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Aim: Extensive ongoing research on probiotics and infant formulas raises a number of safety questions. One concern is the potential influence of d-lactic acid-containing preparations on the health of infants and children. The aim of this review was to summarise the available knowledge on the ingestion of d-lactic acid-producing bacteria, acidified infant formulas and fermented infant formulas as a potential cause of paediatric d-lactic acidosis., Methods: A Medline database search was performed in July 2017, with no restrictions on the language, article type or publication date. The 1715 search results were screened for clinical trials, review articles, case series and case reports of relevance to the topic., Results: We identified five randomised controlled trials from 2005 to 2017 covering 544 healthy infants and some case reports and experimental studies. No clinically relevant adverse effects of d-lactic acid-producing probiotics and fermented infant formulas were described in healthy children. However, a harmless, subclinical accumulation of d-lactate was theoretically possible. The only known cases of paediatric d-lactic acidosis occurred in patients with short bowel syndrome or, historically, in infants fed with acidified formulas., Conclusion: Our main finding was that probiotics and fermented formulas did not cause d-lactic acidosis in healthy children., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Excess or rapid weight gain during the first 2 years of life is associated with an increased risk of later childhood and adult overweight and obesity. When compared with breastfed infants, formula fed infants are more likely to experience excess or rapid weight gain, and this increased risk in formula fed infant populations may be due to a number of different mechanisms. These mechanisms include the nutrient composition of the formula and the way formula is prepared and provided to infants. This systematic literature review examines the association between formula feeding practice and excess or rapid weight gain. This review explores these different mechanisms and provides practical recommendations for best practice formula feeding to reduce rapid weight gain. Eighteen studies are included in this review. The findings are complicated by the challenges in study design and accuracy of measurements. Nevertheless, there are some potential recommendations for best practice formula feeding that may reduce excess or rapid weight gain, such as providing formula with lower protein content, not adding cereals into bottles, not putting a baby to bed with a bottle, and not overfeeding formula. Although further well designed studies are required before more firm recommendations can be made., (© 2018 John Wiley & Sons Ltd.)

Breastfeeding is recommended until 6 months of age, but a wide range of infant formula is available for nonbreastfed or partially breastfed infants. Our aim was to describe infant formula selection and to examine social- and health-related factors associated with this selection. Analyses were based on 13,291 infants from the French national birth cohort Etude Longitudinale Française depuis l'Enfance. Infant diet was assessed at Month 2 by phone interview and monthly from Months 3 to 10 via internet/paper questionnaires. Infant formulas were categorized in 6 groups: extensively or partially hydrolysed, regular with or without prebiotics/probiotics, and thickened with or without prebiotics/probiotics. Associations between type of infant formula used at 2 months and family or infant characteristics were assessed by multinomial logistic regressions. At Month 2, 58.1% of formula-fed infants were fed with formula enriched in prebiotics/probiotics, 31.5% with thickened formula, and 1.4% with extensively hydrolysed formula. The proportion of formula-fed infants increased regularly, but the type of infant formula used was fairly stable between 2 and 10 months. At Month 2, extensively hydrolysed formulas were more likely to be used in infants with diarrhoea or regurgitation problems. Partially hydrolysed formulas were more often used in families with high income, with a history of allergy, or with infants with regurgitation issues. Thickened formulas were used more with boys, preterm infants, infants with regurgitation issues, or in cases of early maternal return to work. The main factors related to the selection of infant formula were family and infant health-related ones., (© 2017 John Wiley & Sons Ltd.)

We investigated the long-term implications of infantile thiamine (vitamin B1) deficiency on motor function in preschoolers who had been fed during the first 2 years of life with a faulty milk substitute. In this retrospective cohort study, 39 children aged 5-6 years who had been exposed to a thiamine-deficient formula during infancy were compared with 30 age-matched healthy children with unremarkable infant nutritional history. The motor function of the participants was evaluated with The Movement Assessment Battery for Children (M-ABC) and the Zuk Assessment. Both evaluation tools revealed statistically significant differences between the exposed and unexposed groups for gross and fine motor development (p < .001, ball skills p = .01) and grapho-motor development (p = .004). The differences were especially noteworthy on M-ABC testing for balance control functioning (p < .001, OR 5.4; 95% CI 3.4-7.4) and fine motor skills (p < .001, OR 3.2; 95% CI 1.8-4.6). In the exposed group, both assessments concurred on the high rate of children exhibiting motor function difficulties in comparison to unexposed group (M-ABC: 56% vs. 10%, Zuk Assessment: 59% vs. 3%, p < .001). Thiamine deficiency in infancy has long-term implications on gross and fine motor function and balance skills in childhood, thiamine having a crucial role in normal motor development. The study emphasizes the importance of proper infant feeding and regulatory control of breast milk substitutes., (© 2017 John Wiley & Sons Ltd.)

Iodine is important for normal growth and psychomotor development. While infants below 6 months of age receive iodine from breast milk or fortified infant formula, the introduction of complementary foods poses a serious risk for deteriorating iodine status. This cross-sectional analysis assessed the iodine status of six-month-old South African infants and explored its associations with feeding practices and psychomotor milestone development. Iodine concentrations were measured in infant (n = 386) and maternal (n = 371) urine (urinary iodine concentration [UIC]), and in breast milk (n = 257 [breast milk iodine concentrations]). Feeding practices and psychomotor milestone development were assessed in all infants. The median (25th-75th percentile) UIC in infants was 345 (213-596) μg/L and was significantly lower in stunted (302 [195-504] μg/L) than non-stunted (366 [225-641] μg/L) infants. Only 6.7% of infants were deficient. Maternal UIC (128 [81-216] μg/L; r s  = 0.218, p < 0.001) and breast milk iodine concentrations (170 [110-270] μg/kg; r s  = 0.447, p < 0.0001) were associated with infant UIC. Most infants (72%) were breastfed and tended to have higher UIC than non-breastfed infants (p = 0.074). Almost all infants (95%) consumed semi-solid or solid foods, with commercial infant cereals (60%) and jarred infant foods (20%) being the most common solid foods first introduced. Infants who reported to consume commercial infant cereals ≥4 days weekly had significantly higher UIC (372 [225-637] μg/L) than those reported to consume commercial infant cereals seldom or never (308 [200-517] μg/L; p = 0.023). No associations between infant UIC and psychomotor developmental scores were observed. Our results suggest that iodine intake in the studied six-month-old infants was adequate. Iodine in breast milk and commercial infant cereals potentially contributed to this adequate intake., (© 2016 John Wiley & Sons Ltd.)

