Short- and Long-Term Morbidities in Preterm Infants with Necrotizing Enterocolitis or Spontaneous Intestinal Perforation

Jung In Kang; Sangjun Park; So-Yeon Shim; Joo Yun Yang; Young Min Youn; Ye Jin Han; Do Kyung Lee; Hyun Kyung Bae; Soeun Park; Jin A Sohn

doi:10.5385/nm.26003

Neonatal Med > Volume 33(1); 2026 > Article

Kang, Park, Shim, Yang, Youn, Han, Lee, Bae, Park, and Sohn: Short- and Long-Term Morbidities in Preterm Infants with Necrotizing Enterocolitis or Spontaneous Intestinal Perforation

Original Article

Neonatal Medicine 2026;33(1):82-92.

Published online: May 31, 2026

DOI: https://doi.org/10.5385/nm.26003

Short- and Long-Term Morbidities in Preterm Infants with Necrotizing Enterocolitis or Spontaneous Intestinal Perforation

Jung In Kang, MD¹

, Sangjun Park, MD¹

, So-Yeon Shim, MD, PhD^1,²

, Joo Yun Yang, MD¹

, Young Min Youn, MD¹

, Ye Jin Han, MD¹

, Do Kyung Lee, MD¹

, Hyun Kyung Bae, MD¹

, Soeun Park, MD¹

, Jin A Sohn, MD, PhD^1,²

¹Department of Pediatrics, Ewha Womans University Seoul Hospital, Seoul, Korea

²Division of Neonatology, Department of Pediatrics, Ewha Womans University College of Medicine, Seoul, Korea

Correspondence to: Jin A Sohn, MD, PhD Division of Neonatology, Department of Pediatrics, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, 260 Gonghang-daero, Gangseo-gu, Seoul 07804, Korea
Tel: +82-2-6986-4227 Fax: +82-2-6986-3024 E-mail: jinasohn@hanmail.net

Received March 24, 2026 Revised May 11, 2026 Accepted May 12, 2026

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

This study compared short-term morbidity, mortality, and long-term neurological outcomes among preterm infants with necrotizing enterocolitis (NEC) and those with spontaneous intestinal perforation (SIP).

Methods

We conducted a retrospective analysis using data collected between 2013 and 2023 from the Korean Neonatal Network. The study included preterm infants born at <32 weeks of gestation or with a birth weight of <1,500 g who were diagnosed with NEC or SIP. A total of 18,446 infants were classified into four groups: control, medical NEC, surgical NEC, and SIP.

Results

Short-term morbidities and mortality were most prevalent in the surgical NEC group, whereas hypotension was most prevalent in the SIP group. Post hoc analysis showed that bronchopulmonary dysplasia and intraventricular hemorrhage were more common in the surgical NEC group than in the SIP group. Compared with the control and medical NEC groups, the surgical NEC group had significantly higher rates of hypotension, seizures, periventricular leukomalacia, sepsis, and retinopathy of prematurity but did not differ significantly from the SIP group. The surgical NEC and SIP groups required a longer time to achieve full enteral feeding, longer duration of total parenteral nutrition, and longer hospital stay. At a corrected age of 18–24 months, cerebral palsy and vision loss were more common in the surgical NEC group. At 33–39 months, cerebral palsy and eye disorders were more prevalent in the surgical NEC group, whereas hearing outcomes were worse in the SIP group.

Conclusion

Surgical NEC was associated with the poorest short- and long-term outcomes in preterm infants, and SIP showed comparable outcomes.

Keywords: Enterocolitis, necrotizing; Intestinal perforation; Morbidity; Mortality; Infant, premature

INTRODUCTION

Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are major gastrointestinal diseases that occur in preterm infants. NEC is a severe inflammatory disease that develops in the immature intestine. Clinically, it presents with feeding intolerance, abdominal distension, and bloody stools, and is radiologically characterized by pneumatosis intestinalis and portal venous gas. Previous studies have suggested that an excessive inflammatory response originating in the immature intestine may spread systemically and affect remote organs, and may be associated with various short-term complications and adverse long-term neurological outcomes [1,2].

In contrast, SIP is considered a distinct disease entity with a different pathophysiology and clinical course from NEC and typically presents as localized intestinal perforation [3,4]. SIP has been regarded as a localized disease with relatively limited systemic inflammatory responses; however, accumulating evidence suggests that infants with SIP may experience adverse short- and long-term clinical outcomes.

Several studies have reported that NEC, particularly that requiring surgical treatment, is significantly associated with an increased risk of adverse long-term neurological or neurodevelopmental outcomes, including cerebral palsy, cognitive impairment, visual impairment, and reduced intellectual function [5,6]. Recent studies have suggested that SIP may be associated with complications during hospitalization in the neonatal intensive care unit (NICU) and long-term neurological impairment [7-9].

