title: Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis.
abstract: OBJECTIVE
  The purpose of this study was to provide an updated summary of the literature regarding the effects of tocolysis with indomethacin on neonatal outcome by systematically reviewing previously and recently reported data.
  
  
  METHODS
  All previously reported studies pertaining to indomethacin tocolysis and neonatal outcomes along with recently reported data were identified with the use of electronic databases that had been supplemented with references that were cited in original studies and review articles. Observational studies that compared neonatal outcomes among preterm infants who were exposed and not exposed to indomethacin were included in this systematic review. Data were extracted and quantitative analyses were performed on those studies that assessed the neonatal outcomes of patients that received antenatal tocolysis with indomethacin.
  
  
  RESULTS
  Twenty-seven observational studies that met criteria for systematic review and metaanalysis were identified. These studies included 8454 infants, of whom 1731 were exposed to antenatal indomethacin and 6723 were not exposed. Relative risks with 95% confidence intervals were calculated for dichotomous outcomes with the use of random and fixed-effects models. Metaanalysis revealed no statistically significant differences in the rates of respiratory distress syndrome, patent ductus arteriosus, neonatal mortality rate, neonatal sepsis, bronchopulmonary dysplasia, or intraventricular hemorrhage (all grades). However, antenatal exposure to indomethacin was associated with an increased risk of severe intraventricular hemorrhage (grade III-IV based on Papile's criteria; relative risk, 1.29; 95% confidence interval, 1.06-1.56), necrotizing enterocolitis (relative risk, 1.36; 95% confidence interval, 1.08-1.71), and periventricular leukomalacia (relative risk, 1.59; 95% confidence interval, 1.17-2.17).
  
  
  CONCLUSIONS
  The use of indomethacin as a tocolytic agent for preterm labor is associated with an increased risk for severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia.
authors.affiliation: Department of Obstetrics and Gynecology, University of Florida College of Medicine-Jacksonville, Jacksonville, FL. Electronic address: amy.hammers@jax.ufl.edu.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Hammers
authors.affiliation: Department of Obstetrics and Gynecology, University of Florida College of Medicine-Jacksonville, Jacksonville, FL.
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Ramos
authors.affiliation: Department of Obstetrics and Gynecology, University of Florida College of Medicine-Jacksonville, Jacksonville, FL.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Kaunitz
mesh_terms: D002552:Cerebral Ventricles; D020345:Enterocolitis, Necrotizing / Q000139:chemically induced*; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000009:adverse effects*; D007231:Infant, Newborn; D007234:Infant, Premature; D020300:Intracranial Hemorrhages / Q000139:chemically induced*; D007969:Leukomalacia, Periventricular / Q000139:chemically induced*; D015233:Models, Statistical; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D015149:Tocolytic Agents / Q000009:adverse effects*
chemical_list: D015149:Tocolytic Agents; D007213:Indomethacin
keywords: intraventricular hemorrhage; necrotizing enterocolitis; periventricular leukomalacia