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ObjectivesLength-for-age z-scores (LAZ) and stunting prevalence (%LAZ <–2) are commonly used to quantify linear growth faltering in young children in low- and middle-income countries (LMICs). The Healthy Birth, Growth and Development knowledge integration (HBGDki) consortium described postnatal linear growth faltering using LAZ-by-age trajectory modelling and child-level LAZ threshold-crossing events, including incident stunting onset (first occurrence of LAZ <–2) and stunting reversal (LAZ rising from <–2 to ≥–2). Using simulations, we assessed the suitability of these LAZ threshold-crossing metrics for characterising linear growth faltering in LMICs.MethodsWe simulated a synthetic cohort with a harmonically downward-shifting LAZ trajectory from birth to 24 months of age, with mean LAZs similar to the HBGDki pooled South Asian cohorts, and without any input parameters intended to differentially affect individuals’ growth across the height distribution or at different ages. We compared HBGDki empirical estimates of age interval-specific frequencies of incident stunting onset and stunting reversal with those from the synthetic cohort. Using synthetic cohorts, we examined how estimates of incident onset and reversal were affected by missing data, magnitude of the whole-population shift in the LAZ distribution and strength of the between-time-point correlation. We also compared the 3–24 month pattern of linear growth faltering expressed as age-related trajectories of average growth delay (chronological age minus height–age), mean LAZ or stunting prevalence.ResultsEmpirical estimates of age interval-specific incident stunting onset and stunting reversal in the HBGDki cohorts were similar to those observed in a synthetic cohort. Variability in LAZ threshold-crossing event rates is explained by starting LAZ, between-time-point correlation and the magnitude of the whole-population shift in the LAZ distribution. Incident stunting onset is also affected by missing data in preceding intervals. Stunting reversal occurs due to within-child variability (ie, imperfect between-time-point correlation) in the absence of any other phenomena that cause stunted children to become non-stunted at a later age. The linear growth faltering pattern based on growth delay differed from corresponding age-related trajectories of mean LAZ or stunting prevalence.ConclusionsIn longitudinal studies of linear growth faltering in LMICs, LAZ threshold-crossing indicators are byproducts of whole-population shifts in LAZ and within-child variability and should be interpreted accordingly. Reporting incident stunting onset and reversal rates, or analyses in which children are grouped by the timing of LAZ threshold-crossing events, may detract from efforts to understand when and why nearly all children in LMICs grow more slowly than expected for their age. Since mean LAZ and stunting prevalence are unsuitable for quantifying the rate and timing of population-average postnatal linear growth faltering, growth delay is recommended for consideration as a preferred metric.

Height-age is the age at which growth-faltered children’s average observed height or length equals the median height or length of a child growth standard, corresponding to a length-for-age z-score (LAZ) of 0. In randomized controlled trials (RCTs) in low- and middle-income countries (LMICs), expression of linear growth outcomes using height-age may enhance the interpretability of intervention effects compared to conventional use of LAZ. Height-age can be used to derive the proportion of maximal benefit (PMB), whereby PMB = 0% indicates no effect and PMB = 100% indicates the intervention promoted growth at the rate expected for healthy children with the same starting height-age. In this proof-of-concept study, height-age and PMB were compared to LAZ in a meta-analysis of RCTs of small-quantity lipid-based nutrient supplements (SQ-LNS). Pooling across 15 trials in 10 LMICs, mean differences (MD; SQ-LNS minus control) in LAZ and height-age were 0.15 (95%CI: 0.12, 0.17) and 12 days (95%CI: 9, 14), respectively (N = 36,970). LAZ MD and height-age MD were highly correlated (rho = 0.74 overall and 0.94 upon exclusion of an outlier). The pooled PMB indicated that SQ-LNS achieves 11% of optimal growth potential (95% CI: [9.4, 12]; N = 19,768; 12 comparisons), but there was a substantial impact of between-trial heterogeneity (I 2  = 90%). In conclusion, the effect of SQ-LNS on linear growth can be alternatively expressed in terms of height-age instead of LAZ. The PMB may enhance the interpretability of effect estimates by quantifying the extent to which an intervention improves growth in relation to a biological threshold, but further research is required to establish its validity and usefulness for assessing and comparing intervention effectiveness.

