Genetic polymorphisms and preterm neonatal respiratory distress syndrome among women treated with betamethasone

Antenatal glucocorticoids can reduce the frequency and severity of neonatal lung disease by 60%. Variations in maternal and fetal steroid metabolism may affect modify the efficacy of this crucial intervention. We studied the associations between maternal and fetal single nucleotide gene polymorphisms (SNPs) and the frequency of respiratory distress syndrome (RDS) after antenatal exposure to betamethasone. A prospective cohort of women received betamethasone to accelerate fetal lung maturity for threatened preterm delivery. DNA samples were obtained from mothers and neonates who delivered prior to 34 weeks gestation and clinical variables and neonatal outcomes were obtained. Neonatal RDS was the primary outcome. Seven SNPs in genes associated with steroid metabolism and lung injury (CENPE, NR3C1, ADCY9, CRHR1, CYP3A5*3, 6 and 7) were evaluated. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression analysis controlling for body mass index, gestational age at delivery and fetal sex. Genetic risk score was created to evaluate the combined effect of the significant SNPs. 77 mothers and 77 neonates including 48 whites and 21 blacks were included in this analysis. 59 (76%) neonates developed RDS. In whites, maternal NR3C1 rs41423247 was marginally associated with higher risk for neonatal RDS (OR 4.50, 0.76 – 26.60, p = 0.098). In blacks, maternal SNPs CENPE rs6533058 was associated with higher risk of neonatal RDS (11.9, 1.11-127.3, p = 0.041). The genetic risk score of these two SNPs were associated with higher risk of RDS in whites (3.12, 0.81-12.06, p = 0.099), blacks (13.43, 1.04-173.0, p = 0.046), and in all patients combined (5.06, 1.78-14.1, p=0.002). Specific SNPs affecting steroid metabolism and lung injury related genes suggest an association with neonatal RDS despite antenatal corticosteroid administration. Future work involving maternal betamethasone pharmacokinetic analysis in women with specific SNPs may explain the variation in efficacy of antenatal steroids in reducing neonatal RDS.View Large Image Figure ViewerDownload Hi-res image Download (PPT)