Current evidence suggests that placing a very small volume of colostrum directly onto the buccal mucosa of preterm infants has no impact on rates of necrotising enterocolitis, late-onset invasive infection or death compared to controls. A robust methodology supports these findings. The authors recommend that further, large well-designed trials are required to evaluate more precisely and reliably the effects of oropharyngeal colostrum on important outcomes for preterm infants.
Overall summary Low risk of bias in the review
All domains were considered at low concern suggesting no limitations regarding the review process. The authors highlighted how the review was limited by the low number of the included studies which impeded analysing the risk of publication bias via a funnel plot, however abstracts and proceedings of relevant conferences were included. Further, to minimise the potential bias resulting from incomplete reporting of the results, the primary study authors were contacted.
|A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4?||Probably yes|
|B. Was the relevance of identified studies to the review's research question appropriately considered?||Probably yes|
|C. Did the reviewers avoid emphasizing results on the basis of their statistical significance?||Probably yes|
|Risk of bias in the review||Low|
|Number of studies||6|
|Number of participants||335|
|Last search date||August 2017|
|Objective||To determine if early (within the first 48 hours of life) oropharyngeal administration of mother’s own fresh or frozen/thawed colostrum can reduce rates of necrotising enterocolitis, late-onset invasive infection and/or mortality in preterm infants compared with controls, and to compare the effects of early oropharyngeal colostrum (OPC) versus no OPC, placebo, late OPC and nasogastric colostrum.|
|Population||Preterm infants (at less than 37 weeks’ gestation) receiving care in any neonatal unit.|
|Interventions||Early oropharyngeal colostrum; oropharyngeal administration of mother’s own fresh or frozen/thawed colostrum to preterm infants in the first 48 hours of life, irrespective of when enteral feeding is initiated, what type of milk is used for enteral feeding, or which feed advancement regimen is applied; instillation of the colostrum inside the cheeks of the infant by oral syringe or by gentle application over the tongue, around the gums, and along the lips using a swab or sponge soaked with a small amount of colostrum (0.1 to 0.5 mL), at least once and usually repeatedly in the first 48 hours of life; any technique of oropharyngeal administration, such as instillation by syringe, direct application to the oral mucosa by swab, or any other means such that the fluid could be absorbed by the buccal mucosa.|
|Comparator||Sham administration of water, oral formula, or donor breast milk, or no intervention, early nasogastric or nasojejunal administration of colostrum, late (after 48 hours) oropharyngeal colostrum.|
|Outcome||Primary outcomes: incidence of necrotising enterocolitis (Bell’s stage 2 or 3) until discharge to home; the incidence of microbiologically confirmed late-onset invasive infection until discharge to home, defined as a blood or cerebrospinal fluid culture positive for microbial infection after 72 hours of life, death before discharge to home.
Secondary outcomes: pneumonia (chest X-ray changes/treated with at least five days of antibiotics before discharge to home); chronic lung disease (defined as the need for oxygen supplementation at 36 weeks’ postmenstrual age); retinopathy of prematurity (all stages and severe stage > 2); death in the first year of life; neurodevelopmental outcome at 18 to 24 months assessed by the clinician or parent-reported questionnaire; formally reported adverse effects (e.g. aspiration, gagging/ choking on administration, bradycardia, desaturation, increase in oxygen requirement, disturbances in vital signs) between the start of the intervention and discharge home; weight gain from birth to discharge home (using weight percentiles or Z-scores); time to regain birth weight; length of hospital stay (days) from birth to discharge home; days to full enteral feeds; days of parenteral nutrition before discharge to home; days of antibiotic therapy before discharge to home; receiving any breast milk at discharge to home; receiving only breast milk (and not formula) at discharge to home.
|Study design||Randomised controlled trials.
Quasi-randomised and non-randomised trials such as controlled before-and-after studies were excluded.
Pooled analysis reported that the time to full enteral feed was reduced for preterm babies receiving OPC compared to control (water, saline or none) (mean difference [MD] -2.58 days, 95% confidence interval [CI] -4.01 to -1.14; 6 studies, n=335 infants).
