CONTEXT

Early enteral feeding has been associated with adverse outcomes such as necrotizing enterocolitis in preterm and low birth weight infants.

OBJECTIVES

To assess effects of early enteral feeding initiation within the first days after birth compared to delayed initiation.

DATA SOURCES

Medline, Scopus, Web of Science, CINAHL from inception to June 30, 2021.

STUDY SELECTION

Randomized trials (RCTs) were included. Primary outcomes were mortality, morbidity, growth, neurodevelopment, feed intolerance, and duration of hospitalization.

DATA EXTRACTION

Data were extracted and pooled with random-effects models.

RESULTS

We included 14 randomized controlled trials with 1505 participants in our primary analysis comparing early (<72 hours) to delayed (≥72 hours) enteral feeding initiation. Early initiation likely decreased mortality at discharge and 28 days (1292 participants, 12 trials, relative risk 0.69, 95% confidence interval [95% CI] 0.48–0.99, moderate certainty evidence) and duration of hospitalization (1100 participants, 10 trials, mean difference −3.20 days, 95%CI −5.74 to −0.66, moderate certainty evidence). The intervention may also decrease sepsis and weight at discharge. Based on low certainty evidence, early feeding may have little to no effect on necrotizing enterocolitis, feed intolerance, and days to regain birth weight. The evidence is very uncertain regarding the effect of initiation time on intraventricular hemorrhage, length, and head circumference at discharge.

CONCLUSIONS

Enteral feeding within 72 hours after birth likely reduces the risk of mortality and length of hospital stay, may reduce the risk of sepsis, and may reduce weight at discharge.

Clinicians debate the optimal timing of enteral feeding initiation for preterm and low birth weight (LBW) infants because of health concerns that early initiation in the first days of life may lead to health complications such as necrotizing enterocolitis (NEC).1  NEC is characterized by inflammation of the gastrointestinal tract of infants and associated with mortality and multiple morbidities. Premature (<37 weeks) and low birth weight (<2500g) infants, especially very preterm (<32 weeks) and very low birth weight (<1500g) infants, have underdeveloped organs and are at high risk for NEC. Additionally, women in communities around the world may delay feeding of infants because of their wish to discard colostrum, pain and discomfort after delivery, and concern about the developmental maturity of the baby including the baby’s inability to digest milk feeds.2 

Although delayed breastfeeding initiation has been linked to increased risk of mortality and morbidity generally, the potential impact of delayed feeding for preterm infants is less clear.35  Three systematic literature reviews completed in the last 10 years report that early trophic feeding (also called minimal enteral nutrition) and nearly full volume feeding improves health outcomes in preterm and LBW babies.68  However, there have been new studies since the publication of these reviews.

Our primary objective was to evaluate the effect of early initiation of enteral feeding in the first days of life compared to delayed initiation of enteral feeding on critical outcomes (mortality, morbidity, growth, neurodevelopment, and disability) in preterm and LBW infants. Additionally, we sought to determine if there is any difference in effect by day of initiation (day 1, 2, 3), gestational age (ie, ≤32 weeks), birth weight (ie, ≤1.5kg), volume of enteral feed, milk type, and receipt of parenteral nutrition.

We registered the protocol with the international prospective register of systematic reviews PROSPERO CRD42021241600. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Protocol (PRISMA-P) guidance. The search strategy was developed in consultation with librarians, and references were managed using Covidence software (Appendix 1).

Randomized controlled trials (RCTs) were the only study design included in this review. We excluded nonhuman studies. There were no language restrictions. Participants were all LBW (<2500g) or preterm (<37 weeks gestational age) infants. The intervention was early initiation of enteral feeding within the first 72 hours of life, and the comparator was delayed initiation of enteral feeding. Enteral feeding was defined as milk feeding with any type of milk (mother’s own milk, donor human milk, or preterm or term formula). Infants could be fed via any method including naso or oro gastric tube, bottle, cup, paladai, or direct breastfeeding. It also included types of feeding such as ‘gastrointestinal priming,’ ‘minimal enteral feeding,’ or ‘trophic feeding.’

Electronic databases were searched to April 2021. Databases included Medline (Ovid), Embase (Ovid), Web of Science, and CINAHL. We also conducted manual checks of existing systematic reviews.6,7  Selection of studies and data extraction was done by 2 authors, and conflicts were resolved in consultation with a third person. We extracted data using a standardized form and included: setting, design, participants, sample size, intervention, comparison, subgroups, and outcomes of interest.

