Effect of Low-Dose Iron Supplementation on Early Development in Breastfed Infants: A Randomized Clinical Trial.

Importance: Breastfed infants are at risk of iron deficiency, which is associated with suboptimal development. There is a paucity of evidence on the effects of iron supplementation on child development, and current guidelines are divergent. Objective: To assess whether daily iron supplementation, 1 mg/kg, between 4 and 9 months in exclusively or predominantly breastfed infants improves psychomotor development at 12 months. Design, Setting, and Participants: This was a randomized, double-blind, placebo-controlled trial conducted between December 2015 and May 2020 with follow-up through May 2023 in an outpatient setting in Poland and Sweden. Participants were healthy singleton infants born at term with birth weight greater than 2500 g who were exclusively or predominantly breastfed (>50%) and did not have anemia (hemoglobin >10.5 g/dL) at age 4 months. Exclusion criteria included major illness, congenital anomaly, food allergy, and difficulty communicating with caregivers. Interventions: Iron (micronized microencapsulated ferric pyrophosphate), 1 mg/kg, or placebo (maltodextrin) once daily from age 4 to 9 months. Main Outcomes and Measures: The primary outcome was psychomotor development assessed by motor score of Bayley Scales of Infant and Toddler Development III at 12 months, adjusted for gestational age, sex, and maternal education. Secondary outcomes included cognitive and language scores at 12 months; motor, cognitive, and language scores at 24 and 36 months; iron deficiency (serum ferritin <12 ng/mL), and iron deficiency anemia (iron deficiency and hemoglobin <10.5 g/dL) at 12 months. Results: Of 221 randomized infants (111 female), 200 (90%) were included in the intention-to-treat analysis (mean [SD] age, 12.4 [0.8] months). Iron supplementation (n = 104) compared to placebo (n = 96) had no effect on psychomotor development (mean difference [MD] for motor score, -1.07 points; 95% CI, -4.69 to 2.55), cognitive score (MD, -1.14; 95% CI, -4.26 to 1.99), or language score (MD, 0.75; 95% CI, -2.31 to 3.82) at 12 months. There were no significant differences at 24 and 36 months. The intervention did not reduce the risk for iron deficiency (relative risk [RR], 0.46; 95% CI, 0.16 to 1.30) or iron deficiency anemia (RR, 0.78; 95% CI, 0.05 to 12.46) at 12 months. Conclusion and Relevance: No benefit was found with daily low-dose iron supplementation between 4 and 9 months with respect to psychomotor development, risk of iron deficiency, or iron deficiency anemia among breastfed infants in a setting of low risk of anemia. Trial Registration: ClinicalTrials.gov Identifier: NCT02242188.

Infant Formulas With Postbiotics: An Updated Systematic Review.

OBJECTIVES: Infant formulas (IF) with postbiotics, defined as inanimate microorganisms and/or their components that confer a health benefit on the host, are available. We systematically updated evidence on the safety and health effects of administering iF with postbiotics (with or without other modifications) compared with standard IF. METHODS: The Cochrane Library, MEDLINE, and EMBASE databases were searched to December 2021. RESULTS: Eleven randomized controlled trials were included. Using the Cochrane Risk of Bias Tool 2, for the primary outcomes, 5 trials had an overall high risk of bias, and 6 trials had some concerns of bias. Most data were available on IF fermented with Bifidobacterium breve C50 and Streptococcus thermophilus (BB/ST). These formulas, compared with the standard IF, were safe and well tolerated. Postbiotic formulas with additional modifications (ie, formula fermented with BB/ST & prebiotics, partly fermented formula with BB/ST and prebiotics with or without modified milk fat, partly fermented antiregurgitation formula with BB/ST and prebiotics) were generally safe and well tolerated but did not offer clear benefits replicated in other studies. Only limited data were available on formula fermented with Lactobacillus paracasei CBA L74. CONCLUSIONS: IF with postbiotics evaluated so far are safe and well tolerated by infants who cannot be breastfed. No firm conclusion can, however, be reached regarding the clinical effects and benefit of one formula over another. It seems reasonable to discuss with healthcare providers current evidence regarding specific modifications in infant formulas and let them decide whether the expected benefits meet expectations and are worth the cost.

Breast-Milk Microbiota Linked to Celiac Disease Development in Children: A Pilot Study From the PreventCD Cohort.

