CONTEXT:

Our aim for this review is to determine if preoperative feeds in neonates with ductal-dependent congenital heart disease are harmful or beneficial.

OBJECTIVES:

To summarize current evidence for preoperative feeding in neonates with ductal-dependent congenital heart disease.

DATA SOURCES:

We used the following databases: Medline, Embase, and Cochrane Central Register of Controlled Trials.

STUDY SELECTION:

We included observational studies in which the following outcomes were addressed: necrotizing enterocolitis (NEC), hospital length of stay (LOS), time to achieve full postoperative enteral feeding, and feeding intolerance.

DATA EXTRACTION:

Two reviewers independently screened each study for eligibility and extracted data. Methodologic quality was assessed by using a standardized item bank, and certainty of evidence for each outcome was assessed by using Grading of Recommendations Assessment, Development and Evaluation criteria.

RESULTS:

Five retrospective cohort studies were eligible for inclusion, for which risk of bias was significant. When comparing neonates who received preoperative feeds with those who did not, there was no significant difference in NEC (pooled odds ratio = 1.09 [95% confidence interval 0.06–21.00; P = .95]; 3 studies, 6807 participants, very low certainty evidence), hospital LOS (mean of 14 days for those not fed versus 9.9 days for those fed preoperatively; P < .01; 1 study, 57 participants, very low certainty evidence), or feeding intolerance (odds ratio = 2.014 [95% confidence interval 0.079–51.703; P = .67]; 1 study, 56 participants, very low certainty evidence). No data were available for the outcome time to achieve full postoperative enteral feeding. All studies were observational and had small sample sizes.

CONCLUSIONS:

There is insufficient evidence to suggest that preoperative enteral feeds in patients with ductal-dependent cardiac lesions adversely influence the rate of NEC, LOS, or feeding intolerance.

Ductal-dependent congenital heart lesions postnatally rely on patent ductus arteriosus to support pulmonary or systemic blood flow. Prostaglandins prevent postnatal ductal constriction to allow for adequate mixing of blood between the pulmonary and systemic circulations.1  In the preoperative period, an imbalance between the 2 circulations can compromise perfusion to multiple organ systems. Mesenteric hypoperfusion is 1 such physiologic risk factor that leads to a significant fear of necrotizing enterocolitis (NEC) in this population.25 

On the basis of the type of cardiac lesion, authors of previous studies report the risk of NEC in neonates with congenital heart disease to be 10-fold higher than that in preterm neonates.68  A recent systematic review of infants with congenital heart disease revealed that in a cohort of 6683 patients, of those who developed NEC, 48% developed NEC before cardiac surgery.9  However, the risk factors for NEC are variable and are still unclear. Consequently, there is a wide variation in preoperative feeding practices as well as a lack of standardization among institutions caring for these infants,10  which makes multicenter studies difficult. Specifically, to date, there are limited data on the safety and benefits of early enteral feeding in this population.

Early enteral feeding is associated with significant health benefits in the preterm neonate, including reduced rates of infection, NEC, and chronic lung disease and improved neurodevelopmental outcomes.11,12  Additionally, early enteral feeding promotes intestinal development and maturation at the cellular level, thereby allowing for establishment of healthy intestinal microbiota.13  Conversely, the absence of enteral feeding contributes to intestinal cellular atrophy and increased intestinal mucosal permeability, which may predispose the neonate to infection and poor gut motility.14  As a result, early enteral feeding in this population is becoming a nationwide practice. Although these benefits have been consistently reported in preterm neonates, the data are often extrapolated to other fragile populations (eg, neonates with ductal-dependent cardiac lesions who require surgery) in whom early enteral feeding has not been adequately studied.

Often, the decision to initiate preoperative enteral feeds in neonates with congenital heart disease is dependent on the medical provider who evaluates the hemodynamic stability of the infant. There is hesitancy in feeding this population because of the risk of poor outcomes, but the concerns have not been validated by good evidence. Although physiologically, the risk of preoperative feeding appears high, there are advantages of feeding as it relates to intestinal function. There is no consensus on the timing and safety of preoperative feeding in infants with ductal-dependent congenital heart disease. Furthermore, in the majority of studies that have been conducted in this population, authors have assessed the risk of feeding and associated NEC in the postoperative period. In this systematic review, we aim to review the safety of preoperative enteral feeding in neonates with ductal-dependent congenital heart disease as it relates to perioperative outcomes.

