Guidance for the Conduct and Reporting of Clinical Trials of Breast Milk Substitutes

Question What is the best way to ensure the validity of clinical trials of breast milk substitutes while protecting trial participants? Findings Through a Delphi consensus project, guidance was developed to address issues specific to trials of breast milk substitutes assessing growth and tolerance, as well as trials of breast milk substitutes with other objectives. This consensus guidance summarizes best practice for the design, conduct, analysis, and reporting of trials of breast milk substitutes. Meaning Use of this guidance, in conjunction with existing clinical trial regulations, should enhance the quality and validity of trials of breast milk substitutes, protect trial participants, and support the evidence base for infant nutrition recommendations. This consensus guidance summarizes best practice for the design, conduct, analysis, and reporting of trials of breast milk substitutes. Importance Breast milk substitutes (BMS) are important nutritional products evaluated in clinical trials. Concerns have been raised about the risk of bias in BMS trials, the reliability of claims that arise from such trials, and the potential for BMS trials to undermine breastfeeding in trial participants. Existing clinical trial guidance does not fully address issues specific to BMS trials. Objectives To establish new methodological criteria to guide the design, conduct, analysis, and reporting of BMS trials and to support clinical trialists designing and undertaking BMS trials, editors and peer reviewers assessing trial reports for publication, and regulators evaluating the safety, nutritional adequacy, and efficacy of BMS products. Design, Setting, and Participants A modified Delphi method was conducted, involving 3 rounds of anonymous questionnaires and a face-to-face consensus meeting between January 1 and October 24, 2018. Participants were 23 experts in BMS trials, BMS regulation, trial methods, breastfeeding support, infant feeding research, and medical publishing, and were affiliated with institutions across Europe, North America, and Australasia. Guidance development was supported by an industry consultation, analysis of methodological issues in a sample of published BMS trials, and consultations with BMS trial participants and a research ethics committee. Results An initial 73 criteria, derived from the literature, were sent to the experts. The final consensus guidance contains 54 essential criteria and 4 recommended criteria. An 18-point checklist summarizes the criteria that are specific to BMS trials. Key themes emphasized in the guidance are research integrity and transparency of reporting, supporting breastfeeding in trial participants, accurate description of trial interventions, and use of valid and meaningful outcome measures. Conclusions and Relevance Implementation of this guidance should enhance the quality and validity of BMS trials, protect BMS trial participants, and better inform the infant nutrition community about BMS products.Peer reviewe

Diet during pregnancy and infancy, and risk of allergic or autoimmune disease: a systematic review and meta-analysis

Background: There is uncertainty about the influence of diet during pregnancy and infancy on a child’s immune development. We assessed whether variations in maternal or infant diet can influence risk of allergic or autoimmune disease. Methods and findings: Two authors selected studies, extracted data, and assessed risk of bias. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess certainty of findings. We searched Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Web of Science, Central Register of Controlled Trials (CENTRAL), and Literatura Latino Americana em Ciências da Saúde (LILACS) between January 1946 and July 2013 for observational studies and until December 2017 for intervention studies that evaluated the relationship between diet during pregnancy, lactation, or the first year of life and future risk of allergic or autoimmune disease. We identified 260 original studies (964,143 participants) of milk feeding, including 1 intervention trial of breastfeeding promotion, and 173 original studies (542,672 participants) of other maternal or infant dietary exposures, including 80 trials of maternal (n = 26), infant (n = 32), or combined (n = 22) interventions. Risk of bias was high in 125 (48%) milk feeding studies and 44 (25%) studies of other dietary exposures. Evidence from 19 intervention trials suggests that oral supplementation with nonpathogenic micro-organisms (probiotics) during late pregnancy and lactation may reduce risk of eczema (Risk Ratio [RR] 0.78; 95% CI 0.68–0.90; I2 = 61%; Absolute Risk Reduction 44 cases per 1,000; 95% CI 20–64), and 6 trials suggest that fish oil supplementation during pregnancy and lactation may reduce risk of allergic sensitisation to egg (RR 0.69, 95% CI 0.53–0.90; I2 = 15%; Absolute Risk Reduction 31 cases per 1,000; 95% CI 10–47). GRADE certainty of these findings was moderate. We found weaker support for the hypotheses that breastfeeding promotion reduces risk of eczema during infancy (1 intervention trial), that longer exclusive breastfeeding is associated with reduced type 1 diabetes mellitus (28 observational studies), and that probiotics reduce risk of allergic sensitisation to cow’s milk (9 intervention trials), where GRADE certainty of findings was low. We did not find that other dietary exposures—including prebiotic supplements, maternal allergenic food avoidance, and vitamin, mineral, fruit, and vegetable intake—influence risk of allergic or autoimmune disease. For many dietary exposures, data were inconclusive or inconsistent, such that we were unable to exclude the possibility of important beneficial or harmful effects. In this comprehensive systematic review, we were not able to include more recent observational studies or verify data via direct contact with authors, and we did not evaluate measures of food diversity during infancy. Conclusions: Our findings support a relationship between maternal diet and risk of immune-mediated diseases in the child. Maternal probiotic and fish oil supplementation may reduce risk of eczema and allergic sensitisation to food, respectively

