Am J Perinatol 2020; 37(03): 281-290
DOI: 10.1055/s-0039-1678535
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

Michael W. Varner
1  Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah
,
Maged M. Costantine
2  Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas
,
Kathleen A. Jablonski
3  Department of Epidemiology and Biostatistics, George Washington University Biostatistics Center, Washington, Disctrict of Columbia
,
Dwight J. Rouse
4  Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama
,
Brian M. Mercer
5  Department of Obstetrics and Gynecology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio
,
Kenneth J. Leveno
6  Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
,
Uma M. Reddy
7  Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
,
Catalin Buhimschi
8  Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio
,
Ronald J. Wapner
9  Department of Obstetrics and Gynecology, Thomas Jefferson University, Philadelphia, Pennsylvania
10  Department of Obstetrics and Gynecology, Drexel University, Philadelphia, Pennsylvania
,
Yoram Sorokin
11  Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan
,
John M. Thorp
12  Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Susan M. Ramin
13  Department of Obstetrics and Gynecology, University of Texas Health Science Center at Houston, Houston, Texas
,
Fergal D. Malone
14  Department of Obstetrics and Gynecology, Columbia University, New York, New York
,
Marshall Carpenter
15  Department of Obstetrics and Gynecology, Brown University, Providence, Rhode Island
,
Mary J. O'sullivan
16  Department of Obstetrics and Gynecology, University of Miami, Miami, Florida
,
Alan M. Peaceman
17  Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
,
Donald J. Dudley
18  Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, Texas
,
Steve N. Caritis
19  Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, Pennsylvania
,
for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network› Author Affiliations
Funding The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke (HD27869, HD34208, HD34116, HD40544, HD27915, HD34136, HD21414, HD27917, HD27860, HD40560, HD40545, HD40485, HD40500, HD27905, HD27861, HD34122, HD40512, HD53907, HD34210, HD21410, HD36801, HD19897, and MO1-RR-000080). Comments and views of the authors do not necessarily represent the views of the NIH.
Further Information

Publication History

04 November 2018

27 December 2018

Publication Date:
07 February 2019 (online)

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.

Note

This study was presented at the 33th Annual Meeting of the Society for Maternal–Fetal Medicine, San Francisco, CA, February 11–16, 2013.


Authors' Contributions

All authors have made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting and revising the article critically for important intellectual content; and approving of the final version of the article submitted.


* The other members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network are listed in Appendix A.