Celiac disease (CeD) is an immune-mediated disorder triggered by exposure to dietary gluten proteins in genetically predisposed individuals. In addition to the host genome, the microbiome has recently been linked to CeD risk and pathogenesis. To progress in our understanding of the role of breast milk microbiota profiles in CeD, we have analyzed samples from a sub-set of mothers (n = 49) included in the PreventCD project, whose children did or did not develop CeD. The results of the microbiota data analysis indicated that neither the BMI, HLA-DQ genotype, the CeD condition nor the gluten-free diet of the mothers could explain the human milk microbiota profiles. Nevertheless, we found that origin country, the offspring's birth date and, consequently, the milk sampling date influenced the abundance and prevalence of microbes in human milk, undergoing a transition from an anaerobic to a more aerobic microbiota, including potential pathogenic species. Furthermore, certain microbial species were more abundant in milk samples from mothers whose children went on to develop CeD compared to those that remained healthy. These included increases in facultative methylotrophs such as Methylobacterium komagatae and Methylocapsa palsarum as well as in species such as Bacteroides vulgatus, that consumes fucosylated-oligosaccharides present in human milk, and other breast-abscess associated species. Theoretically, these microbiota components could be vertically transmitted from mothers-to-infants during breastfeeding, thereby influencing CeD risk.

Effects of prenatal and/or postnatal supplementation with iron, PUFA or folic acid on neurodevelopment: update.

Neurodevelopment has been linked, among other factors, to maternal and early infant diets. The objective of this review, which is part of the NUTRIMENTHE research project 'The effect of diet on the mental performance of children' (www.nutrimenthe.com), was to update current evidence on the effects of nutritional interventions such as iron, folic acid or n-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation during pregnancy and/or in early life on the mental performance and psychomotor development of children. In May 2014, we searched MEDLINE and The Cochrane Database of Systematic Reviews for relevant studies published since 2009. The limited updated evidence suggests that iron supplementation of infants may positively influence the psychomotor development of children, although it does not seem to alter their mental development or behaviour. The use of multivitamin-containing folic acid supplements during pregnancy did not benefit the mental performance of the offspring. Evidence from randomised controlled trials (RCT) did not show a clear and consistent benefit of n-3 LCPUFA supplementation during pregnancy and/or lactation on childhood cognitive and visual development. Caution is needed when interpreting current evidence, as many of the included trials had methodological limitations such as small sample sizes, high attrition rates, and no intention-to-treat analyses. Taken together, the evidence is still inconclusive. Large, high-quality RCT to assess the effects of supplementation with iron, LCPUFA or folic acid are still needed to further clarify the effects of these, and other nutrients, on neurodevelopment. Recent recommendations from scientific societies are briefly presented.

Association between early life (prenatal and postnatal) antibiotic administration and coeliac disease: a systematic review.

OBJECTIVE: Whether prenatal or postnatal exposure to antibiotics is associated with an increased risk of coeliac disease (CD) is unclear. We systematically reviewed studies on the association between early life antibiotic exposure and the risk of CD or CD autoimmunity. DESIGN: Systematic review of observational studies. DATA SOURCES: The PubMed and Embase databases were searched up to December 2018, with no language restrictions. Additional references were obtained from reviewed articles. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Cohort, cross-sectional and case-control studies that assessed the association between prenatal and/or postnatal antibiotic exposure and the odds of developing CD (as defined by authors of the original studies) or CD autoimmunity were eligible for inclusion. RESULTS: Six studies were included. In two large cohort studies that focused on prenatal antibiotic exposure, no association with the risk of CD was found (adjusted OR=1.16; 95% CI 0.94 to 1.43 and adjusted HR=1.33; 95% CI 0.69 to 2.56) in the Norwegian and Swedish cohorts, respectively. In three studies that evaluated the association of postnatal antibiotic exposure with the risk of CD, the results were contradictory, with only the Italian cohort study reporting a significant positive association (adjusted incidence rate ratio=1.24; 95% CI 1.07 to 1.43). A large, multicentre cohort study that evaluated the association between postnatal antibiotic exposure and CD autoimmunity in human leukocyte antigen (HLA)-positive subjects found no association. CONCLUSIONS: We found no evidence of an association between prenatal or postnatal antibiotic exposure and CD.

Infant formulae supplemented with prebiotics: Are they better than unsupplemented formulae? An updated systematic review.

