Mortality and Extrauterine Growth Restriction of Necrotizing Enterocolitis in Very Preterm Infants with Heart Disease: A Multi-Center Cohort Study

Mortality and Extrauterine Growth Restriction of Necrotizing Enterocolitis in Very Preterm Infants with Heart Disease: A Multi-Center Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Mortality and Extrauterine Growth Restriction of Necrotizing Enterocolitis in Very Preterm Infants with Heart Disease: A Multi-Center Cohort Study Pei Lu, Xiaohui Gong, Xinyue Gu, Siyuan Jiang, Yun Cao, Chengjun Sun, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4177286/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Jun, 2024 Read the published version in European Journal of Pediatrics → Version 1 posted 7 You are reading this latest preprint version Abstract OBJECTIVE. Congenital heart disease (CHD) and patent ductus arteriosus (PDA) are risk factors of necrotizing enterocolitis (NEC) in infants. However, it is unclear whether the prognosis of NEC is different between very preterm infants (VPIs) with and without heart diseases. PATIENTS AND METHODS. This was an observational cohort study that enrolled VPIs (born between 24 + 0 and 31 + 6 weeks) admitted to 97 tertiary neonatal intensive care units (NICU) in the Chinese Neonatal Network (CHNN) between 2019 and 2021. The exposure was CHD or isolated PDA, and VPIs with NEC were divided into three groups: complicated with CHD, with isolated PDA, and without heart diseases. The primary outcomes were NEC related adverse outcomes (death or extrauterine growth restriction (EUGR)). Logistic regression models were used to adjust potential confounders and calculate the odds ratios (ORs) and 95% confidential intervals (CIs) for each outcome. RESULTS. A total of 1335 VPIs with NEC were enrolled in this study, including 65 VPIs with CHD, 406 VPIs with isolated PDA. The VPIs with heart diseases had smaller gestational ages and lower body weights at birth, more antenatal steroids use, and requiring inotrope prior to the onset of NEC. While suffering from NEC, death or EUGR were more often observed in VPIs with either CHD (aOR: 2.07; 95% confidence interval [CI]: 1.20–3.60) or isolated PDA (aOR: 1.51; 95% CI: 1.17–1.94) than those without heart diseases. While no significant increased risks in NEC related death in VPIs with either CHD (adjusted OR [aOR]: 1.10; 95% CI: 0.41–2.50) or isolated PDA (aOR: 1.25; 95% CI 0.82–1.87), increased risks in EUGR was identified in either survival VPIs with CHD (aOR: 2.35; 95% CI: 1.31–4.20) or isolated PDA (aOR: 1.53; 95% CI: 1.16–2.01) in survivors. VPIs with either CHD or isolated PDA were associated with significantly prolonged duration of fasting, extended time to achieve full enteral feeding, longer ventilation duration and hospitalization duration. Similar characteristics were also seen in VPIs with isolated PDA, with the exception that VPIs with CHD are more likely to undergo surgical intervention and maintain a prolonged fast after NEC. CONCLUSIONS. In VPIs with NEC, CHD and isolated PDA are associated with an increased risk in worse outcomes. We recommend that VPIs with cardiac NEC be managed with aggressive treatment and nutrition strategies to prevent EUGR. Necrotizing enterocolitis Heart disease Patent ductus arteriosus Very preterm infants Extrauterine growth restriction Mortality Figures Figure 1 What is known: CHD and PDA are risk factors for NEC in infants, which can lead to adverse outcomes such as death and EUGR. NEC in infants with heart disease differs clinically from that in infants without heart disease and should be recognized as a separate disease process. It is unclear whether the prognosis of NEC differs between VPIs with and without heart diseases. What is new: CHD and isolated PDA are associated with increased risks of worse outcomes in VPIs with NEC. Risk factors associated with VPIs with cardiac NEC suggested these patients should be managed with aggressive treatment and nutrition strategies to adverse outcomes. Introduction Necrotizing enterocolitis (NEC) continues to be a serious preterm-related complications, despite rising survival rates in very premature infants (VPIs).[ 1 – 5 ] NEC occurs in 2%-13% of newborn critical care unit hospitalizations,[2; 4–6] and it affects roughly 7% of VPIs[ 7 ] with mortality rates range from 20%-50%.[ 7 – 10 ] Congenital heart disease (CHD) is a risk factor that raises the incidence of NEC in VPIs.[ 11 ] Among infants at gestational ages between 23 + 0 and 34 + 6 weeks, severe CHD (cyanotic heart defects, left-sided obstructive lesions, and congestive heart failure) was associated with a 3.72-fold increase (95% CI 1.37–10.1) in the risk of NEC.[ 12 ] Similarly, CHD significantly increased the incidence of NEC in very low birth weight (< 1500g) infants.[ 13 ] The incidence of NEC in preterm infants with CHD is 8.6%-13.1%,[ 13 – 16 ] higher than that preterm infants without CHD.[14; 16] NEC in infants with CHD differs clinically from that of infants without, it was proposed that NEC in infants with CHD should be recognized as a separate disease process and referred to as cardiac NEC.[ 17 ] The key beginning factors of NEC in preterm infants are believed to be intestinal epithelium degradation, transmural injury, and intestinal ischemia.[ 14 ] Among these factors, intestinal ischemia brought on by decreased cardiac output, cyanosis, and congestive heart failure are assumed to be the main pathophysiological change to cause cardiac NEC in preterm infants.[ 18 – 20 ] In addition to complex CHD, isolated PDA, one of the most prevalent heart diseases in preterm infants, as one of the risk factors resulting in NEC,[21; 22] commonly results in a left-to-right ductal shunt and ductal theft from the systemic circulation,[23; 24] results in retrograde diastolic flow, low diastolic pressure, and reduced mesenteric perfusion.[ 25 – 28 ] Previous study showed that the mortality rate for cardiac NEC in preterm infants can be 3.4 (95% CI 2.8–4.1) times higher than that of non-cardiac NEC in preterm infants.[11; 18] Extrauterine growth restriction (EUGR), one of the key indicators of preterm infants’ short- and long-term health,[29; 30] was commonly observed in infants with cardiac NEC.[20; 31] Due the distinct pathophysiology of cardiac NEC, it can be expected that preterm infants with cardiac NEC will experience worse outcomes than those with non-cardiac NEC. A greater understanding of cardiac NEC outcomes in preterm infants could help to make better clinical decision therefore improve the prognosis for preterm infants. However, the majority of cardiac NEC studies are focused on term and near-term newborns,[17; 32] and studies on cardiac NEC in preterm infants are often limited to single-centered investigations.[ 33 ] Therefore, the current study aims to explore whether cardiac NEC had worse outcomes than non-cardiac NEC in very preterm infants (VPIs) from a national database. We present the study in accordance with the STROBE reporting checklist ( www.equator-network.org ). Materials and methods Study population The Chinese Neonatal Network (CHNN) is a standardized national clinical database of VPIs in the NICU of 97 tertiary hospitals from 25 provinces to monitor care practices and outcomes since January 1, 2019.[ 34 ] All participating NICUs in the CHNN have recognized expertise in caring for high-risk infants in China. The data was directly entered into a customized database by trained data abstractors in each hospital under standard protocols. Data quality was ensured by built-in error checking and data checks at the coordinating center and correction of potentially incorrect data after feedback from participating centers. A waiver of the need for consent and ethics approval for data collection and analysis was granted by the ethics review board of the Children's Hospital of Fudan University (2018 − 296). VPIs included in this prospective observational study were: (1) gestational age (GA) < 32 weeks; (2) diagnosed with NEC; (3) admitted to participating NICUs from January 1, 2019, to December 31, 2021. Necrotizing enterocolitis (NEC) was defined as stage II or above according to Bell's criteria.[35; 36] The diagnosis of CHD was made through a review of echocardiogram reports and clinical management in each patient and categorized as either CHD (cardiac abnormalities confirmed by echocardiography) or isolated PDA (hemodynamically significant PDA requiring medical or surgical treatment without detectable cardiac anomaly). Among all VPIs in CHNN between 2019 and 2021, there were 1509 infants diagnosed with NEC. After excluded 174 infants with missing data NEC diagnosis (n = 49), PDA diagnosis (n = 29), birth weight or discharge weight (n = 96), 1335 VPIs were enrolled and divided into three subgroups (Fig. 1 ): infants with CHD (N = 65), infants with isolated PDA (N = 406), and infants without CHD (N = 864). Outcomes and variables The primary outcomes were death in-hospital or survivors with extrauterine growth restriction (EUGR). EUGR was defined as a decrease in weight Z-score between birth and discharge > 2.[ 37 – 39 ] Weight Z-score was calculated as age-specific and sex-specific Z-scores using the 2013 Fenton growth curve.[ 40 ] The World Health Organization (WHO) growth charts[ 41 ] were used for weight Z-score calculation after corrected GA > 50 weeks. The following variables were considered as covariates in analyses: maternal characteristics (maternal age, maternal hypertension, diabetes mellitus, and whether antenatal steroids had been administered); infant characteristics (gender, single- or multiple-birth, birth weight, gestational age, and Apgar score at 5 minutes); characteristics of NEC (age and GA at NEC diagnosis, stage of NEC, intestinal perforation, and surgical treatment); treatment information (inotrope usage before and after NEC, duration of mechanical ventilation and non-invasive ventilation, day to start enteral feed; days to reach full enteral feed; and hospitalization duration). GA was determined using the hierarchy of the best obstetric estimate based on prenatal ultrasound, menstrual history, obstetric examination, or the Ballard Score if the obstetric estimate was not available.[ 42 ] Small for gestational age (SGA) (weight < 10th percentile) was defined according to the 2013 Fenton growth curve.[ 40 ] Intrauterine Growth Restriction (IUGR), defined as fetuses who failed to achieve normal weight based on previous growth measurements in the pregnancy and diagnosed by intrauterine growth failure with normal head circumference (HC) and/or Doppler velocimetry abnormalities.