Exclusive breastfeeding for 6 months is recommended by the World Health Organisation (WHO) for optimal health and growth of infants, but it is not a common practice in South Africa. A breastfeeding counselling programme was run to inform, encourage and support mothers to exclusively breastfeed their infants for 6 months, and mother-infant pairs were invited to participate in a research project to determine breast milk intake volumes using the dose-to-mother deuterium dilution stable isotope technique. This technique yields objective measurements of breast milk intake volumes and also enables determination of exclusivity of breastfeeding, which is most frequently determined by maternal recall and can be subject to bias. Exclusivity of breastfeeding at 6 weeks, 3 months and 6 months following birth of the infants was correlated with infant fat-free mass at 12 months, which was determined by the dose-to-infant deuterium dilution stable isotope technique. Results showed that infants who were exclusively breastfed for 6 months had a higher per cent fat-free mass at 12 months compared with infants who were not exclusively breastfed for 6 months (P < 0.05). This objective determination of both breastfeeding patterns and infant body composition gives weight to the WHO recommendation of exclusive breastfeeding for 6 months as it demonstrated adequate fat-free mass in infants at 12 months, even in an area with high HIV prevalence. © 2016 John Wiley & Sons Ltd., (© 2016 John Wiley & Sons Ltd.)

Low nutritional value of complementary foods is associated with high incidence of childhood growth stunting in low-income countries. This study was done to test a hypothesis that dietary complementation with lipid-based nutrient supplements (LNS) promotes linear growth and reduces the incidence of severe stunting among at-risk infants. A total of 840 6-month-old healthy infants in rural Malawi were enrolled to a randomised assessor-blinded trial. The participants received 12-month supplementation with nothing, milk-LNS, soy-LNS, or corn-soy blend (CSB). Supplements provided micronutrients and approximately 280 kcal energy per day. Outcomes were incidence of severe and very severe stunting [length-for-age z-score, (LAZ) < -3.00 and <-3.50, respectively], and change in LAZ. The incidence of severe stunting was 11.8%, 8.2%, 9.1% and 15.5% (P = 0.098) and that of very severe stunting 7.4%, 2.9%, 8.0% and 6.4% (P = 0.138) in control, milk-LNS, soy-LNS and CSB groups, respectively. Between 9 and 12 months of age, the mean change in LAZ was -0.15, -0.02, -0.12 and -0.18 (P = 0.045) for control, milk-LNS, soy-LNS and CSB groups, respectively. There was no significant between-group difference in linear growth during other age-intervals. Although participants who received milk-LNS had the lowest incidence of severe and very severe stunting, the differences between the groups were smaller than expected. Thus, the results do not provide conclusive evidence on a causal association between the LNS supplementation and the lower incidence of stunting. Exploratory analyses suggest that provision of milk-LNS, but not soy-LNS promotes linear growth among at-risk infants mainly between 9 and 12 months of age., (© 2013 John Wiley & Sons Ltd.)

To prevent undernutrition in an urban slum in Haiti, a lipid-based nutrient supplement (LNS) was introduced through a randomised control trial. Food supplementation for young child nutrition has a long history in Haiti, but there is little empirical information regarding the effects of supplementation on young child feeding practices. One of the concerns raised by supplementation is that it may disrupt other positive feeding practices such as breastfeeding and use of other complementary foods, with negative consequences for child nutrition. We conducted 29 in-depth interviews with mother-baby pairs from the three comparison groups: control, 3-month LNS supplementation and 6-month LNS supplementation. Findings from those in the LNS groups indicated high acceptance and satisfaction with LNS and perceptions that it positively affects child health and development. LNS was integrated into and enhanced ongoing complementary feeding practices. The effects of LNS use on duration and perceived quantity of breastfeeding were variable, but generally, breastfeeding was maintained during and after the intervention. Interviews generated insights into beliefs regarding infant and young child feeding practices such as introduction and use of complementary foods, and breastfeeding duration, exclusivity and cessation. Implications for the use of LNS in public health nutrition programmes are discussed., (© 2014 John Wiley & Sons Ltd.)

Nutrition interventions have an effect on growth, energy and nutrient intake, and development, but there are mixed reports on the effect of supplementation of energy-dense foods on dietary intake. This substudy aimed at assessing the effect of supplementation with corn-soy blend (CSB) or lipid-based nutrient supplement (LNS) on energy and nutrient intake in moderately underweight children participating in a clinical trial. A total of 188 children aged 8-18 months participated and received daily either 284 kcal from CSB or 220 kcal from LNS and no supplements (control). An interactive 24-h recall method was used to estimate energy and nutrient intakes in the groups. Total mean energy intake was 548 kcal, 551 kcal and 692 kcal in the control, CSB and LNS groups, respectively (P = 0.011). The mean (95% confidence interval) intake of energy and protein were 144 (37-250; P < 0.001) and 46 (1.5-7.6; P < 0.001) larger, respectively, in the LNS group than among the controls. No significant differences were observed between the control and CSB groups. Energy intake from non-supplement foods was significantly lower in the CSB group compared with the control group, but not in the LNS group, suggesting a lower displacement of non-supplement foods with LNS. Both CSB and LNS supplementation resulted in higher intakes of calcium, iron, zinc and vitamin C compared with controls (all P ≤ 0.001). This study indicates that LNS might be superior to CSB to supplement underweight children as it results in higher energy intake, but this requires confirmation in other settings., (© 2014 John Wiley & Sons Ltd.)

