PEDIATRICS Vol. 106 No. 5 November 2000, pp. 1080-1087

Necrotizing Enterocolitis in Neonates With Congenital Heart Disease: Risk Factors and Outcomes

Doff B. McElhinney, MD^*, Holly L. Hedrick, MD, David M. Bush, MD, PhD^*, Gilberto R. Pereira, MD^§, Perry W. Stafford, MD, J. William Gaynor, MD, Thomas L. Spray, MD, and Gil Wernovsky, MD^*

From the Divisions of ^* Cardiology,  General Surgery, ^§ Neonatology, and  Cardiothoracic Surgery, the Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

	ABSTRACT

Top Abstract Methods Results Discussion Conclusion References

Objective.  Necrotizing enterocolitis (NEC) is primarily a disease of the premature infant. Among children born at term, however, congenital heart disease may be an important predisposing factor for this condition. To determine risk factors for NEC in patients with congenital heart disease, we conducted a case-control study of neonates with cardiac disease admitted to the cardiac intensive care unit at our center during the 4-year period from January 1995 to December 1998.

Methods.  Cardiac diagnosis and age at admission were analyzed for association with NEC among the 643-patient inception cohort. Demographic, preoperative, and operative variables were recorded retrospectively in 21 neonates with congenital heart disease who developed NEC and 70 control neonates matched by diagnosis and age at admission. Using parametric and nonparametric analysis, cases and controls were compared with respect to previously identified risk factors for NEC.

Results.  Among the entire cohort of 643 neonates with heart disease admitted to the cardiac intensive care unit, diagnoses of hypoplastic left heart syndrome (odds ratio [OR] = 3.8 [1.6-9.1]) and truncus arteriosus or aortopulmonary window (OR = 6.3 [1.7-23.6]) were independently associated with development of NEC by multivariable analysis. In the case-control analysis, earlier gestational age at birth (36.7 ± 2.7 weeks vs 38.1 ± 2.3 weeks), prematurity (OR = 3.9 [1.2-12.5]), highest dose of prostaglandin >0.05 µg/kg/minute (OR = 3.9 [1.2-12.5]), and episodes of low cardiac output (meeting specific laboratory criteria) or clinical shock (OR = 6.5 [1.8-23.5]) correlated with the development of NEC. Earlier gestational age and episodes of low output were the only factors that remained significantly associated with NEC by multivariable analysis. Although there was no difference in hospital mortality between patients with and without NEC, mean hospital stay was significantly longer in those who developed NEC (36 ± 22 days vs 19 ± 14 days).

Conclusions.  The risk of NEC in neonates with congenital heart disease is substantial. Factors associated with an elevated risk of NEC in infants with heart disease include premature birth, hypoplastic left heart syndrome, truncus arteriosus, and episodes of poor systemic perfusion or shock. Heightened suspicion is warranted in newborns with these risk factors.  Key words:  necrotizing enterocolitis, intestinal ischemia, hypoplastic left heart syndrome, truncus arteriosus.

Necrotizing enterocolitis (NEC) is a disease of the neonate in which the mucosal barrier of the gut is typically damaged and breached by pathogenic enteric bacteria, resulting in intestinal injury, which may progress to bowel necrosis, sepsis, and death in severe cases.^1-3 The risk of developing NEC is inversely related to gestational age at birth, with extremely premature neonates at substantially greater risk than those born at full-term. The predominance of this epidemiologic factor suggests that immaturity of the gut mucosa is an important predisposing factor. There are almost certainly specific cellular/molecular elements of mucosal immaturity that increase the likelihood of NEC,^4-7 along with other contributing conditions,² insofar as many small premature infants do not develop NEC and occasional term infants do. Aside from prematurity, however, no single factor or combination of factors has been found consistently to predispose a neonate to NEC. Nevertheless, a variety of conditions have been suggested to constitute increased risk, generally because of their association with bowel ischemia or colonization with pathogenic bacteria, which may result from decreased mesenteric blood flow, increased metabolic activity of the intestines, or early colonization of the gut with pathogenic organisms. Specific factors that have traditionally been linked with NEC include peripartum asphyxia, patent arterial duct, treatment with indomethacin for closure of an arterial duct, placement of an indwelling umbilical arterial catheter, and decreased umbilical arterial flow in utero.^1-3,8-10 In the majority of rigorous population-based or case-control studies, however, these associations have not been substantiated.^11-17 It is notable that although NEC occurs with decreasing frequency as infants approach full-term, the postnatal age of onset of NEC among patients in whom it does occur becomes progressively earlier.^18-25 This may be an indication that NEC results from 2 different disease processes in premature and term infants.