Growth faltering is widespread in many low- and middle-income countries, but its effects on childhood bone mass accrual are unknown. The objective of this study was to estimate associations between length (conditional length-for-age -scores, cLAZ) and weight (conditional weight-for-age -scores, cWAZ) gain in three age intervals (ages 0-6, 6-12 and 12-24 months) with dual-energy X-ray absorptiometry-derived measures of bone mass (total body less head (TBLH) bone mineral content (BMC), areal bone mineral density (aBMD) and bone area) at 4 years of age. Associations between interval-specific growth parameters (cLAZ and cWAZ) and bone outcomes were estimated using linear regression models, adjusted for maternal, child and household characteristics. Data collection occurred in Dhaka, Bangladesh. 599 healthy children enrolled in the BONe and mUScle Health in Kids Study. cLAZ in each age interval was positively associated with TBLH BMC, aBMD and bone area at 4 years; however, associations attenuated towards null upon adjustment for concurrent height-for-age -scores (HAZ) at age 4 years and confounders. cWAZ from 0 to 6 and 6 to 12 months was not associated with bone mass, but every sd increase in cWAZ between 12 and 24 months was associated with greater BMC (7·6 g; 95 % CI: 3·2, 12·0) and aBMD (0·008 g/cm ; 95 % CI: 0·003, 0·014) after adjusting for concurrent WAZ, HAZ and confounders. Associations of linear growth (birth to 2 years) with bone mass at age 4 years were explained by concurrent HAZ. Weight gain in the second year of life may increase bone mass independently of linear growth in settings where growth faltering is common.

BACKGROUNDThe use of high-throughput technologies has enabled rapid advancement in the knowledge of host immune responses to pathogens. Our objective was to compare the repertoire, protection, and maternal factors associated with human milk antibodies to infectious pathogens in different economic and geographic locations.METHODSUsing multipathogen protein microarrays, 878 milk and 94 paired serum samples collected from 695 women in 5 high and low-to-middle income countries (Bangladesh, Finland, Peru, Pakistan, and the United States) were assessed for specific IgA and IgG antibodies to 1,607 proteins from 30 enteric, respiratory, and bloodborne pathogens.RESULTSThe antibody coverage across enteric and respiratory pathogens was highest in Bangladeshi and Pakistani cohorts and lowest in the U.S. and Finland. While some pathogens induced a dominant IgA response (Campylobacter, Klebsiella, Acinetobacter, Cryptosporidium, and pertussis), others elicited both IgA and IgG antibodies in milk and serum, possibly related to the invasiveness of the infection (Shigella, enteropathogenic E. coli \"EPEC\", Streptococcus pneumoniae, Staphylococcus aureus, and Group B Streptococcus). Besides the differences between economic regions and decreases in concentrations over time, human milk IgA and IgG antibody concentrations were lower in mothers with high BMI and higher parity, respectively. In Bangladeshi infants, a higher specific IgA concentration in human milk was associated with delayed time to rotavirus infection, implying protective properties of antirotavirus antibodies, whereas a higher IgA antibody concentration was associated with greater incidence of Campylobacter infection.CONCLUSIONThis comprehensive assessment of human milk antibody profiles may be used to guide the development of passive protection strategies against infant morbidity and mortality.FUNDINGBill and Melinda Gates Foundation grant OPP1172222 (to KMJ); Bill and Melinda Gates Foundation grant OPP1066764 funded the MDIG trial (to DER); University of Rochester CTSI and Environmental Health Sciences Center funded the Rochester Lifestyle study (to RJL); and R01 AI043596 funded PROVIDE (to WAP).

Background Angiogenesis is essential for placental growth and development. Improper placental vascular development can reduce blood flow to the fetus and increase the risk of adverse pregnancy and birth outcomes. The objectives of this study were to examine the effect of prenatal vitamin D supplementation on placental angiogenic factors and terminal villi, and associations between angiogenic factors, terminal villi and birth outcomes. Methods This is a secondary analysis using data and specimens from the Maternal Vitamin D for Infant Growth trial in Dhaka, Bangladesh ( n  = 1298). Participants were enrolled at 17–24 weeks gestation and randomized to receive (IU/week): placebo, 4200, 16,800 or 28,000 vitamin D 3 supplement until birth. Newborns and placentas were measured at birth. We examined a subset of randomly selected placentas ( n  = 80). Tissue sections were evaluated for vascular endothelial growth factor (VEGF-A) and placental growth factor (PlGF) using immunofluorescence. We measured intensity and percent area of expression for angiogenic factors, and total number and surface area of terminal villi. Vitamin D treatment effect was estimated using ANOVA. Regression models were used to assess associations of markers of placental angiogenesis with birth outcomes. Interactions by infant sex were examined. Results The overall mean (SD) percent area of expression was 17.0 (4.0) for VEGF-A and 15.0 (1.9) for PlGF. The mean (SD) number of terminal villi was 39 (15) per 12 in 2 , and surface area was 0.096 (0.040) in 2 . Vitamin D treatment groups were similar to placebo for all outcomes. No associations were observed between angiogenic factors or terminal villi placental and birth outcomes. Conclusions Vitamin D supplementation starting from mid-pregnancy until birth did not affect expression of two key angiogenic factors or terminal villi in the placenta. Placental angiogenic factors or terminal villi did not have an association with birth outcomes. These results do not support a role of maternal vitamin D starting mid-pregnancy in impacting placental development.

