Our aim was to assess the nutritional safety and suitability of an infant formula manufactured from extensively hydrolyzed protein in comparison to infant formula manufactured from intact protein (both with low and standard protein content). We performed a combined analysis of raw data from two randomized infant feeding studies. An analysis of covariance (ANCOVA) model was used to determine the non-inferiority of daily weight gain (primary outcome; margin -3 g/day), with the intervention group as a fixed factor and geographic region, sex, and baseline weight as covariates (main model). The data of 346 infants exposed to the formula were included in the analysis. The sample size of the per-protocol analysis with 184 infants was too small to achieve sufficient statistical power. The lower limit of the 97.5% confidence interval (-0.807) of the mean group difference in daily weight gain (i.e., 2.22 g/day) was above the -3 g/day margin (full analysis set). Further anthropometric parameters did not differ between the infant formula groups throughout the study. Growth was comparable to breastfed infants. We conclude that the infant formula manufactured from extensively hydrolyzed protein meets infant requirements for adequate growth and does not raise any safety concerns.

In the past two decades, there has been a growing recognition of the need to establish indigenous standards or reference growth charts, particularly following the WHO multicenter growth study in 2006. The availability of accurate and reliable growth charts is crucial for monitoring child health. The choice of an appropriate model for constructing growth charts depends on various data characteristics, including the distribution\'s tails and peak. While Pakistan has reported some reference growth charts, there is a notable absence of indigenous charts for children under two years of age, especially for infants aged 0-6 months who are exclusively breastfed. Additionally, acquiring data poses a significant challenge, particularly for low-income countries, as it demands substantial resources such as finances, time, and expertise. The Multiple Indicator Cluster Survey (MICS) constitutes a large-scale national survey conducted periodically in low-income countries under the auspices of UNICEF. In this study, we propose methods for generating selection variables utilizing the \"Novel Case Selection Method,\" as previously published. Further our approach enables to select and fit appropriate model to the MICS data, selected, and to develop the standard growth charts.
Out of the 11,478 children under 6 months of age included in MICS-6 (Pakistan), 3,655 children (1,831 males and 1,824 females) met the specified criteria and were selected using the \"Novel Case Selection Method\". The sample was distributed across provinces as follows: 841 (23.0%) from KPK, 1,464 (40.1%) from Punjab, 819 (22.4%) from Sindh, and 531 (14.5%) from Balochistan. This sample encompassed both rural (76.4%) and urban (23.6%) populations. Following data cleaning and outlier removal, a total of 3,540 records for weight (1,768 males and 1,772 females) and 3,515 records for height (1,759 males and 1,756 females) were ultimately available for the development of standard charts. The Bayesian Information Criterion (BIC) was employed to determine the optimal degrees of freedom for L, M, and S using RefCurv_0.4.2. Three families within the gamlss class-namely, Box Cox Cole and Green (BCCG), Box Cox T (BCT), and Box Cox Power Exponential (BCPE)-were applied, each with three smoothing techniques: penalized splines (ps), cubic splines (cs), and polynomial splines (poly). The best-fitted model was selected from these nine combinations based on the Akaike Information Criteria.
The Novel Case Selection Method yielded 3655 cases as per criteria. After cleaning the data, this method lead to selection of 3540 children for \"weight for age\" (W/A) and 3515 children for \"height for age\" (H/A). The \"BCPE\" family and \"ps\" as smoothing method proved to be best on AIC for all four curves, i.e. the W/A male, W/A female, H/A male, and H/A female. The optimum selected degrees of freedom for the curve \"W/A\", for both genders were (M = 1, L = 0, S = 0). The optimum degrees of freedom for H/A male were again (M = 1, L = 0, S = 0), but for females the selected degrees of freedom were (M = 1, L = 1, S = 1). The indigenous fitted standard curves for Pakistan were on lower trajectory in comparison to WHO standards.
This study uses the Novel Case Selection Method with introduced algorithms to construct tailored growth charts for lower and middle-income countries. Leveraging extensive MICS data, the methodology ensures representative national samples. The resulting charts hold practical value and await validation from established data sources, offering valuable tools for policy makers and clinicians in diverse global contexts.

The evaluation of secondary parameters of a prospective, randomised, controlled, multicentre intervention trial aimed to analyse gastrointestinal tolerance of an infant formula manufactured from extensively hydrolysed whey protein (eHF) compared to intact cow\'s milk protein (control formula, CF) in healthy term infants. Infants ≤ 25 days of age, who were exclusively formula-fed, were randomised to receive eHF or CF for at least three months up to 120 days of age. An exclusively breastfed reference group (BF) was included for descriptive comparison. Infants\' gastrointestinal tolerance was evaluated based on stool parameters, the Amsterdam Infant Stool Scale (AISS), the Infant Gastrointestinal Symptom Questionnaire (IGSQ), and sleeping patterns. Of 359 infants included, 297 randomised (eHF: n = 149, CF: n = 148) and 41 BF infants completed the study per protocol. All tolerance parameters were comparable between eHF and CF. Stool was predominantly soft and yellow in colour. Stool was more frequently green in eHF than CF. BF infants had more frequent stools, which were mainly watery or soft and yellow, and comparable IGSQ scores (descriptive). Irrespective of group, all gastrointestinal and sleep parameters showed signs of maturation with increasing age. In conclusion, eHF showed gastrointestinal tolerance as good as CF in healthy infants. Both formulae were well-tolerated.

