Abstract
Gestational hypertension (GH) is prevalent, with life-long health burdens for mothers and their children exposed in utero. We analyzed the nation-wide Epic Cosmos dataset and found significantly higher rates of seizures in children of mothers with GH than in children of normotensive mothers. Complementary studies of nested Iowa and Stanford cohorts and a large Taiwanese cohort also revealed significantly increased seizure risk after covariate adjustments. We modeled this association in an angiotensin (ANG) II mouse model of GH. Maternal ANG II significantly increased seizure grade and deaths elicited by pilocarpine among male but not female offspring. Electrical stimulation increased seizure grade and death across sexes in offspring from ANG II-treated dams. Proinflammatory and microglial gene expression in the brain were upregulated only in male offspring from ANG II-treated dams. Chronic phenylephrine, a GH model lacking the maternal proinflammatory aspects of ANG II, induced similar offspring seizure phenotypes. PLX5622-induced depletion of microglia or antiinflammatory pentoxifylline abolished this sensitized seizure response and lowered mortality in the ANG II model. These results suggest that GH programs offspring risk for seizures in a sex-dependent manner in humans and mice. Neuroinflammatory mechanisms may contribute to the elevated sensitivity and mortality from seizures elicited by GH exposure in utero.