We collected data for all outcomes at 28 days chronological age and at latest follow-up. Primary outcomes were all-cause and cause-specific mortality, morbidity (NEC, duration of hospitalization, sepsis, feeding intolerance, intraventricular hemorrhage, chronic lung disease, diarrhea), growth (weight, length, head circumference), and adverse events (hyperglycemia).

Two review authors judged the risk of bias using the Cochrane risk of bias tool (ROB-2).9  Funnel plots and Egger tests were done for outcomes with >10 studies to assess publication bias and small sample effects.

We used intention-to-treat estimates where possible. For binary outcomes, we summarized data using risk ratios with 95% confidence intervals (95% CI). For continuous outcomes, we summarized data using the pooled mean difference with 95% CIs.

For studies that reported median and interquartile ranges only, we used formulas derived Lou (2018) and Wan (2014) to impute the missing mean and variance information.1012  For studies with no events in 1 arm, we added 0.5 to each cell for continuity correction. Studies with no events in either arm were not pooled, because they would not contribute information to the pooled estimate.

We used Dersimonian and Laird random-effects models to calculate pooled estimates for all outcomes.13  We assessed forest plots visually for heterogeneity and considered I2 values >50% to represent substantial heterogeneity. All analyses were conducted by using Stata 16C and RevMan.

Our a priori subgroup analyses were: (i) gestational age and weight at birth (studies enrolling only infants ≤ 32 weeks’ gestation or ≤ 1.5 kg at birth compared to studies that did not restrict enrollment based on gestational age or birth weight), (ii) fortified and nonfortified breast milk, (iii) parenteral nutrition, (iv) site of care, (v) health care provider, (vi) geographic regions, and (vii) income status of country. Additionally, we added subgroups for (i) timing of feed initiation (day 1, 2, 3); (ii) milk volume (higher [≥15 ml/kg/day] versus lower volume [<15 ml/kg/day]); and (iii) milk type (human milk, formula, and mixed human milk with formula).

We prepared a summary of findings table for each outcome using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) and GRADEPro GDT software to assess risk of bias, consistency of effect, imprecision, and indirectness for each outcome.14,15 

We made several changes from our initial protocol based on the data we identified and to provide policy-relevant data. These changes included: excluding observational studies because there was sufficient RCT data available; including abstract-only data from previous Cochrane systematic reviews (Becerra et al 1996)16 ; refining the primary analysis to compare timing of feeding initiation <72 hours vs ≥72 hours; adding subgroups including by time of feeding initiation, type of milk, and by volume of feeding.

We identified 5712 studies (Appendix 2). Of these studies, 22 were RCTs that were eligible for inclusion in the meta-analysis. We conducted the primary analysis using data from 14 studies which included 1505 preterm or LBW infants that compared the effect of enteral feeding initiation <72 hours of age to enteral feeding initiation ≥72 hours.6,7,1618  This analysis allowed us to include the maximum number of studies where the time of initiation was distinct in the early and delayed initiation groups.

For the primary analysis, studies took place in North America (n = 6), South America (n = 2), Asia (n = 2), and Europe (n = 4). None of the studies were from Africa. Eight trials restricted enrollment to infants ≤32 weeks or ≤1.5 kg.16,1824  The remaining 6 studies did not restrict to ≤32 weeks or ≤1.5 kg.17,2529  Three studies enrolled preterm or LBW infants were also born small-for-gestational age.24,25,27 

Early feeding initiation time ranged from day 1 to 3 after birth. Delayed initiation time ranged from 4 to 15 days after birth. Infants in 1 studies initiated feeding by day 1 (<24 hours).17,20  Infants in 8 studies initiated feeding by day 2 (<48 hours).16,18,2224,26,27,29  Infants in 4 studies initiated feeding by day 3(<72 hours).19,21,25,28  12 studies provided ‘low’ volume feeds (<15 ml/kg/day),1821,2329  and 2 provided feeds with volumes ≥15 mL/kg/day (volumes were 15–25 mL/kg/day).16,22  Three studies gave the infants formula milk,19,20,22  two gave mother’s own milk,24,25  and the remaining nine gave a mixture of milks (ie, mother’s own, donor, or formula).1618,21,23,2629  All studies provided supplemental parenteral nutrition to the delayed initiation group, except for Pérez et al 2011, which did not specify.18 

Risk of bias was assessed for all outcomes for the 14 trials included in the primary analysis and we present the overall judgement by outcome (Appendix 4). No studies had high risk of bias. 75% of the assessments had a low risk of bias for the randomization process, and 25% had some concerns. Fifty-six percent showed some concerns due to deviations from intended interventions; the remaining 43.9% had low risk of bias for that domain. We ranked 95% of studies as low risk of bias because of missing data. For measurement of the outcome, 70% of assessments had a low risk of bias, and 30% had some concerns. Finally, for the selection of reported results 77% of assessments had some concerns of risk of bias.