Lipid-based nutrient supplements (LNS) can help treat undernutrition; however, the dietary adequacy of children supplemented with LNS, and household utilisation patterns are not well understood. We assessed diet adequacy and the quality of complementary foods by conducting a diet assessment of 128 Ugandan children, ages 6-59 months, who participated in a 10-week programme for children with moderate acute malnutrition (MAM, defined as weight-for-age z-score < -2). Caregivers were given a weekly ration of 650 kcal day(-1) (126 g day(-1) ) of a peanut/soy LNS. Two 24-h dietary recalls were administered per child. LNS was offered to 86% of targeted children at least once. Among non-breastfed children, over 90% met their estimated average requirement (EAR) cut-points for all examined nutrients. Over 90% of breastfed children met EAR cut-points for nutrient density for most nutrients, except for zinc where 11.7% met cut-points. A lower proportion of both breastfed and non-breastfed children met adjusted EARs for the specific nutritional needs of MAM. Fewer than 20% of breastfed children met EAR nutrient-density guidelines for MAM for zinc, vitamin C, vitamin A and folate. Underweight status, the presence of a father in the child's home, and higher programme attendance were all associated with greater odds of feeding LNS to targeted children. Children in this community-based supplemental feeding programme who received a locally produced LNS exhibited substantial micronutrient deficiencies given the special dietary needs of this population. These results can help inform programme strategies to improve LNS targeting, and highlight potential nutrient inadequacies for consumers of LNS in community-based settings., (© 2015 John Wiley & Sons Ltd.)

The International Lipid-Based Nutrient Supplements (iLiNS) Project began in 2009 with the goal of contributing to the evidence base regarding the potential of lipid-based nutrient supplements (LNS) to prevent undernutrition in vulnerable populations. The first project objective was the development of acceptable LNS products for infants 6-24 months and for pregnant and lactating women, for use in studies in three countries (Burkina Faso, Ghana and Malawi). This paper shares the rationale for a series of decisions in supplement formulation and design, including those related to ration size, ingredients, nutrient content, safety and quality, and packaging. Most iLiNS supplements have a daily ration size of 20 g and are intended for home fortification of local diets. For infants, this ration size is designed to avoid displacement of breast milk and to allow for dietary diversity including any locally available and accessible nutrient-dense foods. Selection of ingredients depends on acceptability of flavour, micronutrient, anti-nutrient and essential fatty acid contents. The nutrient content of LNS designed to prevent undernutrition reflects the likelihood that in many resource-poor settings, diets of the most nutritionally vulnerable individuals (infants, young children, and pregnant and lactating women) are likely to be deficient in multiple micronutrients and, possibly, in essential fatty acids. During ingredient procurement and LNS production, safety and quality control procedures are required to prevent contamination with toxins or pathogens and to ensure that the product remains stable and palatable over time. Packaging design decisions must include consideration of product protection, stability, convenience and portion control., (© 2013 John Wiley & Sons Ltd.)

Malnutrition in children under 5 years of age is pervasive in Ethiopia across all wealth quintiles. The objective of this study was to determine the willingness to pay (WTP) for a week's supply of Nutributter® (a lipid-based nutrient supplement, or LNS) through typical urban Ethiopian retail channels. In February, 2012, 128 respondents from 108 households with 6-24-month-old children had the opportunity to sample Nutributter® for 2 days in their homes as a complementary food. Respondents were asked directly and indirectly what they were willing to pay for the product, and then participated in market simulation where they could demonstrate their WTP through an exchange of real money for real product. Nearly all (96%) of the respondents had a positive WTP, and 25% were willing to pay the equivalent of at least $1.05, which we calculated as the likely minimum, unsubsidised Ethiopian retail price of Nutributter® for 1 week for one child. Respondents willing to pay at least $1.05 included urban men and women with children 6-24 months old from low-, middle- and high-wealth groups from four study sites across three cities. Additionally, we estimated the initial annual market size for Nutributter® in the cities where the study took place to be around $500 000. The study has important implications for retail distribution of LNS in Ethiopia, showing who the most likely customers could be, and also suggesting why the initial market may be too small to be of interest to food manufacturers seeking profit maximisation., (© 2012 Blackwell Publishing Ltd.)

Community-based Management of Acute Malnutrition using ready-to-use therapeutic food (RUTF) has revolutionised the treatment of severe acute malnutrition (SAM). However, 25% milk content in standard peanut-based RUTF (P-RUTF) makes it too expensive. The effectiveness of milk-free RUTF has not been reported hitherto. This non-blinded, parallel group, cluster randomised, controlled, equivalence trial that compares the effectiveness of a milk-free soy-maize-sorghum-based RUTF (SMS-RUTF) with P-RUTF in treatment of children with SAM, closes the gap. A statistician randomly assigned health centres (HC) either to the SMS-RUTF (n = 12; 824 enrolled) or P-RUTF (n = 12; 1103 enrolled) arms. All SAM children admitted at the participating HCs were enrolled. All the outcomes were measured at individual level. Recovery rate was the primary outcome. The recovery rates for SMS-RUTF and P-RUTF were 53.3% and 60.8% for the intention-to-treat (ITT) analysis and 77.9% and 81.8% for per protocol (PP) analyses, respectively. The corresponding adjusted risk difference (ARD) and 95% confidence interval, were -7.6% (-14.9, 0.6%) and -3.5% (-9,6., 2.7%) for ITT (P = 0.034) and PP analyses (P = 0.257), respectively. An unanticipated interaction (interaction P < 0.001 for ITT analyses and 0.0683 for PP analyses) between the study arm and age group was observed. The ARDs were -10.0 (-17.7 to -2.3)% for ITT (P = 0.013) and -4.7 (-10.0 to 0.7) for PP (P = 0.083) analyses for the <24 months age group and 2.1 (-10.3,14.6)% for ITT (P = 0.726) and -0.6 (-16.1, 14.5) for PP (P = 0.939) for the ≥24 months age group. In conclusion, the study did not confirm our hypothesis of equivalence between SMS-RUTF and P-RUTF in SAM management., (© 2013 John Wiley & Sons Ltd.)

