Necrotizing enterocolitis (NEC) is a devastating morbidity usually seen in preterm infants, with extremely preterm neonates (EPT ≤28 weeks) considered at highest risk. Moderately preterm infants (MPT 28–34 weeks) constitute a large percentage of NICU admissions. In our retrospective data analysis of NEC in a single regional perinatal center, NEC was observed in 10% of extremely EPT and 7% of MPT, but only 0.7% of late-preterm/term admissions. There was an inverse relationship between postnatal age at onset of NEC and gestational age at birth. Among MPT infants with NEC, maternal hypertensive disorders (29%) and small for gestational age (SGA-15%) were more common than in EPT infants (11.6 and 4.6%, resp.). Congenital gastrointestinal anomalies were common among late preterm/term infants with NEC. SGA MPT infants born to mothers with hypertensive disorders are particularly at risk and should be closely monitored for signs of NEC. Identifying risk factors specific to each gestational age may help clinicians to tailor interventions to prevent NEC.
Necrotizing enterocolitis (NEC) is an acute inflammatory necrosis of the bowel that primarily affects preterm infants and remains a leading cause of mortality and morbidity in neonatal intensive care units (NICU). Risk factors for classic NEC include prematurity, a feeding insult, abnormal bacterial flora, and intestinal ischemia/reperfusion injury with activation of proinflammatory cytokines [
Most studies have focused on NEC in EPT infants <28-week gestational age (GA), since this group is at highest risk. Yet, it does occur in “older” preterm infants as well. NEC in moderately preterm (MPT) infants is reported to occur at a rate of ~1% [
The purpose of our study was to describe NEC in MPT infants (28–34-week GA at birth). We hypothesized that, in comparison to the EPT group, MPT and late preterm/term (LP/T) infants who develop NEC would have a higher incidence of hemodynamic insults such as congenital heart disease, small for gestational age (SGA), pregnancy-induced hypertension (PIH)/preeclampsia, and perinatal asphyxia evidenced by the need for advanced resuscitation at birth. We also hypothesized that MPT infants who develop NEC will have a lower incidence of surgical NEC compared to EPT neonates.
This was a retrospective data analysis of all infants diagnosed with NEC that were admitted to a single tertiary care NICU over a period of 7 years from July 2009 to July 2016. The State University of New York at Buffalo Institutional Review Board (IRB) approval was obtained prior to data collection, and an exemption to individual parental consent was granted.
Infants were included with a diagnosis of NEC stage 2 or higher by Modified Bell’s staging [
Subjects were divided into three groups based upon GA at birth: extremely preterm (EPT< 28 weeks), moderate preterm (MPT-28 to 33 6/7 weeks), and late preterm/term (LPT/T> 34 weeks). Differences between the groups were tested using Chi-squared test for categorical variables and ANOVA for continuous normally distributed variables. Results were considered significant when p < 0.05.
Out of 6113 admissions to the NICU, 172 patients (2.8%) developed NEC (Table
Baseline characteristics.
Characteristic | EPT | MPT | LPT/T |
---|---|---|---|
Incidence of NEC as % of NICU admits at corresponding GA | 10% (43/399) | 7% (99/1359) | 0.7% (30/4355) |
GA at birth (weeks, mean ± SD) | 25.5±1.4 | 30.5±1.7 | 36.1±1.8 |
Birth weight (kg) | 0.77±0.18 | 1.41±0.37 | 2.54±0.6 |
Postnatal day at onset of NEC (d) | 25.9±18 | 18±15 | 12.7±16.2 |
Postmenstrual age at diagnosis (weeks) | 29.2±2.4 | 33.1±2.2 | 37.9±2.9 |
Inverse relationship between gestational age at birth and postnatal day at diagnosis of NEC. Each infant represented by a circle. Black circles represent the infants with congenital gastrointestinal anomalies (gastroschisis and Hirschsprung’s disease).
The MPT and LPT/T cohorts with NEC had a significantly larger percentage of infants who were SGA (15% and 27% vs 4.6% in EPT) (Table
Ante and Perinatal risk factors for NEC.
Characteristic | EPT (n=43) | MPT (n=99) | LPT/T (n=30) | P value |
---|---|---|---|---|
Chorioamnionitis | 5 (11.6%) | 7 (7) | 1 (3.3%) | 0.4 |
Maternal hypertensive disorders | 5 (11.6%) | 29(29%) | 5 (16%) | 0.04 |
5 min APGAR score ≤ 5 | 3 (6.9%) | 2 (2%) | 1 (3.3%) | NS |
Small for gestational age | 2 (4.6%) | 15 (15%) | 8 (27%) | 0.02 |
Presence of clinical factors that could have contributed to NEC was assessed among the three groups (Table
Clinical factors prior to diagnosis of NEC.