Outcomes that were reported on by 10 trials or more included all-cause mortality, necrotizing enterocolitis, and duration of hospitalization. There was no obvious publication bias or small study effects in any analyses (Funnel plots and Egger’s tests, Appendix 5).

Meta-analysis results are summarized in Table 1, and forest plots are shown in Appendix 6. At latest follow-up (discharge or 28 days), the relative risk of mortality comparing the intervention (early initiation of enteral feeding <72 hours) to the comparison group (delayed feeding initiation ≥72 hours) was 0.69, (95% CI 0.48 to 0.99, I2= 0%, moderate certainty evidence, 12 trials, 1292 participants).

TABLE 1

Summary of Findings

Early Feeding (<72 h) Compared to Delayed Feeding (≥72 h) for Preterm and Low Birth Weight Infants
Patient or population: preterm and low birth wt infants
Setting: hospitals
Intervention: early feeding (<72 h)
Comparison: delayed feeding (≥72 h)
OutcomesN° of Participants (Studies) Follow-upCertainty of the Evidence (GRADE)Relative Effect (95% CI)Anticipated Absolute Effects
Risk With Delayed FeedingRisk Difference With Early Feeding
Mortality (cases) at latest follow-up (at discharge or 28 d) 1292
(12 RCTs) 
⨁⨁⨁◯
Moderatea 
RR 0.69
(0.48–0.99) 
103 per 1000 32 fewer per 1000
(54 fewer to 103 more) 
Necrotizing enterocolitis (cases) at discharge 1484
(13RCTs) 
⨁⨁◯◯
Lowa,b 
RR 1.05
(0.75–1.46) 
84 per 1000 4.2 more per 1000
(21 fewer to 39 more) 
Sepsis (cases) at discharge 626
(5 RCTs) 
⨁⨁◯◯
Lowa,b 
RR 0.90
(0.54–1.52) 
326 per 1000 33 fewer per 1000
(150 fewer to 196 more) 
Intraventricular hemorrhage (cases) at discharge 84
(1 RCT) 
⨁⨁◯◯
Very lowa,c,d 
RR 0.48
(0.18–1.25) 
255 per 1000 419 fewer per 1000
(150 fewer to 134 more) 
Time to regain birth wt (days) 569
(7 RCTs) 
⨁⨁◯◯
Lowa,b 
— Mean time to regain birth weight was 14.68 d MD 0.26 d more
(0.63 fewer to 1.15 more) 
Wt (grams) at latest follow-up (6–12 wk chronological age) 142
(3 RCTs) 
⨁⨁◯◯
Lowa,c 
— Mean wt gain was 1871.6 MD 49.02 gm less
(149.65 fewer to 51.61 more) 
Wt gain (grams) from enrolment to 30 d follow up 40
(1 RCT) 
⨁⨁◯◯
Very lowa,c,d,e 
— The mean wt gain (gm) at 30 d was 213 gm MD 51.00 gm more
(32.40 fewer to 69.60 more) 
Length (cm) at latest follow-up (at 32 wk chronological age) 82
(2 RCT) 
⨁⨁◯◯
Very lowa,c,e 
— The mean length (cm) at 32 wk of age) was 40.73 cm MD 0.62 cm lower
(1.51 fewer to 0.27 more) 
Head circumference (cm) at latest follow-up (at discharge or 32 wk chronological age) 82
(2 RCTs) 
⨁⨁◯◯
Very lowa,c,f 
— Mean head circumference was 29.79cm MD 0.56 cm less
(1.18 fewer to 0.06 more) 
Feed intolerance (cases) at discharge 187
(2 RCTs) 
⨁⨁◯◯
Lowa,c 
RR 1.03
(0.66–1.60) 
277 per 1000 8 more per 1000
(94 fewer to 166 more) 
Duration of hospitalization (days to discharge) 1100
(10 RCTs) 
⨁⨁⨁◯
Moderatea 
— Mean duration was 52.9 d MD 3.20 d fewer
(5.74 fewer to 0.66 fewer) 
