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Sex-Specific Genetic Susceptibility to Adverse Neurodevelopmental Outcome in Offspring of Pregnancies at Risk of Early Preterm Delivery


Varner, Michael W.; Costantine, Maged M.; Jablonski, Kathleen A.; Rouse, Dwight J.; Mercer, Brian M.; Leveno, Kenneth J.; Reddy, Uma M.; Buhimschi, Catalin S.; Wapner, Ronald J.; & Sorokin, Yoram, et al. (2020). Sex-Specific Genetic Susceptibility to Adverse Neurodevelopmental Outcome in Offspring of Pregnancies at Risk of Early Preterm Delivery. American Journal of Perinatology, 37(3), 281-290. PMCID: PMC6685763


OBJECTIVE: To evaluate sex-specific genetic susceptibility to adverse neurodevelopmental outcome (ANO, defined as cerebral palsy [CP], mental, or psychomotor delay) at risk for early preterm birth (EPTB, < 32 weeks).
STUDY DESIGN: Secondary case-control analysis of a trial of magnesium sulfate (MgSO4) before anticipated EPTB for CP prevention. Cases are infants who died by the age of 1 year or developed ANO. Controls, matched by maternal race and infant sex, were neurodevelopmentally normal survivors. Neonatal DNA was evaluated for 80 polymorphisms in inflammation, coagulation, vasoregulation, excitotoxicity, and oxidative stress pathways using Taqman assays. The primary outcome for this analysis was sex-specific ANO susceptibility. Conditional logistic regression estimated each polymorphism's odds ratio (OR) by sex stratum, adjusting for gestational age, maternal education, and MgSO4-corticosteroid exposures. Holm-Bonferroni corrections, adjusting for multiple comparisons (p < 7.3 x 10(-4)), accounted for linkage disequilibrium between markers.
RESULTS: Analysis included 211 cases (134 males; 77 females) and 213 controls (130 males; 83 females). An interleukin-6 (IL6) polymorphism (rs2069840) was associated with ANO in females (OR: 2.6, 95% confidence interval [CI]: 1.5-4.7; p = 0.001), but not in males (OR: 0.8, 95% CI: 0.5-1.2; p = 0.33). The sex-specific effect difference was significant (p = 7.0 x 10(-4)) and was unaffected by MgSO4 exposure. No other gene-sex associations were significant.
CONCLUSION: An IL6 gene locus may confer susceptibility to ANO in females, but not males, after EPTB.


Reference Type

Journal Article

Article Type


Year Published


Journal Title

American Journal of Perinatology


Varner, Michael W.
Costantine, Maged M.
Jablonski, Kathleen A.
Rouse, Dwight J.
Mercer, Brian M.
Leveno, Kenneth J.
Reddy, Uma M.
Buhimschi, Catalin S.
Wapner, Ronald J.
Sorokin, Yoram
Thorp, John M., Jr.
Ramin, Susan M.
Malone, Fergal D.
Carpenter, Marshall W.
O'Sullivan, Mary Jo
Peaceman, Alan M.
Dudley, Donald J.
Caritis, Steve N., for the
Eunice Kennedy Shriver
National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network




United States of America