Pooled analysis reported no significant differences between oropharyngeal colostrum (OPC) and control (water, saline, or no intervention) in the incidence of necrotising enterocolitis (risk ratio (RR) 1.42, 95% CI 0.50 to 4.02, 6 studies, n=335 infants), incidence of late-onset infection (RR 0.86, 95% CI 0.56 to 1.33, 6 studies, n=335 infants), death before hospital discharge (RR 0.76, 95% CI 0.34 to 1.71, 6 studies, n=335 infants), length of hospital stay (MD 0.81, 95% CI -5.87 to 7.5, 4 studies, n=293 infants), risk of pneumonia (RR 2.08, 95% CI 0.54 to 8.06, 3 studies, n=57 infants), incidence of chronic lung disease (RR 0.85, 95% CI 0.60 to 1.20, 3 studies, n=57 infants), the number of days of antibiotic therapy before discharge to home (MD 1.69, 95% CI -4.00 to 7.39, 3 studies, n=141 infants), days of parenteral nutrition (MD 0.37, 95% CI -1.78 to 2.52, 2 studies, n=179 infants) and the incidence of retinopathy of prematurity (typical RR 0.98, 95% CI 0.33 to 2.94, 2 studies, n=165 infants). Similarly, a single study reported no significant differences between OPC and control in infants receiving any fortified breast milk at discharge (RR 0.67, 95% CI 0.44 to 1.02, 1 study, n=99 infants), infants receiving only breast milk (unfortified) at discharge (RR 0.98, 95% CI 0.89 to 1.07, 1 study, n=99 infants) or weight at discharge for preterm infants (MD -15.00, 95% CI -50.83 to 20.83, 1 study, n=149 participants).
While no adverse effects were reported to be associated with OPC, data on adverse effects were insufficient and no numerical data were available from the included studies.
The research objective was clearly stated and appropriate inclusion criteria were defined. The reported restrictions based on the study characteristics and sources of information were considered appropriate.
|1.1 Did the review adhere to pre-defined objectives and eligibility criteria?||Probably yes|
|1.2 Were the eligibility criteria appropriate for the review question?||Probably yes|
|1.3 Were eligibility criteria unambiguous?||Probably yes|
|1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)?||Probably yes|
|1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)?||Probably yes|
|Concerns regarding specification of study eligibility criteria||Low|
CENTRAL, MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature were searched for relevant studies. Moreover, the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov, the World Health Organisation International Clinical Trials Registry Platform and the ISRCTN Registry were searched for ongoing or completed trials. The reference lists of the included studies and previous reviews, proceedings of annual meetings of the Paediatric Academic Societies (1993 to 2017), the European Society for Paediatric Research (1995 to 2017), the Royal College of Paediatrics and Child Health (2000 to 2017), the Perinatal Society of Australia and New Zealand (2000 to 2017), and the National Association of Neonatal Nurses were searched for additional studies. The full search strategy was provided, which appeared to be adequate. No restrictions based on language were reported. Two independent review authors were involved in the study selection process. Disagreements were settled by discussion until consensus was reached.
|2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports?||Probably yes|
|2.2 Were methods additional to database searching used to identify relevant reports?||Probably yes|
|2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible?||Probably yes|
|2.4 Were restrictions based on date, publication format, or language appropriate?||Probably yes|
|2.5 Were efforts made to minimise error in selection of studies?||Yes|
|Concerns regarding methods used to identify and/or select studies||Low|
The data extraction was performed by two authors independently and disagreements were resolved by discussion and by consultation with the third review author. Sufficient study characteristics appear to have been extracted to allow for the interpretation of the results. All relevant study results appear to have been extracted. The methodological quality of the included studies was assessed using the Cochrane ‘Risk of bias’ tool. Two authors were independently involved in the assessment of the risk of bias. Disagreements were resolved by discussion or by consultation with a third assessor.
|3.1 Were efforts made to minimise error in data collection?||Yes|
|3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results?||Probably yes|
|3.3 Were all relevant study results collected for use in the synthesis?||Probably yes|
|3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria?||Probably yes|
|3.5 Were efforts made to minimise error in risk of bias assessment?||Yes|
|Concerns regarding methods used to collect data and appraise studies||Low|
The synthesis appeared to include all of the relevant studies. The method of analysis was explained and appeared to be appropriate. Heterogeneity was assessed and found to be moderate to high for some outcomes – this was explored further in sensitivity analyses. The publication bias could not be assessed due to the low number of studies included in the review. The quality of the individual studies was considered in the synthesis.
|4.1 Did the synthesis include all studies that it should?||Probably yes|
|4.2 Were all pre-defined analyses reported or departures explained?||Probably yes|
|4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies?||Probably yes|
|4.4 Was between-study variation minimal or addressed in the synthesis?||Probably yes|
|4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses?||Probably yes|
|4.6 Were biases in primary studies minimal or addressed in the synthesis?||Probably yes|
|Concerns regarding synthesis and findings||Low|