The Risk of Necrotizing Enterocolitis After Indomethacin Tocolysis

Abstract

Tocolytic agents such as indomethacin are commonly used to prevent preterm delivery despite little evidence of proven benefit. Administration of postnatal indomethacin in preterm infants seems to be associated with an increased incidence of necrotizing enterocolitis (NEC). It has been hypothesized that antenatal indomethacin (AI), which readily crosses the placenta, may also increase the risk for NEC in preterm infants. This historical cohort study was designed to investigate the association between AI and NEC in preterm infants. The cohort included preterm infants at 23 to 32 weeks' gestational age without major congenital anomalies who had been admitted to a hospital NICU (neonatal intensive care unit) between 2004 and 2006. The investigators reviewed and abstracted maternal and neonatal data in medical records for preterm infants. Bivariate analyses, multivariate logistic regression, and propensity score analysis were used to determine the association between AI exposure within 15 days before delivery (predictor variable) and NEC (with NEC defined as modified Bell's stage 2a or higher) in the first 15 days of life (early NEC)—the primary outcome variable. Of the 628 infants who met inclusion criteria, 63 received AI and 28 developed early NEC. Exposure of mothers to AI was significantly associated with multiple gestation, white race, antenatal corticosteroids, and magnesium sulfate. In neonates, AI exposure was associated with lower birth weight and gestational age, a need for an umbilical arterial catheter, respiratory distress syndrome, postnatal vasopressors and antibiotics, patent ductus arteriosus, sepsis, NEC, intraventricular hemorrhage, and mortality. Multivariate logistic regression showed an association between AI exposure and the development of early NEC; the adjusted odds ratio was 7.193, with a 95% confidence interval of 2.514–20.575 (which represents a number needed to harm of 5). The association of AI and early NEC remained significant when multivariate logistic regression was repeated using AI exposure within 5 days before delivery as the predictor variable, when analyses were stratified according to gestational age, and on propensity score analysis. These findings show that multiple clinical factors, including AI, are associated with NEC in preterm infants in the first 15 days of life. Exposure to AI in preterm infants in the first 15 days of life may contribute to the morbidity and mortality of NEC.