Term and preterm neonates with ductal-dependent congenital heart disease requiring prostaglandin therapy before the first surgery were included. Neonates with congenital heart disease not requiring prostaglandin therapy were excluded. Neonates with other congenital anomalies precluding them from receiving enteral feeds shortly after birth, including intestinal atresia, omphalocele, gastroschisis, Hirschsprung disease, imperforate anus, and hypoxic-ischemic encephalopathy requiring therapeutic hypothermia, were excluded.

The intervention was any volume of enteral feeding (by mouth or feeding tube) with human milk or formula given before the neonate’s first surgery. The comparison group was eligible neonates who did not receive any enteral feeds before the first surgery.

The primary outcome of interest was NEC diagnosed before or after the neonate’s first surgery. NEC was defined as stage IIA or above by using the modified Bell staging criteria.15  Secondary outcomes included hospital length of stay (LOS), feeding intolerance, and time to achieve full postoperative enteral feeding. LOS was measured in days and defined as the number of days from the first surgery until the day of hospital discharge. Feeding intolerance was defined as abdominal distention and/or emesis warranting feeds to be stopped without another diagnosis to explain the symptoms. Time to achieve full postoperative enteral feeds was defined as the number of days from the first surgery to reach adequate enteral intake without the need for parenteral nutrition. Studies revealing any of these outcomes were included.

The protocol was registered in PROSPERO (identifier CRD42018093386), international prospective register of systematic reviews. With the assistance of a librarian with expertise in systematic reviews, a search of relevant published articles was performed by using the search strategy in Supplemental Table 5 in August 2018. The review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search of the following databases was conducted without date or language restrictions: Medline (Ovid), Embase (Elsevier), and the Cochrane Library (Cochrane Central Register of Controlled Trials [CENTRAL]). The search strategy was initially developed for Medline by using the following Medical Subject Headings terms: Infant, Newborn; Heart Defects, Congenital; Enteral Nutrition; Milk; Milk, Human; Infant Formula; Preoperative Care; and Postoperative Care. In addition, appropriate synonym keywords and phrases were identified and searched for within article titles, abstracts, and keywords. This search strategy was then adapted to the Embase and CENTRAL databases. The reference lists of identified articles were also searched. Duplicate reports were excluded. The titles and abstracts of studies identified by the search strategy were assessed for inclusion in this review by 2 review authors (S.W.O. and J.K.H.). If this could not be done reliably by using the title and abstract, the full-text version was assessed; decisions on study inclusion were made independently of the data extraction and before the scrutiny of results. Any discrepancies were resolved by mutual discussion. Full-text versions of all eligible studies were then assessed. The methodologic quality of each study was assessed by using the Newcastle-Ottawa Scale16  (Table 1).

TABLE 1

Risk-of-Bias Assessment of Included Studies by Using the Newcastle-Ottawa Scale

SourceSelectionComparabilityOutcomeStudy Quality
Representativeness of Exposed CohortSelection of Nonexposed CohortAscertainment of ExposureOutcome of Interest Not Present at Start of StudyStudy Controls for Gestational AgeStudy Controls for Preoperative DietAssessment of OutcomeFollow-up LengthAdequacy of Follow-up
Becker et al26  * * * — * — * * — Good 
Iliopoulos et al23  — * * * — — * * — Poor 
Willis et al25  * * * — * — * * — Good 
Toms et al24  — * * — * — * * — Fair 
Natarajan et al27  * * * — — — * * — Poor 
SourceSelectionComparabilityOutcomeStudy Quality
Representativeness of Exposed CohortSelection of Nonexposed CohortAscertainment of ExposureOutcome of Interest Not Present at Start of StudyStudy Controls for Gestational AgeStudy Controls for Preoperative DietAssessment of OutcomeFollow-up LengthAdequacy of Follow-up
Becker et al26  * * * — * — * * — Good 
Iliopoulos et al23  — * * * — — * * — Poor 
Willis et al25  * * * — * — * * — Good 
Toms et al24  — * * — * — * * — Fair 
Natarajan et al27  * * * — — — * * — Poor 
*

, criterion within the subsection was fulfilled; —, not applicable.

