Association of Placental Pathology and Antibiotic Exposure after Birth with the Severity of Necrotizing Enterocolitis in Preterm Infants: A Case–Control Study

Parvesh M. Garg; Robbin Riddick; Md Abu Yusuf Ansari; Aubrey Rebentisch; Avinash Shetty; Kristin Adams; William Hillegass; Padma P. Garg

doi:10.1055/a-2663-5723

American Journal of Perinatology, Inhaltsverzeichnis

Am J Perinatol
DOI: 10.1055/a-2663-5723

Original Article

Association of Placental Pathology and Antibiotic Exposure after Birth with the Severity of Necrotizing Enterocolitis in Preterm Infants: A Case–Control Study

Parvesh M. Garg

¹Department of Pediatrics/Neonatology, Wake Forest School of Medicine, Winston-Salem, North Carolina

,

Robbin Riddick

²Department of Pediatrics/Neonatology, University of Mississippi Medical Center, Jackson, Mississippi

,

Md Abu Yusuf Ansari

³Department of Data Science, University of Mississippi Medical Center, Jackson, Mississippi

,

Aubrey Rebentisch

²Department of Pediatrics/Neonatology, University of Mississippi Medical Center, Jackson, Mississippi

,

Avinash Shetty

⁴Department of Pediatrics/Infectious Disease, Wake Forest School of Medicine, Winston-Salem, North Carolina

,

Kristin Adams

⁵Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi

,

William Hillegass

³Department of Data Science, University of Mississippi Medical Center, Jackson, Mississippi

⁶Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi

,

Padma P. Garg

²Department of Pediatrics/Neonatology, University of Mississippi Medical Center, Jackson, Mississippi

› Institutsangaben

Abstract

Objective

This study aimed to assess the relationship between placental lesions, antibiotic exposure duration, and necrotizing enterocolitis (NEC) severity in preterm infants.

Study Design

In this single-center, case–control study, 107 infants with NEC and 130 controls were grouped by antibiotic exposure after birth: ≤3 or >3 days.

Results

Of 212 infants, 103 (48.5%) received antibiotics for ≤3 days, while 109 (51.5%) received antibiotics for >3 days. Multivariate regression analysis demonstrated that prolonged antibiotic duration (>3 vs. ≤3 days) was significantly associated with increased severity of NEC, with adjusted odds ratios (aORs) of 2.65 (95% confidence interval [CI]: 1.36–5.16; p = 0.004) for medical NEC and 3.36 (95% CI: 1.56–7.23; p = 0.002) for surgical NEC. However, prolonged antibiotic duration was not significantly associated with overall mortality (aOR = 1.16, 95% CI: 0.58–2.34; p = 0.7). Among infants diagnosed with NEC (n = 97), antibiotic duration of >3 days significantly increased the odds of mortality (aOR = 7.34, 95% CI: 1.94–48.3; p = 0.011) but was not significantly associated with NEC severity (aOR = 1.20, 95% CI: 0.49–2.94; p = 0.7). Among 64 infants with acute histologic chorioamnionitis, 37 (58%) received antibiotics for >3 days. Longer antibiotic exposure was linked to higher risks of medical NEC (79 vs. 38%; p = 0.021) and surgical NEC (62 vs. 38%; p = 0.021) compared with shorter exposure. In 134 infants with maternal vascular malperfusion (MVM), prolonged antibiotics were also associated with increased risks for medical (60 vs. 36%; p = 0.007) and surgical NEC (67 vs. 36%; p = 0.007). Concordance between clinical and pathologic chorioamnionitis was moderate (first-order agreement coefficient [AC1] = 0.60), while agreement for pregnancy-induced hypertension versus MVM was minimal (AC1 = 0.07).

Conclusion

Prolonged antibiotic exposure (>3 days) in infants with chorioamnionitis or MVM is most likely associated with increased NEC severity. Limiting antibiotic duration may reduce severe NEC risk in preterm infants.

Key Points

Prolonged antibiotics following birth are associated with NEC severity.
Infants exposed to chorioamnionitis and receiving prolonged antibiotics are more likely at NEC risk.
Shorter duration of antibiotics following birth may reduce NEC risk.

