title: Prenatal or postnatal indomethacin exposure and neonatal gut injury associated with isolated intestinal perforation and necrotizing enterocolitis.
abstract: OBJECTIVE
  To examine the role of indomethacin in neonatal gut injury.
  
  
  METHODS
  Infants born at gestational age 23 weeks and with birth weights 400-1200 g were included in this prospective prevalence study of neonatal gut injury. Infants with isolated intestinal perforation (IIP) confirmed at laparotomy or at autopsy or with necrotizing enterocolitis (NEC) were identified. Data were abstracted bi-weekly.
  
  
  RESULTS
  Among 992 study infants, 58 infants exposed solely to prenatal indomethacin did not show an increased rate of neonatal gut injury. Any postnatal indomethacin exposure (n=611) increased the odds of IIP (OR 4.17, CI, 1.24-14.08, P=0.02) but decreased the odds of NEC (OR 0.65, CI 0.43-0.97, P=0.04). There was a negative association between the timing of indomethacin-exposure and the odds of developing IIP (OR 0.30, CI 0.11-0.83, P=0.02). Compared with NEC, IIP occurred at an earlier age (P<0.05) and was more common (P<0.05) among infants who received early indomethacin (first dose at <12 h of age) to prevent intraventricular hemorrhage than among infants who were treated with late indomethacin for closure of a patent ductus arteriosus (PDA). Unlike the classic hemorrhagic ischemic lesions of NEC in which large areas of tissue were inflamed or necrotic, the IIP lesions were small and discrete.
  
  
  CONCLUSIONS
  Early (<12 h) postnatal indomethacin exposure was associated with an increased odds of IIP in very low birth weight infants whereas its later use for closure of a PDA appeared to provide protection against NEC. The paradoxical effect of the timing of indomethacin on IIP versus on NEC may be related to the different pathogeneses of the two diseases. Our findings also suggest that PDA may contribute to NEC.
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Florida College of Medicine at Jacksonville, 655 West 8th Street, Jacksonville, FL 32209-6511, USA. renu.sharma@jax.ufl.edu
authors.forename: R
authors.initials: R
authors.lastname: Sharma
authors.forename: M L
authors.initials: ML
authors.lastname: Hudak
authors.forename: J J
authors.initials: JJ
authors.lastname: Tepas
authors.forename: P S
authors.initials: PS
authors.lastname: Wludyka
authors.forename: R-J
authors.initials: RJ
authors.lastname: Teng
authors.forename: L K
authors.initials: LK
authors.lastname: Hastings
authors.forename: W H
authors.initials: WH
authors.lastname: Renfro
authors.forename: W J
authors.initials: WJ
authors.lastname: Marvin
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D002543:Cerebral Hemorrhage / Q000517:prevention & control; D002552:Cerebral Ventricles; D004334:Drug Administration Schedule; D004374:Ductus Arteriosus, Patent / Q000188:drug therapy; D020345:Enterocolitis, Necrotizing / Q000139:chemically induced*; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000009:adverse effects*; D052577:Infant, Extremely Low Birth Weight; D007231:Infant, Newborn; D019102:Infant, Very Low Birth Weight; D007363:Intensive Care Units, Neonatal; D007416:Intestinal Perforation / Q000139:chemically induced*; D008297:Male; D008895:Milk, Human; D016017:Odds Ratio; D011247:Pregnancy; D011295:Prenatal Care; D012307:Risk Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007213:Indomethacin