Relevant data were extracted from included studies, and additional information to clarify study design or detailed results were sought from the authors via e-mail (Supplemental Table 6). The Cochran Q test was used to test for heterogeneity of results across studies and the I2 statistic was used to quantify the percentage of variation in the treatment effect due to between-study heterogeneity. Because there were substantial differences in study characteristics (eg, patient population and study design), an a priori decision was made to consider treatment effects as random as opposed to fixed. A random-effects model, by using the Mantel-Haenszel method, was used to compute pooled effects across studies. Egger’s test and the LFK Index for funnel plot asymmetry was used to investigate publication bias.17  The MALFK Index function in the Microsoft Excel add-in MetaXL 5.3 (Epigear International, Noosa, Qeensland, Australia) was used to compute the LFK Index, which has been shown to have greater power than the commonly used Egger’s test to detect publication bias when the number of studies is small.18  Review Manager software19  was used for meta-analyses and construction of figures. The weighted κ coefficient20  was used to quantify agreement between raters’ risk-of-bias assessment scores. Observed values of the weighted κ coefficient can be interpreted according to the guidelines provided by Landis and Koch,21  with a coefficient <0 indicating no agreement; 0 to 0.20, slight agreement; 0.21 to 0.40, fair agreement; 0.41 to 0.60, moderate agreement; 0.61 to 0.80, substantial agreement; and 0.81 to 1, almost perfect agreement. The “kappa2” function in the “irr” library in R version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria) was used to compute the weighted κ coefficient.

The overall certainty of the evidence for outcomes was assessed by using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria.22  Data from observational studies started at low certainty. The evidence was downgraded from low certainty by 1 level for serious (or by 2 levels for very serious) study limitations (risk of bias), indirectness of evidence, inconsistency, imprecision of effect estimates, or potential or suspected publication bias.

A total of 1165 articles were identified by our search strategy, of which 856 remained after duplicate articles were removed. Two reviewers screened article titles and abstracts, which resulted in the exclusion of 846 articles. The reviewers then assessed the full text of the remaining 10 articles. Of these, 5 were excluded for the following reasons: the participants of interest were not addressed, the intervention and comparison, or timing of the intervention in relation to outcomes. Five eligible studies were included in the review. A qualitative analysis was performed on all studies, and a quantitative synthesis (meta-analysis) was performed on 3 of the 5 studies for NEC (see PRISMA flow diagram in Fig 1). The weighted κ coefficient was 0.762 for the 2 raters’ risk-of-bias assessment scores, indicating substantial agreement. All studies were retrospective cohort studies conducted in either the NICU or the cardiovascular ICU.

FIGURE 1

PRISMA flow diagram of results of the literature search, including the number of records identified, included, and excluded and the reasons for exclusions. a The participants of interest, the intervention and comparison, or timing of the intervention relative to outcomes was not addressed in 5 excluded studies. Adapted from Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. For more information, visit www.prisma-statement.org.

FIGURE 1

PRISMA flow diagram of results of the literature search, including the number of records identified, included, and excluded and the reasons for exclusions. a The participants of interest, the intervention and comparison, or timing of the intervention relative to outcomes was not addressed in 5 excluded studies. Adapted from Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. For more information, visit www.prisma-statement.org.

In Supplemental Table 3, we list the studies included in the review and outline the study designs, characteristics of participants, outcomes measured, and reported results. The 5 eligible studies were retrospective cohort studies conducted between 2008 and 2016. The studies had different sample sizes and primary outcomes. There was heterogeneity in the gestational ages and types of cardiac lesions included among the studies. The inclusion and exclusion criteria were similar in the included studies, and there was no selective reporting bias. Given the nature of the retrospective studies, there was no attempt in any study to balance allocation between groups. In 3 of the 5 studies, the authors adjusted for gestational age in their data analysis. The list of excluded studies, with reasons for exclusion, is provided in Supplemental Table 4.

