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Effect of prophylactic indomethacin administration and early feeding on spontaneous intestinal perforation in extremely low-birth-weight infants

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Abstract

Objective:

To determine the effect of concomitant administration of prophylactic indomethacin and early enteral feeds on the risk of spontaneous intestinal perforation (SIP) in extremely low-birth-weight (ELBW) infants, and to describe the variation in prophylactic indomethacin use in Canada.

Study design:

A retrospective cohort study of 4268 ELBW infants born at <30 weeks’ gestation admitted to Canadian neonatal units between 2010 and 2014 was conducted. Prophylactic indomethacin (I+ or I−, administered within 24 h) and early feeding (E+ or E−, initiated in the first 2 days) exposures were studied concurrently and independently. The primary outcomes were SIP and death before discharge. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated.

Results:

Compared with the I−/E+ reference group (n=1829), infants in I+/E+ (n=285; aOR 2.92, 95% CI 1.41 to 6.08) and I+/E− (n=213; aOR 2.84, 95% CI 1.35 to 5.98) groups had higher odds of SIP, whereas those in the I−/E− group had similar odds (n=1941; aOR 1.37, 95% CI 0.88 to 2.14). Odds of SIP were higher in the indomethacin exposed group (I+) compared with the unexposed (I−) group when controlled for early feeding (aOR 2.43, 95% CI 1.41 to 4.19), but not in the early feeding group when controlled for indomethacin. The use of prophylactic indomethacin ranged from 0% usage in 13 sites to 78% use in one site.

Conclusion:

Prophylactic indomethacin was associated with increased odds of SIP independently from early feeding in this cohort; however, early enteral feeding was not associated with SIP. Marked variation in the use of prophylactic indomethacin was identified.

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References

  1. Fowlie PW, Davis PG, McGuire W . Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev 2010; (7): CD000174.

  2. Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med 2001; 344: 1966–1972.

    Article  CAS  PubMed  Google Scholar 

  3. Ment LR, Oh W, Ehrenkranz RA, Philip AG, Vohr B, Allan W et al. Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics 1994; 93: 543–550.

    CAS  PubMed  Google Scholar 

  4. Alfaleh K . Indomethacin prophylaxis revisited: changing practice and supportive evidence. Acta Paediatr 2011; 100: 641–646.

    Article  CAS  PubMed  Google Scholar 

  5. Slaughter JL, Reagan PB, Bapat RV, Newman TB, Klebanoff MA . Nonsteroidal anti-inflammatory administration and patent ductus arteriosus ligation, a survey of practice preferences at US children's hospitals. Eur J Pediatr 2016; 175: 775–783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Attridge JT, Clark R, Walker MW, Gordon PV . New insights into spontaneous intestinal perforation using a national data set: (1) SIP is associated with early indomethacin exposure. J Perinatol 2006; 26: 93–99.

    Article  CAS  PubMed  Google Scholar 

  7. Gordon PV, Swanson JR, Clark R . Antenatal indomethacin is more likely associated with spontaneous intestinal perforation rather than NEC. Am J Obstet Gynecol 2008; 198: 725–726.

    Article  PubMed  Google Scholar 

  8. 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.

    Article  PubMed  Google Scholar 

  9. Gordon PV, Swanson JR, Attridge JT, Clark R . Emerging trends in acquired neonatal intestinal disease: is it time to abandon Bell’s criteria? J Perinatol 2007; 27: 661–671.

    Article  CAS  PubMed  Google Scholar 

  10. Holland AJ, Shun A, Martin HC, Cooke-Yarborough C, Holland J . Small bowel perforation in the premature neonate: congenital or acquired? Pediatr Surg Int 2003; 19: 489–494.

    Article  CAS  PubMed  Google Scholar 

  11. Hwang H, Murphy JJ, Gow KW, Magee JF, Bekhit E, Jamieson D . Are localized intestinal perforations distinct from necrotizing enterocolitis? J Pediatr Surg 2003; 38: 763–767.