Keywords

placenta - antibiotics - NEC - preterm infants - surgical NEC

Volltext

Referenzen

References
1 Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011; 364 (03) 255-264
2 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
3 Mowitz ME, Dukhovny D, Zupancic JAF. The cost of necrotizing enterocolitis in premature infants. Semin Fetal Neonatal Med 2018; 23 (06) 416-419
4 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
5 Kurscheid T, Holschneider AM. Necrotizing enterocolitis (NEC)–mortality and long-term results. Eur J Pediatr Surg 1993; 3 (03) 139-143
6 Garzoni L, Faure C, Frasch MG. Fetal cholinergic anti-inflammatory pathway and necrotizing enterocolitis: the brain-gut connection begins in utero. Front Integr Nuerosci 2013; 7: 57
7 Keating ST, El-Osta A. Epigenetics and metabolism. Circ Res 2015; 116 (04) 715-736
8 Nelissen EC, van Montfoort AP, Dumoulin JC, Evers JL. Epigenetics and the placenta. Hum Reprod Update 2011; 17 (03) 397-417
9 Dix L, Roth-Kleiner M, Osterheld MC. Placental vascular obstructive lesions: risk factor for developing necrotizing enterocolitis. Pathol Res Int 2010; 2010: 838917
10 Moore SW, Arnold M, Wright C. Necrotizing enterocolitis and the placenta - a key etiological link. J Pediatr Surg 2013; 48 (02) 359-362
11 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
12 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
13 Garg PP, Weitkamp J-H, McDonald AG. et al. Placenta and intestinal Injury in preterm infants. Am J Perinatol 2025; 42 (04) 415-419
14 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
15 Cuna A, Morowitz MJ, Sampath V. Early antibiotics and risk for necrotizing enterocolitis in premature infants: A narrative review. Front Pediatr 2023; 11: 1112812
16 Vatne A, Hapnes N, Stensvold HJ. et al. ; Norwegian Neonatal Network. Early empirical antibiotics and adverse clinical outcomes in infants born very preterm: A population-based cohort. J Pediatr 2023; 253: 107-114.e5
17 Cotten CM, Taylor S, Stoll B. et al. ; NICHD Neonatal Research Network. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 2009; 123 (01) 58-66
18 Ting JY, Roberts A, Sherlock R. et al. ; Canadian Neonatal Network Investigators. Duration of initial empirical antibiotic therapy and outcomes in very low birth weight infants. Pediatrics 2019; 143 (03) e20182286
19 Dierikx TH, Deianova N, Groen J. et al. Association between duration of early empiric antibiotics and necrotizing enterocolitis and late-onset sepsis in preterm infants: a multicenter cohort study. Eur J Pediatr 2022; 181 (10) 3715-3724
20 Reyman M, van Houten MA, Watson RL. et al. Effects of early-life antibiotics on the developing infant gut microbiome and resistome: a randomized trial. Nat Commun 2022; 13 (01) 893
21 Nguyen DN, Fuglsang E, Jiang P. et al. Oral antibiotics increase blood neutrophil maturation and reduce bacteremia and necrotizing enterocolitis in the immediate postnatal period of preterm pigs. Innate Immun 2016; 22 (01) 51-62
22 Chaaban H, Patel MM, Burge K. et al. Early antibiotic exposure alters intestinal development and increases susceptibility to necrotizing enterocolitis: A mechanistic study. Microorganisms 2022; 10 (03) 519
23 Bell MJ, Ternberg JL, Feigin RD. et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978; 187 (01) 1-7
24 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) 685-694
25 Pinar H, Sung CJ, Oyer CE, Singer DB. Reference values for singleton and twin placental weights. Pediatr Pathol Lab Med 1996; 16 (06) 901-907
26 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
27 Fitzgerald B, Kingdom J, Keating S. Distal villous hypoplasia. Diagn Histopathol (Oxf) 2012; 18 (05) 195-200
28 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
29 Ernst LM. Maternal vascular malperfusion of the placental bed. APMIS 2018; 126 (07) 551-560
30 Khong TY, Mooney EE, Nikkels PGJ, Morgan TK, Gordijn SJ. eds. Villous Oedema, in Pathology of the Placenta: A Practical Guide. Cham: Springer International Publishing; 2019. :pp. 153-155
31 Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33 (01) 159-74
32 Zhu D, Xiao S, Yu J. et al. Effects of one-week empirical antibiotic therapy on the early development of gut microbiota and metabolites in preterm infants. Sci Rep 2017; 7 (01) 8025
33 Garcia TM, van Roest M, Vermeulen JLM. et al. Early life antibiotics influence in vivo and in vitro mouse intestinal epithelium maturation and functioning. Cell Mol Gastroenterol Hepatol 2021; 12 (03) 943-981
34 Greenwood C, Morrow AL, Lagomarcino AJ. et al. Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of Enterobacter . J Pediatr 2014; 165 (01) 23-29
35 Schumann A, Nutten S, Donnicola D. et al. Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome. Physiol Genomics 2005; 23 (02) 235-245
36 Pammi M, Cope J, Tarr PI. et al. Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis. Microbiome 2017; 5 (01) 31
37 Kim CS, Grady N, Derrick M. et al. Effect of antibiotic use within first 48 hours of life on the preterm infant microbiome: A randomized clinical trial. JAMA Pediatr 2021; 175 (03) 303-305
38 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
39 Redline RW, Heller D, Keating S, Kingdom J. Placental diagnostic criteria and clinical correlation–a workshop report. Placenta 2005; 26 (Suppl A): S114-S117
40 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
41 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
42 Dammann O, Allred EN, Leviton A. et al. Fetal vasculitis in preterm newborns: interrelationships, modifiers, and antecedents. Placenta 2004; 25 (10) 788-796
43 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
44 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
45 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

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