Inadequate energy intake and poor diet quality are important causes of chronic child undernutrition. Strategies for improving diet quality using lipid-based nutrient supplements (LNS) are currently being tested in several countries. To date, information on children's dietary intakes during LNS use is available only from Africa. In this study, we collected 24-h dietary recalls at baseline, 3, 6, 9 and 12 months on Honduran children (n = 298) participating in a cluster-randomised trial of LNS. Generalised estimating equations were used to examine differences in number of servings of 12 food groups in the LNS and control arms, and multi-level mixed effects models were used to compare macro- and micronutrient intakes. Models accounted for clustering and adjusted for child's age, season and breastfeeding status. Mean daily servings of 12 food groups did not differ by study arm at baseline and remained similar throughout the study with the exception of groups that were partially or entirely supplied by LNS (nuts and nut butters, fats, and sweets). Baseline intakes of energy, fat, carbohydrates, protein, folate and vitamin A, but not vitamin B12, iron and zinc were lower in the LNS than control arm. The change in all macro- and micronutrients from baseline to each study visit was larger for the LNS arm than the control, except for carbohydrates from baseline to 9 months. These findings indicate that LNS improved the macro- and micronutrient intakes of young non-malnourished Honduran children without replacing other foods in their diet., (© 2015 John Wiley & Sons Ltd.)

Recently, there has been considerable debate regarding the appropriate amount of iron fortification for commercial infant formula. Globally, there is considerable variation in formula iron content, from 4 to 12 mg iron/L. However, how much fortification is necessary is unclear. Human milk is low in iron (0.2-0.5 mg/L), with the majority of infant iron stores accumulated during gestation. Over the first few months of life, these stores are depleted in breastfeeding infants. This decline has been previously largely perceived as pathological; it may be instead an adaptive mechanism to minimize iron availability to pathogens coinciding with complementary feeding. Many of the pathogens involved in infantile illnesses require iron for growth and replication. By reducing infant iron stores at the onset of complementary feeding, infant physiology may limit its availability to these pathogens, decreasing frequency and severity of infection. This adaptive strategy for iron regulation during development is undermined by the excess dietary iron commonly found in infant formula, both the iron that can be incorporated into the body and the excess iron that will be excreted in feces. Some of this excess iron may promote the growth of pathogenic, iron requiring bacteria disrupting synergistic microflora commonly found in breastfed infants. Evolutionarily, mothers who produced milk with less iron and infants who had decreased iron stores at the time of weaning may have been more likely to survive the transition to solid foods by having limited iron available for pathogens. Contemporary fortification practices may undermine these adaptive mechanisms and increase infant illness risk., (Copyright © 2013 Wiley Periodicals, Inc.)

The aim of this study was to determine the concentrations of alpha- and gamma-tocopherols in human breast milk samples from different periods of lactation and to compare them with tocopherol content in commercially available formulas for infants at corresponding ages. The study included 93 breast milk samples obtained on the 2nd (colostrum, n = 17), 14th (n = 30), 30th (n = 27) and 90th day of lactation (n = 19), along with 90 samples of commercially available initial and follow-on infant formulas. Concentrations of tocopherols were determined using normal-phase high-performance liquid chromatography. Depending on the stage of lactation, human breast milk contained 2.07-9.99 mg L⁻¹ of alpha-tocopherol and 0.22-0.60 mg L⁻¹ of gamma-tocopherol. Breast milk concentrations of alpha-tocopherol decreased with the time of lactation, while significant differences in gamma-tocopherol concentration were observed only between the 14th and 30th day of lactation. There was no significant correlation between the dietary intake of vitamin E and its estimated breast milk concentration, also in women who declared vitamin supplementation. Compared with colostrum, infant formulas were characterised by significantly lower concentrations of alpha-tocopherol and vitamin E. This finding indicates the need of additional vitamin E supplementation of bottle-fed infants during the initial 2-3 days of life., (© 2012 John Wiley & Sons Ltd.)

Objectives: Human biologists have documented variability in reproductive maturation, fertility, and cancer risk related to developmental conditions. Yet no previous studies have directly examined the impact of prenatal and postnatal energetic environments on sex steroids in infancy, a critical period for hypothalamic-pituitary-gonadal axis development. Thus, we examined the impact of maternal characteristics, birth size, and feeding practices on fecal sex steroid production in a longitudinal sample of 31 American infants followed from 2 weeks to 12 months of age., Methods: Maternal characteristics and birth size were collected at study enrollment, infant diet was assessed through weekly 24-h food diaries, and anthropometrics were measured weekly. Fecal estradiol and testosterone levels were assessed weekly using validated microassay RIA techniques. Mixed models were used to test for associations between maternal and birth characteristics, feeding practices, and sex steroids across the first year of life. Formal mediation analysis examined whether the relationship between infant feeding and hormone levels was mediated by infant size., Results: Maternal and birth characteristics had persistent effects on fecal sex steroid levels, with taller maternal height and larger birth size associated with lower estradiol levels in girls and higher testosterone levels in boys. Infant diet was also associated with sex steroid levels independently of infant size. Formula feeding was associated with higher estradiol levels in boys and girls and with higher testosterone in girls., Conclusion: These results suggest that markers of early energy availability influence sex hormone levels with potential long-term consequences for reproductive development and function., (Copyright © 2013 Wiley Periodicals, Inc.)

Fatty acid concentrations in blood are potential biomarkers of dietary fat intake, but methodological studies among children are scarce. The large number of fatty acids and their complex interrelationships pose a special challenge in research on fatty acids. Our target was to assess the interrelationships between the total fatty acid profiles in diet and serum of young children. The study subjects were healthy control children from the birth cohort of the Type 1 Diabetes Prediction and Prevention Study. A 3-day food record and a frozen serum sample were available from 135 children at the age of 1 year, from 133 at 2 years, and from 92 at 3 years. The relationship between dietary and serum fatty acid profiles was analysed using canonical correlation analysis. The consumption of fatty milk correlated positively with serum fatty acids, pentadecanoic acid, palmitic acid and conjugated linoleic acid (CLA) at all ages. Correlations between dietary and serum eicosapentaenoic and/or docosahexaenoic acid were observed at 2 and 3 years of age. Serum linoleic acid was positively associated with the consumption of infant formula at the age of 1 year, and with the consumption of vegetable margarine at 2 and 3 years. The results indicate a high quality of the 3-day food records kept by parents and other caretakers of the children, and suitability of non-fasting, un-fractioned serum samples for total fatty acid analyses. The correlation between intake of milk fat and serum proportion of CLA is a novel finding., (© 2011 John Wiley & Sons Ltd.)