As with premature infants, a number of variables have been proposed as risk factors for NEC in term neonates, including polycythemia, respiratory distress, peripartum asphyxia, exchange transfusion, and enteral feeding, with disagreement between studies on the significance of these variables.^18-25 Among the factors that have been associated with NEC in term infants is congenital heart disease, although the significance of this factor has varied from study to study.^18-25 Regardless of whether heart disease is a statistically significant risk factor for NEC, it is our clinical experience that infants with congenital heart disease, regardless of gestational age, develop NEC relatively often and may be at increased risk for poor outcome if they do. Among infants with congenital heart disease, there is a paucity of published data concerning risk factors for and outcomes of NEC. Aside from case reports, small case series, and studies of selected heart defects,^26-33 we are aware of a single systematic study of risk factors for NEC in patients with congenital heart disease, which reviewed cases over 10 years ago.³⁴ Since that time, surgical strategies, cardiopulmonary bypass, and perioperative management have changed substantially, and infants with congenital heart disease are undergoing intervention at increasingly younger ages and lower weights.^35,36 Therefore, we undertook a retrospective case-control study to determine risk factors for and outcomes of NEC in neonates with heart disease admitted to the cardiac intensive care unit (CICU) over a recent 4-year period.

	METHODS

Top Abstract Methods Results Discussion Conclusion References

Patients

The inception cohort was comprised of all 643 patients <1 month of age with structural, electrical, and/or myocardial/metabolic heart disease admitted to the CICU at the Children's Hospital of Philadelphia during the 4-year period from January 1995 through December 1998. This time frame was chosen primarily because clinical management and data collection practices in the CICU were consistent during this period, thus minimizing artifact or bias attributable to these factors. In addition, at our institution, all neonates with significant heart disease, regardless of gestational age or birth weight, are admitted to the CICU. Neonates with minor congenital heart defects (eg, atrial and small ventricular septal defects and patent arterial ducts) who are hospitalized for other reasons are typically admitted to the neonatal intensive care unit. Thus, the inception cohort of the present study was skewed to more complex forms of congenital heart disease. A complete demographic database of all admissions to the CICU, including age, diagnosis, interventions, and complications, has been maintained since January 1995.

The median age at admission to the CICU was 1 day (1-30 days). Of the 643 newborns in the inception cohort, 21 (3.3%) developed NEC, as defined in the modified Bell staging criteria (Table 1).³⁷ After preliminary analysis of patients who developed NEC relative to those in the inception cohort who did not, a control group of 70 patients was selected from the 622 neonates with heart disease who did not develop NEC. Control patients were matched to NEC patients based on cardiac diagnosis and age at admission to the CICU.

Of the 643 neonates with heart disease who were admitted to the CICU during the study, 609 (95%) had primary structural cardiovascular anomalies, 26 (4%) had primary electrical abnormalities, and 8 (1%) had primary myocardial or metabolic anomalies (eg, cardiomyopathy, tumor, etc). Nearly 40% of patients had functionally univentricular heart defects (n = 251), and a total of 258 patients had obstruction of the aortic arch, including 171 of those with functionally univentricular heart disease (68%). The distribution of diagnoses is depicted in Fig 1. Systemic or pulmonary blood flow was dependent on the arterial duct in just over 50% of patients (n = 330). The vast majority of patients (84%) underwent surgical (n = 507) or transcatheter (n = 30) interventions for palliation or repair of their cardiac anomaly during the same hospital admission (not including diagnostic cardiac catheterization). Hospital mortality was 13% (n = 87) among the entire cohort of 643 patients, 25% (n = 63) among patients with functionally univentricular heart defects, and 6% (n = 24) among patients with a biventricular circulation.

View larger version (41K): [in this window] [in a new window]   Fig. 1.   Pie chart demonstrating the breakdown of patients in the inception cohort by major diagnostic category. Functionally single ventricle (SV) defects are separated out by hypoplastic left heart syndrome (HLHS), other forms of functionally univentricular defect with aortic arch obstruction (AO), and univentricular defects without arch obstruction. AP indicates aortopulmonary; COA/IAA, coarctation of the aorta and interrupted aortic arch; TGA, transposition of the great arteries; TOF, tetralogy of Fallot with pulmonary atresia (n = 32), pulmonary stenosis (n = 31), and absent pulmonary valve (n = 9).

Data Analysis

The primary outcome measure was the development of NEC. In the analysis of the entire cohort of 643 neonates, variables analyzed for association with NEC included age at admission, specific cardiac diagnosis, and type of heart disease. The type of heart disease was categorized and analyzed in several ways, with patients grouped according to structural, electrical, or myocardial/metabolic disease as well as into binary categories such as functionally univentricular versus biventricular heart disease, obstruction versus no obstruction of the aortic arch, and presence versus absence of duct-dependent systemic or pulmonary blood flow. Complete and reliable data on cardiac diagnosis were available for all patients, enabling us to analyze this variable across the entire inception cohort and to use it as the basis for matching control patients by diagnosis. Because of the referral bias toward an increased number of patients with hypoplastic left heart syndrome, limited analysis was conducted for the cohort of patients without this diagnosis.

