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|
Abstract - Background Placing a small volume of colostrum directly onto the buccal mucosa of preterm infants during the early neonatal period may provide immunological and growth factors that stimulate the immune system and enhance intestinal growth. These benefits could potentially reduce the risk of infection and necrotising enterocolitis (NEC) and improve survival and long‐term outcome. Objectives 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 NEC, late‐onset invasive infection, and/or mortality in preterm infants compared with controls. To assess trials for evidence of safety and harm (e.g. aspiration pneumonia). To compare effects of early oropharyngeal colostrum (OPC) versus no OPC, placebo, late OPC, and nasogastric colostrum. Search methods We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 8), MEDLINE via PubMed (1966 to August 2017), Embase (1980 to August 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to August 2017). We also searched clinical trials registries for ongoing and recently completed trials ( clinicaltrials.gov ; the World Health Organization International Trials Registry ( www.whoint/ictrp/search/en/ ), and the ISRCTN Registry ), conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi‐randomised trials. We performed the last search in August 2017. We contacted trial investigators regarding unpublished studies and data. Selection criteria We searched for published and unpublished randomised controlled trials comparing early administration of oropharyngeal colostrum (OPC) versus sham administration of water, oral formula, or donor breast milk, or versus no intervention. We also searched for studies comparing early OPC versus early nasogastric or nasojejunal administration of colostrum. We considered only trials that included preterm infants at < 37 weeks' gestation. We did not limit the review to any particular region or language. Data collection and analysis Two review authors independently screened retrieved articles for inclusion and independently conducted data extraction, data analysis, and assessments of 'Risk of bias' and quality of evidence. We graded evidence quality using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We contacted study authors for additional information or clarification when necessary. Main results We included six studies that compared early oropharyngeal colostrum versus water, saline, placebo, or donor, or versus no intervention, enrolling 335 preterm infants with gestational ages ranging from 25 to 32 weeks' gestation and birth weights of 410 to 2500 grams. Researchers found no significant differences between OPC and control for primary outcomes ‐ incidence of NEC (typical risk ratio (RR) 1.42, 95% confidence interval (CI) 0.50 to 4.02; six studies, 335 infants; P = 0.51; I² = 0%; very low‐quality evidence), incidence of late‐onset infection (typical RR 0.86, 95% CI 0.56 to 1.33; six studies, 335 infants; P = 0.50; I² = 0%; very low‐quality evidence), and death before hospital discharge (typical RR 0.76, 95% CI 0.34 to 1.71; six studies, 335 infants; P = 0.51; I² = 0%; very low‐quality evidence). Similarly, meta‐analysis showed no difference in length of hospital stay between OPC and control groups (mean difference (MD) 0.81, 95% CI ‐5.87 to 7.5; four studies, 293 infants; P = 0.65; I² = 49%). Days to full enteral feeds were reduced in the OPC group with MD of ‐2.58 days (95% CI ‐4.01 to ‐1.14; six studies, 335 infants; P = 0.0004; I² = 28%; very low‐quality evidence). The effect of OPC was uncertain because of small sample sizes and imprecision in study results (very low‐quality evidence). No adverse effects were associated with OPC; however, data on adverse effects were insuffici nt, and no numerical data were available from the included studies. Overall the quality of included studies was low to very low across all outcomes. We downgraded GRADE outcomes because of concerns about allocation concealment and blinding, reporting bias, small sample sizes with few events, and wide confidence intervals. Authors' conclusions Large, well‐designed trials would be required to evaluate more precisely and reliably the effects of oropharyngeal colostrum on important outcomes for preterm infants. Plain language summary Review question Does providing a very small volume of maternal colostrum into the mouth of preterm babies (oropharyngeal colostrum (OPC)) prevent complications and improve health outcomes? Background Placing a small volume of colostrum ‐ the first milk produced by the mother during the first few days of life ‐ directly onto the inside of the cheeks of preterm infants may provide immunological and growth factors that stimulate the immune system and enhance growth of the intestine. These benefits could potentially reduce infections, including severe infections in the intestine known as necrotising enterocolitis (NEC), thereby improving survival and long‐term outcomes. Study characteristics We searched for both published and unpublished studies comparing oropharyngeal colostrum versus a control such as water, placebo, or no oral priming. We included only clinical trials reporting outcomes in preterm babies (< 37 weeks' gestation). The evidence is up‐to‐date as of August 2017. We did not limit the review to any particular region or language. Key results Six studies were eligible for inclusion, involving 335 preterm infants with gestational ages ranging from 25 to 32 weeks' gestation and birth weights of 410 to 2500 grams. Reviewers noted no differences between OPC and control for rate of NEC, infection, or death before hospital discharge. Similarly, they observed no difference in length of hospital stay between OPC and control babies. Infants who received OPC achieved full milk feeds on average 2.5 days earlier than those given placebo or no intervention. However, included studies were small, data were insufficient, and study designs were not ideal. Combining study data did not provide sufficient evidence to recommend the use of colostrum for oral priming to prevent complications in preterm infants. Five of the included studies reported no harms (adverse effects); however, no numerical data are available from these studies. Included studies were of very low quality; therefore the effects of OPC remain uncertain. Conclusions Larger, better quality clinical trials would be needed to evaluate more precisely and reliably the effects of OPC on important outcomes for preterm infants. .