However, these studies have several limitations. Some studies were based on single-center or small cohorts, whereas others were limited to follow-up periods of up to a corrected age of 2 years. In addition, some studies did not clearly distinguish between NEC and SIP, or focused only on specific disease groups, limiting the ability to directly compare outcomes between the two diseases. As NEC and SIP have different pathophysiologies, large population-based studies that distinguish between these diseases are required to compare their short-term clinical courses and long-term outcomes.

Therefore, we aimed to compare the short-term morbidity and mortality during NICU hospitalization and long-term neurological outcomes up to 3 years of age in preterm infants with NEC or SIP using data from the Korean Neonatal Network (KNN).

MATERIALS AND METHODS

1. Study population

The KNN is a nationwide registry that enrolls preterm infants with a birth weight of <1,500 g or a gestational age of <32 weeks who are admitted to the NICU at birth or transferred within 28 days after birth. This study included very low birth weight (VLBW) and very preterm infants registered in the KNN between 2013 and 2023. Infants with major congenital anomalies or ambiguous sex were excluded from the study. Detailed inclusion and exclusion criteria are shown in Figure 1.

The study population was divided into four groups: the control group, comprising infants who were not diagnosed with either NEC or SIP; the medical NEC group, consisting of infants with NEC who did not undergo surgical treatment; the surgical NEC group, consisting of infants with NEC who underwent surgical treatment; and the SIP group, comprising infants who were treated for SIP. We compared complications, morbidities, and mortality among the four groups.

2. Definitions

Weight, height, and head circumference were converted into standard deviation (SD; z) scores according to corrected age and sex using the lambda-mu-sigma method, Fenton growth charts [10–12], and World Health Organization growth charts [13].

NEC was defined as stage II or higher according to the modified Bell staging criteria [14]. SIP was defined as perforation of the intestinal wall occurring in the absence of preceding factors, such as NEC or intestinal atresia [15,16].

Respiratory distress syndrome (RDS) was defined as the need for respiratory support in infants with compatible clinical manifestations and typical chest radiographic findings. Bronchopulmonary dysplasia (BPD) was defined as moderate or severe according to the 2001 National Institute of Child Health and Human Development criteria [17]. Patent ductus arteriosus and hypotension were limited to cases requiring treatment. Intraventricular hemorrhage (IVH) was defined as grade 3 or 4 according to the Papile classification system [18]. Retinopathy of prematurity (ROP) was defined as stage 3 or higher based on the highest stage recorded before NICU discharge [19]. Seizures were limited to cases requiring antiepileptic treatment. Periventricular leukomalacia (PVL) was defined as a diagnosis made by a radiologist using ultrasonography or magnetic resonance imaging. Congenital infections were defined as confirmed toxoplasmosis, rubella, cytomegalovirus, herpes virus, or syphilis. Sepsis and meningitis were defined as a positive blood culture or cerebrospinal fluid culture, respectively, requiring systemic antibiotic treatment for at least 5 days. Full feeding was defined as enteral feeding of >100 mL/kg/day.

Cerebral palsy was defined as a diagnosis made by the primary physician or rehabilitation specialist at follow-up visits at corrected ages of 18–24 and 33–39 months. An eye disorder was defined as a prematurity-related ophthalmologic disorder requiring treatment by an ophthalmologist during follow-up visits at corrected ages of 18–24 and 33–39 months. Vision loss and hearing impairment were defined as diagnoses made by an ophthalmologist and otolaryngologist, respectively. Hearing aid use was defined as the use of a hearing aid or cochlear implant as prescribed by an otolaryngologist at the time of follow-up.

3. Statistical analysis

All variables are presented as means with SDs, medians with interquartile ranges (IQR), or numbers with percentages. Anthropometric and physiological variables that showed approximately symmetric distributions, including birth weight, height, head circumference, and Apgar scores at 1 and 5 minutes, are presented as mean±SD. Skewed count variables, including time to full enteral feeding, duration of total parenteral nutrition (TPN), and length of NICU hospitalization, and variables conventionally reported as medians, including maternal age and gestational age, are presented as medians with IQR.

To reduce baseline imbalances among the four groups, covariate balancing propensity scores (CBPS) were estimated using gestational age and birth weight as covariates [20]. CBPS-derived stabilized weights were used to analyze baseline characteristics, short-term complications, mortality, and long-term neurological outcomes. Stabilized weights were applied, and extreme weights below the 1st percentile and above the 99th percentile were excluded to reduce the influence of outliers. The unadjusted baseline characteristics before weighting are presented in Supplementary Table 1.