For the case-control analysis, independent variables were selected to include factors that have been shown or suggested to correlate with NEC, as well as potentially important variables specific to patients with heart defects. Pregnancy and birth-related independent variables included estimated gestational age at birth, prematurity (<36 weeks), birth weight, low birth weight (<2.5 kg), perinatal complications, 1- and 5-minute Apgar scores, presence of major associated congenital anomalies, and prenatal diagnosis of congenital heart disease. Fetal bradycardia or cesarean section for fetal bradycardia were considered perinatal complications, as was the presence of a nuchal cord, despite our recognition that the severity of such factors is variable, that there is potential reporting bias, and that we did not always have sufficient data to clarify the details of the reported episodes. Preeclampsia was not included. Other perinatal complications are enumerated in the "Results" section.

Independent variables relating to neonatal clinical status and management included polycythemia (hematocrit: >65%), exchange transfusion, documented systemic infection, patent arterial duct, treatment with indomethacin, prostaglandin E₁ infusion, highest dose of prostaglandin, complications of prostaglandin infusion (defined as hypotension or apnea requiring a decrease in the prostaglandin dose, initiation of inotropic support, or initiation of mechanical ventilation), respiratory distress, preoperative or pre-NEC mechanical ventilation and duration of such ventilatory support, cardiac arrhythmias, episodes of poor systemic perfusion (as demonstrated by metabolic acidosis with arterial [pH < 7.2] serum creatinine: >1.2 mg/dL; and serum aspartate aminotransferase and serum alanine aminotransferase: >300 U/L), episodes of shock not meeting the aforementioned laboratory criteria for poor systemic perfusion (enumerated in the results section), utilization of preoperative or pre-NEC inotropic support, preoperative or pre-NEC history of enteral feeding for at least 1 full day, substrate and timing of enteral feeding, umbilical arterial catheterization and duration thereof, cardiac catheterization, and treatment with extracorporeal membrane oxygenation.

Independent variables related to cardiac surgery included surgery with cardiopulmonary bypass (vs no surgery or surgery without cardiopulmonary bypass), surgery with deep hypothermic circulatory arrest, intraoperative complications, and the need for early cardiac reoperations. For this analysis, NEC patients were included only if they developed NEC postoperatively, insofar as surgical variables could not predispose to NEC in patients who developed NEC before surgery. Statistical analysis was performed with SPSS for Windows, Version 7.0 (SPSS, Inc, Chicago, IL). Standard parametric and nonparametric statistical techniques were used, including independent sample t test and general factorial analysis of variance for comparison of means between groups, and ² or Fisher's exact test for comparison of dichotomous variables. Multivariable analysis was conducted with logistic regression of variables found to be significant by univariable analysis. Odds ratios (ORs) are presented with 95% confidence intervals (CIs). Data are presented as median and range or mean ± standard deviation.

	RESULTS

Top Abstract Methods Results Discussion Conclusion References

NEC

Of the 643 neonates admitted to the CICU during the 4-year study, 21 (3.3%) developed NEC, as defined in the modified Bell staging criteria (Table 1).³⁷ Primary cardiac diagnoses of the patients who developed NEC included hypoplastic left heart syndrome or a variant thereof in 10 patients, truncus arteriosus in 2, pulmonary atresia with intact ventricular septum in 2, tetralogy of Fallot in 2 (1 with an absent arterial duct), coarctation of the aorta in 2 (1 with complete atrioventricular septal defect), critical aortic stenosis in 1, aortopulmonary window in 1, and double-outlet right ventricle in 1. Diagnostic categories are summarized in Table 2. Among patients with hypoplastic left heart syndrome, the incidence of NEC was 7.6%, while 2.1% of patients with other diagnoses developed NEC. The median age at the time NEC was diagnosed was 7 days (1-24 days). There were no clusters of NEC in the CICU during the period of this study and no evidence to suggest epidemic NEC.

