Increased incidence of necrotizing enterocolitis in very/extremely preterm infants with early hypotension: a retrospective cohort study

Introduction

Necrotizing enterocolitis (NEC) is a severe gastrointestinal emergency in neonates, characterized by inflammation and ischemic damage to the intestinal mucosal lining. Its incidence primarily ranges from 2% to 13% among preterm infants, and the associated mortality rate varies between 20% and 45% (1,2). Surviving infants often experience severe long-term consequences, including growth impairment, and neurodevelopmental delay (3,4). Thus, identifying risk factors for NEC is crucial for decreasing associated morbidity and mortality.

The precise etiology of NEC has yet to be clearly elucidated. Historical evidence implicates numerous contributing factors, including genetic susceptibility, structural and immunological immaturity of the gastrointestinal tract, heightened reactivity of intestinal mucosa, and abnormal colonization of intestinal microbiota (5). Additionally, NEC has been linked to vascular compromise and impaired perfusion, which may initiate inflammatory cascades (6,7). Previous research suggests that neonatal hypotension and associated circulatory disturbances influencing intestinal perfusion might exacerbate NEC development (8,9). However, there is no accurate definition of hypotension in preterm infants, and it remains controversial whether hypotension is a definitive independent risk factor for NEC.

The aim of this study was to clarify the potential association between early neonatal hypotension and NEC. The results are intended to provide a foundation for clinical decision-making and to facilitate earlier and more targeted interventions aimed at reducing NEC incidence. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-416/rc).

Methods

Study population

This retrospective study enrolled preterm infants with a gestational age (GA) of <32 weeks who were admitted to the Neonatal Intensive Care Unit (NICU) at the Seventh Medical Center of the Chinese PLA General Hospital from January 2021 to December 2023. Exclusion criteria included: (I) newborns transferred from other hospitals several days postpartum; (II) incomplete clinical data regarding the perinatal or neonatal periods; (III) prophylactic hydrocortisone administration to extremely preterm infants immediately after birth (0.5 mg/kg per 12 hours for 7 days, followed by a dose of 0.5 mg/kg per day for 3 days); and (IV) severe congenital heart defects or genetic metabolic disorders. Based on the occurrence of hypotension within the first postnatal week, infants were categorized into hypotension and non-hypotension groups. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol received approval from the Seventh Medical Center of Chinese PLA General Hospital ethics committee (No. S2025-032-01), and written informed consent was obtained from all parents/legal guardians upon their infant’s admission to the participating NICU.

Blood pressure (BP) measurement

Mean arterial pressure (MAP) values were retrieved from nursing flowsheets in electronic medical records. All invasive BP (IBP) measurements were obtained via umbilical arterial catheters (UACs) or peripheral ACs (PACs). Non-invasive blood pressure (NIBP) measurements were recorded concurrently at 6-hour intervals during the first week postnatally using a Drager Vista 120 multipara monitor (Draeger, Luebeck, Germany). Measurements displaying dampened arterial waveforms or NIBP values differing by more than 15% from paired IBP readings were excluded from the analyses to avoid potential inaccuracies.

Data collection

Clinical data on neonatal and perinatal factors of very/extremely preterm infants were retrieved from hospital inpatient records.

• Maternal factors comprised maternal age, amniotic fluid contamination, chorioamnionitis, abnormal amniotic fluid volume, fetal intrauterine distress, hypertensive disorders of pregnancy, gestational diabetes mellitus (GDM), placenta previa, placental abruption, hypothyroidism, hyperthyroidism, prenatal infection, anemia during pregnancy, premature rupture of membranes (PROM), and antenatal steroid use.
• Neonatal factors included infant gender, GA, birth weight (BW), mode of delivery, multiple pregnancy status, in vitro fertilization (IVF) conception, Apgar scores evaluated at 1 and 5 minutes, small for gestational age (SGA), surfactant therapy, feeding methods, and routine blood parameters (including hemoglobin concentration, platelet counts, and white blood cell counts) assessed within the initial 24 hours post-delivery.
• Neonatal outcomes, both morbidity and mortality, encompassed bronchopulmonary dysplasia (BPD), moderate-to-severe BPD, respiratory distress syndrome (RDS), pulmonary hemorrhage, invasive mechanical ventilation, hemodynamically significant patent ductus arteriosus (hsPDA), neonatal sepsis, intraventricular hemorrhage (IVH), severe IVH (grade III or IV), periventricular leukomalacia (PVL), NEC, surgically treated NEC, retinopathy of prematurity (ROP), severe ROP, and mortality rate.

