Michael W Varner1, Maged M Costantine2, Kathleen A Jablonski3, Dwight J Rouse4, Brian M Mercer5, Kenneth J Leveno6, Uma M Reddy7, Catalin Buhimschi8, Ronald J Wapner9,10, Yoram Sorokin11, John M Thorp12, Susan M Ramin13, Fergal D Malone14, Marshall Carpenter15, Mary J O'sullivan16, Alan M Peaceman17, Donald J Dudley18, Steve N Caritis19. 1. Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah. 2. Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas. 3. Department of Epidemiology and Biostatistics, George Washington University Biostatistics Center, Washington, Disctrict of Columbia. 4. Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama. 5. Department of Obstetrics and Gynecology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio. 6. Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas. 7. Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland. 8. Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio. 9. Department of Obstetrics and Gynecology, Thomas Jefferson University, Philadelphia, Pennsylvania. 10. Department of Obstetrics and Gynecology, Drexel University, Philadelphia, Pennsylvania. 11. Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan. 12. Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 13. Department of Obstetrics and Gynecology, University of Texas Health Science Center at Houston, Houston, Texas. 14. Department of Obstetrics and Gynecology, Columbia University, New York, New York. 15. Department of Obstetrics and Gynecology, Brown University, Providence, Rhode Island. 16. Department of Obstetrics and Gynecology, University of Miami, Miami, Florida. 17. Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois. 18. Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, Texas. 19. Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Abstract
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 × 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 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. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
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 × 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 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. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
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