Associations between human milk oligosaccharides and infant growth in a Bangladeshi mother-infant cohort.

BACKGROUND: We aimed to estimate associations between human milk oligosaccharides (HMOs) and infant growth (length-for-age (LAZ) and weight-for-length (WLZ) z-scores) at 12 months postnatal age. METHODS: In this secondary analysis of data from a maternal vitamin D trial in Dhaka, Bangladesh (N = 192), absolute concentrations of HMOs were measured in 13 ± 1 week(s) postpartum milk samples, infant anthropometric measurements were obtained soon after birth and at 12 months postpartum, and infant feeding was classified during 6 months postpartum. Associations between individual HMOs or HMO groups and LAZ or WLZ were estimated by multivariable linear regression adjusting for infant feeding pattern, maternal secretor status, and other potential confounders. RESULTS: The concentrations of 6'sialyllactose, lacto-N-neotetraose, and the non-fucosylated non-sialylated HMOs were inversely associated with LAZ at 12 months of age, whereas the fucosylated non-sialylated HMO concentration was positively associated with LAZ at 12 months. These associations were robust in analyses restricted to infants who were primarily exclusively/predominantly fed human milk during the first 3 (or 6) months. CONCLUSIONS: Since HMOs are both positively and negatively associated with postnatal growth, there is a need for randomized trials to estimate the causal benefits and risks of exogenously administered HMOs on infant growth and other health outcomes. IMPACT: 6'sialyllactose, lacto-N-neotetraose, and the non-fucosylated non-sialylated human milk oligosaccharides (HMOs) were inversely associated with length-for-age z-scores (LAZ) at 12 months, whereas the fucosylated non-sialylated HMO concentration was positively associated with LAZ at 12 months among Bangladeshi infants. Associations between individual and grouped HMOs with infant length growth at 12 months were as strong or stronger in analyses restricted to infants who were exclusively or predominantly fed human milk up to 3 (or 6) months. Randomized trials are needed to characterize the effects of specific HMOs on infant growth, particularly in countries where postnatal linear growth faltering is common.

Estimation of skeletal muscle mass in 4-year-old children using the D3-creatine dilution method.

BACKGROUND: Given limited experience in applying the creatine-(methyl-D3) (D3Cr) dilution method to measure skeletal muscle mass (SMM) in young children, the feasibility of deployment in a fielding setting and performance of the method was assessed in a cohort of 4-year-old children in Dhaka, Bangladesh. METHODS: Following D3Cr oral dose (10 mg) administration, single fasting urine samples were collected at 2-4 days (n = 100). Twenty-four-hour post-dose collections and serial spot urine samples on days 2, 3 and 4 were obtained in a subset of participants (n = 10). Urinary creatine, creatinine, D3Cr and D3-creatinine enrichment were analyzed by liquid chromatography-tandem mass spectrometry. Appendicular lean mass (ALM) was measured by dual-energy x-ray absorptiometry and grip strength was measured by a hand-held dynamometer. RESULTS: SMM was measured successfully in 91% of participants, and there were no adverse events. Mean ± SD SMM was greater than ALM (4.5 ± 0.4 and 3.2 ± 0.6 kg, respectively). Precision of SMM was low (intraclass correlation = 0.20; 95% CI: 0.02, 0.75; n = 10). Grip strength was not associated with SMM in multivariable analysis (0.004 kg per 100 g of SMM; 95% CI: -0.031, 0.038; n = 91). CONCLUSIONS: The D3Cr dilution method was feasible in a community setting. However, high within-child variability in SMM estimates suggests the need for further optimization of this approach. IMPACT: The D3-creatine (D3Cr) stable isotope dilution method was considered a feasible method for the estimation of skeletal muscle mass (SMM) in young children in a community setting and was well accepted among participants. SMM was weakly associated with both dual-energy x-ray absorptiometry-derived values of appendicular lean mass and grip strength. High within-child variability in estimated values of SMM suggests that further optimization of the D3Cr stable isotope dilution method is required prior to implementation in community research settings.

Implications for quantifying early life growth trajectories of term-born infants using INTERGROWTH-21st newborn size standards at birth in conjunction with World Health Organization child growth standards in the postnatal period.