    Article  PubMed  Google Scholar 

  12. Tatekawa Y, Muraji T, Imai Y, Nishijima E, Tsugawa C . The mechanism of focal intestinal perforations in neonates with low birth weight. Pediatr Surg Int 1999; 15: 549–552.

    Article  CAS  PubMed  Google Scholar 

  13. Edogawa S, Sakai A, Inoue T, Harada S, Takeuchi T, Umegaki E et al. Down-regulation of collagen I biosynthesis in intestinal epithelial cells exposed to indomethacin: a comparative proteome analysis. J Proteomics 2014; 103: 35–46.

    Article  CAS  PubMed  Google Scholar 

  14. Gordon PV, Herman AC, Marcinkiewicz M, Gaston BM, Laubach VE, Aschner JL . A neonatal mouse model of intestinal perforation: investigating the harmful synergism between glucocorticoids and indomethacin. J Pediatr Gastroenterol Nutr 2007; 45: 509–519.

    Article  CAS  PubMed  Google Scholar 

  15. Gordon PV . Understanding intestinal vulnerability to perforation in the extremely low birth weight infant. Pediatr Res 2009; 65: 138–144.

    Article  PubMed  Google Scholar 

  16. Sharma R, Hudak ML, Tepas JJ III, Wludyka PS, Teng RJ, Hastings LK et al. Prenatal or postnatal indomethacin exposure and neonatal gut injury associated with isolated intestinal perforation and necrotizing enterocolitis. J Perinatol 2010; 30: 786–793.

    Article  CAS  PubMed  Google Scholar 

  17. Wadhawan R, Oh W, Vohr BR, Saha S, Das A, Bell EF et al. Spontaneous intestinal perforation in extremely low birth weight infants: association with indometacin therapy and effects on neurodevelopmental outcomes at 18-22 months corrected age. Arch Dis Child Fetal Neonatal Ed 2013; 98: F127–F132.

    Article  PubMed  Google Scholar 

  18. Clyman R, Wickremasinghe A, Jhaveri N, Hassinger DC, Attridge JT, Sanocka U et al. Enteral feeding during indomethacin and ibuprofen treatment of a patent ductus arteriosus. J Pediatr 2013; 163: 406–411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kelleher J, Salas AA, Bhat R, Ambalavanan N, Saha S, Stoll BJ et al. Prophylactic indomethacin and intestinal perforation in extremely low birth weight infants. Pediatrics 2014; 134: e1369–e1377.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Dinerstein A, Nieto RM, Solana CL, Perez GP, Otheguy LE, Larguia AM . Early and aggressive nutritional strategy (parenteral and enteral) decreases postnatal growth failure in very low birth weight infants. J Perinatol 2006; 26: 436–442.

    Article  CAS  PubMed  Google Scholar 

  21. Ronnestad A, Abrahamsen TG, Medbo S, Reigstad H, Lossius K, Kaaresen PI et al. Late-onset septicemia in a Norwegian national cohort of extremely premature infants receiving very early full human milk feeding. Pediatrics 2005; 115: e269–e276.

    Article  PubMed  Google Scholar 

  22. Shah J, Singhal N, da Silva O, Rouvinez-Bouali N, Seshia M, Lee SK et al. Intestinal perforation in very preterm neonates: risk factors and outcomes. J Perinatol 2015; 35: 595–600.

    Article  CAS  PubMed  Google Scholar 

  23. The Canadian Neonatal Network Abstractor’s Manual, v.2.2.1. [Internet]. Available at http://www.canadianneonatalnetwork.org/Portal/LinkClick.aspx?fileticket=zrcLU_ttnkk%3d&tabid=69 (accessed on 2 March 2016).

  24. Richardson DK, Corcoran JD, Escobar GJ, Lee SK . SNAP-II and SNAPPE-II: Simplified newborn illness severity and mortality risk scores. J Pediatr 2001; 138: 92–100.

