Background
Very preterm (born more than eight weeks early) or very low birth weight (VLBW; less than 1500 grams) newborn babies are at risk of developing a severe bowel disorder called necrotising enterocolitis (where the bowel becomes inflamed and dies). Infants whose growth in the womb is compromised are thought to have a high risk of developing necrotising enterocolitis. Very preterm or VLBW infants are initially fed low amounts of milk, with amounts gradually increased over several days. Delaying the introduction and increase in volume of milk feeds for several days (or longer) after birth may be one possible way to reduce the risk of this condition.
Study characteristics
We searched for clinical trials assessing the effect of delayed (more than four days after birth) versus earlier introduction of milk feeds (where human milk or formula is fed directly by a tube into the stomach) on the risk of necrotising enterocolitis, death and general health in very preterm or VLBW infants. The search is up-to-date as of October 2021.
Key results
We found 14 trials with 1551 infants participating. About half of these infants had evidence of compromised growth while in the womb. Combined analysis of these trials showed that delayed introduction of progressive enteral feeds may not reduce the risk of necrotising enterocolitis or death. Delayed feeding may slightly reduce the risk of feed intolerance, but probably increases the risk of serious infection occurring.
Conclusions and certainty of evidence
This review provides low-certainty evidence that delaying the introduction of enteral feeds may not reduce the risk of necrotising enterocolitis or death for very preterm or VLBW infants, including infants whose growth in the womb was compromised.
Delaying the introduction of progressive enteral feeds beyond four days after birth (compared with earlier introduction) may not reduce the risk of necrotising enterocolitis or death in very preterm or VLBW infants. Delayed introduction may slightly reduce feed intolerance, and probably increases the risk of invasive infection.
Enteral feeding for very preterm or very low birth weight (VLBW) infants is often delayed for several days after birth due to concern that early introduction of feeding may not be tolerated and may increase the risk of necrotising enterocolitis. Concerns exist, however, that delaying enteral feeding may diminish the functional adaptation of the gastrointestinal tract and prolong the need for parenteral nutrition with its attendant infectious and metabolic risks.
To determine the effects of delayed introduction of progressive enteral feeds on the risk of necrotising enterocolitis, mortality and other morbidities in very preterm or VLBW infants.
Search strategies were developed by an information specialist in consultation with the review authors. The following databases were searched in October 2021 without date or language restrictions: CENTRAL (2021, Issue 10), MEDLINE via OVID (1946 to October 2021), Embase via OVID (1974 to October 2021), Maternity and Infant Care via OVID (1971 to October 2021), CINAHL (1982 to October 2021). We also searched for eligible trials in clinical trials databases, conference proceedings, previous reviews, and reference lists of retrieved articles.
Randomised controlled trials that assessed the effects of delayed (four or more days after birth) versus earlier introduction of progressive enteral feeds on necrotising enterocolitis, mortality and other morbidities in very preterm or VLBW infants.
Two review authors separately evaluated trial risk of bias, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of evidence for effects on necrotising enterocolitis, mortality, feed intolerance, and invasive infection.
We included 14 trials in which a total of 1551 infants participated. Potential sources of bias were lack of clarity on methods to generate random sequences and conceal allocation in half of the trials, and lack of masking of caregivers or investigators in all of the trials. Trials typically defined delayed introduction of progressive enteral feeds as later than four to seven days after birth and early introduction as four days or fewer after birth. Infants in six trials (accounting for about half of all of the participants) had intrauterine growth restriction or circulatory redistribution demonstrated by absent or reversed end-diastolic flow velocities in the fetal aorta or umbilical artery.
Meta-analyses showed that delayed introduction of progressive enteral feeds may not reduce the risk of necrotising enterocolitis (RR 0.81, 95% confidence interval (CI) 0.58 to 1.14; RD -0.02, 95% CI -0.04 to 0.01; 13 trials, 1507 infants; low-certainty evidence due risk of bias and imprecision) nor all-cause mortality before hospital discharge (RR 0.97, 95% CI 0.70 to 1.36; RD -0.00, 95% CI -0.03 to 0.03; 12 trials, 1399 infants; low-certainty evidence due risk of bias and imprecision). Delayed introduction of progressive enteral feeds may slightly reduce the risk of feed intolerance (RR 0.81, 95% CI 0.68 to 0.97; RD -0.09, 95% CI -0.17 to -0.02; number needed to treat for an additional beneficial outcome = 11, 95% CI 6 to 50; 6 trials, 581 infants; low-certainty evidence due to risk of bias and imprecision) and probably increases the risk of invasive infection (RR 1.44, 95% CI 1.15 to 1.80; RD 0.10, 95% CI 0.04 to 0.15; number needed to treat for a harmful outcome = 10, 95% CI 7 to 25; 7 trials, 872 infants; moderate-certainty evidence due to risk of bias).