Three observational studies revealed NEC as an outcome. The pooled odds ratios (ORs) across the 3 studies from the random-effects model did not reveal a significant association between preoperative enteral feeding and NEC (OR = 1.09 [95% confidence interval (CI) 0.06–21.00], P = .95; 3 studies, 6807 participants, very low certainty of evidence). Significant heterogeneity was not observed in ORs across studies (Cohen Q test = 2.83; degree of freedom = 1; P = .09; I2 = 65%), Fig 2).

FIGURE 2

Forest plot for the 3 studies in which the effect of preoperative feeding on the outcome of NEC was examined by using the random effects model. The pooled OR with the CI that includes 1 indicates that preoperative feeding does not significantly affect the outcome of NEC. df, degrees of freedom; M-H, Mantel-Haenszel.

FIGURE 2

Forest plot for the 3 studies in which the effect of preoperative feeding on the outcome of NEC was examined by using the random effects model. The pooled OR with the CI that includes 1 indicates that preoperative feeding does not significantly affect the outcome of NEC. df, degrees of freedom; M-H, Mantel-Haenszel.

For hospital LOS, the authors of 1 study reported LOS as a dichotomous outcome (>14 and <7 days).23  This study had 57 participants, a very low certainty of evidence, and a mean LOS of 14 days for those not fed, compared with 9.9 days for those who were fed (P < .01). The median LOS for those not fed was 12 days, compared with 8 days for those who were fed. The necessary data to calculate SDs were not available in the article. Authors of a second study reported LOS as a continuous variable, although the necessary data (ie, sample size and mean and SD for LOS in both groups) were not available in the article to calculate the precision of the effect estimate.24 

In 1 study with 56 participants and very low certainty of evidence, the authors assessed feeding intolerance, for which the OR was 2.014 (95% CI 0.079–51.703; P = .67).25  Authors of another study assessed time to achieve full postoperative enteral feeding; however, the specific data were not available in the article to calculate the precision of the effect estimate. Adverse effects related to preoperative feeding were not described in any of the included studies. The outcomes with GRADE criteria are listed in Table 2 with reasons for downgrading the certainty of evidence.

TABLE 2

Summary of Findings Table: Preoperative Enteral Feeding Compared With No Feeding in Infants With Ductal-Dependent Congenital Heart Disease

OutcomesNo. Participants (Studies) Follow-upCertainty of the Evidence (GRADE)Relative Effect, OR (95% CI)Anticipated Absolute Effects
Risk With No FeedingRisk Difference With Preoperative Enteral Feeding
NEC 6807 (3 observational studies) ⊕OOO very lowa,b,c,d 0.86 (0.08–9.04) 1 per 1000 0 fewer per 1000 (1 fewer to 10 more) 
Feeding intolerance 56 (1 observational study) ⊕OOO very lowa 2.014 (0.079–51.703) 0 per 1000 0 fewer per 1000 (0 fewer to 0 fewer) 
OutcomesNo. Participants (Studies) Follow-upCertainty of the Evidence (GRADE)Relative Effect, OR (95% CI)Anticipated Absolute Effects
Risk With No FeedingRisk Difference With Preoperative Enteral Feeding
NEC 6807 (3 observational studies) ⊕OOO very lowa,b,c,d 0.86 (0.08–9.04) 1 per 1000 0 fewer per 1000 (1 fewer to 10 more) 
Feeding intolerance 56 (1 observational study) ⊕OOO very lowa 2.014 (0.079–51.703) 0 per 1000 0 fewer per 1000 (0 fewer to 0 fewer) 

Patient or population: infants with ductal-dependent congenital heart disease; setting: after birth and before discharge from the hospital; intervention: preoperative enteral feeding; comparison: no feeding. The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence were as follows: high certainty: “We are very confident that the true effect lies close to that of the estimate of the effect”; moderate certainty: “We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different”; low certainty: “Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect”; very low certainty: “We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.”

a

Retrospective cohort studies with selection, detection, and performance bias; lack of blinding.

b

Variability in results despite lack of significant heterogeneity.

c

Limited to patients with certain cardiac lesions.

d

Multiple studies in which investigators looked at effects of enteral feeds and association with NEC (unpublished and therefore inaccessible).

