypoxia, immune dysfunction, angiogenesis, oxidative stress) causes various disruptions in offspring, including ones in white matter/glia, glucocorticoid receptors, neuroimmune outcomes, cerebrovascular structure, and cognition/behavior. This animal work implicates potentially high-yield targets that may be leveraged in the future for clinical application.

Keywords: animal models; neurodevelopment; preeclampsia; prenatal risk.

Figure 1.. Interactions of Preeclampsia Mechanisms with Maternal and Placental Physiology and Implications for Key Neurodevelopmental Processes.

Gestational disruptions (including immune, cardiovascular, renal, and metabolic) across all three trimesters influence placental processes (placentation, immune tolerance, nutrient and oxygen transfer, endothelial remodeling, and growth), which may also alter neurodevelopmental processes that proceed in turn (neurulation and neurogenesis followed by neuronal migration, differentiation, and neurite outgrown, and finally gliogenesis, synaptogenesis, and myelination). The interactions between pregnancy physiology, placental processes, and neurodevelopment are likely impacted at all levels by preeclampsia mechanisms of disruption (inflammation, oxidative stress, hypoxia, abnormal growth, and angiogenic factor levels). These disruptions may be modeled preclinically, for example, in the placental growth factor (PlGF) knockout, reduced uterine perfusion pressure, and arginine vasopressin infusion mouse models, which model preeclamptic angiogenic dysfunction, placental ischemia, and immunovascular dysfunction, respectively. Each of these preclinical models has impacts on the placenta and offspring neurodevelopment (e.g., impaired angiogenesis and cerebrovascular disruptions, respectively, in the PlGF knockout). Abbreviation: HIF-1α, hypoxia-inducible factor 1α.