Myelination is associated with processing speed in early childhood:preliminary insights

Processing speed is an important contributor to working memory performance and fluid intelligence in young children. Myelinated white matter plays a central role in brain messaging, and likely mediates processing speed, but little is known about the relationship between myelination and processing speed in young children. In the present study, processing speed was measured through inspection times, and myelin volume fraction (VFM) was quantified using a multicomponent magnetic resonance imaging (MRI) approach in 2- to 5-years of age. Both inspection times and VFM were found to increase with age. Greater VFM in the right and left occipital lobes, the body of the corpus callosum, and the right cerebellum was significantly associated with shorter inspection times, after controlling for age. A hierarchical regression showed that VFM in the left occipital lobe predicted inspection times over and beyond the effects of age and the VFM in the other brain regions. These findings are consistent with the hypothesis that myelin supports processing speed in early childhood

Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmune Disease

Importance Timing of introduction of allergenic foods to the infant diet may influence the risk of allergic or autoimmune disease, but the evidence for this has not been comprehensively synthesized. Objective To systematically review and meta-analyze evidence that timing of allergenic food introduction during infancy influences risk of allergic or autoimmune disease. Data Sources MEDLINE, EMBASE, Web of Science, CENTRAL, and LILACS databases were searched between January 194

Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis - Fig 8

<p>Randomised controlled trial findings for multifaceted dietary interventions compared with no multifaceted intervention and risk of allergic rhinitis at age ≤4 years (A) or 5–14 years (B), wheeze (C) or recurrent wheeze (D) at age 5–14 years, and wheeze (E) or recurrent wheeze (F) at age ≤4 years. CI, confidence interval; RCT, randomised controlled trial; RR, risk ratio; W, weight.</p

Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis - Fig 9

<p>RCT findings for vitamin supplementation compared with no vitamin supplementation and risk of wheeze (A), recurrent wheeze (B), or eczema (C) at age ≤4 years. CI, confidence interval; RCT, randomised controlled trial; RR, risk ratio; W, weight.</p

Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis - Fig 3

<p>Observational study findings for a relationship between breastfeeding ever (A) or exclusive breastfeeding for ≥3–4 months (B) and type 1 diabetes mellitus. CI, confidence interval; OR, odds ratio; W, weight.</p

Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis - Fig 2

<p>Observational study findings for a relationship between breastfeeding ever and recurrent wheeze at age 5–14 years (A) and a Funnel plot for this analysis showing evidence of publication bias (B). Egger test <i>P</i> = 0.012. CI, confidence interval; OR, odds ratio; W, weight.</p

TSA of intervention trials evaluating the effect of fish oil supplementation on risk of allergic sensitisation to egg.

<p>The vertical red line is the optimal information size, i.e., the cumulative sample size required to establish with 80% power and 5% 2-sided significance whether the intervention reduces risk of the outcome by ≥20%, allowing for repeatedly meta-analysing the accumulating studies. The horizontal green line is a z score of +1.96, equal to two-sided <i>P</i> = 0.05. The cumulative Z-statistic (blue line) does not reach the optimal information size and does not cross the trial sequential monitoring boundary (curved red line), indicating no clear evidence for ≥20% relative risk reduction. Findings were similar for ≥30% relative risk reduction. No., number; TSA, trial sequential analysis.</p

Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis - Fig 5

<p>RCT findings for probiotic supplementation compared with no probiotics and risk of allergic sensitisation to any allergen (A), any inhalant allergen (B), any food allergen (C), egg (D), milk (E), or peanut (F). CI, confidence interval; RCT, randomised controlled trial; RR, risk ratio; W, weight.</p