Overall, this systematic review revealed very low certainty evidence that preoperative enteral feeds in patients with ductal-dependent cardiac lesions adversely influence important postoperative outcomes of NEC, hospital LOS, time to achieve full postoperative enteral feeding, or feeding intolerance. Because of the retrospective nature of the studies, there was a high risk for selection bias from lack of randomization and lack of allocation concealment and risk of performance bias due to lack of blinding health care staff. The decision to initiate preoperative feeds was at the discretion of the medical provider, which varied from 1 patient to another. Although confounding variables within a retrospective study are expected, specifically, the lack of standardization in feeding practices may not include neonates who are critically ill and less likely to be fed preoperatively. Similarly, in the majority of the studies, preoperative information regarding severity of illness (eg, markers of hemodynamic instability) is not available. This again raises the question of whether the authors of these studies involuntarily selected healthier neonates to receive enteral feeds. The certainty of evidence for each outcome is discussed in detail below.

Three studies were pooled to assess this outcome, none of which were randomized controlled trials.24,26,27  A total of 6822 patients were included in the 3 studies. The pooled OR was 1.09 (95% CI 0.06–21.00; P = .95), and there was a moderate degree of heterogeneity according to the interpretation of I2 provided by the Cochrane Handbook for Systematic Reviews of Interventions.28  Given the retrospective cohort design of these studies, there was inherent risk of bias, which was deemed to be serious. For this reason, the certainty of evidence was downgraded to low or very low. Publication bias was apparent from examination of the funnel plot, although the formal hypothesis test for publication bias was slightly above the 0.05 cutoff for statistical significance, presumably due to the small sample size (n = 3) (Fig 3). Although the use of a funnel plot is generally only applicable to ≥10 studies in a meta-analysis, its asymmetry here could also represent small-study effects. The computed LFK Index of −4.62 indicates major asymmetry that is consistent with publication bias.

FIGURE 3

Funnel plot for the outcome of NEC, for which Egger’s test was used to detect publication bias.

FIGURE 3

Funnel plot for the outcome of NEC, for which Egger’s test was used to detect publication bias.

The fact that there were multiple unpublished, and therefore inaccessible, studies of the effects of enteral feeds on NEC in this population is an additional source of publication bias.2931  This could affect the overall results, although more information is needed from each study to make this determination. There was indirectness among the studies in multiple aspects. The study by Toms et al24  was limited to infants with hypoplastic left heart syndrome. Evidence in the literature reveals that neonates with hypoplastic left heart syndrome or other single-ventricle cardiac lesions may be at a higher risk for NEC than others.7,26,3234  Therefore, the information from this study cannot be generalized to all neonates with ductal-dependent congenital heart disease. Additional reasons for inconsistency include variations in the documentation or diagnosis of NEC (documentation based on patient chart), lack of a standardized definition, and large variations in comparison groups.

In the study by Becker et al,26  neonates with a diagnosis of NEC were included on the basis of documentation of the diagnosis by the treating neonatologist. Although cases of expected and presumed NEC were excluded from data collection, the diagnostic criteria for those included were not defined. We speculate that in general, in many units, a diagnosis of NEC is given more commonly than not in an effort to manage these at-risk neonates cautiously before surgical intervention.

The pooled studies were downgraded for inconsistency on the basis of the variability in results, despite lack of significant heterogeneity. On the basis of the pooled OR, it is uncertain if preoperative enteral feeds are associated with NEC. The variability in the results across the 3 studies can be explained, in part, by indirectness and inherent risk of bias in the retrospective studies.