For weighted categorical outcomes, including short-term complications and long-term neurological outcomes, group comparisons were performed using the weighted chi-square test or Fisher’s exact test. When significant differences were observed, post hoc pairwise comparisons were adjusted using the Benjamini–Hochberg (BH) false discovery rate method [21]. Weighted continuous outcomes were analyzed using linear mixed-effects models that incorporated the CBPS weights. Pairwise mean differences between groups, corresponding 95% confidence intervals (CIs), and Tukey honestly significant difference-adjusted P-values were estimated from the estimated marginal means [22]. Long-term neurological outcomes were analyzed using complete-case analysis, which included only infants with available follow-up data at each time point.

The Kruskal–Wallis rank-sum test was used to compare disease onset timing among the three disease groups. To compare the timing of surgery between the two groups, the Wilcoxon rank-sum test, also known as the Mann–Whitney U-test, was used. Fisher’s exact test was used to compare differences across event-time categories.

All statistical analyses were performed using R software version 4.5.3 (R Core Team, 2026). The CBPS estimation was performed using the WeightIt package [23], mixed-effects modeling using the lme4 package [24] and lmerTest package [25], pairwise comparisons using the emmeans package [26], and weighted analyses using the survey package [27]. All tests were two-sided, and P-values of less than 0.05 were considered statistically significant.

RESULTS

Among the 19,437 infants registered with the KNN between 2013 and 2023, 577 were excluded due to major congenital anomalies or ambiguous sex. An additional 414 of the remaining 18,860 infants were excluded based on the NEC- and SIP-related exclusion criteria. The specific reasons for exclusion were unclear classification of NEC or SIP in 153 infants, classification of both diseases in 164, transfer or death before surgery among infants classified as NEC in 79, transfer or death before surgery among infants classified as SIP in 16, and untreated SIP in 2. Finally, 18,446 infants were included in the study (Figure 1). Based on diagnosis and treatment, the study population was classified into control (n=17,075), medical NEC (n=472), surgical NEC (n=584), and SIP (n=315) groups.

1. Maternal and perinatal characteristics

The maternal and perinatal characteristics of the four groups are summarized in Table 1. Among the maternal characteristics, significant differences were observed in the proportion of maternal diabetes history (P=0.017) and amniotic fluid status during pregnancy (P=0.043). Among the perinatal characteristics, the sex distribution differed significantly among the groups (P=0.010). No significant differences were observed in any of the remaining variables.

2. Disease onset and timing of surgery

Both SIP and surgical NEC tended to occur in more immature infants (Supplementary Table 1). The median gestational age was 26.0 weeks in the SIP group, 25.6 weeks in the surgical NEC group, 27.6 weeks in the medical NEC group, and 28.7 weeks in the control group. All three disease groups had significantly lower gestational ages than the control group, respectively (all BH-adjusted, P<0.001). However, the difference in gestational age between the SIP and surgical NEC groups was small at 0.3 weeks (BH-adjusted, P=0.025), and birth weight did not differ significantly between these two groups (P=0.62).

When the recorded date of NEC diagnosis and the date of surgery for SIP in the KNN were converted into days from birth and compared, SIP occurred at a median of 8 days, which was significantly earlier than medical NEC, which occurred at a median of 15 days, and surgical NEC, which occurred at a median of 12 days (all BH-adjusted, P<0.001). The proportion of early-onset disease, defined as occurrence within 7 days after birth, was also the highest in the SIP group: 28.1% in the medical NEC group, 27.9% in the surgical NEC group, and 43.3% in the SIP group (P<0.001) (Table 2). Surgery was performed earlier in the SIP group (median, 8 days) than in the surgical NEC group (median, 15 days) (P<0.001) (Table 2).

3. Short-term neonatal morbidities and mortality

Among short-term neonatal morbidities, significant differences among the four groups were observed for BPD, hypotension, seizure, IVH, PVL, sepsis, and ROP (all P<0.05) (Table 3). BPD (60.2%), seizure (17.0%), IVH (17.3%), PVL (18.6%), sepsis (40.4%), and ROP (20.1%) were most prevalent in the surgical NEC group, whereas hypotension (57.7%) was most prevalent in the SIP group.

In pairwise comparisons between the control group and each disease group, all morbidities were significantly higher in the disease groups, except for PVL, when comparing the control and medical NEC groups (P=0.089) (Table 4). When the control, medical NEC, and surgical NEC groups were compared, the prevalence of complications increased significantly with increasing NEC severity.

In the post hoc comparisons between the surgical NEC and SIP groups, BPD (P=0.008) and IVH (P=0.012) were more frequent in the surgical NEC group. However, hypotension, seizures, PVL, sepsis, and ROP did not differ significantly between the two groups.