Characteristic | EPT (n=43) | MPT (n=99) | LPT/T (n=30) | P value |
---|---|---|---|---|
Hypotension in first 24 hrs after birth | 9 (20.9%) | 4 (4%) | 0 | 0.0005 |
Exclusive breast milk | 2 (4.6%) | 1(1%) | 2 (6.6%) | NS |
Mixed Diet (formula and breast milk) | 32 (74.4%) | 76 (76.8%) | 16 (53.4%) | 0.04 |
Exclusive formula diet | 9 (21%) | 23 (23%) | 12 (40%) | NS |
Antibiotic days prior to NEC | 7.7±4.5 | 4.9±3.5 | 5.8±3.5 | 0.002 |
Hematocrit at diagnosis (%) | 33.5±5.6 | 34.5±6.3 | 41.8±10.4 | 0.005 |
Transfusion in the 48hrs prior to diagnosis | 11 (25.6%) | 12 (12.1%) | 0% | 0.02 |
Congenital Gastrointestinal abnormalities† | 0 | 7 (7%) | 6 (20%) | 0.006 |
Genetic/congenital non GI abnormalities‡ | 0 | 5 (5%) | 3 (10%) | 0.13 |
† Congenital GI anomalies included gastroschisis (4), Hirschsprung’s disease, imperforate anus, jejunal atresia and Meckels diverticulum. ‡ Genetic/non GI abnormalities included Trisomy 13, Trisomy 21, congenital myopathy, meningomyelocele and 17q21 deletion.
Exclusive involvement of the colon was more common, and need for surgery was less common with increasing gestation (Table
Outcome characteristics.
Characteristic | EPT (n=43) | MPT (n=99) | LPT/T (n=30) | P value |
---|---|---|---|---|
Colonic NEC | 0 | 19 (19.19%) | 10 (30.03%) | 0.0006 |
Surgical NEC | 22 (53%) | 20 (21%) | 1 (3.3%) | 0.0031 |
Death before discharge | 8 (18.6%) | 9 (9%) | 1 (3.3%) | 0.08 |
Necrotizing enterocolitis is the most common abdominal emergency of the preterm infant. We present this retrospective review to highlight the large number of MPT infants presenting with NEC and outline the morbidities associated with NEC.
Though GA is a continuum, different GA categories may have characteristic risk factors and clinical signs of disease. Over the last decade, mortality and morbidity among the MPT and LPT infants has received significant attention [
In our single center retrospective study of all inborn infants with stage 2 or greater NEC, we have noted an inverse relation between GA at birth and postnatal age at onset of disease (Figure
We noted a significantly higher percentage of MPT infants with NEC exposed to maternal hypertensive disorders compared to the other GA groups. Maternal hypertensive disorders, especially preeclampsia and eclampsia, are thought to predispose preterm infants to NEC. In a single center observational study, infants born to preeclamptic mothers had a higher incidence of NEC (22.9% vs 14.6%), earlier onset, more advanced stages of disease, and longer duration of illness as compared to infants born to normotensive mothers [
In our study, MPT and LPT/T infants with NEC were more likely to be SGA. A retrospective study on infants with surgical NEC in Stockholm county also noted similar results with a higher incidence of intrauterine growth restriction (IUGR) in more mature infants (>28 weeks) [
Another potential risk factor for NEC with similar pathophysiology is a hypoxic ischemic insult [
Chorioamnionitis and resulting inflammation of the fetoplacental unit are thought to contribute to neonatal morbidity. Recent studies have, however, failed to demonstrate an association of clinical or histological chorioamnionitis with NEC [
Discrete clinical characteristics of NEC in the MPT infants seemed to overlap with EPT groups. MPT infants were similar to EPT in receiving a mixed diet, being anaemic at onset of disease and having a history of PRBC transfusions just prior to diagnosis (Figure
Salient risk factors for NEC noted in term and EPT infants are shown here. MPT infants share some characteristics of both groups, mostly related to a vascular etiology such as anaemia/transfusion and SGA status.
Infants with NEC in the MPT group also share some characteristics similar to LPT/T infants (presence of congenital anomalies, colonic NEC, and decreased need for surgical intervention). Exclusive involvement of the colon was not observed in EPT infants. Colonic involvement is more likely to present with bloody stools, and this finding has been described more commonly in > 28-week gestation infants with NEC than in extremely preterm infants [
This is a retrospective data analysis of infants born at a single regional perinatal center. Only data recorded in the EMR could be collected. We do not have data on control infants at the same GA that did not develop this condition.
The incidence of NEC among MPT infants in our study is considerably higher than the previously reported data. Our institution is a Women and Children’s Hospital with a large maternal transport service leading to a higher number of high-risk obstetric population including hypertensive disorders of pregnancy. However, we feel that the antecedent factors and clinical characteristics observed in our cohort are applicable to general population.
MPT infants who develop NEC may have risk and disease characteristics that overlap with both LPT/T and EPT groups. While reduced intestinal oxygen delivery (from hemodynamic factors such as hypotension or anaemia/transfusion) continues to be associated with NEC in MPT infants, they also tend to have associated congenital anomalies. Prenatal vascular factors (maternal hypertensive disorder and growth restriction) appear to play a major role in NEC in MPT infants. Recognition of these risk factors in this cohort may help in screening for NEC as well as in developing care practices for at risk infants.
The data used to support the findings of this study are included within the article.
Contents of this manuscript have been presented as abstracts at the Medical Students Research forum 2017 (Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY), Pediatric Academic Societies Conference (5/2017), San Francisco, CA, and the NEC Society Annual conference, UC Davis, CA (4/2017).
The authors declare that there are no conflicts of interest regarding the publication of this paper.
This study is funded by 1R01HD072929 (SL), 1 R03 HD086531-01 (JN), National Institutes of Health-Eunice Kennedy Shriver National Institute of Child Health and Human Development, 1 Center Dr, Bethesda, MD 20892, and Department of Pediatrics, University at Buffalo.