Early Feeding (<72 h) Compared to Delayed Feeding (≥72 h) for Preterm and Low Birth Weight Infants
Patient or population: preterm and low birth wt infants
Setting: hospitals
Intervention: early feeding (<72 h)
Comparison: delayed feeding (≥72 h)
OutcomesN° of Participants (Studies) Follow-upCertainty of the Evidence (GRADE)Relative Effect (95% CI)Anticipated Absolute Effects
Risk With Delayed FeedingRisk Difference With Early Feeding
Mortality (cases) at latest follow-up (at discharge or 28 d) 1292
(12 RCTs) 
⨁⨁⨁◯
Moderatea 
RR 0.69
(0.48–0.99) 
103 per 1000 32 fewer per 1000
(54 fewer to 103 more) 
Necrotizing enterocolitis (cases) at discharge 1484
(13RCTs) 
⨁⨁◯◯
Lowa,b 
RR 1.05
(0.75–1.46) 
84 per 1000 4.2 more per 1000
(21 fewer to 39 more) 
Sepsis (cases) at discharge 626
(5 RCTs) 
⨁⨁◯◯
Lowa,b 
RR 0.90
(0.54–1.52) 
326 per 1000 33 fewer per 1000
(150 fewer to 196 more) 
Intraventricular hemorrhage (cases) at discharge 84
(1 RCT) 
⨁⨁◯◯
Very lowa,c,d 
RR 0.48
(0.18–1.25) 
255 per 1000 419 fewer per 1000
(150 fewer to 134 more) 
Time to regain birth wt (days) 569
(7 RCTs) 
⨁⨁◯◯
Lowa,b 
— Mean time to regain birth weight was 14.68 d MD 0.26 d more
(0.63 fewer to 1.15 more) 
Wt (grams) at latest follow-up (6–12 wk chronological age) 142
(3 RCTs) 
⨁⨁◯◯
Lowa,c 
— Mean wt gain was 1871.6 MD 49.02 gm less
(149.65 fewer to 51.61 more) 
Wt gain (grams) from enrolment to 30 d follow up 40
(1 RCT) 
⨁⨁◯◯
Very lowa,c,d,e 
— The mean wt gain (gm) at 30 d was 213 gm MD 51.00 gm more
(32.40 fewer to 69.60 more) 
Length (cm) at latest follow-up (at 32 wk chronological age) 82
(2 RCT) 
⨁⨁◯◯
Very lowa,c,e 
— The mean length (cm) at 32 wk of age) was 40.73 cm MD 0.62 cm lower
(1.51 fewer to 0.27 more) 
Head circumference (cm) at latest follow-up (at discharge or 32 wk chronological age) 82
(2 RCTs) 
⨁⨁◯◯
Very lowa,c,f 
— Mean head circumference was 29.79cm MD 0.56 cm less
(1.18 fewer to 0.06 more) 
Feed intolerance (cases) at discharge 187
(2 RCTs) 
⨁⨁◯◯
Lowa,c 
RR 1.03
(0.66–1.60) 
277 per 1000 8 more per 1000
(94 fewer to 166 more) 
Duration of hospitalization (days to discharge) 1100
(10 RCTs) 
⨁⨁⨁◯
Moderatea 
— Mean duration was 52.9 d MD 3.20 d fewer
(5.74 fewer to 0.66 fewer) 

The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). MD, mean difference; RR, risk ratio; —, not applicable.

GRADE Working Group grades of evidence:

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

Downgraded 1 level for some concerns of bias due to the randomization process (allocation concealment; ie, not blinded), missing outcome data (important levels of loss to follow up), measurement of the outcome (poor allocation concealment or not blinded to intervention group), selection of the reported result (no protocol)

b

Downgraded 1 level for imprecision because of wide confidence interval crossing the line of no effect representing both appreciable benefit and appreciable harm

c.