NEC developed before therapeutic intervention in 13 patients and after cardiac surgery in 8. Of the 13 patients who developed NEC before cardiovascular intervention, 7 underwent subsequent cardiac surgery with cardiopulmonary bypass a median of 8 days (4-14 days) after NEC was diagnosed. Cases of NEC met the criteria for modified Bell stage 1b in 2 patients, stage 2a in 7, stage 2b in 7, stage 3a in 3, and stage 3b in 2. The majority of patients presented initially with hematochezia, followed by radiographic findings and systemic signs and symptoms. All but 2 patients were managed for NEC initially with medical therapy, including triple-coverage antibiotics, cessation of enteral feeds if they were being administered, nasogastric or orogastric suction, antacid medications, and discontinuation of umbilical arterial lines if present. In 2 patients with obstruction of the aortic arch, prostaglandin E₁ infusion was reinitiated after earlier discontinuation. The 2 patients with so-called surgical NEC were both found at surgery to have multiple colonic perforations. One of these underwent resection of the left hemicolon; the other simply had a peritoneal drain placed because of necrosis extending from the duodenum to the rectum, which was not believed to be amenable to resection and survival. Of the patients treated initially with medical therapy, 2 later developed colonic strictures, in 1 case requiring right hemicolectomy.

Analysis of the Inception Cohort

Demographic and diagnostic features of patients in the inception cohort who did and who did not develop NEC are summarized in Table 2. All of the patients who developed NEC had primary structural heart disease. As summarized in Table 2, univariable analysis of the 643-patient cohort revealed that a diagnosis of hypoplastic left heart syndrome or a variant thereof was a significant risk factor for NEC, as were other forms of functionally univentricular heart disease, functionally univentricular heart disease with obstruction of the aortic arch (which includes hypoplastic left heart syndrome), and truncus arteriosus or aortopulmonary window (combined category). By multivariable logistic regression of these variables, only hypoplastic left heart syndrome (P < .001) and truncus arteriosus or aortopulmonary window (P < .001) remained significant. The effect of patients with hypoplastic left heart syndrome accounted for the significance on univariable analysis of functional single ventricle heart defects and functionally univentricular defects with arch obstruction. All but 2 patients who developed NEC underwent surgical (n = 17) or transcatheter (n = 2) treatment for their heart disease; the 2 that did not (1 with hypoplastic left heart syndrome and 1 with truncus arteriosus) both died before planned intervention. When patients with hypoplastic left heart syndrome were excluded from the analysis of the overall inception cohort, a diagnosis of truncus arteriosus or aortopulmonary window was the sole factor associated with NEC (OR = 11.4 [2.8-47]; P = .006). Among patients in the inception cohort, those who developed NEC were not at significantly increased risk of hospital death.

Case-Control Analysis

Gestational age at birth ranged from 31 to 42 weeks and birth weight from 1.2 to 4.4 kg. Fifteen patients were born prematurely (<36 weeks' estimated gestational age) and 26 were low birth weight (<2.5 kg), including 10 who weighed 2.0 kg or less. Other demographic variables are summarized in Table 3, and except for gestational age and premature birth (see below), there were no significant differences between NEC and control patients. All 21 patients who developed NEC had at least 1 factor aside from heart disease that was considered to be a potential risk factor for NEC.

Factors associated with increased risk of NEC in the case-control analysis included prematurity, earlier gestational age, highest dose of prostaglandin >0.05 µg/kg/minute, episodes of low cardiac output or shock (enumerated in the legend of Table 3), and the combination of prematurity and episodes of poor systemic perfusion (Table 3). None of the other factors analyzed for association with NEC were found to be significant. On multivariable analysis of these variables (not including the combined category of prematurity and poor perfusion), episodes of low output or shock (P = .001) and younger gestational age (P = .005) remained significantly associated with NEC. Of the 21 patients who developed NEC, 13 (62%) were premature and/or had episodes of poor systemic perfusion or shock (OR = 7.1 [2.5-20.7]; P < .001). Among the other 8 patients who developed NEC, all had lesions predisposing to pulmonary overcirculation with increased pulse pressure and low diastolic pressure but did not clearly meet criteria for episodes of low output or poor systemic perfusion: 5 had functionally univentricular heart defects (3 with hypoplastic left heart syndrome), 2 had truncus arteriosus or aortopulmonary window, and 1 had double-outlet right ventricle with pulmonary overcirculation. Other variables examined are presented in Table 1, except for polycythemia, exchange transfusion, treatment with indomethacin to facilitate ductal closure, and significant pre-NEC or preoperative arrhythmias, which did not occur in any cases or controls. Among patients with diagnoses other than hypoplastic left heart syndrome, an episode of poor systemic perfusion was the only variable found to correlate with the development of NEC (OR = 11.7 [1.8-76]; P = .01).

Of the 70 control patients, 6 had occult blood in the stool on at least 3 consecutive stool examinations at some point during their hospitalization, with no other signs/symptoms of NEC, and were considered not to have NEC. Another control patient was found to have gastric antral pneumatosis on abdominal radiography without clinical evidence of NEC and was considered not to have NEC.