The aim of this study was to examine infant feeding and the long-chain polyunsaturated fatty acid (LCPUFA) concentration of breast milk and formulas in relation to infant development. The prospective Pregnancy, Infection and Nutrition Study (n=358) collected data on breastfeeding, breast milk samples and the formulas fed through 4months post-partum. At 12months of age, infants' development was assessed (Mullen Scales of Early Learning). Linear regression was used to examine development in relation to breastfeeding, breast milk docosahexaenoic acid (DHA) and arachidonic acid (AA) concentration, and DHA and AA concentration from the combination of breast milk and formula. The median breast milk DHA concentration was 0.20% of total fatty acids [interquartile range (IQR)=0.14, 0.34]; median AA concentration was 0.52% (IQR=0.44, 0.63). Upon adjustment for preterm birth, sex, smoking, race and ethnicity and education, breastfeeding exclusivity was unrelated to development. Among infants exclusively breastfed, breast milk LCPUFA concentration was not associated with development (Mullen composite, DHA: adjusted β=-1.3, 95% confidence interval: -10.3, 7.7). Variables combining DHA and AA concentrations from breast milk and formula, weighted by their contribution to diet, were unassociated with development. We found no evidence of enhanced infant development related to the LCPUFA content of breast milk or formula consumed during the first four post-natal months., (© 2011 Blackwell Publishing Ltd.)

This study aimed to produce a polyclonal antibody against Cronobacter muytjensii (C. muytjensii, formerly called Enterobacter sakazakii) and to develop an immunoassay for its detection. The optimum production of rabbit anti-C. muytjensii immunoglobulin G (IgG) and chicken anti-C. muytjensii IgY was reached in weeks 8 and 9, respectively. Purification of rabbit anti-C. muytjensii IgG from immunized rabbit sera was accomplished using the caprylic acid and ammonium sulfate precipitation method. As a result, sodium dodecyl sulfate-polyacrylamide gel electrophoresis produced two bands around 25 and 50 kDa, corresponding to a light and a heavy chain, respectively. The optimized conditions for sandwich enzyme-linked immunosorbent assay were using rabbit anti-C. muytjensii IgG (1 μg/mL) as a detection antibody and chicken anti-C. muytjensii IgY (10 μg/mL) as a capture antibody. In this assay, no cross-reactivity was observed with the other genera of pathogenic bacteria tested, which included Escherichia coli O157:H7, Salmonella typhimurium, Staphylococcus aureus, Bacillus cereus and Listeria monocytogenes. The developed assay did not show cross-reactivity with other tested species of Cronobacter and Enterobacter genera such as C. turicensis, C. sakazakii, E. aerogenes, E. pulveris and E. helveticus. The detection limit of sandwich ELISA for C. muytjensii was found to be 2.0 × 10(4) colony forming units (CFU)/mL. In addition, detection of C. muytjensii in infant formula powder showed a low matrix effect on the detection curve of sandwich ELISA for C. muytjensii, the detection limit being found to be 6.3 × 10(4) CFU/mL. These findings demonstrate that the developed method is able to detect all strains of C. muytjensii. Hence, this ELISA technique has potent application for the rapid and accurate detection of C. muytjensii in dietary foods., (© 2012 The Societies and Blackwell Publishing Asia Pty Ltd.)

Expressing human milk has become a more common alternative for mothers, as the average work demand has increased. As more mothers must work, bottle feeding trends are increasingly common. The handling and storage of human milk introduce the risk of degradation to expressed human milk and infant formula. In following a 20-minute simulated feeding, Vitamin C has been found to degrade. Vitamin C acts as an anti-oxidant and is responsible for shielding other nutrients from oxidation, such as retinol and alpha-tocopherol. By analyzing a 20-minute simulated feeding, retinol and alpha-tocopherol each displayed decreases over time significantly different than that of the Control, which was milk not exposed to bottle feeding. In human milk, retinol showed as high as a 9.5% decrease compared to the Control. Similar trends were seen with the infant formula samples. The correlation between degradation and bottle feeding systems was dependent upon the formation of bubbles in the milk as the milk was removed from the bottle. The analysis indicated a decrease of up to 12%, as seen in retinol, and 35%, as seen in alpha-tocopherol. These decreases in retinol and alpha-tocopherol should be considered when using a bottle feeding system to deliver either human milk or formula to an infant. More research is necessary to determine the effect of this decrease on the nutritional status of infants, particularly premature infants, who are at higher risk for nutrient deficiencies., (© 2010 Blackwell Publishing Ltd.)

Background: Prebiotic galacto- and fructo-oligosaccharides (scGOS/lcFOS) resembling non-digestible oligosaccharides in human milk reduce the development of atopic disorders. However, the underlying mechanisms are still unclear. Galectins are soluble-type lectins recognizing β-galactoside containing glycans. Galectin-9 has been shown to regulate mast cell degranulation and T-cell differentiation. In this study, the involvement of galectin-9 as a mechanism by which scGOS/lcFOS in combination with Bifidobacterium breve M-16V protects against acute allergic symptoms was investigated., Methods: Mice were sensitized orally to whey, while being fed with a diet containing scGOS/lcFOS and Bifidobacterium breve M-16V (GF/Bb) or a control diet. Galectin-9 expression was determined by immunohistochemistry in the intestine and measured in the serum by ELISA. T-cell differentiation was investigated in the mesenteric lymph nodes (MLN) as well as in galectin-9-exposed peripheral blood mononuclear cells (PBMC) cultures. Sera of the mice were evaluated for the capacity to suppress mast cell degranulation using a RBL-2H3 degranulation assay. In addition, in a double-blind, placebo-controlled multicenter trial, galectin-9 levels were measured in the sera of 90 infants with atopic dermatitis who received hydrolyzed formulae with or without GF/Bb., Results: Galectin-9 expression by intestinal epithelial cells and serum galectin-9 levels were increased in mice and humans following dietary intervention with GF/Bb and correlated with reduced acute allergic skin reaction and mast cell degranulation. In addition, GF/Bb enhanced T(h)1- and T(reg)-cell differentiation in MLN and in PBMC cultures exposed to galectin-9., Conclusions: Dietary supplementation with GF/Bb enhances serum galectin-9 levels, which associates with the prevention of allergic symptoms., (© 2012 John Wiley & Sons A/S.)