Downgraded 1 level for imprecision because of small sample size ie, optimal information size (OIS) not met (ie, the total number of patients included is less than the number of patients generated by a conventional sample size calculation for a single adequately powered trial) for dichotomous outcomes and wide confidence interval crossing the line of no effect representing both appreciable benefit and appreciable harm.

d

Downgraded one level for heterogeneity as only 1 study and could not assess inconsistency.

e

Downgraded 1 level for imprecision because of small sample size ie, optimal information size (OIS) not met (ie, the total number of patients included is less than the number of patients generated by a conventional sample size calculation for a single adequately powered trial) for continuous outcomes and wide confidence interval crossing the line of no effect representing both appreciable benefit and appreciable harm.

f

Downgraded 1 level for serious unexplained heterogeneity as I squared = 98%.

The relative risk of NEC comparing early (<72 hours) to delayed (≥72 hours) feeding was 1.05 (95% CI 0.75–1.46, I2= 0%, low certainty evidence, 13 trials, 1484 participants). The relative risk for sepsis was 0.90 (95% CI (0.54–1.52), I2= 51%, low certainty evidence, 5 trials, 626 participants), and for intraventricular hemorrhage the relative risk was 0.48 (95% CI 0.18–1.25, I2= 0; very low certainty evidence; 1 trial; 84 participants).

At discharge, the mean difference in weight was −49.02 g (95% CI −149.65 to 51.61, I2= 0%, low certainty evidence, 3 trials, 142 participants). The mean difference, measured at discharge or 32 weeks chronological age, in head circumference was −0.56 (95% CI −1.18 to 0.06, I2 = 0%, low certainty evidence, 2 trials, 82 participants). The mean difference in length measured at discharge was -0.62cm (95% CI −1.51 to 0.27), I2= 0%, very low certainty evidence, 2 trials, 82 participants. The mean difference in time days to regain birth weight was 0.26 days (95% CI -0.63 to 1.15, I2 = 18%, low certainty evidence, 7 trials, 569 participants).

There were no data on other primary outcomes. No trials assessed neurodevelopment or serious adverse events such as hypoglycemia.

At discharge there was little or no effect of the intervention on feed intolerance (risk ratio 1.03, 95% CI 0.66–1.60; I2 = 0%, low certainty evidence, 2 trials, 187 participants). The intervention (early initiation of enteral feeding) decreased duration of hospitalization days (mean difference −3.20 days, 95% CI −5.74 to −0.66, I2= 19%, moderate certainty evidence, 10 trials, 1100 participants, Appendix 6).

There were no apparent differences in the effect of the intervention on primary outcomes in studies that enrolled infants ≤32 weeks’ gestation or ≤1.5 kg at birth compared to studies which did not restrict enrollment based on gestational age or birth weight (Appendix 6). There were also no obvious differences in the effect of the intervention on critical outcomes by timing of feed initiation (day 1, 2, 3); milk volume (volume (higher [≥15 ml/kg/day] versus lower volume [< 15 ml/kg/day]) or milk type (human, formula or mixed) (Appendix 6).

Results were generally similar for the outcomes of mortality, necrotizing enterocolitis, sepsis, intraventricular hemorrhage, head circumference gain, length gain, and weight gain, when we included all studies comparing early versus delayed feeding (Appendix 7).

Our systematic review of 14 trials of 1505 preterm or LBW infants found that early initiation of enteral feeding within the first 72 hours of life likely decreased the risk of neonatal mortality and may reduce the risk of sepsis when compared with delayed feeding initiation after 72 hours for hospitalized preterm and low birth weight infants. We also found that early intervention had little impact on necrotizing enterocolitis, intraventricular hemorrhage, feeding intolerance, time to regain birth weight, head circumference, and length at discharge, although the evidence was generally very uncertain for these outcomes. Early initiation of enteral feeding also decreased the number of days an infant stayed in the hospital by just over 3 days. Our results are directionally consistent for all primary outcomes with the most recent (2014) Cochrane review which examined the effect of delayed (>4 days) introduction of progressive enteral feeds compared to early introduction in very low birth weight infants (<1.5 kg).7  We included 9 additional studies, and the certainty of evidence on all primary outcomes (including duration of hospitalization) was higher than the Cochrane review.