The rate of in-hospital death was the highest in the surgical NEC group (26.2%, P<0.001). In pairwise comparisons, the surgical NEC group had a significantly higher rate of in-hospital death than the control group (12.0%, P<0.001), medical NEC group (12.4%, P<0.001), and SIP group (12.9%, P=0.002) (Tables 3, 4). The rate of post-discharge death was the lowest in the SIP group at 0.1%; however, this difference was not statistically significant among the four groups (P=0.328) (Table 3).

4. Enteral feeding, parenteral nutrition, and length of hospital stay

Significant differences were observed among the control, medical NEC, surgical NEC, and SIP groups in the time to full enteral feeding, duration of TPN, and length of NICU hospitalization (P<0.001) (Table 5).

The time to full enteral feeding was the latest in the SIP group at 34 days. The difference compared to the control group was 29 days (95% CI, 26 to 32; P<0.001), and the difference compared to the medical NEC group was 19 days (95% CI, 15 to 23; P<0.001). In contrast, the difference compared to the surgical NEC group was not significant (P=0.991) (Table 6).

The duration of TPN was the longest in the surgical NEC group: 17 days in the control group, 34 days in the medical NEC group, 43 days in the SIP group, and 53 days in the surgical NEC group (Table 5). Post hoc analysis of TPN duration showed significant differences in all pairwise comparisons between the groups (P<0.001) (Table 6).

Similarly, the length of NICU hospitalization was the longest in the surgical NEC group at 93 days. The difference compared to the control group was 36 days (95% CI, 31 to 40; P<0.001), and the difference compared to the medical NEC group was 25 days (95% CI, 18 to 31; P<0.001). No significant difference was observed between the surgical NEC and SIP groups (P=0.221) (Table 6).

5. Long-term neurological outcomes

At the first follow-up assessment at a corrected age of 18 to 24 months, the surgical NEC group showed higher rates of cerebral palsy (P=0.002) and vision loss (P=0.005) than the other groups, whereas no significant differences were observed in other neurological outcomes (Table 7). At the follow-up assessment at 33 to 39 months, the surgical NEC group had higher rates of cerebral palsy (P=0.002) and eye disorders (P=0.002), whereas hearing impairment (P=0.034) and hearing aid use (P<0.001) were most frequent in the SIP group (Table 7).

DISCUSSION

In this study, we retrospectively analyzed prospectively collected data from the KNN and compared short-term morbidities, mortality during hospitalization, and long-term neurological outcomes up to 3 years of age between the control, medical NEC, surgical NEC, and SIP groups. The medical NEC group showed less favorable clinical outcomes than the control group, whereas the surgical NEC group had the highest overall short- and long-term morbidity and mortality rates. The SIP group also showed adverse clinical courses that were as poor as those in the surgical NEC group for several components.

Both SIP and surgical NEC tend to occur in infants of lower gestational ages. Although previous studies have reported that SIP is observed at an earlier gestational age than NEC [6,9], surgical NEC in our cohort also occurred in infants with a degree of immaturity similar to that of infants with SIP, resulting in a substantial overlap in the gestational age distribution between the two diseases. This suggests that both diseases may be associated with intestinal and vascular immaturity related to severe premature birth. In contrast, analysis of disease onset timing revealed more distinct pathophysiological differences between the two diseases. This finding is consistent with previous studies showing that SIP tends to occur relatively early after birth, whereas NEC develops after enteral feeding has progressed to some extent [3,4,7], supporting the notion that the two diseases are pathophysiologically distinct.

Previous studies have supported two key interpretations of our findings. First, surgical NEC is associated with poor short-and long-term outcomes due to a pronounced systemic inflammatory response and extensive intestinal injury [1,5,6]. Second, SIP should not be regarded merely as a localized intestinal disease because extreme immaturity, hemodynamic instability, and the burden of surgery may also affect long-term outcomes [8,9,28].

Consistent with the first perspective, NEC may lead to excessive inflammatory responses originating in the immature intestine that spread systemically and affect remote organs, including the brain. Severe NEC requiring surgical treatment has been associated with worse outcomes than SIP, including an increased risk of neurodevelopmental impairment, cerebral palsy, cognitive impairment, and visual impairment [1,5,6]. Feng et al. [29] reported that VLBW infants with SIP had more favorable preoperative infection markers than those with NEC, supporting the possibility that these two diseases have different clinical and pathophysiological characteristics.

Recent evidence suggests that SIP may be associated with an adverse clinical course and long-term outcomes. Okuyama et al. [7] reported that infants with focal intestinal perforation have a higher rate of concomitant RDS than those with NEC, suggesting that infants with SIP may have a vulnerable clinical course during the early postnatal period. Several large cohort studies have also reported that SIP is associated with pre-discharge mortality, major complications of prematurity, such as BPD and sepsis, and an increased risk of neurodevelopmental impairment [8,9,28].

