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Suitability and safety of L-5-methyltetrahydrofolate as a folate source in infant formula: A randomized-controlled trial.

ABSTRACT: L-5-methyltetrahydrofolate is the predominant folate form in human milk but is currently not approved as a folate source for infant and follow-on formula. We aimed to assess the suitability of L-5-methyltetrahydrofolate as a folate source for infants. Growth and tolerance in healthy term infants fed formulae containing equimolar doses of L-5-methyltetrahydrofolate (10.4 ?g/ 100 ml, n = 120, intervention group) or folic acid (10.0 ?g/ 100 ml, n = 120, control group) was assessed in a randomized, double-blind, parallel, controlled trial. A reference group of breastfed infants was followed. Both formulae were well accepted without differences in tolerance or occurrence of adverse events. The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection. Weight gain (the primary outcome) was equivalent in the two groups (95% CI -2.11; 1.68 g/d). In line with this, there was only a small difference in absolute body weight adjusted for birth weight and sex at visit 4 (95% CI -235; 135 g). Equivalence was also shown for gain in head circumference but not for recumbent length gain and increase in calorie intake. Given the nature of the test, this does not indicate an actual difference, and adjusted means at visit 4 were not significantly different for any of these parameters. Infants receiving formula containing L-5-methyltetrahydrofolate had lower mean plasma levels of unmetabolized folic acid (intervention: 0.73 nmol/L, control: 1.15 nmol/L, p<0.0001) and higher levels of red cell folate (intervention: 907.0 ±192.8 nmol/L, control: 839.4 ±142.4 nmol/L, p = 0.0095). We conclude that L-5-methyltetrahydrofolate is suitable for use in infant and follow-on formula, and there are no indications of untoward effects. Trial registration: This trial was registered at ClinicalTrials.gov (NCT02437721).

SUBMITTER: Troesch B

PROVIDER: S-EPMC6699731 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Suitability and safety of L-5-methyltetrahydrofolate as a folate source in infant formula: A randomized-controlled trial.

Troesch Barbara B Demmelmair Johann J Gimpfl Martina M Hecht Christina C Lakovic Goran G Roehle Robert R Sipka Ljilja L Trisic Branka B Vusurovic Milica M Schoop Rotraut R Zdjelar Sznezana S Koletzko Berthold B

PloS one 20190819 8

L-5-methyltetrahydrofolate is the predominant folate form in human milk but is currently not approved as a folate source for infant and follow-on formula. We aimed to assess the suitability of L-5-methyltetrahydrofolate as a folate source for infants. Growth and tolerance in healthy term infants fed formulae containing equimolar doses of L-5-methyltetrahydrofolate (10.4 μg/ 100 ml, n = 120, intervention group) or folic acid (10.0 μg/ 100 ml, n = 120, control group) was assessed in a randomized, ...[more]

PMID: 31425504

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Project description:Background:Millions of infants are fed breast milk substitutes, and the type of infant formula can impact weight gain patterns. Objective:We conducted a randomized controlled trial to determine the direct impact of 2 types of infant formula (cow milk formula, CMF; extensively protein hydrolyzed formula, EHF) on growth and energy balance. Design:A racially diverse group of formula-fed infants (n = 113) were randomly assigned to either CMF or EHF from the age of 0.75 to 12.5 mo. At each monthly visit, anthropometric measures were obtained to determine growth z scores and weight gain velocity, and to categorize early weight gain patterns as rapid or nonrapid. Also, diet records were collected to determine energy from formula and other sources. Comprehensive assessments of energy balance (intake, expenditure, loss) were made at 0.75, 3.5, and 12.5 mo. Results:Beginning 3 wk after randomization, CMF infants had significantly higher weight, but not length, z scores than did EHF infants, and this persisted after solid foods complemented the formula diet. On average, weight gain velocity from 0.75 to 4.5 mo was within the range of typically growing infants for both groups, yet velocity was 3.9 g/d greater for CMF infants (P = 0.002), who were more likely to be classified as an early rapid weight gainer, than EHF infants (46% compared with 18%; P = 0.007). Early differences in energy intake and fecal loss, yielding greater energy available for deposition among CMF infants, contributed to the differential weight gain patterns. There were no significant differences between the formula treatment groups in total energy expenditure or sleeping energy expenditure. Conclusions:Among healthy infants, the type of formula impacted on early rapid weight gain patterns owing to energy intake and loss mechanisms. Research is needed to identify the macronutrients and other compositional constituents in EHF and breast milk that promote satiation and healthy weight gain during sensitive periods of development. This trial was registered at clinicaltrials.gov as: NCT01700205.