Outcomes

There was no difference in hospital mortality between patients who developed NEC and controls (4 of 21 vs 10 of 70; OR = 1.4 [.4-5.1]; P = .60). However, all 4 of the deaths in patients with NEC were directly attributable to NEC or to associated complications such as multiple organ failure or Escherichia coli sepsis. Among patients who developed NEC, those with stage 3 disease were at significantly greater risk of death than were those with lesser stages (OR = 22.5 [1.5-335]; P = .03). There was no correlation between hospital mortality and the time of onset of NECthat is, before or after cardiac intervention (OR = 2.1 [.2-24.6]; P = .50). Among survivors, the duration of hospital stay was significantly longer in patients with NEC than in controls (36 ± 22 days vs 19 ± 14 days; P = .02).

	DISCUSSION

Top Abstract Methods Results Discussion Conclusion References

Congenital heart disease has been found in several studies to be a predisposing factor for the development of NEC in neonates born at or close to term.^20,23 In addition, there are a number of other reports in which NEC has been described in term infants with congenital heart disease.^26-34 In the present study, the incidence of NEC among 643 neonates with heart disease was 3.3%, which is substantially (10- to 100-fold) higher than the population-wide rates of 3 per 1000 newborns (inception cohort: 8841 live births) reported by Stoll et al,¹¹ 1.3 per 1000 newborns (inception cohort: 264 789 infants) reported by Wiswell et al,²² and .3 per 1000 newborns (inception cohort: 598 579 live births) reported by Palmer et al.¹⁷ The incidence of 3.3% in our study was approximately one half to one third the rates reported for very low birth weight infants in several studies.^15,16 Thus, although the present investigation was not a population-based study and was not designed to determine whether congenital heart disease is a risk factor for NEC, the incidence of 3.3% is consistent with the general belief that heart disease is an important predisposing condition, raising the risk by at least 10-fold over the general population of newborns. Among the 131 patients with hypoplastic left heart syndrome, NEC occurred in 7.6% (vs 2.1% in patients with other forms of congenital heart disease). Thus, although patients with hypoplastic left heart syndrome seem to be at especially high risk, the incidence of NEC in neonates with other forms of congenital heart disease is also substantially higher than in the population at large.

Our study was designed to determine whether risk factors for NEC could be identified in neonates with known heart disease. Clinically, we have observed that neonates with heart disease who develop NEC generally have pathophysiologic conditions or experience events that lead to gastrointestinal hypoperfusion. However, only a minority of infants with forms of heart disease predisposing to such conditions develop NEC, so we sought to examine whether specific factors could be identified that were associated with increased risk. We found that patients with hypoplastic left heart syndrome, univentricular heart disease in general, univentricular heart disease with arch obstruction, and truncus arteriosus or aortopulmonary window (combined diagnostic group) had significantly higher rates of NEC than those without. The increased risk among patients with hypoplastic left heart syndrome accounted for the significance by univariable analysis of functionally univentricular heart disease and univentricular lesions with arch obstruction. In a case-control analysis matched by diagnosis and age at admission to the CICU, we discovered that premature birth (<36 weeks), younger gestational age (continuous variable), episodes of poor systemic perfusion, a combination of these factors, and a maximum dose of prostaglandin of >0.05 µg/kg/minute were significantly associated with NEC. By multivariable analyses, hypoplastic left heart syndrome, truncus arteriosus or aortopulmonary window, gestational age, and episodes of low cardiac output (based on laboratory criteria suggesting end-organ damage) or shock were found to be independently significant risk factors. Of note, a history of previous enteral feeding, the timing of such feeds, and breast milk or formula feeds, did not correlate with NEC. There were no clusters of NEC in the CICU during the study, and no evidence to suggest epidemic NEC, which is a well-described phenomenon in premature infants.¹

Although most cases of NEC in our series were managed successfully with medical measures and hospital mortality did not differ significantly from that in control patients, all of the deaths in patients who developed NEC were directly attributable to NEC, not to their heart disease. Moreover, the duration of hospitalization was significantly longer in patients with NEC. Thus, although NEC occurs in only a small minority of neonates with congenital heart disease, it should be considered an important cause of morbidity and mortality in such patients.

