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

Abstract

Background Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are causes of bowel perforation in premature neonates. Studies have demonstrated that both are associated with acute chorioamnionitis (ACA) of the placenta.

Aim The aim of our study was to identify any histopathological links between placental histopathological abnormalities and the later development of NEC and/or SIP in premature patients presenting at our institution.

Patients and Methods Cases with a diagnosis of NEC/SIP were identified. Entry criteria were the diagnosis of NEC/SIP was confirmed clinically and/or histologically, had been made within the first 7 days of life, neonates were premature, and the placenta had been submitted for histological examination. In those cases with ACA, CD34 immunohistochemistry and Martius scarlet blue staining was performed. Medical records were reviewed for demographics, clinical variables, and clinical outcomes. Statistical analysis was performed using Fisher exact test.

Results In total, 21 cases met defined inclusion criteria (12 NEC, 8 SIP, and 1 clinically indeterminate). Mean gestational age was 27 weeks. Median age of presentation was 5 days. Placental histology showed ACA in 16 of 21 cases (76.2%). Of those with ACA, 13 of 16 (81.3%) had umbilical phlebitis, 12 of 16 (75.0%) had umbilical arteritis, 6 of 16 (37.5%) funisitis, and 12 of 16 (75.0%) had chorionic vasculitis. No differences (p > 0.05) were seen between ACA and diagnosis or clinical outcome (Fisher exact test). Of the 16 cases, 14 with ACA that later developed either NEC or SIP showed vasculitis in the umbilical cord and/or chorionic plate and/or stem villi vasculature. The association between ACA and vasculitis was highly significant (p < 0.01). Of those with ACA on placental histology, 12 of 16 (75.0%) cases were found to have intermediate-advanced stage fetal inflammatory response (FIR), whereas 13 of 16 (81.3%) had grade 2 (severe) FIR. Of the 16 cases, 8 (50.0%) had evidence of fibrin deposition/early thrombus formation within placental and/or umbilical vasculature. These were associated with vascular endothelial injury in vessels with prominent vasculitis.

Conclusion NEC or SIP shows a significant association with ACA with presence of vasculitis as part of the FIR (p < 0.01). In a proportion of cases, the development of fibrin deposition in response to vasculitic endothelial damage of the placental vasculature may form part of the mechanism linking ACA and early postnatal development of NEC and/or SIP.

Keywords

acute chorioamnionitis - necrotizing enterocolitis - spontaneous intestinal perforation

• References

• 1 Neu J, Mihatsch W. Recent developments in necrotizing enterocolitis. JPEN J Parenter Enteral Nutr 2012; 36 (1, Suppl): 30S-35S
• 2 Neu J. Neonatal necrotizing enterocolitis: an update. Acta Paediatr Suppl 2005; 94 (449) 100-105
• 3 Kastenberg ZJ, Sylvester KG. The surgical management of necrotizing enterocolitis. Clin Perinatol 2013; 40 (1) 135-148
• 4 Lin PW, Stoll BJ. Necrotising enterocolitis. Lancet 2006; 368 (9543) 1271-1283
• 5 Hsueh W, Caplan MS, Qu XW, Tan XD, De Plaen IG, Gonzalez-Crussi F. Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts. Pediatr Dev Pathol 2003; 6 (1) 6-23
• 6 Gordon PV. Understanding intestinal vulnerability to perforation in the extremely low birth weight infant. Pediatr Res 2009; 65 (2) 138-144
• 7 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 (5) 763-767
• 8 Holland AJA, Shun A, Martin HCO, Cooke-Yarborough C, Holland J. Small bowel perforation in the premature neonate: congenital or acquired?. Pediatr Surg Int 2003; 19 (6) 489-494
• 9 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 (6) 796-803
• 10 Singh M, Owen A, Gull S, Morabito A, Bianchi A. Surgery for intestinal perforation in preterm neonates: anastomosis vs stoma. J Pediatr Surg 2006; 41 (4) 725-729 , discussion 725–729
• 11 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 (2) 93-99
• 12 Stark AR, Carlo WA, Tyson JE , et al; National Institute of Child Health and Human Development Neonatal Research Network. Adverse effects of early dexamethasone in extremely-low-birth-weight infants. N Engl J Med 2001; 344 (2) 95-101
• 13 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 (11) 667-670
• 14 Sharma R, Hudak ML, Tepas III JJ , et al. Prenatal or postnatal indomethacin exposure and neonatal gut injury associated with isolated intestinal perforation and necrotizing enterocolitis. J Perinatol 2010; 30 (12) 786-793
• 15 Ragouilliaux CJ, Keeney SE, Hawkins HK, Rowen JL. Maternal factors in extremely low birth weight infants who develop spontaneous intestinal perforation. Pediatrics 2007; 120 (6) e1458-e1464
• 16 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 (2) 236-242 , e2
• 17 Moore SW, Arnold M, Wright C. Necrotizing enterocolitis and the placenta - a key etiological link. J Pediatr Surg 2013; 48 (2) 359-362
• 18 Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med 2000; 342 (20) 1500-1507
• 19 Arayici S, Kadioglu Simsek G, Oncel MY , et al. The effect of histological chorioamnionitis on the short-term outcome of preterm infants ≤32 weeks: a single-center study. J Matern Fetal Neonatal Med 2013; (e-pub ahead of print). DOI: 10.3109/1467058.2013.850668
• 20 Perrone S, Toti P, Toti MS , et al. Perinatal outcome and placental histological characteristics: a single-center study. J Matern Fetal Neonatal Med 2012; 25 (Suppl. 01) 110-113
• 21 Redline RW. Inflammatory response in acute chorioamnionitis. Semin Fetal Neonatal Med 2012; 17 (1) 20-25
• 22 Kaplan CG. Fetal and maternal vascular lesions. Semin Diagn Pathol 2007; 24 (1) 14-22
• 23 Redline RW, Faye-Petersen O, Heller D, Qureshi F, Savell V, Vogler C ; Society for Pediatric Pathology, Perinatal Section, Amniotic Fluid Infection Nosology Committee. Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol 2003; 6 (5) 435-448
• 24 Chisholm KM, Heerema MC, Kenney A , et al. Correlation of preterm infant morbidities with placental histology. In: Society of Pediatric Pathology Spring Meeting; March 17–18, 2012; Vancouver, Canada
• 25 Lau J, Magee F, Qiu Z, Houbé J, Von Dadelszen P, Lee SK. Chorioamnionitis with a fetal inflammatory response is associated with higher neonatal mortality, morbidity, and resource use than chorioamnionitis displaying a maternal inflammatory response only. Am J Obstet Gynecol 2005; 193 (3 Pt 1) 708-713
• 26 Lahra MM, Jeffery HE. A fetal response to chorioamnionitis is associated with early survival after preterm birth. Am J Obstet Gynecol 2004; 190 (1) 147-151
• 27 Galinsky R, Polglase GR, Hooper SB , et al. The consequences of chorioamnionitis: preterm birth and effects on development. J Pregnancy 2013; 2013: 412831
• 28 Gantert M, Been JV, Gavilanes AW, Garnier Y, Zimmermann LJ, Kramer BW. Chorioamnionitis: a multiorgan disease of the fetus?. J Perinatol 2010; 30 (Suppl): S21-S30
• 29 Jurd KM, Stephens CJ, Black MM, Hunt BJ. Endothelial cell activation in cutaneous vasculitis. Clin Exp Dermatol 1996; 21 (1) 28-32