Sex-Dependent Immune Dysregulation and Neurodevelopmental Risk in Maternal Substance Use

Introduction/Rationale: Maternal substance use (SU) in pregnancy is associated with adverse neurodevelopmental outcomes in offspring, with males at heightened risk. We investigated how maternal SU impacts maternal and fetal immune responses, and how these alterations may contribute to increased neurodevelopmental risk.

Methods: Maternal and cord plasma and PBMCs were collected from 68 pregnancies, including 17 SU cases and 51 uncomplicated controls matched for gestational age, maternal BMI, and fetal sex. T cell phenotypes and cytokine production were characterized by flow cytometry. Monocyte function and plasma cytokine and chemokine levels were evaluated. Personalized fetal models of brain immune development were created using microglia-like cells derived from placental macrophages from the same pregnancies, and synaptosome phagocytosis by induced microglia was quantified as a proxy for synaptic pruning behavior.

Results: Sexually dimorphic alterations in maternal CD4⁺ T cell frequency were noted in SU, decreased in male pregnancies and increased in female pregnancies compared to sex-matched controls, and cord plasma IL-1β and IFN-γ were significantly reduced in males. Significant impairment in cord blood monocyte function was noted in female SU-exposed pregnancies only. Placenta-derived microglia-like fetal cellular models exhibited decreased synaptosome phagocytosis in males and increased in females.

Conclusion: Our findings suggest that sex differences in maternal-fetal immune activation in the setting of maternal SU correlate with sex-specific vulnerability to adverse neurodevelopmental outcomes.