Project description:BackgroundWith increased use of telehealth, interventions to improve infant sleep environments have not been explored. This study sought to assess the feasibility and efficacy of using electronic health record patient portals to transmit photographs of infant sleep between mothers and healthcare professionals as part of an intervention to promote sleep environments consistent with AAP guidelines.MethodsOne hundred eighty-four mother-newborn dyads consented to participate in a randomized trial requiring patient portal registration within 1 month of delivery. We first assessed feasibility as measured by a) the proportion of consented mothers enrolling in the portal and b) maternal adherence to prompts to submit photographs of their infant sleeping to the research team through the patient portal. Intervention group mothers were prompted at 1 and 2 months; controls were prompted only at 2 months. Efficacy was determined via research assistant review of submitted photographs. These assistants were trained to detect sudden unexplained infant death risk factors utilizing AAP guidelines. Standardized feedback was returned to mothers through the patient portal. We used Fisher's Exact test to assess group differences in guideline adherence at 2 months.ResultsOne hundred nine mothers (59%) enrolled in the patient portal and were randomized to intervention (N = 55) and control (N = 54) groups. 21 (38, 95% CI 25-52%) intervention group participants sent photographs at 1 month and received personalized feedback. Across both groups at 2 months, 40 (37, 95% CI 28-46%) sent photographs; 56% of intervention group participants who submitted photographs met all safe sleep criteria compared with 46% of controls (difference 0.10, 95% CI - 0.26 to 0.46, p = .75). Common reasons for guideline non-adherence were sleeping in a room without a caregiver (43%), loose bedding (15%) and objects (8%) on the sleep surface.ConclusionsUtilizing the patient portal to individualize safe infant sleep is possible, however, we encountered numerous barriers in this trial to assess its effects on promoting safe infant sleep. Photographs of infants sleeping showed substantial non-adherence to AAP guidelines, suggesting further needs for improvement to promote safe infant sleep practices.Trial registrationName: Improving Infant Sleep Safety With the Electronic Health Record; Clinicaltrials.gov: NCT03662048 ; Date of Registration: September 7, 2018; Data Sharing Statement: None.

Project description:IMPORTANCE:The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of ?-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins. OBJECTIVE:To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children. DESIGN, SETTING, AND PARTICIPANTS:A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows' milk-based formula. The participants were observed to April 16, 2013. INTERVENTIONS:The participants received either a casein hydrolysate or a conventional cows' milk formula supplemented with 20% of the casein hydrolysate. MAIN OUTCOMES:AND MEASURES: Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated-2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years). RESULTS:The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups. CONCLUSIONS AND RELEVANCE:Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00179777.

Project description:There is little or no information available on the impact of funding by the food industry on trial outcomes and methodological quality of synbiotics, probiotics and prebiotics research in infants. The objective of this study was to compare the methodological quality, outcomes of food industry sponsored trials versus non industry sponsored trials, with regards to supplementation of synbiotics, probiotics and prebiotics in infant formula.A comprehensive search was conducted to identify published and unpublished randomized clinical trials (RCTs). Cochrane methodology was used to assess the risk of bias of included RCTs in the following domains: 1) sequence generation; 2) allocation concealment; 3) blinding; 4) incomplete outcome data; 5) selective outcome reporting; and 6) other bias. Clinical outcomes and authors' conclusions were reported in frequencies and percentages. The association between source of funding, risk of bias, clinical outcomes and conclusions were assessed using Pearson's Chi-square test and the Fisher's exact test. A p-value < 0.05 was statistically significant.Sixty seven completed and 3 on-going RCTs were included. Forty (59.7%) were funded by food industry, 11 (16.4%) by non-industry entities and 16 (23.9%) did not specify source of funding. Several risk of bias domains, especially sequence generation, allocation concealment and blinding, were not adequately reported. There was no significant association between the source of funding and sequence generation, allocation concealment, blinding and selective reporting, majority of reported clinical outcomes or authors' conclusions. On the other hand, source of funding was significantly associated with the domains of incomplete outcome data, free of other bias domains as well as reported antibiotic use and conclusions on weight gain.In RCTs on infants fed infant formula containing probiotics, prebiotics or synbiotics, the source of funding did not influence the majority of outcomes in favour of the sponsors' products. More non-industry funded research is needed to further assess the impact of funding on methodological quality, reported clinical outcomes and authors' conclusions.