A synbiotic containing Lactiplantibacillus plantarum [American Type Culture Collection (ATCC) strain identifier 202195] and fructooligosaccharide was reported to reduce the risk of sepsis in young infants in rural India. Here, the whole genome of two isolates of L. plantarum ATCC 202195, which were deposited to the ATCC approximately 20 years apart, were sequenced and analyzed to verify their taxonomic and strain-level identities, identify potential antimicrobial resistant genes and virulence factors, and identify genetic characteristics that may explain the observed clinical effects of L. plantarum ATCC 202195. Minimum inhibitory concentrations for selected antimicrobial agents were determined using broth dilution and gradient strip diffusion techniques. The two L. plantarum ATCC 202195 isolates were genetically identical with only three high-quality single nucleotides polymorphisms identified, and with an average nucleotide identity of 99.99%. In contrast to previously published reports, this study determined that each isolate contained two putative plasmids. No concerning acquired or transferable antimicrobial resistance genes or virulence factors were identified. Both isolates were sensitive to several clinically important antibiotics including penicillin, ampicillin and gentamicin, but resistant to vancomycin. Genes involved in stress response, cellular adhesion, carbohydrate metabolism and vitamin biosynthesis are consistent with features of probiotic organisms.

Objectives To estimate the effects of vitamin D supplementation during pregnancy on 11 maternal and 27 neonatal/infant outcomes; to determine frequencies at which trial outcome data were missing, unreported, or inconsistently reported; and to project the potential contributions of registered ongoing or planned trials.Design Systematic review and meta-analysis of randomised controlled trials; systematic review of registered but unpublished trials.Data sources Medline, Embase, PubMed, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials from inception to September 2017; manual searches of reference lists of systematic reviews identified in the electronic search; and online trial registries for unpublished, ongoing, or planned trials.Eligibility criteria for study selection Trials of prenatal vitamin D supplementation with randomised allocation and control groups administered placebo, no vitamin D, or vitamin D ≤600 IU/day (or its equivalent), and published in a peer reviewed journal.Results 43 trials (8406 participants) were eligible for meta-analyses. Median sample size was 133 participants. Vitamin D increased maternal/cord serum concentration of 25-hydroxyvitamin D, but the dose-response effect was weak. Maternal clinical outcomes were rarely ascertained or reported, but available data did not provide evidence of benefits. Overall, vitamin D increased mean birth weight of 58.33 g (95% confidence interval 18.88 g to 97.78 g; 37 comparisons) and reduced the risk of small for gestational age births (risk ratio 0.60, 95% confidence interval 0.40 to 0.90; seven comparisons), but findings were not robust in sensitivity and subgroup analyses. There was no effect on preterm birth (1.0, 0.77 to 1.30; 15 comparisons). There was strong evidence that prenatal vitamin D reduced the risk of offspring wheeze by age 3 years (0.81, 0.67 to 0.98; two comparisons). For most outcomes, meta-analyses included data from a minority of trials. Only eight of 43 trials (19%) had an overall low risk of bias. Thirty five planned/ongoing randomised controlled trials could contribute 12 530 additional participants to future reviews.Conclusions Most trials on prenatal vitamin D published by September 2017 were small and of low quality. The evidence to date seems insufficient to guide clinical or policy recommendations. Future trials should be designed and powered to examine clinical endpoints, including maternal conditions related to pregnancy (such as pre-eclampsia), infant growth, and respiratory outcomes.Systematic review registration PROSPERO CRD42016051292