[43; 44] Statistical analysis The baseline characteristics were described using frequencies (percentages) and compared using the chi-square test (χ2) for categorical variable between two groups. Continuous variables were first analyzed by the normality test. The normally distributed continuous variables were displayed as means and standard deviations (SDs) and compared by Student’s t-test, while the abnormally distributed continuous variables were displayed as medians and interquartile ranges (IQRs) and compared by Wilcoxon signed-rank test. To determine whether NEC infants with heart diseases had a higher risk of NEC-related mortality or EUGR, logistic regression models were used to adjust potential confounders and calculate the adjusted odds ratios (aORs) and 95% confidential intervals (CIs) for mortality and EUGR among infants with CHD or isolated PDA as compared with NEC infants without CHD (noncardiac NEC). In order to determine whether NEC infants with CHD had a higher risk of adverse outcomes than those with isolated PDA, comparisons between the two groups were also conducted. Statistical significance was defined as p < 0.05. Data management and statistical analyses were performed using R (version 4.2.2, www.r-project.org ). Results Infant Characteristics A total of 471 VPIs had cardiac NEC in our cohort. There are 65 infants with CHD and 52 of them are atrial septal defect (Table 1 ). Table 1 Types and Frequencies of CHDs in the Group of 471 VPIs With NEC Type of CHD N = 471 CHD 65 Ventricular septal defect 6 Atrial septal defect 52 Atrioventricular septal defect 1 Pulmonary valve stenosis 1 Other congenital malformations of the heart 3 Coarctation of the aorta 2 Isolated PDA 406 CHD = congenital heart disease; N = number; PDA = patent ductus arteriosus Table 2 shows differences in clinical features of infants with CHD or isolated PDA compared to those without. Between VPIs with heart diseases and those without, there was no significant difference in maternal age, maternal diabetes, maternal hypertension, infant gender, or IUGR. VPIs with CHD and isolated PDA had lower birth weights and more frequently received prenatal steroids. VPIs with isolated PDA were more frequently administered with inotrope prior to the onset of NEC (Table 2 ). Table 2 Characteristics and outcomes of NEC VPIs with and without CHD CHD Isolated PDA Normal N = 65 N = 406 N = 864 Maternal characteristics Maternal age (y) 31 (28–33) 31 (28–34) 31 (28–34) Maternal diabetes 12 (18.5%) 87 (21.4%) 156 (18.1%) Maternal hypertension and preeclampsia 16 (24.6%) 82 (20.2%) 157 (18.2%) Infants’ characteristics Antenatal steroids 51 (78.5%) 304 (74.9%) c 593 (68.6%) Male 35 (53.8%) 231 (56.9%) 513 (59.4%) Multiple birth 17 (26.2%) 140 (34.5%) c 216 (25%) Gestational weeks (w) 29.6 (28.3–30.9) 28.9 (27.2–30) c 29.9 (28.3–30.9) Birth weight (g) 1280 (1080–1400) 1150 (950–1390) c 1330 (1100–1550) SGA or IUGR 7 (10.8%) 58 (14.3%) 92 (10.6%) Used inotropes before NEC 11 (16.9%) 97 (23.9%) c 156 (18.1%) NEC related characteristics Age at NEC diagnosis 20 (12–30) 20.5 (11–32) c 19 (11–28) Gestational weeks (w) at NEC diagnosis 32.7 (30.4–34.1) 32.1 (30.6–33.6) c 32.4 (31.1–33.7) NEC stage III 28 (43.1%) 159 (39.2%) 322 (37.3%) Outcomes Adverse outcome (death or EUGR) 34 (52.3%) 200 (49.3%) c 351 (40.6%) Death 7 (10.8%) 46 (11.3%) 83 (9.6%) Survival with EUGR 27 (46.6%) 154 (42.8%) c 268 (34.3%) NEC Surgery 35 (53.8%) 160 (39.4%) 360 (41.7%) Days to re-entero-feeding 11 (8–15) b 9 (6–13.25) 9 (7–12) Days to full-entero-feeding 25 (13–41) b 21 (12–33) 19 (11–30) MV duration after NEC 4 (0–14) b 4 (0–14) c 2 (0–7) Inotropes after NEC 24 (36.9%) 138 (34%) 283 (32.8%) Intestinal perforation 19 (29.2%) 89 (21.9%) 217 (25.1%) Hospitalization duration (d) 56 (44–72) b 58 (38–81.75) c 47 (31.75–65) Comparisons are made between patients with CHD and without. SGA = small for gestational age; IUGR = intrauterine growth restriction; EUGR = extrauterine growth restriction; significant results ( p < 0.05) are shown in bold. The median postnatal age at diagnosis of NEC among VPIs with CHD, with isolated PDA, and VPIs without heart diseases, was 20 days, 20.5 days, and 19 days after birth, respectively (Table 2 ). The Bell stages did not differ significantly across groups: the frequency of stage III NEC in VPIs with CHD, isolated PDA, and those without heart disease were 43.1%, 39.2%, and 37.3%, respectively. Despite no statistically significant difference, infants with CHD trended to receive surgical treatment more frequently. VPIs with CHD recovered later from NEC than VPIs without heart disease as VPIs with CHD or isolated PDA required more prolonged mechanical ventilation, started feeding later, and spent more time in the hospital, when compared to VPIs with classic NEC. Outcomes Table 3 showed that NEC infants with CHD (aOR: 2.07; 95% CI: 1.20–3.60) or isolated PDA (aOR: 1.51; 95% CI: 1.17–1.94) were associated with higher risks in NEC related death or EUGR. Although NEC infants with CHD or isolate PDA not associated with higher risks in NEC related death (aOR: 1.10; 95% CI: 0.41–2.50 and aOR: 1.25; 95% CI: 0.82–1.87, respectively) than non-cardiac NEC, higher risk of EUGR were observed in survival VPIs with CHD (aOR: 2.35; 95% CI: 1.31–4.20) and isolated PDA (aOR: 1.53; 95% CI: 1.16–2.01). When compare to VPIs without heart diseases, VPIs with CHD were associated with significantly higher rate of receiving surgical treatment (aOR 1.79, 95% CI: 1.03–1.31), prolonged duration of fasting (aOR 6.14, 95% CI: 2.31–15.4), extended time to full enteral feeding achievement > 21 days (aOR 2.49 95% CI: 1.32–4.62), ventilation duration > 14 days (aOR 2.8 95% CI: 1.46–5.15) and hospitalization duration > 60 days (aOR 2.04 95% CI: 1.17–3.53). Similar characteristics were also seen in VPIs with isolated PDA compared to VPIs without cardiac NEC, with the exception that VPIs with CHD are more likely to undergo surgical intervention and maintain a prolonged fast after NEC. Table 3 Multiple logistic regression analysis of outcomes among infants with CHD. CHD vs . Normal Isolated PDA vs . Normal CHD vs . Isolated PDA OR (95% CI) OR (95% CI) OR (95% CI) Outcome Uni-Variable Multi-Variable Uni-Variable Multi-Variable Uni-Variable Multi-Variable Adverse outcome (death or EUGR) 1.60 (0.97–2.67) 2.07 (1.20–3.60) 1.42 (1.12–1.80) 1.51 (1.17–1.94) 1.13 (0.67–1.91) 1.39 (0.79–2.47) Death 1.14 (0.46–2.41) 1.10 (0.41–2.50) 1.20 (0.82–1.75) 1.25 (0.82–1.87) 0.94 (0.37–2.07) 1.65 (0.36–2.32) Survival with EUGR 1.77 (0.97–2.85) 2.35 (1.31–4.20) 1.36 (1.11–1.85) 1.53 (1.16–2.01) 1.30 (0.66–2.03) 1.51 (0.83–2.75) NEC Surgery 1.63 (0.99–2.72) 1.79 (1.03–1.31) 0.91 (0.72–1.16) 0.95 (0.74–1.05) 1.79 (1.06–3.05) 1.83 (1.03–1.32) Days to re-entero-feeding > 21d 4.36 (1.75–9.88) 6.14 (2.31–15.4) 2.07 (1.14–3.74) 2.24 (1.19–4.23) 2.11 (0.84–4.82) 2.76 (1.04–6.88) Days to full-entero-feeding > 30d 1.77 (0.97–3.16) 2.49 (1.32–4.62) 1.43 (1.08–1.90) 1.45 (1.07–1.97) 1.24 (0.66–2.25) 1.59 (0.83–2.99) MV duration > 14d after NEC 1.11 (1.01–1.21) 2.80 (1.46–5.15) 1.11 (1.06–1.16) 2.06 (1.49–2.84) 1.00 (0.89–1.12) 1.29 (0.67–2.40) Inotropes after NEC 1.20 (0.70–2.01) 1.14 (0.63–2.00) 1.06 (0.82–1.36) 1.06(0.81–1.39) 1.14 (0.65–1.94) 1.10 (0.60–1.96) Intestinal perforation 1.04 (0.93–1.16) 1.33 (0.71–2.37) 0.97 (0.92–1.02) 0.80 (0.59–1.08) 1.07 (0.96–1.20) 1.84 (0.95–3.46) Hospitalization duration > 60d 1.63 (0.97–2.72) 2.04 (1.17–3.53) 2.06 (1.62–2.63) 2.00 (1.54–2.60) 0.79 (0.46–1.34) 0.97 (0.54–1.71) Comparisons are made between patients with CHD and normal patients, significant results ( p < 0.05) are shown in bold Comparisons between VPIs with CHD and isolated PDA shows that aside from VPIs with CHD had a higher risk of receiving surgical treatment (aOR 1.83, 95% CI: 1.03–1.32) and prolonged duration of fasting (aOR 2.76, 95% CI: 1.04–6.88), the other clinical outcomes are similar between VPIs with CHD or isolated PDA. Discussion Using data from a national cohort of VPIs, our findings showed that although no increased risk of mortality, cardiac NEC in VPIs is associated with increased risks of EUGR at discharge in survivors, and prolonged fasting and hospitalization duration. In current opinion, it is believed that the pathophysiology of cardiac NEC predominantly caused by hemodynamic disturbances in CHDs (either complicated CHD or isolated PDA).[24; 45] Hemodynamic abnormalities in CHD cause decreased tissue perfusion, oxygen deficit,[19; 46–48] and, as a result, intestinal ischemia and hypoxia.[24; 28; 32] Cardiac NEC, on the other hand, often occurred slightly later than non-cardiac NEC in premature newborns (23 days vs 20 days after birth).[ 49 – 51 ] Similarly, preterm infants with PDA-associated NEC were also diagnosed later after birth.[ 52 ] Our study confirmed that cardiac NEC develops later than classic NEC at 20 days after birth in VPIs. The cause of different clinical presentation could be due to other underlying factors, for instance the delay in both initiation of enteral feeding and prolonged time to reach full enteral feeding owing to concerns about gastrointestinal ischemia in preterm infants. The clinical practice in the management of VPIs with NEC can vary among centers owing to variations in clinical practice, healthcare policies, and social and cultural norms.[53; 54] It has been found in previous studies that infants with cardiac NEC require less supportive critical care (such as the usage of vasopressors and ventilation),[ 55 ] whereas others showed that infants with cardiac NEC was more frequently treated with inotropes and respiratory support.[20; 56] Similarly, rates of surgical intervention for cardiac NEC varied (15–38% among centers).[20; 49; 56] Several studies found that infants with cardiac NEC were less likely to have surgery than infants without CHD.[11; 33] However, while the trend of receiving more critical care was similar in our cohort, the VPIs with NEC were more likely to be treated by surgery in both infants with CHD (53.8%) and without (41.7%) in the present study. The higher rate of surgery in our cohort could be subjected to the increased severity of NEC in infants with CHD and lower birth weight in the cohort.[15; 31; 50; 56; 57] In our study, the mortality rate was 10.8% for infants with CHD, 11.3% for those with isolated PDA, and 9.6% for those without heart diseases. The risk of mortality in cardiac NEC varied among studies, when some study did not identify increased mortality in infants with cardiac NEC,[ 20 ] many others have shown that cardiac NEC had a higher mortality rate, with in-hospital mortality rates ranging from 13 to 26%.[11; 13; 20; 32; 33; 49; 50; 58] Similar results were also observed in cardiac NEC related to isolated PDA.[ 52 ] The difference in mortality rates of cardiac NEC can be subjected to variations in inclusion and other clinical practice factors. In contrast to our finding that cardiac NEC increased the risk of EUGR, Gong et al. showed in 50 ductal-dependent cardiac NEC that the risk for EUGR is similar to non-cardiac NEC in term infants.