Aim: To determine the effect of neutral oligosaccharides [small-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides (scGOS/lcFOS)] in combination with acidic oligosaccharides (pAOS) on stool viscosity, stool frequency and stool pH in preterm infants., Methods: In this explorative RCT, preterm infants with gestational age <32 weeks and/or birth weight <1500 g received enteral supplementation with scGOS/lcFOS/pAOS or placebo (maltodextrin) between days 3 and 30 of life. Stool samples were collected at day 30 after birth., Results: In total, 113 infants were included. Baseline and nutritional characteristics were not different between both groups. Stool viscosity at day 30 was lower in the prebiotics group (16.8N) (3.9-67.8) compared with the placebo group (26.3N) (1.3-148.0) (p = 0.03; 95% CI -0.80 to 0.03). There was a trend towards higher stool frequency in the prebiotics group (3.1 ± 0.8) compared with the placebo group (2.8 ± 0.7) (p = 0.15; 95% CI -0.08 to 0.52). Stool pH at day 30 was lower in the in the prebiotics group (5.9 ± 0.6) compared with the placebo group (6.2 ± 0.3) (p = 0.009; 95% CI 0.08 to 0.53)., Conclusions: Enteral supplementation of a prebiotic mixture consisting of neutral (scGOS/lcFOS) and acidic oligosaccharides (pAOS) decreases stool viscosity and stool pH with a trend towards increased stool frequency in preterm infants. The inclusion of pAOS in a formula containing a mixture of scGOS/lcFOS does not add specific advantages to the formula in terms of stool viscosity, frequency, pH as well as feeding tolerance., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

Aim: The international Trial to Reduce IDDM in the Genetically at Risk (TRIGR) was launched to determine whether weaning to a highly hydrolysed formula in infancy reduces the incidence of type 1 diabetes in children at increased genetic disease susceptibility. We describe here the findings on feasibility and compliance from the pilot study., Methods: The protocol was tested in 240 children. The diet of the participating children was assessed by self-administered dietary forms, a structured questionnaire and a food record. Blood samples were taken and weight and height measured at birth and at 3, 6, 9, 12, 18 and 24 months., Results: A majority of the subjects (84%) were exposed to the study formula at least for 2 months. Linear growth or weight gain over the first 2 years of life was similar in the two study groups. The levels of IgA and IgG antibodies to cow's milk and casein were higher in the cow's milk-based formula group than in the hydrolysed formula group during the intervention period (p<0.05), reflecting the difference in the intake of cow's milk protein., Conclusion: This randomized trial on infant feeding turned out to be feasible, and dietary compliance was acceptable. Valuable experience was gained for the planning and sample size estimation of the study proper., (© 2010 The Author(s)/Acta Paediatrica © 2010 Foundation Acta Paediatrica.)

In this observational study, we compared erythrocyte membrane fatty acids in infants consuming formula supplemented with docosahexaenoic acid (DHA) and arachidonic acid (ARA) with those consuming other types of milks. In 110 infants who were participants in a cohort study of otherwise healthy children at risk for developing type 1 diabetes, erythrocytes were collected at approximately 9 months of age, and fatty acid content was measured as a percentage of total lipids. Parents reported the type of milk the infants consumed in the month of and prior to erythrocyte collection: infant formula supplemented with ARA and DHA (supplemented formula), formula with no ARA and DHA supplements (non-supplemented formula), breast milk, or non-supplemented formula plus breast milk. Membrane DHA (4.42 versus 1.79, P < 0.001) and omega-3 fatty acid (5.81 versus 3.43, P < 0.001) levels were higher in infants consuming supplemented versus non-supplemented formula. Omega-6 fatty acids were lower in infants consuming supplemented versus non-supplemented formula (26.32 versus 29.68, P = 0.023); ARA did not differ between groups. Infants given supplemented formula had higher DHA (4.42 versus 2.81, P < 0.001) and omega-3 fatty acids (5.81 versus 4.45, P = 0.008) than infants drinking breast milk. In infants whose mothers did not receive any dietary advice, use of supplemented formula is associated with higher omega-3 and lower omega-6 fatty acid status., (© 2010 Blackwell Publishing Ltd.)

Weaning formulas served in hospitals and care facilities in Japan should conform to dietary reference intakes (DRIs). We examined whether the DRI for breastfed infants aged 6-11 months can be satisfied in dietary practice, with a particular focus on the fulfilment rates for vitamins, minerals, trace elements and electrolytes in weaning formulas containing energy and protein at levels either greater than or equal to the DRIs, as well as on the dietary profiles of weaning formulas to achieve the DRI for every nutrient. The results showed that no weaning formulas examined in this study fulfilled the DRI for pantothenic acid (5 mg), vitamin D (4 microg), manganese (1.2 mg) or iron (5.5 mg). Furthermore, their vitamin A content exceeded the DRI (350 microg RE). The discrepancy between the guidelines and actual dietary practice is probably because of the fact that the estimated reference values poorly reflect the actual dietary intake in the target population; for example, the pantothenic acid and manganese DRIs for breastfed infants aged 6-11 months were set based on the breast milk intake of younger infants (0-5 months) in combination with the breast milk contents. Our results suggest that dietary guidance for infants should include information to promote proper intakes of vitamins A and D, and iron by reducing the amount of vitamin A-rich foods and utilizing dietary vitamin D and iron supplements including government-approved specified health foods.