We found no apparent sources of heterogeneity in our subgroup analyses. There was no difference in effect by volume of initial enteral feeding (<15 ml/kg/day compared to ≥15 mL/kg/day), although there were only 2 studies of 229 infants which used volumes above 15 mL/kg/day, and our results are inconclusive. However, a 2015 Cochrane review by Walsh and colleagues compared the effect of early full enteral feeding (60–80 ml/kg/day) to lower volume feeds (20–30 mL/kg/day) and found that use of higher volumes was associated with 3 days shorter hospital duration than lower volumes (mean difference −3.09, 95% CI −4.13, −2.02; 4 trials; 290 infants), and there was little to no difference in mortality, morbidities such as necrotizing enterocolitis, and growth.8  We also found no difference in effect between trials that enrolled infants who were ≤ 32 weeks or ≤ 1.5 kg and trials that did not, but additional data are needed. We also found no difference in the effect of early initiation between the trials that used human or formula milk in our review. This is in contrast to the evidence that infant formula likely increases the risk of necrotizing enterocolitis in preterm infants.30  However, only 2 of our included studies used human milk, and only 3 used infant formula as the sole diet; sample sizes were limited, and results are inconclusive.

We also found no difference by day of initiation and no evidence of a dose response by day of initiation of feeding, although there were only 2 studies including 74 infants that initiated feeding with the first 24 hours of life. This is in contrast to community-based studies including both preterm and term infants which found a dose-response relationship between increasing delay in initiation (<1 hour, 2–23 hours, ≥24 hours after birth) and increasing risk of neonatal mortality.3,5  These observational studies are subject to selection bias and confounding, although the quality of evidence was graded at high certainty because of the consistent, large effect size, and evidence of a dose-response relationship.3,5 

Our findings that early feeding initiation is linked to reduced risk of mortality and sepsis are clinically plausible. When infants are not fed enterally, they must receive parenteral nutrition or water and dextrose through intravenous or enteral routes. Use of intravenous fluids and parenteral nutrition increases risks of blood stream infection and metabolic derangements. This may also explain why the trials showed a reduced length of hospital stay.

Health and survival benefits, as well as reduced time in the hospital, have important economic benefits for the health system and caregivers. A 2021 Canadian study including nearly 30 000 preterm infants in the NICU estimated the costs related to longer length of hospital stays; an infant who has a gestational age of 27 weeks had a mean cost per day of CAD $1759.31  Costs associated with infant health complications can be astronomical. In the United States, preterm and low birth weight infants with NEC could cost the hospital USD $100 000 compared to USD $20 300 for those without NEC.32  Additionally, out-of-pocket payments in low- and middle-income countries can be very high. In Ghana, Enweronu-Laryea et al found that costs associated with preterm and low birth weight hospital stays accounted for 8.1% of a family’s average annual income.33  Further research is needed to estimate the potential impact, including reduced economic burden (direct and indirect costs), of implementing improved infant feeding protocols for infants in low-and middle-income countries.

There are several important limitations to our study. In our review, all included studies took place in hospital settings and the average length of hospital stay for study participants was >50 days. Most study participants were very preterm or very low birth weight infants. The majority of studies were conducted in middle- or high-income countries, except the study conducted by Tewari and colleagues in India.24  Thus, this evidence should be applied to other contexts with caution. However, a systematic review of observational, community-based studies from Tanzania, Ghana, India, and Nepal found that early breastfeeding initiation within the first 24 hours of life was associated with reduced neonatal mortality.5  Our results were heterogeneous, and evidence was of low or very low certainty for all outcomes except mortality and duration of hospitalization. There were no studies on neurodevelopment, and evidence was insufficient to understand effects on short- and long-term growth outcomes.

In conclusion, we found that early enteral feeding initiation likely decreases the risk of mortality and the duration of hospitalization. This evidence comes from studies of hospitalized newborns and adds to evidence supporting early breastfeeding initiation for preterm and LBW infants in all settings, including babies born and managed at home.

Thank you to the George Washington University librarians Stacy Brody, MI, and Susan Koening, MA, for their contribution to the design and execution of search for this meta-analysis.

Dr Smith, Ms Chitale, and Ms Ferguson conceptualized the study, designed the data collection instruments, designed and carried out the initial analysis, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Edmond assisted with the conceptualization of the study, analyzed the data, and reviewed and revised the manuscript; Ms Talej, Dr He, and Dr Yang collected data, carried out the initial analysis, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of this work.

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest relevant to this article to disclose.

FUNDING: All phases of this study were supported by WHO Department of Maternal, Child, Adolescent Health and Aging. The sponsor (WHO) commissioned the review for a guideline development group (GDG) meeting for the development of WHO recommendations on care of the preterm or low birth weight infant. The sponsor assisted in formulating the research question and provided inputs on the synthesis of the results and manuscript.

