The Impact of Human Milk on Necrotizing Enterocolitis: A Systematic Review and Meta-Analysis

Background. Premature infants receiving breastfeed have a lower incidence of NEC than those fed preterm formula. This study aimed: (1) to update a systematic review and meta-analyses to evaluate the relationship between feeding and necrotizing enterocolitis (NEC) in low weight premature infants; (2) to conduct meta-regression analyses by subgroups; (3) to describe geographical distribution of milk banks in the world. Methods. Papers included in the meta-analysis were updated as of June 2019. Relative risks were used as a measure of effect size. Random effect models were used to account for different sources of variation among studies. For milk banks, the data reviewed by the literature were integrated with the information collected from countries’ institutional sites and milk bank networks. Results. Thirty-two papers were included in meta-analysis: six randomized controlled trials (RCTs) and 26 observational studies (OS). The census has found 572 milk banks around in the world. Brazil has the most active milk banks. RCTs meta-analysis indicates a risk reduction of NEC using human milk respect to formula: Relative risk (RR) = 0.62 (0.42–0.93). Seven OS compared quantities lower than human milk or higher than the 50th quantile showing a risk reduction of NEC:RR = 0.51 (0.31–0.85); 3 OS that evaluated human milk versus mixed feeding showing that human milk has a protective role on the development of NEC:RR = 0.74 (0.63–0.91). Results of subgroups analysis show that the risk reduction is statistically significant only for studies in which premature infants are given both their own and donated breastmilk. Conclusions. The possibility of preserving human milk and promoting donations guarantees an improvement in the health of newborns.


Rationale
3 Describe the rationale for the review in the context of what is already known. 1-2 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). 1-2

Protocol and registration 5
Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
Not applicable Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.
2 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. 2 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. 2 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). 2 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
2 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 2

12
Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

Summary of evidence 24
Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

10-12
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

10-12
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 10-12

Funding 27
Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
Not applicable   * statistically significant difference between human milk and preterm formula.

1) Assessment of Outcome
For some outcomes (e.g. fractured hip), reference to the medical record is sufficient to satisfy the requirement for confirmation of the fracture. This would not be adequate for vertebral fracture outcomes where reference to x-rays would be required. a) Independent or blind assessment stated in the paper, or confirmation of the outcome by reference to secure records (x-rays, medical records, etc.) b) Record linkage (e.g. identified through ICD codes on database records) c) Self-report (i.e. no reference to original medical records or x-rays to confirm the outcome) d) No description.

2) Was Follow-Up Long Enough for Outcomes to Occur
a) An acceptable length of time should be decided before quality assessment begins (e.g. 5 yrs. for exposure to breast implants)

3) Adequacy of Follow Up of Cohorts
a) This item assesses the follow-up of the exposed and non-exposed cohorts to ensure that losses are not related to either the exposure or the outcome. Allocation of stars as per rating sheet Figure S1. Meta-analysis: results from RCT and observational studies. Forest plot for selected outcomes.