The relationship between infant feeding patterns and the later development of food allergies has been the focus of much debate and research over the last decade. National recommendations have been made by many countries on how to feed infants to reduce the risk of food allergy but due to the lack of firm evidence the recommendations differ widely. This review has been developed as part of EuroPrevall, a European multicentre research project funded by the European Union, to document the differing feeding recommendations made across Europe, to investigate the current evidence base for any allergy prevention feeding recommendations and to identify areas where further research is needed. This review will also provide information which, when combined with the infant feeding data collected as part of EuroPrevall, will give an indication of compliance to national feeding guidelines which can be utilised to assess the effectiveness of current dissemination and implementation strategies.

Background: Breast milk oligosaccharides such as galacto-oligosaccharides (scGOS) and fructo-oligosaccharides (lcFOS) can influence the intestinal microbial flora. The latter, in turn, can modulate several intestinal and extraintestinal functions, including bilirubin metabolism. Supplementing infant formula with a prebiotic mixture might then be a novel and safe intervention to manage mild neonatal hyperbilirubinaemia., Aim: To investigate the effect of dietary supplementation with prebiotics on moderate hyperbilirubinaemia in healthy, term infants., Methods: A prospective, double-blind, clinical trial was performed on seventy-six consecutive newborns who were randomly assigned to receive a formula containing 0.8 g/dL of a mixture from scGOS and lcFOS (ratio 9:1), or maltodextrines as placebo for 28 days. Bilirubin levels were determined by the transcutaneous bilirubin measurement within 2 h after birth (T1), at 24, 48 and 72 h and at 5, 7, 10 and 28 days of life. The number of stool per day was also recorded., Results: Neonates receiving prebiotics showed a larger number of stools over all the duration of dietary intervention compared to that of those on placebo (Repeated Measures ANOVA p < 0.001; day 28 3.4 +/- 0.0.9 vs 1.7 +/- 0.9, respectively; Dunn test p < 0.05). Neonates whose formula was supplemented with prebiotics showed a lower transcutaneous bilirubin that was statistically significant from 72 h of life (5.46 +/- 1.6 vs 7.07 +/- 2.49, post hoc Dunn test, p < 0.05) throughout the duration of the dietary intervention (day 28 2.41 +/- 0.4 vs 2.85 +/- 0.5, post hoc Dunn test, p < 0.05)., Conclusion: The addition of prebiotics to standard infant diet might represent a novel strategy to help control neonatal hyperbilirubinaemia.

Background: It has been suggested that human breast milk oligosaccharides play a role in the development of the immune system in infants, and may consequently inhibit the onset of allergy. A specific prebiotic mixture of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (GOS/FOS) has been shown to reduce the incidence of atopic dermatitis (AD) at 6 months of age in infants at risk for allergy., Aim of the Study: This study was aimed to analyze the effect of GOS/FOS on the immune response in these infants., Methods: In a double-blind randomized placebo-controlled study, infants received a hypoallergenic whey formula with either 8 g/l GOS/FOS in a 9 : 1 ratio (IMMUNOFORTIS) or 8 g/l maltodextrine (placebo) for 6 months. At 3 months of age, children were vaccinated with Hexavac against a.o. diphteria, tetanus, polio (DTP). At 6 months of age, plasma samples were collected from 84 infants (verum group n = 41, placebo group n = 43). Levels of total immunoglobulins (Ig) and of cow's milk protein (CMP-) and DTP-specific Ig were measured., Results: GOS/FOS supplementation led to a significant reduction in the plasma level of total IgE, IgG1, IgG2 and IgG3, whereas no effect on IgG4 was observed. CMP-specific IgG1 was significantly decreased. DTP-specific Ig levels were not affected., Conclusions: This study shows that GOS/FOS supplementation induces a beneficial antibody profile. GOS/FOS reduces the total Ig response and modulates the immune response towards CMP, while leaving the response to vaccination intact. This suggests that oral GOS/FOS supplementation is a safe method to restrain the atopic march.

Increasing concern has been recently raised on the possible effects of soy-derived phyto-oestrogens on the development of cognitive functions in infants. However, limited studies have been conducted to date, and no data have been made available for determining whether infant soy formula can affect normal development of the human brain. We compared electroencephalographic (EEG) spectral power derived from high-density recordings of infants fed milk-based or soy formula (46 fed milk-based formula and 39 fed soy formula) at 3 and 6 months of age. The spectral parameters included absolute power, relative power and spectral edge frequency (SEF) at 85%, 90% and 95% levels. The frequency domain contained four bands (0.1-3, 3-6, 6-9 and 9-12 Hz). EEG signals were collected from eight brain areas in each hemisphere. The results showed that the highest spectral power was mainly distributed in the low-frequency bands and was predominant in the frontal and anterior temporal areas. None of the spectral variables significantly differed between the soy- and milk-fed infants (anova, all P > 0.2). However, significant effects were indicated on the SEFs for factors of sex, age and brain area (all P < 0.01). Hemispheric differences in the absolute and relative power were also indicated. Our results suggest that the EEG power spectral development of soy-fed infants does not differ from that of infants fed milk-based formula. In addition, EEG spectral development appears more advanced in female than in male infants at 6 months.

Carbon ((13)C/(12)C) and nitrogen ((15)N/(14)N) stable isotope ratios were longitudinally measured in fingernail and hair samples from mother-infant pairs where infants were exclusively breastfed (n = 5), breast- and formula-fed (n = 2), or exclusively formula-fed (n = 1) from birth. All exclusively breastfed infants had a dual enrichment in carbon ( approximately 1 per thousand) and nitrogen ( approximately 2-3 per thousand) when compared to maternal values. In contrast, breast- and formula-fed subjects had reduced enrichments compared to exclusively breastfed subjects, and the exclusively formula-fed infant showed no increase in delta(13)C or delta(15)N values. This finding of a carbon trophic level effect in breastfeeding infants suggests that (13)C-enrichments of approximately 1 per thousand in archaeological populations are not necessarily the result of the consumption of C(4)-based weaning foods such as maize or millet. During the weaning process, the delta(13)C results for breastfed infants declined to maternal levels more rapidly than the delta(15)N results. This suggests that delta(13)C values have the potential to track the introduction of solid foods into the diet, whereas delta(15)N values monitor the length of time of breast milk consumption. These findings can be used to refine the isotopic analysis of breastfeeding and weaning patterns in past and modern populations.