The pathophysiology of NEC in the preterm infant that results in intestinal injury and inflammation is thought to be multifactorial, including decreased blood flow secondary to patent ductus arteriosus, medications, hypotension, inflammation due to milk components, and abnormal intestinal flora.3540  The immune system has a dysregulated response, which then generates a cascade of events that ultimately result in NEC. The unique components of human milk appear to play a protective role in this cascade, although studies are still ongoing.3840 

The immune system is typically more developed in term infants, leading to a decreased risk of NEC. Congenital heart disease, specifically lesions that require prostaglandin therapy for ductal patency, poses a new risk of ischemia as a result of diastolic steal and hypoperfusion. Much like in the preterm infant, this decrease in blood flow to the intestines may prompt a similar cascade of events. Similarly, however, human milk may be protective against these inflammatory insults by positively impacting the intestinal microbiota.41  Infants with congenital heart disease are a particularly vulnerable population subject to multiple inflammatory insults that could alter the intestinal microbiota. These include hypoxia, infection, hospitalization, surgery, and exposure to antibiotics. Additionally, the absence of enteral feeding serves as another trigger because it causes intestinal mucosal atrophy, leading to a loss of important cell-wall barriers. This loss of cell-wall barriers promotes bacterial overgrowth and can trigger an inflammatory response.42,43 

Hospital LOS was assessed in 2 studies; however, the necessary data in the article by Toms et al24  were not available for analysis. There was a total of 57 patients included in the analysis for the study by Iliopoulos et al.23  For this study, the difference in LOS between both groups reveals a significant reduction in LOS from preoperative feeding, although there are plausible confounders that could significantly affect these results, for which the certainty of evidence was downgraded. First, the study is subject to the same degree of bias as the other retrospective studies. The hospital LOS was reported as a dichotomous outcome (<7 or >14 days). The clinical significance of this is unclear, thereby making the clinical application difficult. In addition, although mechanical ventilation was not considered a contraindication to feeding, all patients who received feeds were not intubated. This may suggest that the neonates who were fed were possibly healthier to begin with, which might have led to a shorter LOS. Similarly, the long-stay group had more frequent use of inotropes and longer cardiopulmonary bypass time, which may imply a sicker population that might have then had a longer hospital LOS. There is no information available regarding differences in preoperative hemodynamics that may reveal that the short-stay group was potentially healthier to start with. Second, the evidence was downgraded for indirectness in that these results applied to infants who had an arterial switch operation or infants with hypoplastic left heart syndrome, thereby not making them generalizable to our population of interest. Neither inconsistency nor publication bias was an apparent issue between the studies. On the basis of this analysis, there is very low certainty of evidence that preoperative enteral feeds in the target population lead to a shorter hospital LOS.

In their study, Willis et al25  reported no changes in feeding intolerance postoperatively due to preoperative feeding (OR = 2.014; 95% CI 0.079–51.703; P = .67). There was a similar risk of bias, including selection, performance, and detection biases, for which the certainty of evidence was downgraded. Similar to in the other studies, the neonates who were sicker might not have been fed, thereby not capturing the population of interest. However, the authors of this study did control for gestational age by excluding infants who were born <35 weeks’ gestational age. The certainty of evidence was downgraded for indirectness because the outcome of choice, despite being defined, had a wide spectrum, which made its clinical application difficult. Publication bias was difficult to assess because of the small number of studies. Inconsistency was difficult to determine with only 1 study. On the basis of the results, the CI was large likely because of the small sample size and the study not being adequately powered for the outcome. The precision of the effect estimate was low, suggesting no important benefit or harm; therefore, there is very low certainty evidence that preoperative enteral feeds increase feeding intolerance.

In their study, Toms et al24  also looked at time to full postoperative enteral feeding. The data were unavailable for analysis and inherent risk of bias with this retrospective cohort study. The study was downgraded for risk of bias and indirectness given the homogeneous population. On the basis of the information available, there is very low certainty evidence that preoperative enteral feeds increase or decrease the time to reach full enteral feeding postoperatively.

