Published online June 1, 2006
PEDIATRICS Vol. 117 No. 6 June 2006, pp. 1901-1906 (doi:10.1542/10.1542/peds.2005-1414)
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Familial and Genetic Susceptibility to Major Neonatal Morbidities in Preterm Twins

Vineet Bhandari, MD, DMa, Matthew J. Bizzarro, MDa, Anupama Shetty, MDa, Xiaoyun Zhong, PhDb, Grier P. Page, PhDc, Heping Zhang, PhDb, Laura R. Ment, MDa, Jeffrey R. Gruen, MDa for the Neonatal Genetics Study Group

a Departments of Pediatrics
b Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut
c Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama

BACKGROUND. Intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia remain significant causes of morbidity and mortality in preterm newborns.

OBJECTIVES. Our goal was to assess the familial and genetic susceptibility to intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia.

METHODS. Mixed-effects logistic-regression and latent variable probit model analysis were used to assess the contribution of several covariates in a multicenter retrospective study of 450 twin pairs born at ≤32 weeks of gestation. To determine the genetic contribution, concordance rates in a subset of 252 monozygotic and dizygotic twin pairs were compared.

RESULTS. The study population had a mean gestational age of 29 weeks and birth weight of 1286 g. After controlling for effects of covariates, the twin data showed that 41.3%, 51.9%, and 65.2%, respectively, of the variances in liability for intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia could be accounted for by genetic and shared environmental factors. Among the 63 monozygotic twin pairs, the observed concordance for bronchopulmonary dysplasia was significantly higher than the expected concordance; 12 of 18 monozygotic twin pairs with ≥1 affected member had both members affected versus 3.69 expected. After controlling for covariates, genetic factors accounted for 53% of the variance in liability for bronchopulmonary dysplasia.

CONCLUSIONS. Twin analyses show that intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia are familial in origin. These data demonstrate, for the first time, the significant genetic susceptibility for bronchopulmonary dysplasia in preterm infants.

Key Words: premature newborn • intraventricular hemorrhage • necrotizing enterocolitis • bronchopulmonary dysplasia • logistic regression • zygosity

Abbreviations: IVH—intraventricular hemorrhage • NEC—necrotizing enterocolitis • BPD—bronchopulmonary dysplasia • BW—birth weight • GA—gestational age • RDS—respiratory distress syndrome • INST—treating institution • OR—odds ratio • CI—confidence interval • TNF—tumor necrosis factor • IL—interleukin

Accepted Nov 7, 2005.


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