Metrics to quantify child growth vary across studies of the developmental origins of health and disease. We conducted a scoping review of child growth studies in which length/height, weight or body mass index (BMI) was measured at ≥ 2 time points. From a 10% random sample of eligible studies published between Jan 2010-Jun 2016, and all eligible studies from Oct 2015-June 2016, we classified growth metrics based on author-assigned labels (e.g., 'weight gain') and a 'content signature', a numeric code that summarized the metric's conceptual and statistical properties. Heterogeneity was assessed by the number of unique content signatures, and label-to-content concordance. In 122 studies, we found 40 unique metrics of childhood growth. The most common approach to quantifying growth in length, weight or BMI was the calculation of each child's change in z-score. Label-to-content discordance was common due to distinct content signatures carrying the same label, and because of instances in which the same content signature was assigned multiple different labels. In conclusion, the numerous distinct growth metrics and the lack of specificity in the application of metric labels challenge the integration of data and inferences from studies investigating the determinants or consequences of variations in childhood growth.

The dual burden of enteric infection and childhood malnutrition continues to be a global health concern and a leading cause of morbidity and death among children. Campylobacter infection, in particular, is highly prevalent in low- and middle-income countries, including Bangladesh. We examined longitudinal data to evaluate the trajectories of change in child growth, and to identify associations with Campylobacter infection and household factors. The study analyzed data from 265 children participating in the MAL-ED Study in Mirpur, Bangladesh. We applied latent growth curve modelling to evaluate the trajectories of change in children’s height, as measured by length-for-age z-score (LAZ), from age 0–24 months. Asymptomatic and symptomatic Campylobacter infections were included as 3- and 6-month lagged time-varying covariates, while household risk factors were included as time-invariant covariates. Maternal height and birth order were positively associated with LAZ at birth. An inverse association was found between increasing age and LAZ. Campylobacter infection prevalence increased with age, with over 70% of children 18–24 months of age testing positive for infection. In the final model, Campylobacter infection in the preceding 3-month interval was negatively associated with LAZ at 12, 15, and 18 months of age; similarly, infection in the preceding 6-month interval was negatively associated with LAZ at 15, 18, and 21 months of age. Duration of antibiotic use and access to treated drinking water were negatively associated with Campylobacter infection, with the strength of the latter effect increasing with children’s age. Campylobacter infection had a significant negative effect on child’s growth and this effect was most powerful between 12 and 21 months. The treatment of drinking water and increased antibiotic use have a positive indirect effect on linear child growth trajectory, acting via their association with Campylobacter infection.

Background Antenatal vitamin D status may be associated with the risk of adverse pregnancy and neonatal outcomes; however, the benefits of vitamin D supplementation during pregnancy remain unknown. Methods We conducted a double-blind placebo-controlled randomized trial to evaluate the effect of high-dose prenatal 3 rd trimester vitamin D3 supplementation on maternal and neonatal (cord blood) serum 25-hydroxyvitamin D (25(OH)D) concentration (primary biochemical efficacy outcome) and maternal serum calcium concentration (primary safety measure). Eligibility criteria were pregnant women aged 18 to <35 years, at 26 to 29 weeks gestation, and residing in Dhaka, Bangladesh. 160 women were randomized by 1:1 allocation to one of two parallel intervention groups; placebo (n = 80) or 35,000 IU/week of vitamin D3 (n = 80) until delivery. All participants, study personnel and study investigators were blind to treatment allocation. Results Mean maternal 25(OH)D concentration was similar in the vitamin D and placebo groups at baseline (45 vs. 44 nmol/L; p = 0.66), but was significantly higher in the vitamin D group vs. placebo group among mothers at delivery (134 vs. 38 nmol/L; p < 0.001) and newborns (cord blood: 103 vs. 39; p < 0.001). In the vitamin D group, 95% of neonates and 100% of mothers attained 25(OH)D >50 nmol/L, versus 21% mothers and 19% of neonates in the placebo group. No participants met criteria for hypercalcemia, there were no known supplement-related adverse events, and major pregnancy outcomes were similar between groups. Conclusions Antenatal 3 rd -trimester vitamin D3 supplementation (35,000 IU/week) significantly raised maternal and cord serum 25(OH)D concentrations above 50 nmol/L in almost all participants without inducing hypercalcemia or other observed safety concerns. Doses up to 35,000 IU/week may be cautiously used in further research aimed at establishing the clinical effects and safety of vitamin D3 supplementation in pregnancy. Trial registration This trial was registered at ClinicalTrials.gov ( NCT01126528 ).