We aimed to demonstrate that healthy term infants experience noninferior growth with infant formula manufactured from extensively hydrolysed whey protein (eHF) compared to intact cow\'s milk protein (control formula, CF). This prospective, randomised, double-blind, parallel-group, controlled, multicentre trial included healthy term infants who were exclusively formula-fed. Infants ≤ 25 days of age received eHF or CF for at least three months up to 120 days of age, with a follow-up until 180 days of age. A reference group included exclusively breastfed infants (BF). Of 318 infants randomised, 297 (148 CF, 149 eHF) completed the study per protocol. Weight gain up to 120 days of age was noninferior (margin -3.0 g/day) in eHF (28.95 (95% CI: 27.21; 30.68) g/day) compared to CF (28.85 (95% CI: 27.10; 30.61) g/day) with a difference in means of 0.09 g/day and a lower limit of the one-sided 97.5% CI of -0.86 g/day (p < 0.0001 for noninferiority testing). Weight gain remained comparable during follow-up. Further anthropometric parameters did not differ between the infant formula groups throughout the study. Growth was comparable in BF. No relevant safety issues were observed. To conclude, eHF meets infant requirements for adequate growth during the first six months of life and can be considered safe and suitable.

UNASSIGNED: Exclusive breastfeeding promotes gut microbial compositions associated with lower rates of metabolic and autoimmune diseases. Its cessation is implicated in increased microbiome-metabolome discordance, suggesting a vulnerability to dietary changes. Formula supplementation is common within our low-income, ethnic-minority community. We studied exclusively breastfed (EBF) neonates\' early microbiome-metabolome coupling in efforts to build foundational knowledge needed to target this inequality.
UNASSIGNED: Maternal surveys and stool samples from seven EBF neonates at first transitional stool (0-24 hours), discharge (30-48 hours), and at first appointment (days 3-5) were collected. Survey included demographics, feeding method, medications, medical history and tobacco and alcohol use. Stool samples were processed for 16S rRNA gene sequencing and lipid analysis by gas chromatography-mass spectrometry. Alpha and beta diversity analyses and Procrustes randomization for associations were carried out.
UNASSIGNED: Firmicutes, Proteobacteria, Bacteroidetes and Actinobacteria were the most abundant taxa. Variation in microbiome composition was greater between individuals than within (p=0.001). Palmitic, oleic, stearic, and linoleic acids were the most abundant lipids. Variation in lipid composition was greater between individuals than within (p=0.040). Multivariate composition of the metabolome, but not microbiome, correlated with time (p=0.030). Total lipids, saturated lipids, and unsaturated lipids concentrations increased over time (p=0.012, p=0.008, p=0.023). Alpha diversity did not correlate with time (p=0.403). Microbiome composition was not associated with each samples\' metabolome (p=0.450).
UNASSIGNED: Neonate gut microbiomes were unique to each neonate; respective metabolome profiles demonstrated generalizable temporal developments. The overall variability suggests potential interplay between influences including maternal breastmilk composition, amount consumed and living environment.

Vitamin K deficiency bleeding (VKDB) is closely associated with the hemorrhagic disease of the newborn (HDN) and can have a late onset, after one week of birth up to six months of age. It is a major concern in developing countries where vitamin K prophylaxis is not often given to newborns and can lead to significant mortality and morbidity. We report a case of a three-month-old child who was exclusively breastfed. He presented with repeated vomiting and was eventually diagnosed as a case of acute-on-chronic subdural hemorrhage. Timely diagnosis and surgical intervention played a key role in ensuring a favorable outcome for the child.