[ 59 ] Given that lower birth weight was one of the risk factors for EUGR,[60; 61] the risk for EUGR can be unique to VPIs with cardiac NEC. The underlying cause of EUGR in VPIs with cardiac NEC is multifactorial. First, infants were not receiving adequate nutrition from the current nutrition strategy. The types and amounts of minerals and micronutrients that are needed might not be supplied adequately. In our cohort, VPIs with cardiac NEC were associated with significantly prolonged fasting duration, and extended time to achieve full enteral feeding, suggesting additional delay in enteral feeding which may further enhance nutrition impairment. Second, fluid restriction due to CHD or hemodynamically significant PDA leading to inadequate nutrition supply may also contribute to malnutrition. Third, higher comorbidity of CHD (such as bronchopulmonary dysplasia, BPD) contributes to additional nutrition demand and nutrient losses and could potentially alter postnatal growth.[62; 63] Similarly, longer ventilation duration in VPIs with both CHD and isolated PDA may also cause additional nutrition consumption. Lastly, compared to those without heart disease, infants with CHD frequently born SGA, which was one of the main risk factors for developing EUGR.[ 61 ] Future studies can seek aggressive strategy to fulfill adequate energy supply and nutritional support to cardiac NEC in VPIs. 5. Limitations Our study is limited owing to its retrospective design, relatively small number of NEC patients with CHD especially in the calculation of mortality risk. In addition, the relative short observation duration limited our conclusion primarily to NICU practice. Further studies are required to evaluate whether there are modifiable factors that can reduce negative outcome in VPIs with cardiac NEC with improved long-term outcome. Conclusions In summary, the current study showed that infants with cardiac NEC have an increased risk of EUGR in comparison to that of infants with non-cardiac NEC. We recommend that infants with cardiac NEC be managed with aggressive treatment and nutrition strategies due to the worse prognosis. Abbreviations CHNN Chinese Neonatal Network CHD Congenital heart disease CI Confidence interval EUGR Extrauterine growth restriction GA Gestational age HC Head circumference IUGR Intrauterine Growth Restriction IQR Interquartile range NEC Necrotizing enterocolitis NICU Neonatal intensive care unit OR Odds ratio PDA Patent ductus arteriosus SD Standard deviations SGA Small for gestational age VPI Very preterm infant WHO The World Health Organization Declarations Acknowledgements We acknowledge all the participants in this study, the Chinese Neonatal Network, and Shanghai Children's Hospital for supporting the current study (2022YLYM08). Funding and support This study is supported by the Canadian Institutes of Health Research (CTP87518) and the Chinese Neonatal Network coordinating center. Role of funder Funding agencies had no role in the study design, collection, analyses or interpretation of data, the writing of the report and the decision to submit the paper for publication in this study. Authors' contributions Pei Lu : Conceptualization, Methodology, Writing - Original draft. Juan Du : Investigation, Writing - Review & Editing, Visualization. Xinyue Gu : Data Curation, Software, Formal analysis, Visualization. Chengjun Sun : Data Curation, Software, Formal analysis, Visualization. Siyuan Jiang : Investigation, Methodology, Writing - Review & Editing. Shoo K Lee : Funding acquisition, Writing - Review & Editing, Supervision. Yun Cao : Writing - Review & Editing, Project administration. Xiaohui Gong : Conceptualization, Writing - Review & Editing, Validation. Xiaoping Lei : Conceptualization, Methodology, Writing - Review & Editing, Supervision. Availability of data and material The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request Code availability The codes are available on request. Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the ethics review board of the Children's Hospital of Fudan University (2018-296). Consent to participate Waiver of consent were granted at all participating sites owing to the use of deidentified patient data. Consent for publication The study does not publish personal identifying information. Conflicts of interest The authors have no conflicts of interest to disclose and confirm that there is no prior presentation of study data as an abstract or poster. 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Journal of perinatology : official journal of the California Perinatal Association 35:949-953 Fisher JG, Bairdain S, Sparks EA, Khan FA, Archer JM, Kenny M, Edwards EM, Soll RF, Modi BP, Yeager S, Horbar JD, Jaksic T (2015) Serious congenital heart disease and necrotizing enterocolitis in very low birth weight neonates. Journal of the American College of Surgeons 220:1018-1026.e1014 Neu J, Walker WA (2011) Necrotizing enterocolitis. The New England journal of medicine 364:255-264 Bain J, Benjamin DK, Jr., Hornik CP, Benjamin DK, Clark R, Smith PB (2014) Risk of necrotizing enterocolitis in very-low-birth-weight infants with isolated atrial and ventricular septal defects. Journal of perinatology : official journal of the California Perinatal Association 34:319-321 Battersby C, Santhalingam T, Costeloe K, Modi N (2018) Incidence of neonatal necrotising enterocolitis in high-income countries: a systematic review. Archives of disease in childhood Fetal and neonatal edition 103:F182-f189 Pickard SS, Feinstein JA, Popat RA, Huang L, Dutta S (2009) Short- and long-term outcomes of necrotizing enterocolitis in infants with congenital heart disease. Pediatrics 123:e901-906 Giannone PJ, Luce WA, Nankervis CA, Hoffman TM, Wold LE (2008) Necrotizing enterocolitis in neonates with congenital heart disease. Life sciences 82:341-347 Carlo WF, Kimball TR, Michelfelder EC, Border WL (2007) Persistent diastolic flow reversal in abdominal aortic Doppler-flow profiles is associated with an increased risk of necrotizing enterocolitis in term infants with congenital heart disease. Pediatrics 119:330-335 McElhinney DB, Hedrick HL, Bush DM, Pereira GR, Stafford PW, Gaynor JW, Spray TL, Wernovsky G (2000) Necrotizing enterocolitis in neonates with congenital heart disease: risk factors and outcomes. Pediatrics 106:1080-1087 Mitra S, de Boode WP, Weisz DE, Shah PS (2023) Interventions for patent ductus arteriosus (PDA) in preterm infants: an overview of Cochrane Systematic Reviews. The Cochrane database of systematic reviews 4:Cd013588 Dollberg S, Lusky A, Reichman B (2005) Patent ductus arteriosus, indomethacin and necrotizing enterocolitis in very low birth weight infants: a population-based study. Journal of pediatric gastroenterology and nutrition 40:184-188 Hamrick SEG, Sallmon H, Rose AT, Porras D, Shelton EL, Reese J, Hansmann G (2020) Patent Ductus Arteriosus of the Preterm Infant. Pediatrics 146 Diez S, Tielesch L, Weiss C, Halbfass J, Müller H, Besendörfer M (2020) Clinical Characteristics of Necrotizing Enterocolitis in Preterm Patients With and Without Persistent Ductus Arteriosus and in Patients With Congenital Heart Disease. Front Pediatr 8:257 Freeman-Ladd M, Cohen JB, Carver JD, Huhta JC (2005) The hemodynamic effects of neonatal patent ductus arteriosus shunting on superior mesenteric artery blood flow. Journal of perinatology : official journal of the California Perinatal Association 25:459-462 Coombs RC, Morgan ME, Durbin GM, Booth IW, McNeish AS (1992) Abnormal gut blood flow velocities in neonates at risk of necrotising enterocolitis. Journal of pediatric gastroenterology and nutrition 15:13-19 Coombs RC, Morgan ME, Durbin GM, Booth IW, McNeish AS (1990) Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin. Archives of disease in childhood 65:1067-1071 Polglase GR, Ong T, Hillman NH (2016) Cardiovascular Alterations and Multiorgan Dysfunction After Birth Asphyxia. Clinics in perinatology 43:469-483 Gidi NW, Goldenberg RL, Nigussie AK, McClure E, Mekasha A, Worku B, Siebeck M, Genzel-Boroviczeny O, Muhe LM (2020) Incidence and associated factors of extrauterine growth restriction (EUGR) in preterm infants, a cross-sectional study in selected NICUs in Ethiopia. BMJ Paediatr Open 4:e000765 Ordonez-Diaz MD, Perez-Navero JL, Flores-Rojas K, Olza-Meneses J, Munoz-Villanueva MC, Aguilera-Garcia CM, Gil-Campos M (2020) Prematurity With Extrauterine Growth Restriction Increases the Risk of Higher Levels of Glucose, Low-Grade of Inflammation and Hypertension in Prepubertal Children. Front Pediatr 8:180 Roychaudhuri S, Grewal G, Vijayashankar SS, Lavoie P, Maheshwari A (2022) Necrotizing Enterocolitis Associated with Congenital Heart Disease-A Review Article. Newborn (Clarksville, Md) 1:170-176 Bubberman JM, van Zoonen A, Bruggink JLM, van der Heide M, Berger RMF, Bos AF, Kooi EMW, Hulscher JBF (2019) Necrotizing Enterocolitis Associated with Congenital Heart Disease: a Different Entity? Journal of pediatric surgery 54:1755-1760 Kelleher ST, McMahon CJ, James A (2021) Necrotizing Enterocolitis in Children with Congenital Heart Disease: A Literature Review. Pediatric cardiology 42:1688-1699 Cao Y, Jiang S, Sun J, Hei M, Wang L, Zhang H, Ma X, Wu H, Li X, Sun H, Zhou W, Shi Y, Wang Y, Gu X, Yang T, Lu Y, Du L, Chen C, Lee SK, Zhou W (2021) Assessment of Neonatal Intensive Care Unit Practices, Morbidity, and Mortality Among Very Preterm Infants in China. JAMA network open 4:e2118904 Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T (1978) Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Annals of surgery 187:1-7 Walsh MC, Kliegman RM (1986) Necrotizing enterocolitis: treatment based on staging criteria. Pediatric clinics of North America 33:179-201 Shah PS, Wong KY, Merko S, Bishara R, Dunn M, Asztalos E, Darling PB (2006) Postnatal growth failure in preterm infants: ascertainment and relation to long-term outcome. Journal of perinatal medicine 34:484-489 Peila C, Spada E, Giuliani F, Maiocco G, Raia M, Cresi F, Bertino E, Coscia A (2020) Extrauterine Growth Restriction: Definitions and Predictability of Outcomes in a Cohort of Very Low Birth Weight Infants or Preterm Neonates. Nutrients 12 Lyu Y, Zhu D, Wang Y, Jiang S, Lee SK, Sun J, Li L, Cao Y (2022) Current epidemiology and factors contributing to postnatal growth restriction in very preterm infants in China. Early human development 173:105663 Fenton TR, Kim JH (2013) A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC pediatrics 13:59 WHO Child Growth Standards based on length/height, weight and age. Acta paediatrica (Oslo, Norway : 1992) Supplement 450:76-85 Ballard JL, Novak KK, Driver M (1979) A simplified score for assessment of fetal maturation of newly born infants. The Journal of pediatrics 95:769-774 ACOG Practice Bulletin No. 204: Fetal Growth Restriction. Obstetrics and gynecology 133:e97-e109 Goldberg DL, Becker PJ, Brigham K, Carlson S, Fleck L, Gollins L, Sandrock M, Fullmer M, Van Poots HA (2018) Identifying Malnutrition in Preterm and Neonatal Populations: Recommended Indicators. Journal of the Academy of Nutrition and Dietetics 118:1571-1582 del Castillo SL, Moromisato DY, Dorey F, Ludwick J, Starnes VA, Wells WJ, Jeffries HE, Wong PC (2006) Mesenteric blood flow velocities in the newborn with single-ventricle physiology: modified Blalock-Taussig shunt versus right ventricle-pulmonary artery conduit. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 7:132-137 Ostlie DJ, Spilde TL, St Peter SD, Sexton N, Miller KA, Sharp RJ, Gittes GK, Snyder CL (2003) Necrotizing enterocolitis in full-term infants. Journal of pediatric surgery 38:1039-1042 Ryder RW, Shelton JD, Guinan ME (1980) Necrotizing enterocolitis: a prospective multicenter investigation. American journal of epidemiology 112:113-123 Coombs RC, Morgan ME, Durbin GM, Booth IW, McNeish AS (1991) Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin. Archives of disease in childhood 66:1261 Lau PE, Cruz SM, Ocampo EC, Nuthakki S, Style CC, Lee TC, Wesson DE, Olutoye OO (2018) Necrotizing enterocolitis in patients with congenital heart disease: A single center experience. Journal of pediatric surgery 53:914-917 Becker KC, Hornik CP, Cotten CM, Clark RH, Hill KD, Smith PB, Lenfestey RW (2015) Necrotizing enterocolitis in infants with ductal-dependent congenital heart disease. American journal of perinatology 32:633-638 Cikrit D, Mastandrea J, West KW, Schreiner RL, Grosfeld JL (1984) Necrotizing enterocolitis: factors affecting mortality in 101 surgical cases. Surgery 96:648-655 Kessler U, Schulte F, Cholewa D, Nelle M, Schaefer SC, Klimek PM, Berger S (2016) Outcome in neonates with necrotizing enterocolitis and patent ductus arteriosus. World journal of pediatrics : WJP 12:55-59 Ou J, Courtney CM, Steinberger AE, Tecos ME, Warner BW (2020) Nutrition in Necrotizing Enterocolitis and Following Intestinal Resection. Nutrients 12 Patel EU, Wilson DA, Brennan EA, Lesher AP, Ryan RM (2020) Earlier re-initiation of enteral feeding after necrotizing enterocolitis decreases recurrence or stricture: a systematic review and meta-analysis. Journal of perinatology : official journal of the California Perinatal Association 40:1679-1687 Overman RE, Jr., Criss CN, Gadepalli SK (2019) Necrotizing enterocolitis in term neonates: A different disease process? Journal of pediatric surgery 54:1143-1146 ElHassan NO, Tang X, Gossett J, Zakaria D, Ross A, Kona SK, Prodhan P (2018) Necrotizing Enterocolitis in Infants with Hypoplastic Left Heart Syndrome Following Stage 1 Palliation or Heart Transplant. Pediatric cardiology 39:774-785 Natarajan G, Anne SR, Aggarwal S (2011) Outcomes of congenital heart disease in late preterm infants: double jeopardy? Acta paediatrica (Oslo, Norway : 1992) 100:1104-1107 Kessler U, Hau EM, Kordasz M, Haefeli S, Tsai C, Klimek P, Cholewa D, Nelle M, Pavlovic M, Berger S (2018) Congenital Heart Disease Increases Mortality in Neonates With Necrotizing Enterocolitis. Front Pediatr 6:312 Gong X, Chen X, Wang L, Zhang M, Nappi F, Zampi JD, Zheng J, Xu Z, Bao N (2022) Analysis of clinical features of neonates with congenital heart disease who develop necrotizing enterocolitis: a retrospective case-control study. Annals of translational medicine 10:879 Shan HM, Cai W, Cao Y, Fang BH, Feng Y (2009) Extrauterine growth retardation in premature infants in Shanghai: a multicenter retrospective review. Eur J Pediatr 168:1055-1059 Rochow N, Landau-Crangle E, So HY, Pelc A, Fusch G, Däbritz J, Göpel W, Fusch C (2019) Z-score differences based on cross-sectional growth charts do not reflect the growth rate of very low birth weight infants. PloS one 14:e0216048 Makker K, Ji Y, Hong X, Wang X (2021) Antenatal and neonatal factors contributing to extra uterine growth failure (EUGR) among preterm infants in Boston Birth Cohort (BBC). Journal of perinatology : official journal of the California Perinatal Association 41:1025-1032 Norman M, Håkansson S, Kusuda S, Vento M, Lehtonen L, Reichman B, Darlow BA, Adams M, Bassler D, Isayama T, Rusconi F, Lee S, Lui K, Yang J, Shah PS (2020) Neonatal Outcomes in Very Preterm Infants With Severe Congenital Heart Defects: An International Cohort Study. Journal of the American Heart Association 9:e015369 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 01 Jun, 2024 Read the published version in European Journal of Pediatrics → Version 1 posted Editorial decision: Revision requested 13 Apr, 2024 Reviews received at journal 09 Apr, 2024 Reviewers agreed at journal 28 Mar, 2024 Reviewers invited by journal 28 Mar, 2024 Editor assigned by journal 28 Mar, 2024 Submission checks completed at journal 28 Mar, 2024 First submitted to journal 27 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4177286","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":285687567,"identity":"9e33abb4-b30f-4054-8075-93c0d150d37b","order_by":0,"name":"Pei Lu","email":"","orcid":"","institution":"Shanghai Children's Hospital, school of medicine, Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Pei","middleName":"","lastName":"Lu","suffix":""},{"id":285687568,"identity":"a48666fc-8e31-4abc-8e2d-a08edc0cf674","order_by":1,"name":"Xiaohui Gong","email":"","orcid":"","institution":"Shanghai Children's Hospital, school of medicine, Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Xiaohui","middleName":"","lastName":"Gong","suffix":""},{"id":285687570,"identity":"a15ee756-27cd-4f1e-9462-9d3b6cdcbaca","order_by":2,"name":"Xinyue Gu","email":"","orcid":"","institution":"Children's Hospital of Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Xinyue","middleName":"","lastName":"Gu","suffix":""},{"id":285687573,"identity":"c716f79a-0f81-40e0-9dca-7516eb235ad8","order_by":3,"name":"Siyuan Jiang","email":"","orcid":"","institution":"Children's Hospital of Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Siyuan","middleName":"","lastName":"Jiang","suffix":""},{"id":285687574,"identity":"245068c9-6cd2-48f9-b3bd-53f7d12e5935","order_by":4,"name":"Yun Cao","email":"","orcid":"","institution":"Children's Hospital of Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Yun","middleName":"","lastName":"Cao","suffix":""},{"id":285687575,"identity":"14c32485-6d02-4521-8bdc-869043b72b0d","order_by":5,"name":"Chengjun Sun","email":"","orcid":"","institution":"Children's Hospital of Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Chengjun","middleName":"","lastName":"Sun","suffix":""},{"id":285687576,"identity":"73e95259-b261-4664-9e44-aa100a031a6a","order_by":6,"name":"Juan Du","email":"","orcid":"","institution":"Beijing Children's Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Du","suffix":""},{"id":285687577,"identity":"9b19b3af-1ca0-4c35-b0fa-3656f994794d","order_by":7,"name":"Xiaoping Lei","email":"data:image/png;base64,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","orcid":"","institution":"Affiliated Hospital of Southwest Medical University","correspondingAuthor":true,"prefix":"","firstName":"Xiaoping","middleName":"","lastName":"Lei","suffix":""},{"id":285687580,"identity":"086758e3-e8f3-4e33-a420-c39767ea590b","order_by":8,"name":"Shoo K. Lee","email":"","orcid":"","institution":"Mount Sinai Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shoo","middleName":"K.","lastName":"Lee","suffix":""}],"badges":[],"createdAt":"2024-03-27 15:54:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4177286/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4177286/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00431-024-05599-z","type":"published","date":"2024-06-01T09:22:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":53967342,"identity":"ff50f19e-d007-4821-8410-67ffe4adfe80","added_by":"auto","created_at":"2024-04-02 19:56:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":59302,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow diagram of patient\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGA = gestational week; NEC = necrotizing enterocolitis; N = number; PDA = patent ductus arteriosus; EUGR = extrauterine growth restriction; CHD = congenital heart defect\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4177286/v1/98f41f28b8f85d7e7ee86f65.png"},{"id":60802778,"identity":"9d3b9420-aee8-4902-9089-ea8c6fec1909","added_by":"auto","created_at":"2024-07-22 09:22:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":790839,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4177286/v1/20bfb6b8-5322-4b50-b43e-d0997adc3490.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Mortality and Extrauterine Growth Restriction of Necrotizing Enterocolitis in Very Preterm Infants with Heart Disease: A Multi-Center Cohort Study","fulltext":[{"header":"What is known:","content":"\u003cul\u003e\n \u003cli\u003eCHD and PDA are risk factors for NEC in infants, which can lead to adverse outcomes such as death and EUGR.\u003c/li\u003e\n \u003cli\u003eNEC in infants with heart disease differs clinically from that in infants without heart disease and should be recognized as a separate disease process.\u003c/li\u003e\n \u003cli\u003eIt is unclear whether the prognosis of NEC differs between VPIs with and without heart diseases.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eWhat is new:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eCHD and isolated PDA are associated with increased risks of worse outcomes in VPIs with NEC.\u003c/li\u003e\n \u003cli\u003eRisk factors associated with VPIs with cardiac NEC suggested these patients should be managed with aggressive treatment and nutrition strategies to adverse outcomes.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eNecrotizing enterocolitis (NEC) continues to be a serious preterm-related complications, despite rising survival rates in very premature infants (VPIs).[\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] NEC occurs in 2%-13% of newborn critical care unit hospitalizations,[2; 4\u0026ndash;6] and it affects roughly 7% of VPIs[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] with mortality rates range from 20%-50%.[\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eCongenital heart disease (CHD) is a risk factor that raises the incidence of NEC in VPIs.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Among infants at gestational ages between 23\u003csup\u003e+\u0026thinsp;0\u003c/sup\u003e and 34\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e weeks, severe CHD (cyanotic heart defects, left-sided obstructive lesions, and congestive heart failure) was associated with a 3.72-fold increase (95% CI 1.37\u0026ndash;10.1) in the risk of NEC.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] Similarly, CHD significantly increased the incidence of NEC in very low birth weight (\u0026lt;\u0026thinsp;1500g) infants.