Abstract
Objective:
To examine the role of indomethacin in neonatal gut injury.
Study Design:
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.
Result:
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.
Conclusion:
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lin PW, Nasr TR, Stoll BJ . Necrotizing enterocolitis: recent scientific advances in pathophysiology and prevention. Semin Perinatol 2008; 32: 70–82.
Sharma R, Tepas III JJ, Mollitt DL, Pieper P, Wludyka P . Surgical management of bowel perforation and outcome in very low birth weight infants. J Pediatr Surg 2004; 39: 190–194.
Abbasi S, Jeffrey S, Gerdes JS, Sehdev HM, Samimi SS, Ludmir J . Neonatal outcome after exposure to indomethacin in utero: a retrospective case cohort study. A J Obstet Gynecol 2003; 189: 782–785.
Amin BS, Sinkin R, Glantz JC . Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes. Am J Obstet Gynecol 2007; 486: e1–e10.
Feigin MD, Delpino ML, Bidiwala KS . Isolated small bowel perforation following intrauterine treatment with indomethacin. Am J Perinatol 1994; 11: 295–296.
Fujii AM, Brown E, Microchnick M, O'Brien S, Kaufman G . Neonatal necrotizing enterocolitis with intestinal perforation in extremely premature infants receiving early indomethacin treatment for patent ductus arteriosus. J Perinatol 2002; 22: 545–550.
Madan J, Fiascone J, Balasubramanian V, Griffith J, Hagadorn JI . Predictors of ductal closure and intestinal complications in very low birth weight infants treated with indomethacin. Neonatology 2008; 94: 45–51.
Macones GA, Marder SJ, Clothier B, Stamilio DM . The controversy surrounding indomethacin for tocolysis. Am J Obstet Gynecol 2001; 184: 264–272.
Ment LR, Oh W, Ehrenkranz RA, Philip AG, Vohr B, Allan W et al. Low-dose indomehtacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics 1994; 93: 543–550.
Bada HS, Green RS, Pourcyrous M, Leffler CW, Korones SB, Maqill HL et al. Indomethacin reduces the risks of severe intraventricular hemorrhage. J Pediatr 1989; 115: 631–637.
Shorter NA, Liu JY, Mooney DP, Harmon BJ . Indomethacin-associated bowel perforations: a study of possible risk factors. J Pedaitr Surg 1999; 34: 442–444.
Kawase Y, Ishii T, Arai H, Uga N . Gastrointestinal perforation in very low-birth weight infants. Pediatr Int 2006; 48: 599–603.
Attridge JT, Clark R, Walker MW, Gordon PV . New insights into intestinal perforation using a national data set: (1) SIP is associated with early indomethacin-exposure. J perinatol 2006; 26: 93–99.
Grosfeld JL, Chaet M, Molinari F, Engle W, Engum SA, West KW et al. Increased risk of necrotizing enterocolitis in premature infants with patent ductus arteriosus treated with indomethacin. Ann Surg 1996; 224: 350–357.
Bell MJ, Ternberg JL, Feign RD, Keating JP, Marshall R, Barton L et al. Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging. Ann Surg 1978; 187: 1–7.
Halliday HL, Ehrenkranz RA, Doyle LW . Early (<8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2010 (1). Art. No. CD001146.
SAS Institute Inc.. World Headquarters, version 9. SAS Institute Inc: Cary, NC 27513.
Morales W, Madhav H . Efficacy of indomethacin compared with magnesium sulfate in the management of preterm labor: randomized study. Am J Obstet Gynecol 1993; 169: 97–102.
Kurki T, Enronen M, Lumme R, Ylikorkala O . A randomized double-dummy comparison between indomethacin and nylidrin in threatened preterm labor. Obstet Gynecol 1991; 78: 1093–1097.
Vermillion ST, Newman RB . Recent indomethacin tocolysis is not associated with neonatal complications in preterm infants. Am J Obstet Gynecol 1999; 181: 1083–1086.
Parilla BV, Grobman WA, Holtzman RB, Thomas HA, Dolley SL . Indomethacin tocolysis and risk of necrotizing enterocolitis. Obstet Gynecol 2000; 96: 120–123.
Norton ME, Merrill J, Cooper B, Kuller JA, Clyman RI . Neonatal complications after the administration of indomethacin for preterm labor. N Engl J Med 1993; 329: 1602–1607.
Major CA, Lewis DF, Harding JA, Porto MA, Garite TJ . Tocolysis with indomethacin increases the incidence of necrotizing enterocolitis in the low birth weight neonates. Am J Obstet Gynecol 1994; 170: 102–106.
Doyle NM, Gardner MO, Wells L, Qualls C, Papile LA . Outcome of very low birth weight infants exposed to antenatal indomethacin for tocolysis. J Perinatol 2005; 25: 336–340.
Weintraub Z, Solovechick M, Reichman B, Rotschild A, Waisman D, Davkin O et al. Effect of maternal tocolysis on the incidence of severe periventricular/intraventricular haemorrhage in very low birth weight infants. Arch Dis Child Fetal Neonatal Ed 2001; 85: F13–F17.
Gardner M, Owen J, Skelly S, Hauth J . Preterm delivery after indomethacin: a risk factor for neonatal complications? J Reprod Med 1996; 41: 903–906.
Loe SM, Sanchez-Ramos L, Kaunitz AM . Assessing the neonatal safety of indomethacin tocolysis. Obstet Gynecol 2005; 106: 173–179.
Pumberger W, Mayr M, Kohlhauser C, Weninger M . Spontaneous localized intestinal perforation in very low birth weight infants: a distinct clinical entity different from necrotizing enterocolitis. J Am Coll Surg 2002; 195: 796–803.
