Long-term impact of intrauterine neuroinflammation and treatment with magnesium sulphate and betamethasone: Sex-specific differences in a preterm labor murine model

Abstract

Preterm infants are at significantly increased risk for lifelong neurodevelopmental disability with male offspring disproportionately affected. Corticosteroids (such as betamethasone) and magnesium sulphate (MgSO4) are administered to women in preterm labor to reduce neurologic morbidity. Despite widespread use of MgSO4 in clinical practice, its effects on adult offspring are not well known nor have sex-specific differences in therapeutic response been explored. The objective of our study was to examine the long-term effects of perinatal neuroinflammation and the effectiveness of prenatal MgSO4/betamethasone treatments between males and females in a murine model via histologic and expression analyses. Our results demonstrate that male but not female offspring exposed to intrauterine inflammation demonstrated impaired performance in neurodevelopmental testing in early life assessed via negative geotaxis, while those exposed to injury plus treatment fared better. Histologic analysis of adult male brains identified a significant reduction in hippocampal neural density in the injured group compared to controls. Evaluation of key neural markers via qRT-PCR demonstrated more profound differences in gene expression in adult males exposed to injury and treatment compared to female offspring, which largely showed resistance to injury. Prenatal treatment with MgSO4/betamethasone confers long-term benefits beyond cerebral palsy prevention with sex-specific differences in response.