In this study, the surgical NEC group had the worst outcomes in terms of short-term complications, mortality, and long-term neurological prognoses. This finding is generally consistent with previous studies reporting that NEC requiring surgical treatment is associated with increased risks of mortality, neurodevelopmental impairment, and cerebral palsy [5,6], and is also in line with the literature showing higher mortality in surgical NEC than in SIP [30,31].

Adverse long-term neurological outcomes were also observed in the SIP group compared with the control and other comparison groups. This finding is consistent with recent studies suggesting that SIP may not simply be a localized intestinal disease, but may instead represent an important high-risk condition in terms of long-term outcomes [8,9,28]. These results suggest that SIP tends to occur in infants with a lower gestational age and often develops during the early postnatal period when infants are hemodynamically unstable. Therefore, the systemic deterioration caused by intestinal perforation and the burden of surgery may contribute to adverse outcomes. In addition, the finding that the duration of TPN and length of NICU hospitalization in the SIP group were nearly comparable to those in the surgical NEC group supports the possibility that SIP is associated with an adverse clinical course. Although there was no significant difference in time to full enteral feeding between the surgical NEC and SIP groups, the duration of TPN was longer in the surgical NEC group. This may suggest that more extensive intestinal injury and more complex surgical procedures in NEC resulted in a longer need for parenteral nutritional supplementation, even after recovery of intestinal function. Indeed, a previous study reported that NEC is associated with more complex surgical treatment and longer parenteral nutrition duration than SIP [32].

At the second follow-up assessment, hearing-related abnormalities were more frequently observed in the SIP group; however, evidence directly supporting this association was limited. SIP has been reported to be associated with vulnerability during long-term neurodevelopment [33], and the findings of the present study may reflect this vulnerability. Nevertheless, because there is insufficient evidence to directly support the association between SIP and hearing abnormalities, this result should be interpreted with caution. The possibility that the small sample size and differences in baseline clinical characteristics influenced the results cannot be excluded.

The findings of this study suggest that SIP should be recognized as not a simple localized intestinal disease but an important high-risk condition of long-term complications and neurodevelopmental impairment along with surgical NEC. Therefore, preterm infants with surgically treated intestinal disease should be classified as a high-risk group requiring careful growth and neurodevelopmental follow-up after NICU discharge, and long-term monitoring and early intervention should be actively considered.

This study had several limitations. First, a substantial proportion of the cohort was lost to follow-up for long-term neurological outcomes, and imputation was not performed for missing data. Loss to follow-up may not have occurred randomly, and complete-case estimates for outcomes such as cerebral palsy, vision loss, and hearing impairment may have been affected by attrition bias. Therefore, the findings should be interpreted with caution. Second, because this was a multicenter registry study, the diagnostic criteria for NEC and SIP, surgical indications, and follow-up protocols may have varied among the participating centers, and this inter-institutional variability may have affected the results. Third, in the comparison of disease timing, the exact date of SIP diagnosis was not collected separately; therefore, the date of surgery was used as an approximation of disease onset, which may have resulted in a somewhat delayed estimate of the actual onset timing. Fourth, we did not perform a separate stratified analysis comparing the outcomes of early- and late-onset NEC.

Despite these limitations, this study had several strengths. Many previous studies on the prognosis of NEC or SIP have been limited by single-center designs or relatively small sample sizes. In contrast, the present study was conducted using a nationwide cohort collected according to a systematic and standardized protocol. The large population-based study design enhanced the reliability and generalizability of our findings. In addition, whereas many previous studies focused on follow-up assessments around corrected ages of 18 to 24 months, this study included data up to 33 to 39 months, allowing the evaluation of longer-term neurological outcomes.

In conclusion, surgical NEC was associated with the worst short- and long-term outcomes among VLBW preterm infants, while SIP was associated with adverse outcomes comparable to those of surgical NEC compared with other groups. These findings suggest that preterm infants with intestinal diseases requiring surgical treatment represent a clinically high-risk group that requires careful long-term follow-up.

Supplementary materials

Supplementary materials related to this article can be found online at https://doi.org/10.5385/nm.26003.

Supplementary Table 1.

Unweighted Maternal and Perinatal Characteristics

nm-26003-Supplementary-Table-1.pdf

ARTICLE INFORMATION

Ethical statement

This study was approved by the Institutional Review Board (IRB) of the Ewha Womans University Seoul Hospital (IRB No.: SEUMC 2021-02-035-002). Informed consent was obtained from all parents prior to their participation in the Korean Neonatal Network registry and enrollment in this study. All the procedures adhered to the ethical guidelines established by our institution's research committee and complied with the principles outlined in the 1964 Helsinki Declaration and its subsequent revisions.

