Primary outcomes

• Diagnosis of definite NEC during the study period, defined as clinical evidence of gastrointestinal and systemic illness, confirmed by pneumatosis intestinalis, pneumoperitoneum, portal venous gas, surgery or postmortem.

Secondary outcomes

• Suspected NEC during the study period.

• Surgery for NEC during the study period.

• NEC‐related death; by 28 days post‐delivery, by discharge and by one year (late or post‐discharge).

• Length of stay in hospital (days).

• Hospital re‐admissions within the first year of life.

• Days receiving total parenteral nutrition.

• Growth and development in childhood.

• Parental emotional and financial costs.

• Adverse effects of treatment.

Random sequence generation (checking for possible selection bias)

For each included study, we described the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. We assessed the risk of bias methods as:

• low risk (any truly random process, e.g. random number table; computer random number generator);

• high risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);

• unclear risk.

Allocation concealment (checking for possible selection bias)

For each included study, we described the method used to conceal the allocation sequence in sufficient detail and determine whether intervention allocation could have been foreseen in advance of, or during, recruitment, or changed after assignment. We assessed the risk of bias methods as:

• low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

• high risk (open random allocation; unsealed or non‐opaque envelopes; alternation; date of birth);

• unclear risk.

Blinding (checking for possible performance bias)

For each included study, we described the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We judged the study to be at low risk of bias if it was blinded, or if we judged that the lack of blinding could not have affected the results. We assessed blinding separately for different outcomes and classes of outcomes. We assessed the risk of bias methods as:

• adequate, inadequate or unclear for participants;

• adequate, inadequate or unclear for personnel;

• adequate, inadequate or unclear for outcome assessors.

Incomplete outcome data (checking for possible attrition bias through withdrawals, drop‐outs and protocol deviations)

For each included study and for each outcome or class of outcome, we described the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we planned to re‐include missing data in the analyses. We assessed the risk of bias methods as:

• adequate (less than 20% missing data);

• inadequate;

• unclear.

Selective reporting bias

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the risk of bias methods as:

• low risk (where it was clear that all of the study's pre‐specified outcomes and all expected outcomes of interest to the review were reported);

• high risk (where not all of the study's pre‐specified outcomes had been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest were reported incompletely and so could not be used; study did not include results of a key outcome that would have been expected to have been reported);

• unclear risk.

Other sources of bias

For each included study, we described any important concerns that we had about other possible sources of bias (e.g. early termination of trial due to data‐dependant process, extreme baseline imbalance, etc.). We assessed whether each study was free of other problems that could put it at risk of bias. We assessed other sources of bias as:

• low risk;

• high risk;

• unclear.

Overall risk of bias

We made judgements as to whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to overall risk of bias, we assessed the likely magnitude and direction of the bias and whether we considered it likely to impact on the findings.

Quality of Evidence

We assessed the quality of evidence for the main comparison at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Guyatt 2011a). This methodological approach considers evidence from randomised controlled trials as high quality that may be downgraded based on consideration of any of five areas: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates and presence of publication bias. (Guyatt 2011a). The GRADE approach results in an assessment of the quality of a body of evidence in one of four grades: 1) High: We are very confident that the true effect lies close to that of the estimate of the effect; 2) Moderate: 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; 3) Low: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect; 4) Very Low: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect (Schunemann 2013).

The review authors independently assessed the quality of the evidence found for outcomes identified as critical or important for clinical decision making. These outcomes include: diagnosis of definite NEC during the study period, defined as clinical evidence of gastrointestinal and systemic illness, confirmed by pneumatosis intestinalis, pneumoperitoneum, portal venous gas, surgery or postmortem; surgery for NEC during the study period; NEC‐related death; by 28 days post‐delivery, by discharge and by one year (late or post‐discharge); overall mortality; duration of hospitalisation.

In cases where we considered the risk of bias arising from inadequate concealment of allocation, randomised assignment, complete follow‐up or blinded outcome assessment to reduce our confidence in the effect estimates, we downgraded the quality of evidence accordingly (Guyatt 2011b). We evaluated consistency by similarity of point estimates, extent of overlap of confidence intervals and statistical criteria including measurement of heterogeneity (I2). We downgraded the quality of evidence when large and unexplained inconsistency across studies results was present (i.e. some studies suggest important benefit and others no effect or harm without a clinical explanation) (Guyatt 2011d). Precision was assessed based on the width of the 95% confidence interval (CI) and by calculating the optimal information size (OIS). If the total number of patients included in the pooled effect estimation was less than the number of patients generated by a conventional sample size calculation for a single adequately powered trial, we considered rating down for imprecision (Guyatt 2011c). When trials were conducted in populations other than the target population, we downgraded the quality of evidence because of indirectness (Guyatt 2011e).

We entered data (i.e. pooled estimates of the effects and corresponding 95% confidence Interval) and explicit judgments for each of the above aspects assessed into the Guideline Development Tool, the software used to create ‘Summary of findings’ tables (GRADEpro 2008). We explained all judgements involving the assessment of the study characteristics described above in footnotes or comments in the ‘Summary of findings’ table.