The only previously published systematic investigation of factors associated with NEC in neonates with congenital heart disease was a report by Leung et al³⁴ in 1988. Their study included 133 symptomatic neonates with congenital heart disease seen during a 2-year period, 9 of who developed NEC (6.8%). The only risk factors identified were prostaglandin infusion (8 of 9 patients who developed NEC), apnea induced by prostaglandin infusion (4 of 9 patients), and hypotension induced by prostaglandin infusion (5 of 9 patients; among the 3 factors identified, this had the lowest likelihood of association by chance). The authors did not specify whether the neonates who developed hypotension and apnea attributable to prostaglandin therapy were the same patients and they do not specify the criteria that they used for diagnosing apnea or hypotension. The authors proposed that hypotension and apnea secondary to prostaglandin infusion resulted in a diving reflex, with consequent bowel ischemia. Although the existence of a so-called diving reflex in full-term human newborns is questionable,⁹ the occurrence of NEC in patients with congenital heart disease receiving prostaglandin therapy is well-documented.³⁸ Moreover, it may be difficult to determine whether apnea related to prostaglandin therapy is truly a risk factor for NEC, inasmuch as: 1) a substantial number of neonates at risk are maintained on mechanical ventilatory support, which may mask apnea, and 2) apnea may be a symptom of NEC. Multivariable analysis in the aforementioned study may have clarified this ambiguity. With respect to this issue, it is interesting to note that, although we did not find prostaglandin therapy or complications thereof to be significantly associated with NEC, a maximum prostaglandin dose >0.05 µg/kg/minute was associated with NEC in our univariable analysis. All patients who were treated with a prostaglandin dose >0.05 µg/kg/minute had this dose initiated at the referring institution, and the dose of prostaglandin was reduced to 0.05 µg/kg/minute or less on arrival at our institution.

It is also worth mentioning that the incidence of NEC in the study by Leung et al³⁴ was twice that in our experience. It is not clear why this is the case, insofar as the authors provided few details on their system for diagnosing NEC and limited information on the characteristics of their inception cohort, other than noting simply that they included all neonates admitted with symptomatic congenital heart disease. Moreover, it is interesting that the composition of their study population differed substantially from ours with respect to types of heart disease. Only a small minority of their study population was comprised of patients with functionally univentricular heart disease (14%; 9 with hypoplastic left heart syndrome and 10 with pulmonary atresia and intact ventricular septum), and only 1 of the patients who developed NEC (11%) had such a diagnosis, and this patient had pulmonary atresia with intact ventricular septum. In contrast, functionally univentricular heart disease was present in 40% of the neonates in our inception cohort and 62% of those who developed NEC in our experience. Excluding patients with hypoplastic left heart syndrome, the incidence of NEC in the series of Leung et al³⁴ was 7.3%, compared with 2.1% in our experience. Similarly, there were no patients in their study population with truncus arteriosus or aortopulmonary window, which together accounted for 14% of our cases of NEC.

Regardless of the differences in findings between our investigation and that of Leung et al,³⁴ both studies support the belief that NEC is an important concern in the neonate with congenital heart disease. Although the results of the present study will not allow us to predict specifically which neonates with congenital heart disease will develop NEC, it does confirm our suspicions about which patients are at greatest risk and provides evidence to support our tendency toward heightened awareness in patients with the risk factors that we have identified. It also supports the hypothesis that altered mesenteric blood flow may be an important factor in the pathophysiology of NEC in neonates with heart disease.

The relationship between heart disease and NEC in full-term infants is almost certainly circulatory. Patients with critical congenital heart disease are predisposed to mesenteric circulatory insufficiency for several reasons. A common feature to many of the structural lesions associated with NEC is the combination of a widened pulse pressure and low diastolic pressure. This is seen preoperatively in patients with shunting at the level of the great arteries, as with truncus arteriosus and aortopulmonary window, as well as those in whom a patent arterial duct is necessary to perfuse either the systemic or pulmonary vascular bed. Patients with this abnormal physiology have been shown to have retrograde diastolic flow in the descending aorta,³⁹ potentially resulting in mesenteric ischemia. Some of these patients (eg, those with coarctation of the aorta and hypoplastic left heart syndrome) may present with circulatory collapse and gut ischemia on ductal closure. In addition, many of these children are monitored with umbilical arterial catheters, and some undergo cardiac catheterization, which have been reported as risk factors for NEC.^9,10,28,29 Although prostaglandin use, indwelling umbilical catheters, and cardiac catheterization have been reported as probable causative factors for NEC,^{9,10,28,29,34} it may in fact be the underlying congenital heart disease and its management, rather than the prostaglandins or umbilical lines per se, that are most contributory, inasmuch as the circulatory physiology in these patients results in decreased reserve. We acknowledge that the variable "episodes of shock not meeting laboratory criteria" in our analysis is not as discrete as the others and may, thus, be difficult to interpret. However, we believed that it was important to account for the circulatory events that these patients experienced, although they did not meet our laboratory criteria for episodes of low cardiac output. Challenges awaiting study in this area include the development of methods that will improve our ability to predict cardiac patients at highest risk of NEC, such as noninvasive assessment of mesenteric hemodynamics,⁴⁰ and means of detecting NEC in its earliest stages, possibly allowing intervention before the disease progresses to its more fulminant forms.

