Am J Perinatol
DOI: 10.1055/a-2347-4135

Padma Garg

1   Department of Pediatric Critical Care, University of Mississippi Medical Center, Jackson, Mississippi

,

Jörn-Hendrik Weitkamp

2   Department of Pediatrics/Neonatology, Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee

,

Anna G. McDonald

3   Department of Pathology, Atrium Health Wake Forest Baptist, Wake Forest School of Medicine, Winston-Salem, North Carolina

,

Sarah N. Cilvik

4   Department of Pediatrics/Neonatology, Atrium Health Wake Forest Baptist, Wake Forest School of Medicine, Winston-Salem, North Carolina

,

5   Department of Pediatrics/Neonatology, UT Southwestern Medical Center, Dallas, Texas

,

Jeffrey S. Shenberger

6   Department of Pediatrics/Neonatology, Connecticut Children's, Hartford, Connecticut

,

Oluwabunmi Olaloye

7   Division of Neonatology, Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut

,

7   Division of Neonatology, Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut

8   Human and Translational Immunology Program, Department of Immunobiology, Department of Obstetrics Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut

,

Suhas G. Kallapur

9   Department of Pediatrics/Neonatology, UCLA Mattel Children's Hospital, Los Angeles, California

,

Parvesh M. Garg

4   Department of Pediatrics/Neonatology, Atrium Health Wake Forest Baptist, Wake Forest School of Medicine, Winston-Salem, North Carolina

› Author Affiliations Funding P.M.G. is partially supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number 5U54GM115428. S.N.C. is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number 1R01HL164434.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
› Further Information Also available at    Buy Article Permissions and Reprints Abstract

Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal conditions affecting 6 to 10% of low-birth-weight infants and remains a leading cause of death. The risk factors associated with NEC are complex and multifactorial, including preterm birth and intrauterine exposure to inflammation and hypoxia. Chorioamnionitis has been associated with intestinal injury in animal and human clinical studies. This review presents current evidence about the clinical impact of the intrauterine environment on intestinal injury during pregnancy and postpregnancy. We present information from our own clinical and laboratory research in conjunction with information collected from an extensive search in the databases PubMed, EMBASE, and Scopus. Prospective multicenter studies, including accurate and precise clinical, maternal, and laboratory predictors (e.g., inflammatory biomarkers), will help identify the mechanisms associated with the placental pathology, the development of NEC, and the impact of in utero-triggered inflammation on the clinical outcomes. Filling the knowledge gap to link the inflammatory surge to postnatal life will aid in identifying at-risk infants for NEC in a timely manner and facilitate the development of novel immunomodulatory treatments or interventions to improve the outcomes of these vulnerable infants.

Key Points

Placental inflammatory and vascular lesions are associated with NEC severity.

Higher grade chorioamnionitis with a fetal response is associated with an increased risk of surgical NEC.

There is a need for routine bedside utilization of placenta pathology in clinical decision-making.

Keywords placenta - chorioamnionitis - NEC - intestinal injury - preterm infant Authors' Contributions

P.M.G., A.G.M., P.G., S.N.C., J-H.W., J.S.S., I.M., and S.G.K. wrote the article. All the authors approved the manuscript.

Publication History

Received: 02 May 2024

Accepted: 13 June 2024

Accepted Manuscript online:
18 June 2024

Article published online:
11 July 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