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Author contributions

Conception or design: J.I.K., S.Y.S., J.A.S.

Acquisition, analysis, or interpretation of data: J.I.K., S.P. (Sangjun Park), S.Y.S., J.Y.Y., Y.M.Y., Y.J.H., D.K.L., H.K.B., S.P. (Soeun Park), J.A.S.

Drafting the work or revising: J.I.K., S.P. (Sangjun Park), S.Y.S., J.Y.Y., Y.M.Y., J.A.S.

Final approval of the manuscript: All authors read and approved the final manuscript.

Funding

This research was supported by the National Institutes of Health (NIH) research project (2025-ER0601-01#).

Acknowledgments

None

Figure 1.

Flow chart of study population and group classification. Abbreviations: GA, gestational age; KNN, Korean Neonatal Network; NEC, necrotizing enterocolitis; SIP, spontaneous intestinal perforation.

Table 1.

Maternal and Perinatal Characteristics

Characteristic	Control (n=17,075)	Medical NEC (n=472)	Surgical NEC (n=584)	SIP (n=315)	P-value
Maternal characteristic
Maternal age (yr)	34 (31–36)	34 (31–37)	34 (31–36)	34 (31–36)	0.489
IVF	5,334 (28.8)	4,453 (24.0)	4,998 (27.0)	4,949 (26.7)	0.575
DM	2,135 (11.5)	2,052 (11.1)	2,116 (11.4)	953 (5.2)	0.017
Hypertension	4,082 (22.0)	4,349 (23.5)	4,367 (23.6)	3,843 (20.8)	0.804
PROM	6,858 (37.3)	7,090 (38.4)	6,361 (35.2)	6,496 (36.3)	0.811
Chorioamnionitis	5,735 (35.8)	5,589 (33.4)	4,683 (31.1)	4,166 (25.9)	0.082
Amniotic fluid					0.043
Normal	14,391 (84.2)	15,217 (86.8)	14,870 (90.1)	13,439 (80.4)
Oligohydramnios	2,487 (14.5)	2,210 (12.6)	1,406 (8.5)	2,913 (17.4)
Polyhydramnios	224 (1.3)	114 (0.7)	223 (1.4)	367 (2.2)
Antenatal steroids	15,794 (86.2)	16,309 (88.4)	15,568 (87.4)	15,892 (88.9)	0.693
Perinatal characteristic
GA (wk)	28 (26–30)	28 (26–30)	28 (26–30)	28 (26–30)	0.961
Birth weight (g)	1,052±289	1,052±272	1,052±286	1,052±264	0.989
Birth weight z-score	–0.2±0.9	–0.2±0.9	–0.2±1.0	–0.2±1.0	0.465
Birth height (cm)	36±4	36±4	36±4	36±3	0.423
Birth height z-score	–0.3±1.1	–0.2±1.3	–0.4±1.2	–0.4±1.1	0.292
Birth HC (cm)	26±2	26±2	26±2	26±3	0.583
Birth HC z-score	–0.2±1.1	–0.2±1.3	–0.2±1.3	–0.2±1.3	0.950
Multiple gestations	6,929 (37.4)	5,750 (31.1)	7,328 (39.8)	7,773 (42.0)	0.073
Delivery method					0.147
Cesarean	14,687 (79.3)	15,244 (82.3)	14,283 (77.1)	15,500 (83.7)
Vaginal	3,832 (20.7)	3,275 (17.7)	4,236 (22.9)	3,020 (16.3)
Apgar 1 minute	5±2	4±2	5±2	5±2	0.115
Apgar 5 minutes	7±2	7±2	7±2	7±2	0.549
Sex					0.010
Female	9,242 (49.9)	7,834 (42.3)	8,075 (43.6)	6,382 (34.5)
Male	9,277 (50.1)	10,686 (57.7)	10,844 (56.4)	12,138 (65.5)

Values are expressed as median (interquartile range), number (%), or mean±standard deviation. Values represent covariate balancing propensity scoresweighted sample sizes; percentages are weighted proportions. Weights were derived from a covariate balancing propensity score adjusting for gestational age and birth weight. Unweighted baseline characteristics are presented in Supplementary Table 1.

Abbreviations: NEC, necrotizing enterocolitis; SIP, spontaneous intestinal perforation; IVF, in vitro fertilization; DM, diabetes mellitus; PROM, premature rupture of membranes; GA, gestational age; HC, head circumference.

Table 2.