     
  • GRADE

    Grading of Recommendations Assessment, Development, and Evaluation

  •  
  • LBW

    low birth weight

  •  
  • NEC

    necrotizing enterocolitis

  •  
  • RCT

    randomized controlled trial

1
Shulhan
J
,
Dicken
B
,
Hartling
L
,
Larsen
BM
.
Current knowledge of necrotizing enterocolitis in preterm infants and the impact of different types of enteral nutrition products
.
Adv Nutr
.
2017
;
8
(
1
):
80
91
2
Mukunya
D
,
Tumwine
JK
,
Nankabirwa
V
, et al
.
Factors associated with delayed initiation of breastfeeding: a survey in Northern Uganda
.
Glob Health Action
.
2017
;
10
(
1
):
1410975
3
NEOVITA Study Group
.
Timing of initiation, patterns of breastfeeding, and infant survival: prospective analysis of pooled data from three randomised trials
.
Lancet Glob Health
.
2016
;
4
(
4
):
e266
e275
4
Smith
ER
,
Locks
LM
,
Manji
KP
,
McDonald
CM
,
Kupka
R
,
Kisenge
R
, et al
.
Delayed breastfeeding initiation is associated with infant morbidity
.
The Journal of Pediatrics
.
2017
;
191
:
57
62.e52
5
Smith
ER
,
Hurt
L
,
Chowdhury
R
,
Sinha
B
,
Fawzi
W
,
Edmond
KM
;
Neovita Study Group
.
Delayed breastfeeding initiation and infant survival: A systematic review and meta-analysis
.
PLoS One
.
2017
;
12
(
7
):
e0180722
6
Morgan
J
,
Bombell
S
,
McGuire
W
.
Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants
.
Cochrane Database Syst Rev
.
2013
;(
3
)
7
Morgan
J
,
Young
L
,
McGuire
W
.
Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants
.
Cochrane Database Syst Rev
.
2014
;(
12
)
8
Walsh
V
,
Brown
JVE
,
Copperthwaite
BR
,
Oddie
SJ
,
McGuire
W
.
Early full enteral feeding for preterm or low birth weight infants
.
Cochrane Database Syst Rev
.
2020
;(
12
)
9
Sterne
JA
,
Savović
J
,
Page
MJ
,
Elbers
RG
,
Blencowe
NS
,
Boutron
I
, et al
.
RoB 2: a revised tool for assessing risk of bias in randomised trials
.
BMJ
.
2019
;
366
.
10
Luo
D
,
Wan
X
,
Liu
J
,
Tong
T
.
Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range
.
Stat Methods Med Res
.
2018
;
27
(
6
):
1785
1805
11
Wan
X
,
Wang
W
,
Liu
J
,
Tong
T
.
Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range
.
BMC Med Res Methodol
.
2014
;
14
(
1
):
135
12
Department of Mathematics HKBU
.
Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range
.
Available at: www.math.hkbu.edu.hk/∼tongt/papers/median2mean.html. Accessed December 1, 2021
13
DerSimonian
R
,
Laird
N
.
Meta-analysis in clinical trials
.
Control Clin Trials
.
1986
;
7
(
3
):
177
188
14
GSGGDT [computer program]
.
Evidence Prime Inc
.
Available at: gradepro.org. Accessed July 14, 2022
15
Schünemann
H
,
Brożek
J
,
Guyatt
G
,
Oxman
A
.
Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach
.
Updated
.
2013
; (
October
):
2013
16
Becerra
M
,
Ambiado
S
,
Kuntsman
G
, et al
.
Feeding VLBW infants: effect of early enteral stimulation (EES).† 1811
.
Pediatr Res
.
1996
;
39
(
4
):
304
304
17
Sáenz de Pipaón
M
,
VanBeek
RH
,
Quero
J
,
Pérez
J
,
Wattimena
DJ
,
Sauer
PJ
.
Effect of minimal enteral feeding on splanchnic uptake of leucine in the postabsorptive state in preterm infants
.
Pediatr Res
.
2003
;
53
(
2
):
281
287
18
Pérez
LA
,
Pradilla
GL
,
Díaz
G
,
Bayter
SM
.
Incidencia de enterocolitis necrosante en niños prematuros alimentados precozmente
.
Biomedica
.
2011
;
31