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] The incidence of NEC in preterm infants with CHD is 8.6%-13.1%,[\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] higher than that preterm infants without CHD.[14; 16]\u003c/p\u003e \u003cp\u003eNEC in infants with CHD differs clinically from that of infants without, it was proposed that NEC in infants with CHD should be recognized as a separate disease process and referred to as cardiac NEC.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] The key beginning factors of NEC in preterm infants are believed to be intestinal epithelium degradation, transmural injury, and intestinal ischemia.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] Among these factors, intestinal ischemia brought on by decreased cardiac output, cyanosis, and congestive heart failure are assumed to be the main pathophysiological change to cause cardiac NEC in preterm infants.[\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] In addition to complex CHD, isolated PDA, one of the most prevalent heart diseases in preterm infants, as one of the risk factors resulting in NEC,[21; 22] commonly results in a left-to-right ductal shunt and ductal theft from the systemic circulation,[23; 24] results in retrograde diastolic flow, low diastolic pressure, and reduced mesenteric perfusion.[\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003cp\u003ePrevious study showed that the mortality rate for cardiac NEC in preterm infants can be 3.4 (95% CI 2.8\u0026ndash;4.1) times higher than that of non-cardiac NEC in preterm infants.[11; 18] Extrauterine growth restriction (EUGR), one of the key indicators of preterm infants\u0026rsquo; short- and long-term health,[29; 30] was commonly observed in infants with cardiac NEC.[20; 31] Due the distinct pathophysiology of cardiac NEC, it can be expected that preterm infants with cardiac NEC will experience worse outcomes than those with non-cardiac NEC. A greater understanding of cardiac NEC outcomes in preterm infants could help to make better clinical decision therefore improve the prognosis for preterm infants. However, the majority of cardiac NEC studies are focused on term and near-term newborns,[17; 32] and studies on cardiac NEC in preterm infants are often limited to single-centered investigations.[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] Therefore, the current study aims to explore whether cardiac NEC had worse outcomes than non-cardiac NEC in very preterm infants (VPIs) from a national database. We present the study in accordance with the STROBE reporting checklist (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.equator-network.org\u003c/span\u003e\u003cspan address=\"http://www.equator-network.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003e The Chinese Neonatal Network (CHNN) is a standardized national clinical database of VPIs in the NICU of 97 tertiary hospitals from 25 provinces to monitor care practices and outcomes since January 1, 2019.[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] All participating NICUs in the CHNN have recognized expertise in caring for high-risk infants in China. The data was directly entered into a customized database by trained data abstractors in each hospital under standard protocols. Data quality was ensured by built-in error checking and data checks at the coordinating center and correction of potentially incorrect data after feedback from participating centers. A waiver of the need for consent and ethics approval for data collection and analysis was granted by the ethics review board of the Children's Hospital of Fudan University (2018\u0026thinsp;\u0026minus;\u0026thinsp;296).\u003c/p\u003e \u003cp\u003eVPIs included in this prospective observational study were: (1) gestational age (GA)\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks; (2) diagnosed with NEC; (3) admitted to participating NICUs from January 1, 2019, to December 31, 2021. Necrotizing enterocolitis (NEC) was defined as stage II or above according to Bell's criteria.[35; 36] The diagnosis of CHD was made through a review of echocardiogram reports and clinical management in each patient and categorized as either CHD (cardiac abnormalities confirmed by echocardiography) or isolated PDA (hemodynamically significant PDA requiring medical or surgical treatment without detectable cardiac anomaly). Among all VPIs in CHNN between 2019 and 2021, there were 1509 infants diagnosed with NEC. After excluded 174 infants with missing data NEC diagnosis (n\u0026thinsp;=\u0026thinsp;49), PDA diagnosis (n\u0026thinsp;=\u0026thinsp;29), birth weight or discharge weight (n\u0026thinsp;=\u0026thinsp;96), 1335 VPIs were enrolled and divided into three subgroups (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e): infants with CHD (N\u0026thinsp;=\u0026thinsp;65), infants with isolated PDA (N\u0026thinsp;=\u0026thinsp;406), and infants without CHD (N\u0026thinsp;=\u0026thinsp;864).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes and variables\u003c/h2\u003e \u003cp\u003eThe primary outcomes were death in-hospital or survivors with extrauterine growth restriction (EUGR). EUGR was defined as a decrease in weight Z-score between birth and discharge\u0026thinsp;\u0026gt;\u0026thinsp;2.[\u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] Weight Z-score was calculated as age-specific and sex-specific Z-scores using the 2013 Fenton growth curve.[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] The World Health Organization (WHO) growth charts[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] were used for weight Z-score calculation after corrected GA\u0026thinsp;\u0026gt;\u0026thinsp;50 weeks.\u003c/p\u003e \u003cp\u003eThe following variables were considered as covariates in analyses: maternal characteristics (maternal age, maternal hypertension, diabetes mellitus, and whether antenatal steroids had been administered); infant characteristics (gender, single- or multiple-birth, birth weight, gestational age, and Apgar score at 5 minutes); characteristics of NEC (age and GA at NEC diagnosis, stage of NEC, intestinal perforation, and surgical treatment); treatment information (inotrope usage before and after NEC, duration of mechanical ventilation and non-invasive ventilation, day to start enteral feed; days to reach full enteral feed; and hospitalization duration). GA was determined using the hierarchy of the best obstetric estimate based on prenatal ultrasound, menstrual history, obstetric examination, or the Ballard Score if the obstetric estimate was not available.[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] Small for gestational age (SGA) (weight\u0026thinsp;\u0026lt;\u0026thinsp;10th percentile) was defined according to the 2013 Fenton growth curve.[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] Intrauterine Growth Restriction (IUGR), defined as fetuses who failed to achieve normal weight based on previous growth measurements in the pregnancy and diagnosed by intrauterine growth failure with normal head circumference (HC) and/or Doppler velocimetry abnormalities.[43; 44]\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe baseline characteristics were described using frequencies (percentages) and compared using the chi-square test (χ2) for categorical variable between two groups. Continuous variables were first analyzed by the normality test. The normally distributed continuous variables were displayed as means and standard deviations (SDs) and compared by Student\u0026rsquo;s t-test, while the abnormally distributed continuous variables were displayed as medians and interquartile ranges (IQRs) and compared by Wilcoxon signed-rank test.\u003c/p\u003e \u003cp\u003eTo determine whether NEC infants with heart diseases had a higher risk of NEC-related mortality or EUGR, logistic regression models were used to adjust potential confounders and calculate the adjusted odds ratios (aORs) and 95% confidential intervals (CIs) for mortality and EUGR among infants with CHD or isolated PDA as compared with NEC infants without CHD (noncardiac NEC). In order to determine whether NEC infants with CHD had a higher risk of adverse outcomes than those with isolated PDA, comparisons between the two groups were also conducted. Statistical significance was defined as p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Data management and statistical analyses were performed using R (version 4.2.2, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.r-project.org\u003c/span\u003e\u003cspan address=\"http://www.r-project.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eInfant Characteristics\u003c/h2\u003e \u003cp\u003eA total of 471 VPIs had cardiac NEC in our cohort. There are 65 infants with CHD and 52 of them are atrial septal defect (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTypes and Frequencies of CHDs in the Group of 471 VPIs With NEC\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of CHD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;471\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVentricular septal defect\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtrial septal defect\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtrioventricular septal defect\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulmonary valve stenosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther congenital malformations of the heart\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCoarctation of the aorta\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsolated PDA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e406\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eCHD\u0026thinsp;=\u0026thinsp;congenital heart disease; N\u0026thinsp;=\u0026thinsp;number; PDA\u0026thinsp;=\u0026thinsp;patent ductus arteriosus\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows differences in clinical features of infants with CHD or isolated PDA compared to those without. Between VPIs with heart diseases and those without, there was no significant difference in maternal age, maternal diabetes, maternal hypertension, infant gender, or IUGR. VPIs with CHD and isolated PDA had lower birth weights and more frequently received prenatal steroids. VPIs with isolated PDA were more frequently administered with inotrope prior to the onset of NEC (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics and outcomes of NEC VPIs with and without CHD\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCHD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIsolated PDA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;406\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;864\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMaternal characteristics\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal age (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (28\u0026ndash;33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (28\u0026ndash;34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31 (28\u0026ndash;34)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal diabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (18.