A small number of studies were eligible for this review, some without enough reported data for analysis. However, this limitation reveals the need for further studies on this subject to guide evidence-based feeding practices. In the Mantel-Haenszel random-effects model, which is used to compute pooled effects for the NEC outcome, it is assumed that the intervention effect is normally distributed. This assumption of normality cannot be substantiated with only 3 studies. The pooled estimates for NEC should be interpreted with caution because the Becker et al26  study had much more weight than the other studies because of its substantially larger sample size. Second, despite the extensive standardized search strategy, it is possible that we missed some potentially relevant studies. In addition, there are important limitations to the studies themselves that must be taken into account. There were inherent confounders because of the retrospective nature of the studies, including a propensity of infants who were sicker to not receive enteral feeds at baseline because of provider discretion. This could potentially inadvertently eliminate a high-risk population that could likely benefit the most from enteral feeds. Along with the benefits of early enteral feeding in the preterm population, there is a wealth of information in the literature to suggest that human milk is superior to formula, and possibly even donor human milk, in the preterm population.44,45  A major limitation to these studies is that none of them accounted for human milk exposure as it relates to the outcomes. As mentioned before, the literature regarding human milk and its impact on outcomes, particularly NEC, in preterm infants is vast; however, this has not been studied in other high-risk populations. Although human milk might have been used as an option for feeding in the studies, those patients who received it and those who did not were not identified in the data. To the best of our knowledge, there are no studies specifically on the types of preoperative enteral feeds in infants with ductal-dependent congenital heart disease and their effects on postoperative outcomes. Additionally, the feeding approach used in these studies was not standardized. A lack of standardization and opportunity for significant variability in feeding practices is another limitation to this evidence. A strength of this review is that it is, to the best of our knowledge, the first systematic review of the association of preoperative enteral feeds with outcomes in this population, performed according to PRISMA guidelines.

We found insufficient evidence that preoperative enteral feeds in patients with ductal-dependent cardiac lesions adversely influence important postoperative outcomes. The high risk of bias in the identified studies limit their interpretation or use in predicting outcomes; therefore, it is unclear whether preoperative enteral feeds increase or decrease the risk for NEC, longer hospital LOS, feeding intolerance, or time to achieve full postoperative enteral feeding. Although a randomized controlled trial to study this would not be feasible, a well-designed prospective study is needed to assess the effects of preoperative enteral feeds on these outcomes in such a high-risk population. Ideally, this would be a multicenter prospective study that allows for implementation of a standardized preoperative feeding protocol that all units can agree on. Given the national movement toward the use of human milk (maternal or donor human milk), the protocol should emphasize its use if either 1 is available or not contraindicated. Clinical parameters that indicate gut or systemic perfusion may help the clinicians determine readiness to feed (eg, absence of the need for vasopressors, normal pH and lactate values, urine output, cerebral and somatic near-infrared spectroscopy). Although some cardiac lesions are thought to be higher risk than others, the lesion itself should not be used to dictate feeding readiness without taking other clinical parameters into consideration. Although the decision to stop and restart feeds will still be at the discretion of the provider, the protocol will still provide a standardized approach to enteral feeding to eliminate practice variation that is not supported by the clinical picture. In a pediatric cardiology multicenter quality improvement collaborative, researchers assessed best nutritional practices and developed guidelines for infants with single-ventricle physiology. They found that development and implementation of standardized feeding practices can significantly decrease practice variation and potentially lead to improved outcomes. This concept has been supported by other studies in infants who are critically ill and preterm or have congenital heart disease.32,4648  Despite the wide variation in feeding practices nationally, our review reveals that this has not been validated in the literature. Additionally, it may be helpful to further characterize the type of milk as it relates to outcomes as well as the effects of feeding on specific cardiac lesions. We are conducting a prospective study in our NICU to address this knowledge gap.

We thank Amy Sisson, MS, MLS, for her assistance with the search strategy and literature search.

Dr Kataria-Hale conceptualized and designed the review, performed the literature search, screened the articles, identified and assessed the articles for inclusion, analyzed and interpreted the data, drafted the article, and revised it critically for important intellectual content; Dr Osborne made a substantial contribution to the conception and design of the review, screened the articles, identified and assessed the articles for inclusion, analyzed and interpreted the data, and revised the manuscript critically for important intellectual content; Dr Hair made a substantial contribution to interpretation of data and revised the manuscript critically for important intellectual content; Dr Hagan made a substantial contribution to data analysis and interpretation of data and revised the manuscript critically for important intellectual content; Dr Pammi made a substantial contribution to acquisition of data and data analysis and interpretation and revised the manuscript critically for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work, ensuring that questions related to the accuracy and integrity of any part of the work are appropriately investigated and resolved.

This trial has been registered with PROSPERO (https://www.crd.york.ac.uk/prospero/) (identifier CRD42018093386).

FUNDING: No external funding.

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

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