Disease Onset and Operation Timing by Groups

Variable	Medical NEC (n=376)	Surgical NEC (n=442)	SIP^* (n=255)	P-value
Diagnosis day basis
Event day (d; after birth)	15 (7–28)	12 (7–24)	8 (5–14)	<0.001^†
Onset timing				<0.001
1–7 days	105 (28.1)	122 (27.9)	109 (43.3)
8–14 days	78 (20.9)	120 (27.4)	80 (31.7)
≥15 days	191 (51.1)	196 (44.7)	63 (25.0)
Operation day basis
Operation day (d; after birth)	-	15 (8–28)	8 (5–14)	<0.001
Operation timing				<0.001
1–7 days	-	105 (23.9)	109 (43.3)
8–14 days	-	110 (25.0)	80 (31.7)
≥15 days	-	225 (51.1)	63 (25.0)

Values are expressed as median (interquartile range) or number (%).

^* For SIP, operation day was used as a proxy for onset because the Korean Neonatal Network does not record a separate SIP diagnosis date; this proxy is expected to lag the true onset by hours to a few days;

^† Subgroup analysis: SIP vs. medical NEC P<0.001, SIP vs. surgical NEC P<0.001, and medical NEC vs. surgical NEC P=0.16.

Abbreviations: NEC, necrotizing enterocolitis; SIP, spontaneous intestinal perforation.

Table 3.

Short-Term Morbidities and Mortality

Variable	Control (n=17,075)	Medical NEC (n=472)	Surgical NEC (n=584)	SIP (n=315)	P-value
RDS	15,266 (82.4)	15,468 (83.5)	15,384 (83.1)	14,597 (78.8)	0.595
BPD (≥moderate)	5,433 (33.4)	7,183 (44.4)	8,764 (60.2)	7,703 (48.4)	<0.001
Steroids for BPD	4,788 (25.9)	5,492 (29.7)	4,962 (26.8)	5,817 (31.4)	0.293
PDA with treatment	4,642 (25.8)	5,099 (27.9)	6,227 (33.6)	5,694 (31.5)	0.140
Hypotension	5,018 (27.1)	5,570 (30.1)	9,411 (50.8)	10,691 (57.7)	<0.001
Seizure	1,439 (7.8)	2,334 (12.6)	3,150 (17.0)	2,649 (14.3)	0.002
IVH (grade ≥III)	1,546 (8.7)	1,984 (10.8)	3,102 (17.3)	1,870 (10.5)	<0.001
PVL	2,007 (10.8)	2,151 (11.6)	3,450 (18.6)	3,295 (17.8)	0.015
Congenital infection	219 (1.2)	309 (1.7)	493 (2.7)	156 (0.8)	0.207
Sepsis	3,376 (18.2)	6,022 (32.5)	7,485 (40.4)	6,991 (37.8)	<0.001
Meningitis	92 (0.5)	111 (0.6)	205 (1.1)	260 (1.4)	0.420
ROP (stage ≥3)	1,997 (12.3)	1,940 (11.8)	2,981 (20.1)	3,056 (18.9)	<0.001
In-hospital death	1,812 (12.0)	86 (12.4)	206 (26.2)	80 (12.9)	<0.001
Post-discharge death	78 (0.5)	3 (0.4)	6 (0.5)	3 (0.1)	0.328

Values are expressed as number (%). Values represent covariate balancing propensity scores-weighted sample sizes; percentages are weighted proportions.

Weights were derived from a covariate balancing propensity score adjusting for gestational age and birth weight.

Abbreviations: NEC, necrotizing enterocolitis; SIP, spontaneous intestinal perforation; RDS, respiratory distress syndrome; BPD, bronchopulmonary dysplasia; PDA, patent ductus arteriosus; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity.

Table 4.

Comparison of Short-Term Morbidities and Mortality between Subgroups

	Medical NEC vs. Control	Surgical NEC vs. Control	SIP vs. Control	Surgical NEC vs. Medical NEC	SIP vs. Medical NEC	SIP vs. Surgical NEC
BPD	<0.001	<0.001	<0.001	<0.001	<0.001	0.008
Hypotension	<0.001	<0.001	<0.001	<0.001	<0.001	0.086
Seizure	<0.001	<0.001	<0.001	<0.001	0.013	0.256
IVH	<0.001	<0.001	<0.001	<0.001	0.232	0.012
PVL	0.089	<0.001	<0.001	0.006	0.029	0.879
Sepsis	<0.001	<0.001	<0.001	0.001	0.178	0.094
ROP	0.004	<0.001	<0.001	<0.001	<0.001	0.286
In-hospital death	0.861	<0.001	0.861	<0.001	0.861	0.002

Values are expressed as P-value.