  References 1 Keating ST, El-Osta A. Epigenetics and metabolism. Circ Res 2015; 116 (04) 715-736 2 Nelissen EC, van Montfoort AP, Dumoulin JC, Evers JL. Epigenetics and the placenta. Hum Reprod Update 2011; 17 (03) 397-417 3 Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011; 364 (03) 255-264 4 Sankaran K, Puckett B, Lee DS. et al; Canadian Neonatal Network. Variations in incidence of necrotizing enterocolitis in Canadian neonatal intensive care units. J Pediatr Gastroenterol Nutr 2004; 39 (04) 366-372 5 Mowitz ME, Dukhovny D, Zupancic JAF. The cost of necrotizing enterocolitis in premature infants. Semin Fetal Neonatal Med 2018; 23 (06) 416-419 6 Ganapathy V, Hay JW, Kim JH, Lee ML, Rechtman DJ. Long term healthcare costs of infants who survived neonatal necrotizing enterocolitis: a retrospective longitudinal study among infants enrolled in Texas Medicaid. BMC Pediatr 2013; 13: 127 7 Garzoni L, Faure C, Frasch MG. Fetal cholinergic anti-inflammatory pathway and necrotizing enterocolitis: the brain-gut connection begins in utero. Front Integr Neurosci 2013; 7: 57 8 Tita AT, Andrews WW. Diagnosis and management of clinical chorioamnionitis. Clin Perinatol 2010; 37 (02) 339-354 9 Stras SF, Werner L, Toothaker JM. et al. Maturation of the human intestinal immune system occurs early in fetal development. Dev Cell 2019; 51 (03) 357-373.e5 10 Khong TY, Mooney EE, Ariel I. et al. Sampling and definitions of placental lesions: Amsterdam Placental Workshop Group Consensus Statement. Arch Pathol Lab Med 2016; 140 (07) 698-713 11 Redline RW, Ravishankar S, Bagby CM, Saab ST, Zarei S. Four major patterns of placental injury: a stepwise guide for understanding and implementing the 2016 Amsterdam consensus. Mod Pathol 2021; 34 (06) 1074-1092 12 Fitzgerald B, Kingdom J, Keating S. Distal villous hypoplasia. Diagn Histopathol 2012; 18 (05) 195-200 13 Stevens DU, de Nobrega Teixeira JA, Spaanderman MEA, Bulten J, van Vugt JMG, Al-Nasiry S. Understanding decidual vasculopathy and the link to preeclampsia: a review. Placenta 2020; 97: 95-100 14 Ernst LM. Maternal vascular malperfusion of the placental bed. APMIS 2018; 126 (07) 551-560 15 Kelehan P, Downey P. Villous oedema. In: Khong TY, Mooney EE, Nikkels PGJ, Morgan TK, Gordjin SK. eds. Pathology of the Placenta: A Practical Guide. Cham: 16 Garg PM, Paschal JL, Ansari MAY. et al. Association of placental pathologic findings with the severity of necrotizing enterocolitis in preterm infants - a matched case-control study. Fetal Pediatr Pathol 2023; 42 (02) 187-197 17 Mir IN, Sánchez-Rosado M, Reis J. et al. Impact of fetal inflammatory response on the severity of necrotizing enterocolitis in preterm infants. Pediatr Res 2024; 95 (05) 1308-1315 18 Been JV, Lievense S, Zimmermann LJ, Kramer BW, Wolfs TG. Chorioamnionitis as a risk factor for necrotizing enterocolitis: a systematic review and meta-analysis. J Pediatr 2013; 162 (02) 236-42.e2 19 Dix L, Roth-Kleiner M, Osterheld MC. Placental vascular obstructive lesions: risk factor for developing necrotizing enterocolitis. Pathol Res Int 2010; 2010: 838917 20 Moore SW, Arnold M, Wright C. Necrotizing enterocolitis and the placenta - a key etiological link. J Pediatr Surg 2013; 48 (02) 359-362 21 Garg PM, Paschal JL, Ansari MAY. et al. Correlation of placental pathology with the postoperative outcomes and white matter injury in preterm infants following necrotizing enterocolitis. J Neonatal Perinatal Med 2023; 16 (01) 93-103 22 Woodward LJ, Anderson PJ, Austin NC, Howard K, Inder TE. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med 2006; 355 (07) 685-94 23 Redline RW, Heller D, Keating S, Kingdom J. Placental diagnostic criteria and clinical correlation–a workshop report. Placenta 2005; 26 (suppl A): S114-S117 24 Redline RW, Minich N, Taylor HG, Hack M. Placental lesions as predictors of cerebral palsy and abnormal neurocognitive function at school age in extremely low birth weight infants (<1 kg). Pediatr Dev Pathol 2007; 10 (04) 282-292 25 Ducey J, Owen A, Coombs R, Cohen M. Vasculitis as part of the fetal response to acute chorioamnionitis likely plays a role in the development of necrotizing enterocolitis and spontaneous intestinal perforation in premature neonates. Eur J Pediatr Surg 2015; 25 (03) 284-291 26 Dammann O, Allred EN, Leviton A. et al. Fetal vasculitis in preterm newborns: interrelationships, modifiers, and antecedents. Placenta 2004; 25 (10) 788-796 27 Satar M, Turhan E, Yapicioglu H, Narli N, Ozgunen FT, Cetiner S. Cord blood cytokine levels in neonates born to mothers with prolonged premature rupture of membranes and its relationship with morbidity and mortality. Eur Cytokine Netw 2008; 19 (01) 37-41 28 Hatzidaki E, Gourgiotis D, Manoura A. et al. Interleukin-6 in preterm premature rupture of membranes as an indicator of neonatal outcome. Acta Obstet Gynecol Scand 2005; 84 (07) 632-638 29 Skrablin S, Lovric H, Banovic V, Kralik S, Dijakovic A, Kalafatic D. Maternal plasma interleukin-6, interleukin-1beta and C-reactive protein as indicators of tocolysis failure and neonatal outcome after preterm delivery. J Matern Fetal Neonatal Med 2007; 20 (04) 335-341 30 Mir IN, Chalak LF, Liao J. et al. Fetal-placental crosstalk occurs through fetal cytokine synthesis and placental clearance. Placenta 2018; 69: 1-8 31 Wolfs TG, Kallapur SG, Polglase GR. et al. IL-1α mediated chorioamnionitis induces depletion of FoxP3+ cells and ileal inflammation in the ovine fetal gut. PLoS ONE 2011; 6 (03) e18355 32 Wolfs TG, Buurman WA, Zoer B. et al. Endotoxin induced chorioamnionitis prevents intestinal development during gestation in fetal sheep. PLoS ONE 2009; 4 (06) e5837 33 Yan X, Managlia E, Tan XD, De Plaen IG. Prenatal inflammation impairs intestinal microvascular development through a TNF-dependent mechanism and predisposes newborn mice to necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2019; 317 (01) G57-G66 34 McCulloh CJ, Olson JK, Zhou Y, Wang Y, Besner GE. Stem cells and necrotizing enterocolitis: A direct comparison of the efficacy of multiple types of stem cells. J Pediatr Surg 2017; 52 (06) 999-1005 35 Weis VG, Deal AC, Mekkey G. et al. Human placental-derived stem cell therapy ameliorates experimental necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2021; 320 (04) G658-G674