Clinical definitions

Hypotension was defined as a MAP persisting below the preterm infant’s GA threshold for longer than 15 minutes, accompanied by signs of hypoperfusion such as lactic acidosis, prolonged capillary refill time, oliguria, or supportive echocardiographic findings (e.g., low cardiac output or a hsPDA) (10). Management required adherence to a standardized protocol, including administration of inotropic agents, hydrocortisone or volume expansion to elevate BP.

RDS was determined by early-onset respiratory compromise confirmed through chest X-ray findings, necessitating mechanical respiratory assistance via endotracheal intubation and surfactant replacement therapy (11).

BPD was defined as the continued need for supplementary oxygen or respiratory support beyond 28 days postnatally in infants born before 32 weeks’ gestation. Moderate BPD was defined as a required FiO₂ <30%, while severe BPD indicated FiO₂ ≥30% or ongoing positive pressure/mechanical ventilation at 36 weeks postmenstrual age (12).

Neonatal sepsis was defined as either the identification of pathogens in blood or cerebrospinal fluid cultures, or a laboratory-confirmed infection accompanied by non-specific systemic symptoms (13).

HsPDA diagnosis integrated echocardiographic findings with clinical features (14).

IVH was diagnosed by transcranial ultrasonography, with severe IVH defined as grade III–IV (15).

Definite NEC was characterized by a modified Bell’s staging ≥II, requiring clinical signs and symptoms along with radiographic evidence of pneumatosis intestinalis or portal venous gas (16).

Surgically treated NEC was defined as severe cases requiring surgical intervention, which encompassed either exploratory laparotomy or drainage procedure (17).

Severe ROP was determined as threshold ROP (stage ≥ III) necessitating laser or ranibizumab treatment (18).

Other clinical diagnoses adhered to established neonatal data collection protocols.

Statistical analysis

Statistical analysis was conducted using SPSS software (version 26.0). Continuous variables were presented as mean ± standard deviation (SD) for normally distributed data or median with interquartile range (IQR) for non-normally distributed data following normality assessment. Comparisons of continuous data between groups were performed using either the Mann-Whitney U test or independent-sample t-test, depending on data distribution. Frequencies (n) and proportions (%) were employed to summarize categorical variables, and χ² tests were utilized to evaluate differences between groups. Univariate and multivariate logistic regression models were used to evaluate associations between neonatal morbidity or mortality and hypotension during the early neonatal period, adjusting for potential confounding factors. Adjusted odds ratios (ORs) along with their respective 95% confidence intervals (CIs) were computed. P<0.05 was considered statistically significant.

Results

Comparison of participant characteristics between the two groups

A total of 355 very/extremely preterm infants were enrolled and categorized into a hypotensive group (n=130, 36.6%) and a non-hypotensive group (n=225, 63.4%). Significant differences were observed between the two groups in terms of GA, BW, cesarean delivery, GDM, prenatal infections, and antenatal steroid therapy exposure (Z=4.250, P<0.001; t=2.452, P=0.02; χ²=9.481, P=0.002; χ²=7.643, P=0.006; χ²=4.128, P=0.042; χ²=4.196, P=0.041, respectively). Other clinical and demographic variables showed no statistically significant differences between the cohorts (all P>0.05). Tables 1,2 provide detailed summaries of participant characteristics.

Comparison of neonatal morbidity/mortality between the two groups

As shown in Table 3, significantly higher incidences of hsPDA, NEC, surgically treated NEC, and mortality were observed in the hypotensive group (all P<0.05). Conversely, the frequencies of other complications showed no significant intergroup differences (all P>0.05).

Correlation analysis between hypotension and neonatal morbidity/mortality

Table 4 illustrates the outcomes of multivariate logistic regression analyses, with early hypotension serving as the independent variable to assess associations with neonatal morbidities and mortality. Results indicated that infants in the hypotension group had a significantly higher incidence of NEC, surgically treated NEC, hsPDA, and death (all P<0.05). Adjusted for potential confounders that were significantly associated with the outcome in univariate analyses (P<0.05), including GA, WB, cesarean delivery, GDM, prenatal infections, and antenatal steroid therapy exposure, the association between neonatal early hypotension and NEC remained statistically significant (OR =2.80, 95% CI: 1.25–6.28, P=0.01).