(
4
):
485
491
19
Meetze
WH
,
Valentine
C
,
McGuigan
JE
,
Conlon
M
,
Sacks
N
,
Neu
J
.
Gastrointestinal priming prior to full enteral nutrition in very low birth weight infants
.
J Pediatr Gastroenterol Nutr
.
1992
;
15
(
2
):
163
170
20
Ostertag
SG
,
LaGamma
EF
,
Reisen
CE
,
Ferrentino
FL
.
Early enteral feeding does not affect the incidence of necrotizing enterocolitis
.
Pediatrics
.
1986
;
77
(
3
):
275
280
21
Weiler
HA
,
Fitzpatrick-Wong
SC
,
Schellenberg
JM
, et al
.
Minimal enteral feeding within 3 d of birth in prematurely born infants with birth weight < or = 1200 g improves bone mass by term age
.
Am J Clin Nutr
.
2006
;
83
(
1
):
155
162
22
Dunn
L
,
Hulman
S
,
Weiner
J
,
Kliegman
R
.
Beneficial effects of early hypocaloric enteral feeding on neonatal gastrointestinal function: preliminary report of a randomized trial
.
J Pediatr
.
1988
;
112
(
4
):
622
629
23
Mosqueda
E
,
Sapiegiene
L
,
Glynn
L
,
Wilson-Costello
D
,
Weiss
M
.
The early use of minimal enteral nutrition in extremely low birth weight newborns
.
J Perinatol
.
2008
;
28
(
4
):
264
269
24
Tewari
VV
,
Dubey
SK
,
Kumar
R
,
Vardhan
S
,
Sreedhar
CM
,
Gupta
G
.
Early versus late enteral feeding in preterm intrauterine growth restricted neonates with antenatal Doppler abnormalities: an open-label randomized trial
.
J Trop Pediatr
.
2018
;
64
(
1
):
4
14
25
Abdelmaaboud
M
,
Mohammed
A
.
A randomized controlled trial on early versus late minimal enteral feeding in preterm growth-restricted neonates with abnormal antenatal Doppler studies
.
J Neonatal Perinatal Med
.
2012
;
5
(
2
):
155
162
26
Davey
AM
,
Wagner
CL
,
Cox
C
,
Kendig
JW
.
Feeding premature infants while low umbilical artery catheters are in place: a prospective, randomized trial
.
J Pediatr
.
1994
;
124
(
5 Pt 1
):
795
799
27
Leaf
A
,
Dorling
J
,
Kempley
S
, et al;
Abnormal Doppler Enteral Prescription Trial Collaborative Group
.
Early or delayed enteral feeding for preterm growth-restricted infants: a randomized trial
.
Pediatrics
.
2012
;
129
(
5
):
e1260
e1268
28
McClure
RJ
,
Newell
SJ
.
Randomised controlled study of clinical outcome following trophic feeding
.
Arch Dis Child Fetal Neonatal Ed
.
2000
;
82
(
1
):
F29
F33
29
van Elburg
RM
,
van den Berg
A
,
Bunkers
CM
, et al
.
Minimal enteral feeding, fetal blood flow pulsatility, and postnatal intestinal permeability in preterm infants with intrauterine growth retardation
.
Arch Dis Child Fetal Neonatal Ed
.
2004
;
89
(
4
):
F293
F296
30
Quigley
M
,
Embleton
ND
,
McGuire
W
.
Formula versus donor breast milk for feeding preterm or low birth weight infants
.
Cochrane Database Syst Rev
.
2018
;
6
(
6
):
CD002971
31
Rios
JD
,
Shah
PS
,
Beltempo
M
,
Louis
D
,
Mukerji
A
,
Premji
S
, et al
.
Costs of neonatal intensive care for Canadian infants with preterm birth
.
J Pediatr
.
2021
;
229
:
161
167. e112
32
Russell
RB
,
Green
NS
,
Steiner
CA
, et al
.
Cost of hospitalization for preterm and low birth weight infants in the United States
.
Pediatrics
.
2007
;
120
(
1
):
e1
e9
33
Enweronu-Laryea
CC
,
Andoh
HD
,
Frimpong-Barfi
A
,
Asenso-Boadi
FM
.
Parental costs for in-patient neonatal services for perinatal asphyxia and low birth weight in Ghana
.
PLoS One
.
2018
;
13
(
10
):
e0204410
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