In 2011, the Committee on Nutrition of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition systematically reviewed published evidence related to the safety and health effects of the administration of formulae supplemented with pro- and/or prebiotics compared with unsupplemented formulae. We updated evidence on the effects of the administration of prebiotic-supplemented infant formulae (IF) compared with unsupplemented IF. Five databases were searched up to March 2017 for randomised controlled trials. In all, forty-one publications were identified, including twenty-five new publications. The administration of currently evaluated prebiotic-supplemented formulae to healthy infants does not raise safety concerns with regard to growth and adverse effects. Some favourable clinical effects are possible, primarily stool softening, which may be beneficial in some infants. Currently, there is no existing robust evidence to recommend the routine use of prebiotic-supplemented formulae. The latter conclusion may reflect the small amount of data on specific prebiotics and outcomes, rather than a genuine lack of an effect. The efficacy and safety should be considered for each prebiotic(s)-supplemented formula.

Systematic review: Early infant feeding practices and the risk of wheat allergy.

AIM: Wheat is a common allergen. Early feeding practices (breastfeeding, potentially allergenic foods) might affect the risk of allergy. To systematically evaluate the association between early feeding practices and the risk of wheat allergy and sensitisation. METHODS: Five databases were searched for studies of any design up to July 2015. RESULTS: We included seven studies (five observational, low to moderate quality, two randomised controlled trials (RCTs), high quality). The results come from observational studies unless stated otherwise. Longer breastfeeding was associated with wheat allergy (two studies, n = 1847) and sensitisation (one study, n = 3781). Evidence for exclusive breastfeeding was contradictory; longer exclusive breastfeeding was associated with either lower (one study, n = 408) or higher (one study, n = 3781) risk of wheat sensitisation. Breastfeeding at gluten introduction did not affect the risk of wheat allergy (two studies, n = 2581). Introducing cereal ≥7 months of age increased the risk of wheat allergy (one study, n = 1612), but results from an RCT (n = 1303) showed no effect. Early introduction of gluten was associated with a reduced risk of wheat sensitisation up to 5 years in one observational study (n = 3781) but not in RCTs (n = 1303). CONCLUSIONS: Based on limited evidence, the influence of breastfeeding and an early exposure to gluten on the risk of wheat allergy remain uncertain. There is no evidence supporting breastfeeding at gluten introduction as modifying the risk. Early introduction of gluten might reduce the risk of sensitisation, but currently, no evidence exists that it affects the risk of wheat allergy.

Systematic Review: Early Infant Feeding and the Risk of Type 1 Diabetes.

BACKGROUND: In addition to genetic background, a number of environmental factors have been claimed to influence the development of type 1 diabetes (T1D), including infant diet. OBJECTIVE: The aim of the study was to systematically update evidence on the possible relation between early feeding practices and the risk of T1D. METHODS: The Cochrane Library, MEDLINE, EMBASE, Web of Science, and CINAHL were searched for studies of any design up to July 2015. MEDLINE and EMBASE were additionally searched in March 2016. The primary outcome measures were the development of T1D or T1D-associated autoimmunity (T1DA). RESULTS: Nine publications were identified. Breastfeeding at the time of gluten introduction, as compared to gluten introduction after weaning, did not reduce the risk of developing T1DA or T1D. In children at high risk of developing T1D, except for gluten introduction at 3 months or younger age compared with gluten introduction at older than 3 months, which increased the risk of T1DA, the age of gluten introduction in infants had no effect on the risk of developing T1DA. CONCLUSIONS: Current evidence, mainly from observational studies, does not support the claim that early infant feeding practices, such as breastfeeding at gluten introduction or the age of the infant at the time of gluten introduction, may decrease the risk of developing T1D. More robust data are needed from randomized controlled trials.

Primary Prevention of Celiac Disease: Environmental Factors with a Focus on Early Nutrition.

Celiac disease (CD) is a common autoimmune disorder caused by ingestion of gluten. When diagnosed, it should be treated with a lifelong, strict gluten-free diet. Early infant feeding practices have been suggested as a means of preventing CD. In the last few decades, observational data have suggested that breastfeeding, especially at the time of introducing gluten into the infant's diet, as well as the time and mode of gluten first being given to a child could prevent or delay the occurrence of CD. As a result, recommendations advised that it is prudent to avoid both early (<4 months) and late (>7 months) introduction of gluten, and to introduce gluten gradually while the infant is still being breastfed, as this may reduce the risk of celiac disease, type 1 diabetes mellitus, and wheat allergy. Recently, the results of two large randomized trials have shown that breastfeeding in general, breastfeeding during gluten introduction, and early or delayed gluten introduction do not influence the total risk of CD in genetically predisposed individuals. Introducing gluten at 4 versus 6 months in very small amounts, or at 6 versus 12 months, resulted in similar rates of CD in these children. Thus, early feeding practices seem to have no impact on the risk of developing CD during childhood. In children without the genetic predisposition, the age and mode of gluten introduction do not influence the risk anyway.