Sharma R, Hudak ML, Tepas III JJ, Wludyka PS, Marvin WJ, Bradshaw JA et al. Impact of gestational age on the clinical presentation and surgical outcome of necrotizing enterocolitis. J Perinatol 2006; 26: 342–347.
Stark AR, Carlo WA, Tyson JE, Papile LA, Wright LL, Shankaran S et al. Adverse effects of early dexamethasone in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med 2001; 344: 95–101.
Attridge JT, Clark R, Gordon PV . New insights into spontaneous intestinal perforation using a national data set (3): antenatal steroids have no adverse association with spontaneous intestinal perforation. J Perinatol 2006; 26: 667–670.
Couser RJ, Ferrara TB, Wright GB, Cabalka AK, Schilling CG, Hoekstra RE et al. Prophylactic indomethacin therapy in the first twenty-four hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room. J Pediatr 1996; 128: 631–637.
Bandstra ES, Montalvo BM, Goldberg RN, Pacheco I, Ferrer PL, Flynn J et al. Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. Pediatrics 1988; 82: 533–542.
Dollberg S, Lusky A, Reichman B . Patent ductus arteriosus, indomethacin and necrotizing enterocolitis in very low birth weight infants: a population-based study. J Pediatr Gastroenterol Nutr 2005; 40: 184–188.
Cassady G, Crouse DT, Kirklin JW, Strange MJ, Joiner CH, Godoy G et al. A randomized, controlled trial of very early prophylactic ligation of the ductus arteriosus in babies who weighed 1000 g or less at birth. N Engl J Med 1989; 320: 1511–1516.
Clyman RI . Recommendations for the postnatal use of indomethacin: an analysis of four separate treatment strategies. J Pediatr 1996; 128: 601–607.
Meyers RL, Alpan G, Lin E, Clyman RI . Patent ductus arteriosus, indomethacin, and intestinal distension: effects on intestinal blood flow and oxygen consumption. Pediatr Res 1991; 29: 569–574.
O'Donovan DJ, Baetiong A, Adams K, Chen A, Smith EO, Adams JM et al. Necrotizing enterocolitis and gastrointestinal complications after indomethacin therapy and surgical ligation in premature infants with patent ductus arteriosus. J Perinatol 2003; 23: 286–290.
Jacobs JE, Birnbaum BA, Maglinte DDT . Vascular disorders of the small intestine. In: Herlinger H, Maglinte DDT, Birnbaum BA (eds). Clinical imaging of the small intestine. Springer-Verlag: New York, 1999, pp 439–465.
Hoodbhoy SA, Cutting HA, Seddon JA, Campbell ME . Cerebral and splanchnic hemodynamics after duct ligation in very low birth weight infants. J Pediatr 2009; 154: 196–200.
Nowicki PT, Miller CE, Edwards RC . Effects of hypoxia and ischemia on autoregulation in postnatal intestine. Am J Physiol 1991; 261: G152–G157.
Nankervis CA, Reber KM, Nowicki PT . Age-dependent changes in the postnatal intestinal microcirculation. Microcirculation 2001; 8: 377–387.
Miserez M, Barten S, Geboes K, Naulaers G, Devlieger H, Penninckx F . Surgical therapy and histological abnormalities in functional isolated small bowel obstruction and idiopathic gastrointestinal perforation in the very low birth weight infant. World J Surg 2003; 27: 350–355.
Hwang H, Murphy JJ, Gow KW, Magee F, Bekhit E, Jamison D . Are localized intestinal perforations distinct from necrotizing enterocolitis? J Pediatr Surg 2003; 38: 763–769.
Huston JM . An epidemic of isolated perforation: how can we stop it? Pediatr Surg Int 2004; 20: 75–76.
Koshinaga T, Gotoh H, Sugito K, Ikeda T, Hagiwara N, Tomita R . Spontaneous localized intestinal perforation and intestinal dilatation in very-low-birth weight infants. Acta Paediatr 2006; 95: 1381–1388.
Tarrado X, Castañón M, Thió M, Valderas JM, Garcia AL, Morales L . Comparative study between isolated intestinal perforation and necrotizing enterocolitis. Eur J Pediatr Surg 2005; 15: 88–94.
Gordon PV, Attridge JT . Understanding clinical literature relevant to spontaneous intestinal perforations. Am J Perinatol 2009; 26: 309–316.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Presented at the Annual Pediatric Societies' meeting, 2004, San Francisco.
Rights and permissions
About this article
Cite this article
Sharma, R., Hudak, M., Tepas, J. et al. Prenatal or postnatal indomethacin exposure and neonatal gut injury associated with isolated intestinal perforation and necrotizing enterocolitis. J Perinatol 30, 786–793 (2010). https://doi.org/10.1038/jp.2010.59
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/jp.2010.59
Keywords
This article is cited by
-
Risk factors and epidemiology of spontaneous intestinal perforation among infants born at 22–24 weeks’ gestational age
Journal of Perinatology (2024)
-
Prophylactic indomethacin, antenatal betamethasone, and the risk of intestinal perforation in infants <28 weeks’ gestation
Journal of Perinatology (2023)
-
Patent ductus arteriosus and spontaneous intestinal perforation in a cohort of preterm infants
Journal of Perinatology (2022)
-
Impaired antimicrobial response and mucosal protection induced by ibuprofen in the immature human intestine
Pediatric Research (2018)
-
Effect of prophylactic indomethacin administration and early feeding on spontaneous intestinal perforation in extremely low-birth-weight infants
Journal of Perinatology (2017)