    Article  CAS  PubMed  Google Scholar 

  25. Lee SK, Zupancic JA, Pendray M, Thiessen P, Schmidt B, Whyte R et al. Transport risk index of physiologic stability: a practical system for assessing infant transport care. J Pediatr 2001; 139: 220–226.

    Article  CAS  PubMed  Google Scholar 

  26. Kramer MS, Platt RW, Wen SW, Joseph KS, Allen A, Abrahamowicz M et al. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics 2001; 108: E35.

    Article  CAS  PubMed  Google Scholar 

  27. Walsh MC, Kliegman RM . Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986; 33: 179–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Papile LA, Burstein J, Burstein R, Koffler H . Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92: 529–534.

    Article  CAS  PubMed  Google Scholar 

  29. Fisher JG, Jones BA, Gutierrez IM, Hull MA, Kang KH, Kenny M et al. Mortality associated with laparotomy-confirmed neonatal spontaneous intestinal perforation: a prospective 5-year multicenter analysis. J Pediatr Surg 2014; 49: 1215–1219.

    Article  PubMed  Google Scholar 

  30. Alpan G, Eyal F, Vinograd I, Udassin R, Amir G, Mogle P et al. Localized intestinal perforations after enteral administration of indomethacin in premature infants. J Pediatr 1985; 106: 277–281.

    Article  CAS  PubMed  Google Scholar 

  31. Kuhl G, Seyberth HW . Intestinal perforations after enteral administration of indomethacin in premature infants. J Pediatr 1986; 108: 327–328.

    Article  CAS  PubMed  Google Scholar 

  32. Nagaraj HS, Sandhu AS, Cook LN, Buchino JJ, Groff DB . Gastrointestinal perforation following indomethacin therapy in very low birth weight infants. J Pediatr Surg 1981; 16: 1003–1007.

    Article  CAS  PubMed  Google Scholar 

  33. Clyman RI, Saha S, Jobe A, Oh W . Indomethacin prophylaxis for preterm infants: the impact of 2 multicentered randomized controlled trials on clinical practice. J Pediatr 2007; 150: 46–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. Watterberg KL, Gerdes JS, Cole CH, Aucott SW, Thilo EH, Mammel MC et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics 2004; 114: 1649–1657.

    Article  PubMed  Google Scholar 

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Acknowledgements

We acknowledge Eugene Yoon, MSc, for statistical analyses of these data and Natasha Musrap, PhD, for editorial assistance in the preparation of this manuscript. Both are affiliated with the Maternal-Infant Care Research Centre at Mount Sinai Hospital, Toronto. Although no specific funding has been received for this study, organizational support was provided by the Maternal-Infant Care Research Centre (MiCare) at Mount Sinai Hospital in Toronto. MiCare is supported by a Canadian Institutes of Health Research (CIHR) Team Grant (FRN87518). PSS holds an Applied Research Chair in Reproductive and Child Health Services and Policy Research awarded by the CIHR (APR-126340).

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Author notes

  1. M Stavel, J Wong, Z Cieslak, R Sherlock, M Claveau and P S Shah: Investigators of the Canadian Neonatal Network (CNN) are listed before Conflict of Interest.

Authors and Affiliations

  1. Neonatal Intensive Care Unit, Royal Columbian Hospital, New Westminster, BC, Canada

    M Stavel & Z Cieslak

  2. Department of Paediatrics, Mount Sinai Hospital, Toronto, ON, Canada

    M Stavel & P S Shah

  3. Department of Pediatrics, University of Toronto, Toronto, ON, Canada

    J Wong & P S Shah

  4. Neonatal Intensive Care Unit, Surrey Memorial Hospital, Surrey, BC, Canada

    R Sherlock

  5. Department of Pediatrics, McGill University Health Centre, Montreal, QC, Canada

    M Claveau

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Correspondence to P S Shah.

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Stavel, M., Wong, J., Cieslak, Z. et al. Effect of prophylactic indomethacin administration and early feeding on spontaneous intestinal perforation in extremely low-birth-weight infants. J Perinatol 37, 188–193 (2017). https://doi.org/10.1038/jp.2016.196

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