	CONCLUSION

Top Abstract Methods Results Discussion Conclusion References

In a population of 643 neonates with complex congenital heart disease, the risk of NEC in the current era is substantially higher than in the general population. However, the incidence in our experience is lower than that reported in series published over a decade ago, despite the concentration of extremely high-risk patients (20% with hypoplastic left heart syndrome and 40% with functionally univentricular heart defects). Unexpectedly, NEC did not significantly increase the risk of hospital mortality among neonates with congenital heart disease, although it was the direct cause of death in nearly 20% of patients in whom it did develop. The present study adds to our understanding of this vexing problem. Nevertheless, several important questions remain unanswered, most importantly those surrounding the issue of the mechanism by which congenital heart disease predisposes patients to NEC.

	FOOTNOTES

Received for publication Jan 31, 2000; accepted May 15, 2000.

Address correspondence to Gil Wernovsky, MD, the Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104. E-mail: wernovsky{at}email.chop.edu

	ABBREVIATIONS

NEC, necrotizing enterocolitis; CICU, cardiac intensive care unit; OR, odds ratio; CI, confidence interval.

	REFERENCES

Top Abstract Methods Results Discussion Conclusion References

1. Stoll BJ Epidemiology of necrotizing enterocolitis. Clin Perinatol 1994; 21:205-218 [Medline]
2. Vasan U, Gotoff SP Prevention of neonatal necrotizing enterocolitis. Clin Perinatol 1994; 21:425-435 [Medline]
3. Kanto WP, Hunter JE, Stoll BJ Recognition and medical management of necrotizing enterocolitis. Clin Perinatol 1994; 21:335-346 [Medline]
4. Ford H, Watkins S, Reblock K, Rowe M The role of inflammatory cytokines and nitric oxide in the pathogenesis of necrotizing enterocolitis. J Pediatr Surg 1997; 32:275-282 [CrossRef][Medline]
5. Zamora SA, Amin HJ, McMillan DD, Plasma L-arginine concentrations in premature infants with necrotizing enterocolitis. J Pediatr 1997; 131:226-232 [CrossRef][Medline]
6. Muguruma K, Gray PW, Tjoelker LW, Johnston JM The central role of PAF in necrotizing enterocolitis development. Adv Exp Med Biol 1997; 407:379-382 [Medline]
7. Caplan MS, MacKendrick W Inflammatory mediators and intestinal injury. Clin Perinatol 1994; 21:235-246 [Medline]
8. Grosfeld JL, Chaet M, Molinari F, Increased risk of necrotizing enterocolitis in premature infants with patent ductus arteriosus treated with indomethacin. Ann Surg 1996; 224:350-357 [CrossRef][Medline]
9. Nowicki PT, Nankervis CA The role of the circulation in the pathogenesis of necrotizing enterocolitis. Clin Perinatol 1994; 21:219-234 [Medline]
10. Rand T, Weninger M, Kohlhauser C, Effects of umbilical arterial catheterization on mesenteric hemodynamics. Pediatr Radiol 1996; 26:435-438 [CrossRef][Medline]
11. Stoll BJ, Kanto WP, Glass RI, Nahmias AJ, Brann AW Epidemiology of necrotizing enterocolitis: a case control study. J Pediatr 1980; 96:447-451 [CrossRef][Medline]
12. Cassady G, Crouse DT, Kirklin JW, A randomized, controlled trial of very early prophylactic ligation of the ductus arteriosus in babies who weighed 1000 g or less at birth. N Engl J Med 1989; 320:1511-1516 [Abstract]
13. Kliegman RM, Fanaroff AA Neonatal necrotizing enterocolitis: a nine-year experience. Am J Dis Child 1981; 135:603-607 [Abstract]
14. Lui K, Nair A, Giles W, Morris J, John E Necrotizing enterocolitis in a perinatal centre. J Paediatr Child Health 1992; 28:47-49 [Medline]
15. Uauy RD, Faranoff AA, Korones SB, Phillips EA, Philips JB, Wright LL Necrotizing enterocolitis in very low birth weight infants: biodemographic and clinical correlates. J Pediatr 1991; 119:630-638 [CrossRef][Medline]
16. Kliegman RM, Hack M, Jones P, Faranoff AA Epidemiologic study of necrotizing enterocolitis among low-birth-weight infants: absence of identifiable risk factors. J Pediatr 1982; 100:440-444 [CrossRef][Medline]
17. Palmer SR, Biffin A, Gamsu HR Outcome of neonatal necrotizing enterocolitis: results of the BAPM/CDSC surveillance study, 1981-1984. Arch Dis Child 1989; 64:388-394 [Abstract]
