{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:52:23Z","timestamp":1792180343455,"version":"4.4.0"},"reference-count":56,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T00:00:00Z","timestamp":1588896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Spontaneous intestinal perforation (SIP) is a devastating complication of prematurity, and extremely low birthweight (ELBW &lt; 1000 g) infants born prior to 28 weeks are at highest risk. The role of nutrition and feeding practices in prevention and complications of SIP is unclear. The purpose of this review is to compile evidence to support early nutrition initiation in infants at risk for and after surgery for SIP. Methods: A search of PubMed, EMBASE and Medline was performed using relevant search terms according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Abstracts and full texts were reviewed by co-first authors. Studies with infants diagnosed with SIP that included information on nutrition\/feeding practices prior to SIP and post-operatively were included. Primary outcome was time to first feed. Secondary outcomes were incidence of SIP, time to full enteral feeds, duration of parenteral nutrition, length of stay, neurodevelopmental outcomes and mortality. Results: Nineteen articles met inclusion criteria\u2014nine studies included feeding\/nutrition data prior to SIP and ten studies included data on post-operative nutrition. Two case series, one cohort study and sixteen historical control studies were included. Three studies showed reduced incidence of SIP with initiation of enteral nutrition in the first three days of life. Two studies showed reduced mortality and neurodevelopmental impairment in infants with early feeding. Conclusions: Available data suggest that early enteral nutrition in ELBW infants reduces incidence of SIP without increased mortality.<\/jats:p>","DOI":"10.3390\/nu12051347","type":"journal-article","created":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T11:26:00Z","timestamp":1588937160000},"page":"1347","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Role of Nutrition in Prevention of Neonatal Spontaneous Intestinal Perforation and Its Complications: A Systematic Review"],"prefix":"10.3390","volume":"12","author":[{"given":"Oluwabunmi","family":"Olaloye","sequence":"first","affiliation":[{"name":"Division of Newborn Medicine, University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA"},{"name":"Department of Pediatrics, Yale Medical School, New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Swatski","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liza","family":"Konnikova","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA"},{"name":"Department of Pediatrics, Yale Medical School, New Haven, CT 06520, USA"},{"name":"Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1203\/PDR.0b013e31818c7920","article-title":"Understanding intestinal vulnerability to perforation in the extremely low birth weight infant","volume":"65","author":"Gordon","year":"2009","journal-title":"Pediatr. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"159","DOI":"10.3233\/NPM-16915100","article-title":"ELGAN Study co-investigators The antecedents and correlates of necrotizing enterocolitis and spontaneous intestinal perforation among infants born before the 28th week of gestation","volume":"9","author":"Singh","year":"2016","journal-title":"J. Neonatal. Perinatal. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/jp.2015.41","article-title":"Canadian Neonatal Network Intestinal perforation in very preterm neonates: Risk factors and outcomes","volume":"35","author":"Shah","year":"2015","journal-title":"J. Perinatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1542\/peds.93.1.32","article-title":"Clinical comparison of localized intestinal perforation and necrotizing enterocolitis in neonates","volume":"93","author":"Buchheit","year":"1994","journal-title":"Pediatrics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/S1072-7515(02)01344-3","article-title":"Spontaneous localized intestinal perforation in very-low-birth-weight infants: A distinct clinical entity different from necrotizing enterocolitis","volume":"195","author":"Pumberger","year":"2002","journal-title":"J. Am. Coll. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1007\/s00383-007-1984-9","article-title":"Focal intestinal perforation in extremely-low-birth-weight neonates: Etiological consideration from histological findings","volume":"23","author":"Kubota","year":"2007","journal-title":"Pediatr. Surg. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1007\/s00383-002-0839-7","article-title":"A comparison of the clinical presentation and outcome of focal intestinal perforation and necrotizing enterocolitis in very-low-birth-weight neonates","volume":"18","author":"Okuyama","year":"2002","journal-title":"Pediatr. Surg. Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1097\/MPG.0b013e3182a7dc74","article-title":"Pathogenesis implication for necrotizing enterocolitis prevention in preterm very-low-birth-weight infants","volume":"58","author":"Chen","year":"2014","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/0022-3468(91)90017-N","article-title":"Spontaneous, isolated intestinal perforations in neonates with birth weight less than 1,000 g not associated with necrotizing enterocolitis","volume":"26","author":"Meyer","year":"1991","journal-title":"J. Pediatr. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/S0022-3476(88)80285-3","article-title":"Spontaneous focal gastrointestinal perforation in very low birth weight infants","volume":"113","author":"Aschner","year":"1988","journal-title":"J. Pediatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s00383-003-0967-8","article-title":"Small bowel perforation in the premature neonate: Congenital or acquired?","volume":"19","author":"Holland","year":"2003","journal-title":"Pediatr. Surg. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/0741-5214(92)90252-4","article-title":"Heparin-induced thrombocytopenia in the newborn","volume":"15","author":"Spadone","year":"1992","journal-title":"J. Vasc. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/sj.jp.7200269","article-title":"Early postnatal dexamethasone increases the risk of focal small bowel perforation in extremely low birth weight infants","volume":"19","author":"Gordon","year":"1999","journal-title":"J. Perinatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1016\/S0022-3468(89)80224-6","article-title":"Segmental agenesis of intestinal muscularis: A case report","volume":"24","author":"Alawadhi","year":"1989","journal-title":"J. Pediatr. Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1055\/s-0036-1593990","article-title":"Spontaneous Intestinal Perforation: The Long-Term Outcome","volume":"27","author":"Houben","year":"2017","journal-title":"Eur. J. Pediatr. Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1016\/j.jpedsurg.2018.07.020","article-title":"Outcomes of surgery for necrotizing enterocolitis and spontaneous intestinal perforation in Finland during 1986-2014","volume":"53","author":"Karila","year":"2018","journal-title":"J. Pediatr. Surg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.1016\/j.jpedsurg.2019.03.017","article-title":"Outcomes of infants born at 23 and 24 weeks\u2019 gestation with gut perforation","volume":"54","author":"Berry","year":"2019","journal-title":"J. Pediatr. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1159\/000444387","article-title":"Surgical Necrotizing Enterocolitis versus Spontaneous Intestinal Perforation in White Matter Injury on Brain Magnetic Resonance Imaging","volume":"110","author":"Shin","year":"2016","journal-title":"Neonatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.clp.2016.11.009","article-title":"Necrotizing enterocolitis and human milk feeding: A systematic review","volume":"44","author":"Cacho","year":"2017","journal-title":"Clin. Perinatol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Wang, K., Tao, G., and Sylvester, K.G. (2019). Recent advances in prevention and therapies for clinical or experimental necrotizing enterocolitis. Dig. Dis. Sci., 1\u20138.","DOI":"10.1007\/s10620-019-05618-2"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e1369","DOI":"10.1542\/peds.2014-0183","article-title":"GDB Subcommittee, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Prophylactic indomethacin and intestinal perforation in extremely low birth weight infants","volume":"134","author":"Kelleher","year":"2014","journal-title":"Pediatrics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1111\/j.1442-200X.2006.02282.x","article-title":"Gastrointestinal perforation in very low-birthweight infants","volume":"48","author":"Kawase","year":"2006","journal-title":"Pediatr. Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"F79","DOI":"10.1136\/archdischild-2017-312917","article-title":"Growth and morbidity of extremely preterm infants after early full enteral nutrition","volume":"103","author":"Maas","year":"2018","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/jp.2016.196","article-title":"Effect of prophylactic indomethacin administration and early feeding on spontaneous intestinal perforation in extremely low-birth-weight infants","volume":"37","author":"Stavel","year":"2017","journal-title":"J. Perinatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1097\/MPG.0000000000002128","article-title":"Use of breast milk and other feeding practices following gastrointestinal surgery in infants","volume":"68","author":"Varma","year":"2019","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1177\/0148607117722755","article-title":"Predictive Value of the Aspartate Aminotransferase to Platelet Ratio Index for Parenteral Nutrition-Associated Cholestasis in Premature Infants With Intestinal Perforation","volume":"42","author":"Vongbhavit","year":"2018","journal-title":"JPEN J. Parenter Enteral Nutr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1053\/jpsu.2000.18299","article-title":"Peritoneal drainage as definitive treatment for neonates with isolated intestinal perforation","volume":"35","author":"Cass","year":"2000","journal-title":"J. Pediatr. Surg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1515\/JPM.2006.065","article-title":"To drain or not to drain: A single institution experience with neonatal intestinal perforation","volume":"34","author":"Chiu","year":"2006","journal-title":"J. Perinat Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1159\/000335325","article-title":"Surgical management of extremely low birth weight infants with neonatal bowel perforation: A single-center experience and a review of the literature","volume":"101","author":"Eicher","year":"2012","journal-title":"Neonatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1016\/j.jpedsurg.2003.08.029","article-title":"Peritoneal drainage as definitive management of intestinal perforation in extremely low-birth-weight infants","volume":"38","author":"Gollin","year":"2003","journal-title":"J. Pediatr. Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/jp.2015.23","article-title":"Definitive peritoneal drainage in the extremely low birth weight infant with spontaneous intestinal perforation: Predictors and hospital outcomes","volume":"35","author":"Jakaitis","year":"2015","journal-title":"J. Perinatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"135.e1","DOI":"10.1016\/j.jpeds.2016.09.016","article-title":"Blood Level of Inter-Alpha Inhibitor Proteins Distinguishes Necrotizing Enterocolitis From Spontaneous Intestinal Perforation","volume":"180","author":"Shah","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"F127","DOI":"10.1136\/archdischild-2011-300659","article-title":"Spontaneous intestinal perforation in extremely low birth weight infants: Association with indometacin therapy and effects on neurodevelopmental outcomes at 18-22 months corrected age","volume":"98","author":"Wadhawan","year":"2013","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1056\/NEJMoa1501917","article-title":"NEUROSIS Trial Group Early inhaled budesonide for the prevention of bronchopulmonary dysplasia","volume":"373","author":"Bassler","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/jp.2017.170","article-title":"Management of neonatal spontaneous intestinal perforation by peritoneal needle aspiration","volume":"38","author":"Michel","year":"2018","journal-title":"J. Perinatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.jpedsurg.2018.10.043","article-title":"Intestinal failure associated cholestasis in surgical necrotizing enterocolitis and spontaneous intestinal perforation","volume":"54","author":"Karila","year":"2019","journal-title":"J. Pediatr. Surg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.cld.2015.08.009","article-title":"Total Parenteral Nutrition-Induced Cholestasis: Prevention and Management","volume":"20","author":"Beath","year":"2016","journal-title":"Clin. Liver Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/jp.2013.128","article-title":"NICHD Neonatal Research Network Neurodevelopmental outcomes of extremely low birth weight infants with spontaneous intestinal perforation or surgical necrotizing enterocolitis","volume":"34","author":"Wadhawan","year":"2014","journal-title":"J. Perinatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"616","DOI":"10.11622\/smedj.2016002","article-title":"Benefits of early enteral nutrition in extremely low birth weight infants","volume":"57","author":"Manea","year":"2016","journal-title":"Singapore Med. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1177\/0148607114552848","article-title":"Standardized slow enteral feeding protocol and the incidence of necrotizing enterocolitis in extremely low birth weight infants","volume":"39","author":"Viswanathan","year":"2015","journal-title":"JPEN J. Parenter Enteral Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Greer, D., Karunaratne, Y.G., Karpelowsky, J., and Adams, S. (2019). Early Enteral Feeding after Pediatric Abdominal Surgery: A Systematic Review of the Literature. J. Pediatr. Surg.","DOI":"10.1016\/j.jpedsurg.2019.08.055"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"687","DOI":"10.3945\/an.112.002683","article-title":"Nutritional factors influencing intestinal health of the neonate","volume":"3","author":"Jacobi","year":"2012","journal-title":"Adv. Nutr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.3945\/jn.110.135145","article-title":"Intestinal threonine utilization for protein and mucin synthesis is decreased in formula-fed preterm pigs","volume":"141","author":"Puiman","year":"2011","journal-title":"J. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3062","DOI":"10.3389\/fimmu.2019.03062","article-title":"Bovine colostrum before or after formula feeding improves systemic immune protection and gut function in newborn preterm pigs","volume":"10","author":"Li","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1111\/j.1440-1754.2006.00941.x","article-title":"Effects of extremely early enteral feeding on plasma glicentin levels in very-low-birthweight infants","volume":"42","author":"Shimizu","year":"2006","journal-title":"J. Paediatr. Child. Health"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.jpeds.2009.11.021","article-title":"Breast milk as the gold standard for protective nutrients","volume":"156","author":"Walker","year":"2010","journal-title":"J. Pediatr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"107","DOI":"10.2174\/2211536607666180206150503","article-title":"Variation in Immune-Related microRNAs Profile in Human Milk Amongst Lactating Women","volume":"7","author":"Perri","year":"2018","journal-title":"Microrna"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.pedneo.2017.04.003","article-title":"Early provision of oropharyngeal colostrum leads to sustained breast milk feedings in preterm infants","volume":"58","author":"Snyder","year":"2017","journal-title":"Pediatr. Neonatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.nut.2004.10.003","article-title":"Early enteral feeding in newborn surgical patients","volume":"21","author":"Ekingen","year":"2005","journal-title":"Nutrition"},{"key":"ref_50","first-page":"38","article-title":"Early enteral nutrition for upper digestive tract malformation in neonate","volume":"24","author":"Jiang","year":"2015","journal-title":"Asia Pac. J. Clin. Nutr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1097\/MPG.0b013e31818c5281","article-title":"Neonatal outcome of gastroschisis is mainly influenced by nutritional management","volume":"48","author":"Rousseau","year":"2009","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"140.e1","DOI":"10.1016\/j.jpeds.2017.11.058","article-title":"Postoperative Enteral Nutrition Guidelines Reduce the Risk of Intestinal Failure-Associated Liver Disease in Surgical Infants","volume":"195","author":"Shores","year":"2018","journal-title":"J. Pediatr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.jss.2010.01.004","article-title":"Early postoperative oral intake accelerates upper gastrointestinal anastomotic healing in the rat model","volume":"169","author":"Tadano","year":"2011","journal-title":"J. Surg. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"S54","DOI":"10.1007\/BF02237227","article-title":"Effect of early postoperative feeding on the healing of colonic anastomoses in the presence of intra-abdominal sepsis in rats","volume":"43","author":"Kiyama","year":"2000","journal-title":"Dis. Colon Rectum"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"231","DOI":"10.3233\/NPM-181773","article-title":"Slow enteral feeding decreases risk of transfusion associated necrotizing enterocolitis","volume":"11","author":"Dako","year":"2018","journal-title":"J. Neonatal. Perinatal. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.clp.2012.12.001","article-title":"Feeding practices and necrotizing enterocolitis","volume":"40","author":"Ramani","year":"2013","journal-title":"Clin. Perinatol"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/5\/1347\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:26:55Z","timestamp":1760174815000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/5\/1347"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,8]]},"references-count":56,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["nu12051347"],"URL":"https:\/\/doi.org\/10.3390\/nu12051347","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,8]]}}}