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87 (21.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e156 (18.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal hypertension and preeclampsia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (24.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82 (20.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e157 (18.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eInfants\u0026rsquo; characteristics\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntenatal steroids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (78.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e304 (74.9%)\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e593 (68.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (53.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e231 (56.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e513 (59.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple birth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (26.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e140 (34.5%)\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e216 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational weeks (w)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.6 (28.3\u0026ndash;30.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e28.9 (27.2\u0026ndash;30)\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.9 (28.3\u0026ndash;30.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight (g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1280 (1080\u0026ndash;1400)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1150 (950\u0026ndash;1390)\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1330 (1100\u0026ndash;1550)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSGA or IUGR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58 (14.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e92 (10.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUsed inotropes before NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (16.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e97 (23.9%)\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e156 (18.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eNEC related characteristics\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at NEC diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (12\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e20.5 (11\u0026ndash;32)\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (11\u0026ndash;28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational weeks (w) at NEC diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.7 (30.4\u0026ndash;34.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e32.1 (30.6\u0026ndash;33.6)\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32.4 (31.1\u0026ndash;33.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNEC stage III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (43.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e159 (39.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e322 (37.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eOutcomes\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse outcome (death or EUGR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (52.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e200 (49.3%)\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e351 (40.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (11.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83 (9.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurvival with EUGR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (46.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e154 (42.8%)\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e268 (34.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNEC Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (53.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e160 (39.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e360 (41.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays to re-entero-feeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e11 (8\u0026ndash;15)\u003c/b\u003e \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (6\u0026ndash;13.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (7\u0026ndash;12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays to full-entero-feeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e25 (13\u0026ndash;41)\u003c/b\u003e \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (12\u0026ndash;33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (11\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMV duration after NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e4 (0\u0026ndash;14)\u003c/b\u003e \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e4 (0\u0026ndash;14)\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (0\u0026ndash;7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInotropes after NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (36.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e138 (34%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e283 (32.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntestinal perforation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (29.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e89 (21.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e217 (25.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalization duration (d)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e56 (44\u0026ndash;72)\u003c/b\u003e \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e58 (38\u0026ndash;81.75)\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47 (31.75\u0026ndash;65)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eComparisons are made between patients with CHD and without. SGA\u0026thinsp;=\u0026thinsp;small for gestational age; IUGR\u0026thinsp;=\u0026thinsp;intrauterine growth restriction; EUGR\u0026thinsp;=\u0026thinsp;extrauterine growth restriction; significant results (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) are shown in bold.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe median postnatal age at diagnosis of NEC among VPIs with CHD, with isolated PDA, and VPIs without heart diseases, was 20 days, 20.5 days, and 19 days after birth, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The Bell stages did not differ significantly across groups: the frequency of stage III NEC in VPIs with CHD, isolated PDA, and those without heart disease were 43.1%, 39.2%, and 37.3%, respectively. Despite no statistically significant difference, infants with CHD trended to receive surgical treatment more frequently. VPIs with CHD recovered later from NEC than VPIs without heart disease as VPIs with CHD or isolated PDA required more prolonged mechanical ventilation, started feeding later, and spent more time in the hospital, when compared to VPIs with classic NEC.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e showed that NEC infants with CHD (aOR: 2.07; 95% CI: 1.20\u0026ndash;3.60) or isolated PDA (aOR: 1.51; 95% CI: 1.17\u0026ndash;1.94) were associated with higher risks in NEC related death or EUGR. Although NEC infants with CHD or isolate PDA not associated with higher risks in NEC related death (aOR: 1.10; 95% CI: 0.41\u0026ndash;2.50 and aOR: 1.25; 95% CI: 0.82\u0026ndash;1.87, respectively) than non-cardiac NEC, higher risk of EUGR were observed in survival VPIs with CHD (aOR: 2.35; 95% CI: 1.31\u0026ndash;4.20) and isolated PDA (aOR: 1.53; 95% CI: 1.16\u0026ndash;2.01). When compare to VPIs without heart diseases, VPIs with CHD were associated with significantly higher rate of receiving surgical treatment (aOR 1.79, 95% CI: 1.03\u0026ndash;1.31), prolonged duration of fasting (aOR 6.14, 95% CI: 2.31\u0026ndash;15.4), extended time to full enteral feeding achievement\u0026thinsp;\u0026gt;\u0026thinsp;21 days (aOR 2.49 95% CI: 1.32\u0026ndash;4.62), ventilation duration\u0026thinsp;\u0026gt;\u0026thinsp;14 days (aOR 2.8 95% CI: 1.46\u0026ndash;5.15) and hospitalization duration\u0026thinsp;\u0026gt;\u0026thinsp;60 days (aOR 2.04 95% CI: 1.17\u0026ndash;3.53). Similar characteristics were also seen in VPIs with isolated PDA compared to VPIs without cardiac NEC, with the exception that VPIs with CHD are more likely to undergo surgical intervention and maintain a prolonged fast after NEC.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultiple logistic regression analysis of outcomes among infants with CHD.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCHD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003evs\u003c/em\u003e. Normal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIsolated PDA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003evs\u003c/em\u003e. Normal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCHD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cem\u003evs\u003c/em\u003e. Isolated PDA\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUni-Variable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMulti-Variable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUni-Variable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMulti-Variable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eUni-Variable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMulti-Variable\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse outcome (death or EUGR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.60 (0.97\u0026ndash;2.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e2.07 (1.20\u0026ndash;3.60)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.42 (1.12\u0026ndash;1.80)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.51 (1.17\u0026ndash;1.94)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.13 (0.67\u0026ndash;1.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.39 (0.79\u0026ndash;2.47)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.14 (0.46\u0026ndash;2.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.10 (0.41\u0026ndash;2.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.20 (0.82\u0026ndash;1.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.25 (0.82\u0026ndash;1.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.94 (0.37\u0026ndash;2.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.65 (0.36\u0026ndash;2.32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurvival with EUGR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.77 (0.97\u0026ndash;2.