Genetic Predisposition To Brain Injury After Preterm Birth May Be Sex-Specific

Main Category: Pregnancy / Obstetrics
Also Included In: Neurology / Neuroscience;  Men's Health;  Genetics
Article Date: 13 Feb 2013 - 1:00 PST


In a study to be presented on February 14 between 1:15 p.m., and 3:30 p.m. PST, at the Society for Maternal-Fetal Medicine's annual meeting, The Pregnancy Meeting ™, in San Francisco, researchers will report that variation in a gene involved in inflammation is associated with developmental problems after preterm birth in females, but not males.

This randomized study, Sex-specific genetic susceptibility to adverse neurodevelopmental outcome after early preterm birth, may improve understanding of how developmental problems occur after preterm birth and may help identify prevention strategies.

"Preterm birth is the leading cause of childhood brain injury," said the study's author, Erin Clark, MD. "Compared to preterm girls, preterm boys are more likely to die, and survivors are more likely to have long-term problems, including disability and cerebral palsy. We don't understand why preterm boys are at a disadvantage compared to girls."

Through her study, Clark, assistant professor of Maternal-Fetal Medicine at the University of Utah School of Medicine, determined whether genetic variants influence the risk of developmental problems after a preterm birth, and whether there is a difference in risk factors between males and females.

Clark evaluated patients previously enrolled in a randomized trial of magnesium sulfate before preterm birth for prevention of cerebral palsy. She evaluated children that died before their first birthday, or developed cerebral palsy or other developmental problems by age 2 years, and compared them to healthy children.

The research shows a variant in the inflammation gene, interleukin 6, was associated with developmental problems in females but not in males. Treatment with magnesium sulfate before birth didn't appear to change this risk.

"These results add to the evidence that inflammation genes play a role in risk of brain injury in preterm children. In addition, they suggest that genetic risk factors for brain injury after early delivery may be different in boys and girls," said Clark. "However, the effect of genes and gender on outcomes after preterm birth remains poorly understood. Additional research is necessary in order to better understand the differences in outcomes between males and females born preterm."

Abstract 21: Sex-specific genetic susceptibility to adverse neurodevelopmental outcome after early preterm birth

OBJECTIVE: In-vivo and in-vitro data suggest neurobiological differences between male and female susceptibility and response to brain injury. We aimed to determine if sex-specific genetic susceptibility loci are associated with adverse neurodevelopmental outcome after early preterm birth.

STUDY DESIGN: Secondary case-control analysis of a randomized trial of magnesium sulfate (MgSO4) before anticipated early preterm birth (<32 weeks) for prevention of cerebral palsy (CP). Cases died by age 1 year or developed CP, mental or psychomotor delay (defined as Bayley MDI or PDI<70) by age 2. Controls were survivors with normal neurodevelopment. Neonatal DNA was evaluated for 80 polymorphisms (33 genes) in inflammation, coagulation, vasoregulation, excitotoxicity and oxidative stress pathways using Taqman assays. Cases and controls were matched by maternal race and infant sex. Conditional logistic regression determined the odds ratio for each polymorphism (additive model) by sex stratum and adjusted for gestational age at birth, maternal education level, and exposure to MgSO4 and antenatal corticosteroids. An interaction term between infant sex and genotype tested heterogeneity across strata. Holm-Bonferroni method was used to adjust for multiple comparisons (p<7.3x10-4).

RESULTS: Analysis included 211 cases (134 males and 77 females) and 215 controls (130 males and 83 females). A polymorphism in the inflammatory cytokine interleukin-6 (IL6) gene (rs2069840) was associated with adverse neurodevelopmental outcome in females (OR 2.6, 95% CI 1.5-4.7; p0.001), but not in males (OR 0.8, 95% CI 0.5-1.2; p0.33). The effect difference between males and females was significant (p7.0x10-4). MgSO4 exposure did not modify this association. The remaining gene-sex associations were not significant after correction for multiple comparisons.

CONCLUSION: An IL6 gene locus may confer sex-specific susceptibility to adverse neurodevelopmental outcome in females after early preterm birth.

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