Discussion

Hypotension frequently occurs in very/extremely preterm infants during the initial postnatal days, particularly within the first 72 hours, and is closely associated with GA and BW (19). Various factors, including immature myocardial function, perinatal asphyxia, early-onset sepsis, hsPDA, and adrenal insufficiency, significantly impact systemic BP regulation in neonates (20-22). Decreased BP often coincides with impaired cardiac output and inadequate systemic perfusion, potentially disrupting the balance between oxygen supply and demand, thereby initiating hypoxic cellular injury, metabolic disturbances, and ultimately multi-organ dysfunction (23,24). Previous studies have linked early neonatal hypotension to severe complications such as BPD, IVH, adverse neurological outcomes, and mortality (25,26). Additionally, hypotension may compromise gastrointestinal perfusion and blood flow, triggering inflammatory responses and ischemic mucosal injury, thereby potentially elevating the risk of NEC (8,27). However, reported associations differ among studies (28).

This investigation revealed notably increased incidences of hsPDA, NEC, surgically treated NEC, and mortality among neonates experiencing hypotension. Multivariate logistic regression analysis, adjusting for confounders such as GA, BW, cesarean delivery rate, GDM, prenatal infections, and exposure to antenatal steroid therapy, confirmed a persistent association between neonatal early hypotension and NEC. These findings align with prior research by Youn et al. (29), which reported significant correlations between NEC and hypotension during the first postnatal week in VLBW infants (OR =2.0, 95% CI: 1.0–3.9). Gephart et al. (7) developed the GutCheckNEC model, integrating multiple clinical risk factors, including neonatal hypotension requiring vasoactive medication, which was independently associated with increased NEC risk (OR =1.51, 95% CI: 1.36–1.69). Additionally, a 14-year retrospective analysis from Korea identified hypotension requiring vasoactive support within the first week of life as a predictor of increased mortality risk. Moreover, surviving infants with medical NEC were also more likely to require surgical intervention, which is consistent with our study findings (30). However, after adjusting for confounders, no statistically significant association was observed between hypotension and either death or surgically treated NEC. These findings suggest that hypotension might contribute to NEC incidence but does not appear to be a critical determinant of disease progression requiring surgery. Collectively, these results suggest that closely monitoring of BP and systemic perfusion in neonates, particularly those with risk factors such as prematurity or low BW, may represent a crucial preventive strategy against NEC.

Definitions of neonatal hypotension differ widely across studies. Although many NICUs commonly define hypotension as MAP lower than the neonate’s GA in weeks, this simplistic criterion overlooks the complex hemodynamic dynamics experienced by preterm infants during early adaptation. In VLBW infants born at <29 weeks GA, median minMAP typically ranges from 1 to 2 mmHg below GA in completed weeks. This discrepancy may result in systematic BP overestimation in clinically stable infants (31). Batton et al. (32) reported that extremely preterm infants are particularly vulnerable to hypotension due to cardiovascular immaturity. Their findings showed that BP typically declines during the first 3 hours after birth, reaches the lowest point at 4–5 hours, and spontaneously improves during the subsequent 24 hours. Moreover, the rate of BP increase between 4 and 24 hours was comparable in untreated infants and those receiving antihypotensive therapy. Additionally, BP in preterm infants tends to increase with greater body mass and age. Clinically stable infants who do not require ventilation typically achieve stabilized BP comparable to term infants at approximately 14 days of life (33). Unfortunately, 16–98% of preterm infants are subjected to cardiovascular interventions in the neonatal period to mitigate associated complications (34). Kharrat et al. (35) emphasized that BP is only one aspect of the intricate hemodynamic state during the early neonatal period, correlating poorly with left ventricular output and organ perfusion, independent of GA or underlying conditions. Consequently, given the limitations of defining hypotension solely by a low MAP, a standardized assessment must also incorporate clinical signs of impaired perfusion resulting from low cardiac output for a more accurate diagnosis. If active management of neonatal early hypotension effectively reduces NEC incidence, our research design could have significant clinical implications.

Conclusions

In conclusion, neonatal early hypotension was found to be associated with an increased risk of NEC. Timely management of circulatory compromise and hypotension may reduce NEC incidence. Nonetheless, the limited sample size and retrospective design necessitate cautious interpretation of our findings.

Acknowledgments

We would like to thank Zibo Yimore Translation CO. LTD for their help in polishing our paper.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-416/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-416/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-416/prf

Funding: This study was jointly supported by the National Key Research and Development Program of China (No.2022YFC2704804) and Innovation Talented Fund of Senior Department of Pediatrics, the Seventh Medical Center of PLA General Hospital (Nos. QZX-04-EKCLJH-16 and QZX-04-EKCLJH-25).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-416/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol received approval from the Seventh Medical Center of Chinese PLA General Hospital ethics committee (No. S2025-032-01), and written informed consent was obtained from all parents/legal guardians upon their infant’s admission to the participating NICU.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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