Project description:The relationships between nutrition, metabolic response, early growth and later body weight have been investigated in human studies. The aim of this follow-up study was to assess the long-term effect of infant feeding on growth and to study whether the infant metabolome at the age of 4 months might predict anthropometry at 4 years of age. The Belgrade-Munich infant milk trial (BeMIM) was a randomized controlled trial in which healthy term infants received either a protein-reduced infant formula (1.89 g protein/100 kcal) containing alpha-lactalbumin enriched whey and long-chain polyunsaturated fatty acids (LC-PUFA), or a standard formula (2.2 g protein/100 kcal) without LC-PUFA, focusing on safety and suitability. Non-randomized breastfed infants were used as a reference group. Of the 259 infants that completed the BeMIM study at the age of 4 months (anthropometry assessment and blood sampling), 187 children participated in a follow-up visit at 4 years of age. Anthropometry including weight, standing height, head circumference, and percent body fat was determined using skinfolds (triceps, subscapular) and bioelectrical impedance analysis. Plasma metabolite concentration, collected in samples at the age of 4 months, was measured using flow-injection tandem mass spectrometry. A linear regression model was applied to estimate the associations between each metabolite and growth with metabolites as an independent variable. At 4 years of age, there were no significant group differences in anthropometry and body composition between formula groups. Six metabolites (Asn, Lys, Met, Phe, Trp, Tyr) measured at 4 months of age were significantly associated with changes in weight-for-age z-score between 1 to 4 months of age and BMI-for-age z-score (Tyr only), after adjustment for feeding group. No correlation was found between measured metabolites and long-term growth (up to 4 years of age). No long-term effects of early growth patterns were shown on anthropometry at 4 years of age. The composition of infant formula influences the metabolic profile and early growth, while long-term programming effects were not observed in this study.

Project description:BACKGROUND:The microorganism present in breast milk, added to other factors, determine the colonization of infants. The objective of the present study is to evaluate the safety, tolerance and effects of the consumption of a milk formula during the first year of life that is supplemented with L. fermentum CECT5716 or Bifidobacterium breve CECT7263, two strains originally isolated from breast milk. METHODS:A randomized, double blind, controlled, parallel group study including healthy, formula-fed infants was conducted. Two hundred and thirty-six 1-month-old infants were selected and randomly divided into three study groups according to a randomization list. Infants in the control group received a standard powdered infant formula until 12?months of age. Infants in the probiotic groups received the same infant formula but supplemented with L. fermentum CECT5716 Lc40 or B. breve CECT7263. Main outcome was weigh-gain of infants as safety marker. RESULTS:One hundred and eighty-nine infants completed the eleven months of intervention (61 in control group, 65 in Lf group and 63 in Bb group). The growth of infants in the three groups was consistent with standards. No significant differences were observed in the main outcome, weight-gain (Control group: 5.77 Kg?±?0.95, Lf group: 5.77 Kg?±?1.31, Bb group: 5.58 Kg?±?1.10; p?=?0.527). The three milk formulae were well tolerated, and no adverse effects were related to the consumption of any of the formula. Infants receiving B. breve CECT7263 had a 1.7 times lower risk of crying than the control group (OR?=?0.569, CI 95% 0.568-0.571; p?=?0.001). On the other hand, the incidence of diarrhoea in infants receiving the formula supplemented with L. fermentum CECT5716 was a 44% lower than in infants receiving the control formula (p?=?0.014). The consumption of this Lactobacillus strain also reduced the duration of diarrhoea by 2.5?days versus control group (p?=?0.044). CONCLUSIONS:The addition of L. fermentum CECT5716 Lc40 or B. breve CECT7263, two probiotic strains naturally found in breast milk, to infant formulae is safe and induces beneficial effects on the health of infants. TRIAL REGISTRATION:The trial was retrospectively registered in the US Library of Medicine ( www.clinicaltrial.gov ) with the number NCT03204630 . Registered 11 August 2016.

Dataset Information

Suitability and safety of L-5-methyltetrahydrofolate as a folate source in infant formula: A randomized-controlled trial.

Publications

Suitability and safety of L-5-methyltetrahydrofolate as a folate source in infant formula: A randomized-controlled trial.

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