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e2.35 (1.31\u0026ndash;4.20)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.36 (1.11\u0026ndash;1.85)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.53 (1.16\u0026ndash;2.01)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.30 (0.66\u0026ndash;2.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.51 (0.83\u0026ndash;2.75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNEC Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.63 (0.99\u0026ndash;2.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.79 (1.03\u0026ndash;1.31)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.91 (0.72\u0026ndash;1.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.95 (0.74\u0026ndash;1.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e1.79 (1.06\u0026ndash;3.05)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e1.83 (1.03\u0026ndash;1.32)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays to re-entero-feeding\u0026thinsp;\u0026gt;\u0026thinsp;21d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e4.36 (1.75\u0026ndash;9.88)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e6.14 (2.31\u0026ndash;15.4)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e2.07 (1.14\u0026ndash;3.74)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e2.24 (1.19\u0026ndash;4.23)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.11 (0.84\u0026ndash;4.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e2.76 (1.04\u0026ndash;6.88)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays to full-entero-feeding\u0026thinsp;\u0026gt;\u0026thinsp;30d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.77 (0.97\u0026ndash;3.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e2.49 (1.32\u0026ndash;4.62)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.43 (1.08\u0026ndash;1.90)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.45 (1.07\u0026ndash;1.97)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.24 (0.66\u0026ndash;2.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.59 (0.83\u0026ndash;2.99)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMV duration\u0026thinsp;\u0026gt;\u0026thinsp;14d after NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1.11 (1.01\u0026ndash;1.21)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e2.80 (1.46\u0026ndash;5.15)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.11 (1.06\u0026ndash;1.16)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e2.06 (1.49\u0026ndash;2.84)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.00 (0.89\u0026ndash;1.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.29 (0.67\u0026ndash;2.40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInotropes after NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.20 (0.70\u0026ndash;2.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.14 (0.63\u0026ndash;2.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.06 (0.82\u0026ndash;1.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.06(0.81\u0026ndash;1.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.14 (0.65\u0026ndash;1.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.10 (0.60\u0026ndash;1.96)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntestinal perforation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.04 (0.93\u0026ndash;1.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.33 (0.71\u0026ndash;2.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.97 (0.92\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.80 (0.59\u0026ndash;1.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.07 (0.96\u0026ndash;1.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.84 (0.95\u0026ndash;3.46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalization duration\u0026thinsp;\u0026gt;\u0026thinsp;60d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.63 (0.97\u0026ndash;2.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e2.04 (1.17\u0026ndash;3.53)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e2.06 (1.62\u0026ndash;2.63)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e2.00 (1.54\u0026ndash;2.60)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.79 (0.46\u0026ndash;1.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.97 (0.54\u0026ndash;1.71)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eComparisons are made between patients with CHD and normal patients, significant results (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) are shown in bold\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eComparisons between VPIs with CHD and isolated PDA shows that aside from VPIs with CHD had a higher risk of receiving surgical treatment (aOR 1.83, 95% CI: 1.03\u0026ndash;1.32) and prolonged duration of fasting (aOR 2.76, 95% CI: 1.04\u0026ndash;6.88), the other clinical outcomes are similar between VPIs with CHD or isolated PDA.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eUsing data from a national cohort of VPIs, our findings showed that although no increased risk of mortality, cardiac NEC in VPIs is associated with increased risks of EUGR at discharge in survivors, and prolonged fasting and hospitalization duration.\u003c/p\u003e \u003cp\u003eIn current opinion, it is believed that the pathophysiology of cardiac NEC predominantly caused by hemodynamic disturbances in CHDs (either complicated CHD or isolated PDA).[24; 45] Hemodynamic abnormalities in CHD cause decreased tissue perfusion, oxygen deficit,[19; 46\u0026ndash;48] and, as a result, intestinal ischemia and hypoxia.[24; 28; 32] Cardiac NEC, on the other hand, often occurred slightly later than non-cardiac NEC in premature newborns (23 days vs 20 days after birth).[\u003cspan additionalcitationids=\"CR50\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] Similarly, preterm infants with PDA-associated NEC were also diagnosed later after birth.[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e] Our study confirmed that cardiac NEC develops later than classic NEC at 20 days after birth in VPIs. The cause of different clinical presentation could be due to other underlying factors, for instance the delay in both initiation of enteral feeding and prolonged time to reach full enteral feeding owing to concerns about gastrointestinal ischemia in preterm infants.\u003c/p\u003e \u003cp\u003eThe clinical practice in the management of VPIs with NEC can vary among centers owing to variations in clinical practice, healthcare policies, and social and cultural norms.[53; 54] It has been found in previous studies that infants with cardiac NEC require less supportive critical care (such as the usage of vasopressors and ventilation),[\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e] whereas others showed that infants with cardiac NEC was more frequently treated with inotropes and respiratory support.[20; 56] Similarly, rates of surgical intervention for cardiac NEC varied (15\u0026ndash;38% among centers).[20; 49; 56] Several studies found that infants with cardiac NEC were less likely to have surgery than infants without CHD.[11; 33] However, while the trend of receiving more critical care was similar in our cohort, the VPIs with NEC were more likely to be treated by surgery in both infants with CHD (53.8%) and without (41.7%) in the present study. The higher rate of surgery in our cohort could be subjected to the increased severity of NEC in infants with CHD and lower birth weight in the cohort.[15; 31; 50; 56; 57]\u003c/p\u003e \u003cp\u003eIn our study, the mortality rate was 10.8% for infants with CHD, 11.3% for those with isolated PDA, and 9.6% for those without heart diseases. The risk of mortality in cardiac NEC varied among studies, when some study did not identify increased mortality in infants with cardiac NEC,[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] many others have shown that cardiac NEC had a higher mortality rate, with in-hospital mortality rates ranging from 13 to 26%.[11; 13; 20; 32; 33; 49; 50; 58] Similar results were also observed in cardiac NEC related to isolated PDA.[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e] The difference in mortality rates of cardiac NEC can be subjected to variations in inclusion and other clinical practice factors.\u003c/p\u003e \u003cp\u003eIn contrast to our finding that cardiac NEC increased the risk of EUGR, Gong et al. showed in 50 ductal-dependent cardiac NEC that the risk for EUGR is similar to non-cardiac NEC in term infants.[\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e] Given that lower birth weight was one of the risk factors for EUGR,[60; 61] the risk for EUGR can be unique to VPIs with cardiac NEC. The underlying cause of EUGR in VPIs with cardiac NEC is multifactorial. First, infants were not receiving adequate nutrition from the current nutrition strategy. The types and amounts of minerals and micronutrients that are needed might not be supplied adequately. In our cohort, VPIs with cardiac NEC were associated with significantly prolonged fasting duration, and extended time to achieve full enteral feeding, suggesting additional delay in enteral feeding which may further enhance nutrition impairment. Second, fluid restriction due to CHD or hemodynamically significant PDA leading to inadequate nutrition supply may also contribute to malnutrition. Third, higher comorbidity of CHD (such as bronchopulmonary dysplasia, BPD) contributes to additional nutrition demand and nutrient losses and could potentially alter postnatal growth.[62; 63] Similarly, longer ventilation duration in VPIs with both CHD and isolated PDA may also cause additional nutrition consumption. Lastly, compared to those without heart disease, infants with CHD frequently born SGA, which was one of the main risk factors for developing EUGR.[\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e] Future studies can seek aggressive strategy to fulfill adequate energy supply and nutritional support to cardiac NEC in VPIs.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e5. Limitations\u003c/h2\u003e \u003cp\u003eOur study is limited owing to its retrospective design, relatively small number of NEC patients with CHD especially in the calculation of mortality risk. In addition, the relative short observation duration limited our conclusion primarily to NICU practice. Further studies are required to evaluate whether there are modifiable factors that can reduce negative outcome in VPIs with cardiac NEC with improved long-term outcome.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, the current study showed that infants with cardiac NEC have an increased risk of EUGR in comparison to that of infants with non-cardiac NEC. We recommend that infants with cardiac NEC be managed with aggressive treatment and nutrition strategies due to the worse prognosis.