Abbreviations: NEC, necrotizing enterocolitis; SIP, spontaneous intestinal perforation; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity.

Table 5.

Enteral and Parenteral Nutrition, and Hospital Staying

Variable	Control (n=17,075)	Medical NEC (n=472)	Surgical NEC (n=584)	SIP (n=315)	P-value
Full feeding day (d)	16 (9–29)	26 (14–38)	31 (15–51)	34 (23–51)	<0.001
TPN duration (d)	17 (9–33)	34 (23–49)	53 (30–92)	43 (26–67)	<0.001
Hospital staying (d)	63 (45–89)	71 (56–91)	93 (52–129)	85 (57–111)	<0.001

Values are expressed as median (interquartile range). Values represent covariate balancing propensity scores-weighted sample sizes; percentages are weighted proportions. Weights were derived from a covariate balancing propensity score adjusting for gestational age and birth weight.

Abbreviations: NEC, necrotizing enterocolitis; SIP, spontaneous intestinal perforation; TPN, total parenteral nutrition.

Table 6.

Comparison of Enteral and Parenteral Nutrition, and Hospital Staying between Subgroups

	Comparison	Difference	95% CI	P-value
Full feeding day (d)	Medical NEC vs. Control	10	7 to 13	<0.001
	Surgical NEC vs. Control	29	26 to 31	<0.001
	SIP vs. Control	29	26 to 32	<0.001
	Surgical NEC vs. Medical NEC	19	15 to 22	<0.001
	SIP vs. Medical NEC	19	15 to 23	<0.001
	SIP vs. Surgical NEC	1	–4 to 5	0.991
TPN duration (d)	Medical NEC vs. Control	17	14 to 20	<0.001
	Surgical NEC vs. Control	50	47 to 52	<0.001
	SIP vs. Control	37	34 to 41	<0.001
	Surgical NEC vs. Medical NEC	32	28 to 36	<0.001
	SIP vs. Medical NEC	20	15 to 25	<0.001
	SIP vs. Surgical NEC	–12	–17 to –8	<0.001
Hospital staying (d)	Medical NEC vs. Control	11	6 to 16	<0.001
	Surgical NEC vs. Control	36	31 to 40	<0.001
	SIP vs. Control	30	24 to 36	<0.001
	Surgical NEC vs. Medical NEC	25	18 to 31	<0.001
	SIP vs. Medical NEC	19	11 to 27	<0.001
	SIP vs. Surgical NEC	–6	–13 to 2	0.221

Abbreviations: CI, confidence interval; NEC, necrotizing enterocolitis; SIP, spontaneous intestinal perforation; TPN, total parenteral nutrition.

Table 7.

Long-Term Neurologic Outcomes with Significant between-Group Differences: Pairwise Contrasts Added

Variable	Control	Medical NEC	Surgical NEC	SIP	Global P-value	Medical NEC vs. Control	Surgical NEC vs. Control	SIP vs. Control	Surgical NEC vs. Medical NEC	SIP vs. Medical NEC	SIP vs. Surgical NEC
1st follow-up	8,175	220	230	131
Cerebral palsy	158 (4.6)	5 (5.3)	9 (10)	2 (3.4)	0.002	0.613	0.002	0.520	0.092	0.516	0.040
Eye disorder	264 (7.7)	9 (9.0)	12 (14)	5 (7.8)	0.089
Vision loss	13 (0.4)	0 (0.1)	1 (1.6)	0 (0.2)	0.005	0.397	0.018	0.503	0.018	0.847	0.028
Hearing impairment	56 (1.9)	2 (1.9)	2 (3.5)	2 (2.5)	0.533
Hearing aid	27 (0.8)	1 (1.0)	1 (1.5)	1 (1.6)	0.500
2nd follow-up	5,100	147	165	80
Cerebral palsy	73 (5.6)	2 (5.1)	5 (14)	3 (10)	0.002	0.804	<0.001	0.271	0.017	0.271	0.570
Eye disorder	150 (12)	5 (13)	9 (27)	3 (14)	0.002	0.879	<0.001	0.879	0.028	0.879	0.211
Vision loss	11 (0.8)	0 (0.4)	1 (2.1)	0 (0.3)	0.238
Hearing impairment	22 (1.9)	1 (1.7)	1 (4.4)	2 (7.2)	0.034	0.878	0.160	0.160	0.376	0.237	0.628
Hearing aid	12 (0.9)	1 (1.6)	1 (2.7)	2 (6.4)	<0.001	0.534	0.127	0.006	0.582	0.269	0.413

Values are expressed as number (%) or P-value.

Abbreviations: NEC, necrotizing enterocolitis; SIP, spontaneous intestinal perforation.

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