18. Snyder CL, Gittes GK, Murphy JP, Sharp RJ, Ashcraft KW, Amoury RA Survival after necrotizing enterocolitis in infants weighing less than 1,000 g: 25 years' experience at a single institution. J Pediatr Surg 1997; 32:434-437 [CrossRef][Medline]
19. Thilo EH, Lazarte RA, Hernandez JA Necrotizing enterocolitis in the first 24 hours of life. Pediatrics 1984; 73:476-480 [Abstract/Free Full Text]
20. Polin RA, Pollack PF, Barlow B, Necrotizing enterocolitis in term infants. J Pediatr 1976; 89:460-462 [CrossRef][Medline]
21. Wilson R, del Portillo M, Schmidt E, Feldman RA, Kanto WP Risk factors for necrotizing enterocolitis in infants weighing more than 2,000 grams at birth: a case-control study. Pediatrics 1983; 71:19-22 [Abstract/Free Full Text]
22. Wiswell TE, Robertson CF, Jones TA, Tuttle DJ Necrotizing enterocolitis in full-term infants: a case-control study. Am J Dis Child 1988; 142:532-535 [Abstract]
23. Martinez-Tallo E, Claure N, Bancalari E Necrotizing enterocolitis in full-term or near-term infants: risk factors. Biol Neonate 1997; 71:292-298 [CrossRef][Medline]
24. Andrews DA, Sawin RS, Ledbetter DJ, Schaller RT, Hatch EI Necrotizing enterocolitis in term neonates. Am J Surg 1990; 159:507-509 [CrossRef][Medline]
25. de Gamarra E, Helardot P, Moriette G, Murat I, Relier JP Necrotizing enterocolitis in full-term newborns. Biol Neonate 1983; 44:185-192 [Medline]
26. Kleinman PK, Winchester P, Brill PW Necrotizing enterocolitis after open heart surgery employing hypothermia and cardiopulmonary bypass. AJR Am J Roentgenol 1976; 127:757-760 [Abstract]
27. Shapiro AJ, Kavey RE, Dangman BC, Gersony WM Necrotizing enterocolitis in symptomatic infants with congenital heart disease. Pediatr Res 1977; 11:542
28. Cooke RWI, Meradji M, de Villeneuve VH Necrotising enterocolitis after cardiac catheterization in infants. Arch Dis Child 1980; 55:66-68 [Abstract]
29. Sweet DG, Craig B, Halliday HL, Mulholland C Gastro-intestinal complications following neonatal cardiac catheterisation. J Perinat Med 1998; 26:196-200 [Medline]
30. Hajivassiliou CA, Pitkin J Recurrent necrotizing enterocolitis associated with episodes of supraventricular tachycardia. J Pediatr Surg 1998; 33:1569-1570 [CrossRef][Medline]
31. Lin YT, Teng RJ, Wang JK, Chang MH, Chen CC, Chang CI Successful arterial switch operation in a low-birth-weight neonate who had transposition of the great arteries and advanced necrotizing enterocolitis. J Pediatr Surg 1998; 33:647-649 [CrossRef][Medline]
32. Hebra A, Brown MF, Hirschl RB, Mesenteric ischemia in hypoplastic left heart syndrome. J Pediatr Surg 1993; 28:606-611 [CrossRef][Medline]
33. Hasegawa T, Yoshioka Y, Sasaki T, Necrotizing enterocolitis in a term infant with coarctation of the aorta complex. Pediatr Surg Int 1997; 12:57-58 [Medline]
34. Leung MP, Chau KT, Hui PW, Necrotizing enterocolitis in neonates with symptomatic congenital heart disease. J Pediatr 1988; 113:1044-1046 [CrossRef][Medline]
35. Castaneda AR, Jonas RA, Mayer JE, Hanley FL. Cardiac Surgery of the Neonate and Infant. Philadelphia, PA: WB Saunders; 1994
36. Reddy VM, McElhinney DB, Sagrado T, Parry AJ, Teitel DF, Hanley FL Results of 102 cases of complete repair of congenital heart defects in patients weighing 700 to 2500 grams. J Thorac Cardiovasc Surg 1999; 117:324-331 [Abstract/Free Full Text]
37. Walsh MC, Kliegman RM Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986; 33:179-201 [Medline]
38. Singh GK, Fong LV, Salmon AP, Keeton BR Study of low dosage prostaglandinusages and complications. Eur Heart J 1994; 15:377-381 [Abstract/Free Full Text]
39. Rychik J, Spray TL, Gaynor JW, Wernovsky G Assessment of pulmonary-to-systemic flow ratio after first stage palliation for hypoplastic left heart syndrome: development of a new index using Doppler echocardiography. J Thorac Cardiovasc Surg 2000; 120:81-87 [Abstract/Free Full Text]
40. Deeg KH, Rupprecht T, Schmid E Doppler sonographic detection of increased flow velocities in the celiac trunk and superior mesenteric artery in infants with necrotizing enterocolitis. Pediatr Radiol 1993; 23:578-582 [CrossRef][Medline]