Aim: Protein hydrolysates have been introduced in preterm formulae, but it is not clear whether they are needed for the feeding of preterm infants. We designed a randomized, controlled trial to test the effects of a preterm formula with hydrolysed cow's milk proteins on short-term growth and urinary and plasma amino acids levels., Methods: Infants with a birthweight < or = 1750 g and gestational age < or = 34 wk fed a conventional preterm infant formula (formula B) or a hydrolysed formula (formula A). Weight was measured daily; length, head circumference, mid-arm circumference and total skinfold thickness were measured weekly. Blood and urine were analysed for amino acid concentrations at start, 14 and 28 d., Results: Twenty-one infants met the criteria for randomization. The daily feeding volumes were: formula A 172.8 +/- 5.6 vs formula B 170.1 +/- 2.8 ml/kg/d. Infants fed with formula A showed slower weight gain (17.4 +/- 3.4 vs 20.5 +/- 3.3 g/kg/d; p = 0.045) and lower mean change in Z-scores for weight (-0.18 +/- 0.16 vs 0.00 +/- 0.09; p = 0.009) and for head circumference (-0.06 +/- 0.13 vs 0.06 +/- 0.13; p = 0.049). After 14 d, infants receiving formula A had statistically significant higher urinary levels of essential amino acids compared to infants receiving formula B., Conclusion: Our results support the hypothesis of less nutritional value of hydrolysed versus conventional preterm formulae. Higher renal excretion of essential amino acids may be one of the mechanisms involved. These findings must be confirmed by further studies with larger sample sizes and protein hydrolysates with different degrees of hydrolysis.

Unlabelled: The use of hydrolysed cow's milk formula seems to increase beyond what is recommended based on evidence regarding allergy-preventive effect. Infants born preterm are sometimes given such formulas without proven effect., Conclusion: If the use of hydrolysed cow's milk formula is based on allergy-preventive aspects, evidence-based recommendations should be followed.

Aim: A randomized, double-blind study was conducted to evaluate whether use of protein hydrolysate-based preterm formulas in infants with an atopic predisposition helps prevent the development of allergic diseases., Methods: Preterm infants (n = 122) with at least one first-degree relative (parent or sibling) with allergic disease were randomly assigned to receive an extensively or partially hydrolysed preterm formula (intervention groups) or a standard preterm formula until 4 to 5 mo of age. Infants whose parents preferred that they be breastfed received their mothers' fortified breast milk., Results: Intention-to-treat analysis showed that the overall incidence of allergic diseases did not significantly differ between groups at both 4-5 and 12 mo of age. However, by 12 mo, use of the extensively hydrolysed versus the standard preterm formula had significantly reduced the risk of atopic dermatitis. At 4-5 and 12 mo, there was a significantly increased risk of non-acceptance of the extensively hydrolysed formula compared with the other formulas., Conclusions: This study failed to show that extensively or partially hydrolysed preterm formulas in comparison with a standard preterm formula reduced the overall incidence of allergic diseases in infants at high risk for atopic disease. However, use of the extensively hydrolysed compared with a standard preterm formula significantly reduced the incidence of atopic dermatitis observed at 12 mo. Infants who received extensively hydrolysed formulas were at increased risk for intervention discontinuation for any reason, particularly non-acceptance of the formula. Because of the small number of patients eligible for this analysis, these results should be interpreted with caution.

Hypoallergenic formulas are processed by enzymatic hydrolysis of different protein sources such as bovine casein/whey and soy followed by further processing such as heat treatment and/or ultrafiltration, or they are based on amino acid mixtures. The products have been classified according to the degree of protein hydrolysis as 'extensively' or 'partially' hydrolysed protein products. Product properties may be characterized by biochemical techniques, and reduction of allergenicity may be assessed in vitro with various immunological methods, and in vivo with skin prick tests, patch tests and challenge tests. In vitro tests do not predict the allergenic effects in humans, and at present there is no evidence of a specific threshold of immunogenic protein. Only pure amino acid mixtures are considered to be nonallergenic. Other 'hypoallergenic' products contain residual allergenicity. At present, the potential of a product for treatment and prevention of food allergy can only be determined by clinical trials using scientifically appropriate standards. It has been recommended that dietary products for treatment of cow's milk protein allergy in infants should be tolerated by at least 90% (with 95% confidence) of infants with documented cow's milk protein allergy. Some extensively hydrolysed products and amino-acid-based products have met these criteria. Formulas intended for prevention should have a very low, if any, allergenic activity until otherwise proven. So far there are no firm criteria available for the design of hypoallergenic foods for prevention. Newborns included in prevention studies should be from high-risk families; they should be randomized at birth and fed the formula when supplements are needed for at least the first 4-6 months of life. Follow-up should be at least 18 months, and children should be investigated when symptoms appear. Validated clinical criteria, including controlled food challenges, should be used for diagnosis. Infants fed formulas that claim to prevent or delay allergy should have a statistically significant lower prevalence of allergy when compared with infants fed a standard cow's milk formula. Feeding high-risk infants a documented hypoallergenic formula combined with avoidance of solid foods during the first 4-6 months reduces the cumulative incidence of cow's milk protein allergy and atopic dermatitis as compared with a standard cow's-milk-based formula. Partially hydrolysed formulas may have an effect, though it seems to be less than that of extensively hydrolysed formulas at present. Thus, if exclusive breast-feeding for 4-6 months is not possible in high-risk infants, a documented hypoallergenic formula and avoidance of solid foods are recommended for the first 4 months of life., (Copyright 2004 Blackwell Munksgaard)