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCHNN \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Chinese Neonatal Network\u003c/p\u003e\n\u003cp\u003eCHD \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Congenital heart disease\u003c/p\u003e\n\u003cp\u003eCI \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Confidence interval\u003c/p\u003e\n\u003cp\u003eEUGR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Extrauterine growth restriction\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGA \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Gestational age\u003c/p\u003e\n\u003cp\u003eHC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Head circumference\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIUGR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Intrauterine Growth Restriction\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIQR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Interquartile range\u003c/p\u003e\n\u003cp\u003eNEC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Necrotizing enterocolitis\u003c/p\u003e\n\u003cp\u003eNICU \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Neonatal intensive care unit\u003c/p\u003e\n\u003cp\u003eOR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Odds ratio\u003c/p\u003e\n\u003cp\u003ePDA \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Patent ductus arteriosus\u003c/p\u003e\n\u003cp\u003eSD \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Standard deviations\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSGA \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Small for gestational age\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVPI \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Very preterm infant\u003c/p\u003e\n\u003cp\u003eWHO \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; The World Health Organization\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e We acknowledge all the participants in this study, the Chinese Neonatal Network, and Shanghai Children\u0026apos;s Hospital for supporting the current study (2022YLYM08).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding and support\u0026nbsp;\u003c/strong\u003eThis study is supported by the Canadian Institutes of Health Research (CTP87518) and the Chinese Neonatal Network coordinating center.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRole of funder\u0026nbsp;\u003c/strong\u003eFunding agencies had no role in the study design, collection, analyses or interpretation of data, the writing of the report and the decision to submit the paper for publication in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePei Lu\u003c/strong\u003e: Conceptualization, Methodology, Writing - Original draft.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJuan Du\u003c/strong\u003e: Investigation, Writing - Review \u0026amp; Editing, Visualization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eXinyue Gu\u003c/strong\u003e: Data Curation, Software, Formal analysis, Visualization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChengjun Sun\u003c/strong\u003e: Data Curation, Software, Formal analysis, Visualization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSiyuan Jiang\u003c/strong\u003e: Investigation, Methodology, Writing - Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eShoo K Lee\u003c/strong\u003e: Funding acquisition, Writing - Review \u0026amp; Editing, Supervision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYun Cao\u003c/strong\u003e: Writing - Review \u0026amp; Editing, Project administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eXiaohui Gong\u003c/strong\u003e: Conceptualization, Writing - Review \u0026amp; Editing, Validation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eXiaoping Lei\u003c/strong\u003e: Conceptualization, Methodology, Writing - Review \u0026amp; Editing, Supervision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e The codes are available on request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the ethics review board of the Children\u0026apos;s Hospital of Fudan University (2018-296).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e Waiver of consent were granted at all participating sites owing to the use of deidentified patient data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e The study does not publish personal identifying information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e The authors have no conflicts of interest to disclose and confirm that there is no prior presentation of study data as an abstract or poster.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eEhrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK (2006) Growth in the Neonatal Intensive Care Unit Influences Neurodevelopmental and Growth Outcomes of Extremely Low Birth Weight Infants. 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Front Pediatr 6:312\u003c/li\u003e\n\u003cli\u003eGong X, Chen X, Wang L, Zhang M, Nappi F, Zampi JD, Zheng J, Xu Z, Bao N (2022) Analysis of clinical features of neonates with congenital heart disease who develop necrotizing enterocolitis: a retrospective case-control study. Annals of translational medicine 10:879\u003c/li\u003e\n\u003cli\u003eShan HM, Cai W, Cao Y, Fang BH, Feng Y (2009) Extrauterine growth retardation in premature infants in Shanghai: a multicenter retrospective review. Eur J Pediatr 168:1055-1059\u003c/li\u003e\n\u003cli\u003eRochow N, Landau-Crangle E, So HY, Pelc A, Fusch G, D\u0026auml;britz J, G\u0026ouml;pel W, Fusch C (2019) Z-score differences based on cross-sectional growth charts do not reflect the growth rate of very low birth weight infants. PloS one 14:e0216048\u003c/li\u003e\n\u003cli\u003eMakker K, Ji Y, Hong X, Wang X (2021) Antenatal and neonatal factors contributing to extra uterine growth failure (EUGR) among preterm infants in Boston Birth Cohort (BBC). Journal of perinatology : official journal of the California Perinatal Association 41:1025-1032\u003c/li\u003e\n\u003cli\u003eNorman M, H\u0026aring;kansson S, Kusuda S, Vento M, Lehtonen L, Reichman B, Darlow BA, Adams M, Bassler D, Isayama T, Rusconi F, Lee S, Lui K, Yang J, Shah PS (2020) Neonatal Outcomes in Very Preterm Infants With Severe Congenital Heart Defects: An International Cohort Study. Journal of the American Heart Association 9:e015369\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Necrotizing enterocolitis, Heart disease, Patent ductus arteriosus, Very preterm infants, Extrauterine growth restriction, Mortality","lastPublishedDoi":"10.21203/rs.3.rs-4177286/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4177286/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eOBJECTIVE.\u003c/strong\u003e Congenital heart disease (CHD) and patent ductus arteriosus (PDA) are risk factors of necrotizing enterocolitis (NEC) in infants. However, it is unclear whether the prognosis of NEC is different between very preterm infants (VPIs) with and without heart diseases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePATIENTS AND METHODS.\u003c/strong\u003e This was an observational cohort study that enrolled VPIs (born between 24\u003csup\u003e+ 0\u003c/sup\u003e and 31\u003csup\u003e+ 6\u003c/sup\u003e weeks) admitted to 97 tertiary neonatal intensive care units (NICU) in the Chinese Neonatal Network (CHNN) between 2019 and 2021. The exposure was CHD or isolated PDA, and VPIs with NEC were divided into three groups: complicated with CHD, with isolated PDA, and without heart diseases. The primary outcomes were NEC related adverse outcomes (death or extrauterine growth restriction (EUGR)). Logistic regression models were used to adjust potential confounders and calculate the odds ratios (ORs) and 95% confidential intervals (CIs) for each outcome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRESULTS.\u003c/strong\u003e A total of 1335 VPIs with NEC were enrolled in this study, including 65 VPIs with CHD, 406 VPIs with isolated PDA. The VPIs with heart diseases had smaller gestational ages and lower body weights at birth, more antenatal steroids use, and requiring inotrope prior to the onset of NEC. While suffering from NEC, death or EUGR were more often observed in VPIs with either CHD (aOR: 2.07; 95% confidence interval [CI]: 1.20–3.60) or isolated PDA (aOR: 1.51; 95% CI: 1.17–1.94) than those without heart diseases. While no significant increased risks in NEC related death in VPIs with either CHD (adjusted OR [aOR]: 1.10; 95% CI: 0.41–2.50) or isolated PDA (aOR: 1.25; 95% CI 0.82–1.87), increased risks in EUGR was identified in either survival VPIs with CHD (aOR: 2.35; 95% CI: 1.31–4.20) or isolated PDA (aOR: 1.53; 95% CI: 1.16–2.01) in survivors. VPIs with either CHD or isolated PDA were associated with significantly prolonged duration of fasting, extended time to achieve full enteral feeding, longer ventilation duration and hospitalization duration. Similar characteristics were also seen in VPIs with isolated PDA, with the exception that VPIs with CHD are more likely to undergo surgical intervention and maintain a prolonged fast after NEC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONCLUSIONS.\u003c/strong\u003e In VPIs with NEC, CHD and isolated PDA are associated with an increased risk in worse outcomes. We recommend that VPIs with cardiac NEC be managed with aggressive treatment and nutrition strategies to prevent EUGR.\u003c/p\u003e","manuscriptTitle":"Mortality and Extrauterine Growth Restriction of Necrotizing Enterocolitis in Very Preterm Infants with Heart Disease: A Multi-Center Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-02 19:56:11","doi":"10.21203/rs.3.rs-4177286/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-13T14:53:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-09T09:24:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"dd3dd669-e11a-457e-bd44-ce3d902e3f90","date":"2024-03-28T17:12:47+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-28T15:53:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-28T05:53:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-28T05:52:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2024-03-27T15:53:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"df133813-d4db-4589-9e99-014d8fce6708","owner":[],"postedDate":"April 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-07-22T09:22:34+00:00","versionOfRecord":{"articleIdentity":"rs-4177286","link":"https://doi.org/10.1007/s00431-024-05599-z","journal":{"identity":"european-journal-of-pediatrics","isVorOnly":false,"title":"European Journal of Pediatrics"},"publishedOn":"2024-06-01 09:22:34","publishedOnDateReadable":"June 1st, 2024"},"versionCreatedAt":"2024-04-02 19:56:11","video":"","vorDoi":"10.1007/s00431-024-05599-z","vorDoiUrl":"https://doi.org/10.1007/s00431-024-05599-z","workflowStages":[]},"version":"v1","identity":"rs-4177286","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4177286","identity":"rs-4177286","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}