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

Michael W. Varner*, Maged M. Costantine, Kathleen A. Jablonski, Dwight J. Rouse, Brian M. Mercer, Kenneth J. Leveno, Uma M. Reddy, Catalin Buhimschi, Ronald J. Wapner, Yoram Sorokin, John M. Thorp, Susan M. Ramin, Fergal D. Malone, Marshall Carpenter, Mary J. O'Sullivan, Alan M. Peaceman, Donald J. Dudley, Steve N. Caritis

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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 (MgSO 4) 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 MgSO 4 -corticosteroid exposures. Holm-Bonferroni corrections, adjusting for multiple comparisons (p < 7.3 × 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 × 10 -4) and was unaffected by MgSO 4 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.

Original languageEnglish (US)
Pages (from-to)281-290
Number of pages10
JournalAmerican journal of perinatology
Issue number3
StatePublished - Feb 1 2020


  • genetic
  • interleukin-6
  • neurodevelopmental delay
  • polymorphisms
  • preterm birth
  • sex
  • single-nucleotide polymorphisms

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Pediatrics, Perinatology, and Child Health


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