Fermented infant formulas without live bacteria: a systematic review.

UNLABELLED: Fermented formulas, i.e., those fermented with lactic acid-producing bacteria during the production process and not containing significant amounts of viable bacteria in the final product, are widely available in many countries. Our aim was to systematically review published evidence related to the safety and health effects of the administration of fermented infant formulas compared with standard infant formulas. The Cochrane Library, MEDLINE, and EMBASE databases and major pediatric conference proceedings were searched. Five randomized controlled trials (RCTs) involving 1326 infants met the inclusion criteria. Compared with standard formula, the use of fermented formula resulted in a similar weight gain and length gain during the study period. Data from one RCT, albeit large, suggest the effectiveness of fermented formula in preventing and treating acute diarrhea. Fermented formula has the potential to reduce some, albeit not well-defined, digestive symptoms. Current evidence does not support the use of fermented formula for preventing cow's milk allergy. CONCLUSION: Limited available evidence suggests that the use of fermented infant formula, compared with the use of standard infant formula, does not offer clear additional benefits, although some benefit on gastrointestinal symptoms cannot be excluded. What is known • Fermented formulas, i.e., those fermented with lactic acid-producing bacteria during the production process and not containing significant amounts of viable bacteria in the final product, are widely available in many countries. What is new • Limited evidence available suggests that the use of fermented infant formula, compared with the use of standard infant formula, does not offer clear additional benefits, although some benefit on gastrointestinal symptoms cannot be excluded. At the same time, no negative health effects have been documented.

Lactobacillus GG (LGG) and smectite versus LGG alone for acute gastroenteritis: a double-blind, randomized controlled trial.

UNLABELLED: Diarrhea treatment with either Lactobacillus GG (LGG) or smectite as an adjuvant to standard rehydration therapy has proven efficacy. In countries where both LGG and smectite are available, concomitant use is frequently practiced. We investigated whether LGG plus smectite is superior to LGG alone in the management of children with acute gastroenteritis (AGE). A double-blind, placebo-controlled, randomized trial was performed. Children aged 4 to 60 months with AGE received LGG 6 × 10(9) colony forming units/day plus randomly either smectite (3 g) or placebo as an adjuvant to the standard rehydration therapy. Of the 88 children randomized, 81 (92 %) were available for intention-to-treat analysis. The duration of diarrhea in the LGG/smectite group (n = 44) compared with the LGG/placebo group (n = 37) was similar (P = 0.43). There were no significant differences between the study groups for the secondary outcomes, with three exceptions. On day 4, in the LGG/placebo group compared to the LGG/smectite group, there was significantly reduced stool frequency (P = 0.03). While there was a significant (P = 0.05) difference in stool consistency on the Bristol Stool Form Scale on day 4, it was not of clinical relevance. Finally, in the LGG/smectite group compared to the LGG/placebo group, there was a significantly shorter duration of intravenous therapy after randomization (P = 0.02). No adverse events were observed in the study groups. CONCLUSION: LGG plus smectite and LGG alone are equally effective for treating young children with AGE. Combined use of the two interventions is not justified.

Efficacy and safety of a new apple-flavoured oral rehydration solution in children with acute gastroenteritis: a double-blind randomized controlled trial.

AIM: To assess the efficacy and safety of a new oral rehydration solution (ORS) with improved flavour in the management of children with acute gastroenteritis (AGE). METHODS: Children 4 to 48 months of age with AGE (≥3 loose or watery stools per day for >1 but <5 days) with mild-to-moderate dehydration (3% to 9% loss of body weight) according to the World Health Organization criteria randomly received regular hypotonic ORS (Na 60 mmol/L, glucose 78 mmol/L) or the same hypotonic ORS with an apple taste. RESULTS: Of the 147 children randomized, 130 (88.4%) were available for intention-to-treat analysis. The proportion of children with the resolution of signs of dehydration in the experimental group compared with the control group was similar at 24 h (49/63 vs. 57/67, respectively, p = 0.28). There were also no significant differences in adequate weight gain (p = 0.48) and urine production at 24 h (p = 0.95) between groups. There were no differences between groups in any of the secondary outcome measures, including ORS intake. No adverse events were observed in the study groups. CONCLUSIONS: In an outpatient setting, there was no difference in efficacy between the study products. Both ORSs were equally effective and may be used interchangeably.