Background: The effects of breastfeeding on neurodevelopmental outcomes are unclear. Inconsistent findings have been reported and confounding factors make interpretation of studies difficult. The World Health Organization published a systematic review on breastfeeding and intelligence in 2013, demonstrating a positive association with improved performance on intelligence tests. The objective of this review is to explore published literature since 2013 to examine the association between breastfeeding, cognition, executive function, and behavior. Methods: Duplicate searches were carried out using Web of Science and OVID for publications between January 2012 and March 2022. Non-English articles and those not correcting for maternal IQ or home environment were excluded. Results: Twenty-three studies were included, examining the effects of breastfeeding on cognition (21), executive function (3), and behavior (6). Most studies showed a modest dose-dependent increase in cognitive scores in children who were breastfed, test score differences ranging from 0.19 to 0.96 points per month of breastfeeding comparing any breastfeeding, predominant and exclusive breastfeeding. Four out of six studies showed a positive correlation between breastfeeding and behavior. One out of three studies assessing breastfeeding and executive function showed a positive dose-dependent correlation. Discussion: Recent evidence demonstrates that breastfeeding has a small positive effect on IQ in later childhood. Evidence suggesting that breastfeeding is a protective factor in developing conduct disorders and achieving higher executive function is limited. Further research is required. Limitations include potential confounders and recall bias of breastfeeding.

Although infantile tremor syndrome is considered a rare entity, we present a typical case of this disorder. This case reinforces the association of infantile tremor syndrome with exclusive breastfeeding in infants and the absence of proper complementary feeding. A nine-month-old, irritable, listless, exclusively breastfed female presented with grade 2 malnutrition, tremors, hyperpigmentation, scarce scalp hair, and delayed developmental milestones. Laboratory investigations revealed macrocytic anemia and a low serum vitamin B12 value of 205 pg/dL. Cerebral and mild cerebellar atrophy were noted on the MRI brain scan. Accordingly, the patient was diagnosed with infantile tremor syndrome and treated with vitamin B12 and nutrient supplementation with zinc, magnesium, folic acid, and iron. The tremors improved and the child became responsive and interested in her surroundings. It is essential to recognize this condition at the earliest and initiate treatment. Basic interventions such as the promotion of proper nutrition, timely introduction of complementary feeding, and weaning practices are key factors in decreasing the incidence of this condition.

A major polymorphism in the fucosyltransferase2 (FUT2) gene influences risk of multiple gut diseases, but its impact on the microbiome of breastfed infants was unknown. In individuals with an active FUT2 enzyme (“secretors”), the intestinal mucosa is abundantly fucosylated, providing mutualist bacteria with a rich endogenous source of fucose. Non-secretors comprise approximately one-fifth of the population, and they lack the ability to create this enzyme. Similarly, maternal secretor status influences the abundance of a breastfeeding mother’s fucosylated milk oligosaccharides. We compared the impact of maternal secretor status, measured by FUT2 genotype, and infant secretor status, measured by FUT2 genotype and phenotype, on early infant fecal microbiome samples collected from 2-month-old exclusively breastfed infants (n = 59). Infant secretor status (19% non-secretor, 25% low-secretor, and 56% full-secretor) was more strongly associated with the infant microbiome than it was with the maternal FUT2 genotype. Alpha diversity was greater in the full-secretors than in the low- or non-secretor infants (p = 0.049). Three distinct microbial enterotypes corresponded to infant secretor phenotype (p = 0.022) and to the dominance of Bifidobacterium breve, B. longum, or neither (p < 0.001). Infant secretor status was also associated with microbial metabolic capacity, specifically, bioenergetics pathways. We concluded that in exclusively breastfed infants, infant—but not maternal—secretor status is associated with infant microbial colonization and metabolic capacity.

BACKGROUND: Humans are widely exposed to chemicals with known or suspected endocrine disrupting effects. Among those are several benzophenones, bisphenols and other phenols commonly used in consumer products.
OBJECTIVE: To provide human biomonitoring data from young families including infants and their parents as well as longitudinal data of infants exclusively breastfed versus on mixed diet.
METHODS: Twenty-two benzophenones, bisphenols and other phenols, were measured in urine sample sets collected from more than 100 infants and their parents (the TRIO study) and in paired samples from 61 infants when exclusively breastfed and after introduction of mixed diet (the FOOD study).
RESULTS: Twelve out of 22 substances were detectable in more than half of the urine samples from infants, mothers or fathers. Large variation in excreted levels of almost all the substances were observed. The TRIO study showed that infants had comparable or even significantly higher daily urinary excretion (DUE) of benzophenone, 4-hydroxy-benzophenone, bisphenol A, bisphenol S, triclosan and 2-phenylphenol than their parents. In the FOOD study, exclusively breastfed infants had higher or similar DUE of triclosan and benzophenones compared to when they received mixed diet. Urinary levels of triclosan and the benzophenones, BP-1 and BP-3 were significantly correlated between all trio members, indicating exposure from the same sources at home. For triclosan, BP-1 and BP-3, the within family variation was lower than between families in the TRIO study. Many substances were positively correlated both within infants and parents, indicating that some families were exposed to several of these substances concurrently.
CONCLUSIONS: Participants in this study excreted relatively low chemical levels, however, simultaneous exposure to several chemicals with endocrine disrupting abilities is of concern due to the dose-additive effects of these substances in combination with other chemicals.