BACKGROUND: The INTERGROWTH-21st sex and gestational age (GA) specific newborn size standards (IG-NS) are intended to complement the World Health Organization Child Growth Standards (WHO-GS), which are not GA-specific. We examined the implications of using IG-NS at birth and WHO-GS at postnatal ages in longitudinal epidemiologic studies. OBJECTIVES: The aim of this study was to quantify the extent to which standardised measures of newborn size and growth are affected when using WHO-GS versus IG-NS at birth among term-born infants. METHODS: Data from two prenatal trials in Bangladesh (n = 755) and The Gambia (n = 522) were used to estimate and compare size at birth and growth from birth to 3 months when using WHO-GS only ('WHO-GS') versus IG-NS at birth and WHO-GS postnatally ('IG-NS'). Mean length-for-age (LAZ), weight-for-age (WAZ) and head circumference-for-age (HCAZ), and the prevalence of undernutrition (stunting: LAZ < -2SD; underweight: WAZ < -2SD; and microcephaly: HCAZ < -2SD) were estimated overall and by GA strata [early-term (370/7 -386/7 ), full-term (390/7 -406/7 ) and late-term (410/7 -430/7 )]. We used Bland-Altman plots to compare continuous indices and Kappa statistic to compare categorical indicators. RESULTS: At birth, mean LAZ, WAZ and HCAZ, and the prevalence of undernutrition were most similar among newborns between 39 and 40 weeks of GA when using WHO-GS versus IG-NS. However, anthropometric indices were systematically lower among early-term infants and higher among late-term infants when using WHO-GS versus IG-NS. Early-term and late-term infants demonstrated relatively faster and slower growth, respectively, when using WHO-GS versus IG-NS, with the direction and magnitude of differences varying between anthropometric indices. Individual-level differences in attained size and growth, when using WHO-GS versus IG-NS, were greater than 0.2 SD in magnitude for >60% of infants across all anthropometric indices. CONCLUSIONS: Using IG-NS at birth with WHO-GS postnatally is acceptable for full-term infants but may give a misleading interpretation of growth trajectories among early- and late-term infants.

Effect of maternal vitamin D supplementation on nasal pneumococcal acquisition, carriage dynamics and carriage density in infants in Dhaka, Bangladesh.

BACKGROUND: Invasive pneumococcal disease is a major cause of infant morbidity and death worldwide. Vitamin D promotes anti-pneumococcal immune responses in vitro, but whether improvements in infant vitamin D status modify risks of nasal pneumococcal acquisition in early life is not known. METHODS: This is a secondary analysis of data collected in a trial cohort in Dhaka, Bangladesh. Acute respiratory infection (ARI) surveillance was conducted from 0 to 6 months of age among 1060 infants of women randomized to one of four pre/post-partum vitamin D dose combinations or placebo. Nasal swab samples were collected based on standardized ARI criteria, and pneumococcal DNA quantified by qPCR. Hazards ratios of pneumococcal acquisition and carriage dynamics were estimated using interval-censored survival and multi-state modelling. RESULTS: Pneumococcal carriage was detected at least once in 90% of infants by 6 months of age; overall, 69% of swabs were positive (2616/3792). There were no differences between any vitamin D group and placebo in the hazards of pneumococcal acquisition, carriage dynamics, or carriage density (p > 0.05 for all comparisons). CONCLUSION: Despite in vitro data suggesting that vitamin D promoted immune responses against pneumococcus, improvements in postnatal vitamin D status did not reduce the rate, alter age of onset, or change dynamics of nasal pneumococcal colonization in early infancy. Trial registration Registered in ClinicalTrials.gov with the registration number of NCT02388516 and first posted on March 17, 2015.

A Bayesian adaptive design for clinical trials of rare efficacy outcomes with multiple definitions.

INTRODUCTION: Bayesian adaptive designs for clinical trials have gained popularity in the recent years due to the flexibility and efficiency that they offer. We consider the scenario where the outcome of interest comprises events with relatively low risk of occurrence and different case definitions resulting in varying control group risk assumptions. This is a scenario that occurs frequently for infectious diseases in global health research. METHODS: We propose a Bayesian adaptive design that incorporates different case definitions of the outcome of interest that vary in stringency. A set of stopping rules are proposed where superiority and futility may be concluded with respect to different outcome definitions and therefore maintain a realistic probability of stopping in trials with low event rates. Through a simulation study, a variety of stopping rules and design configurations are compared. RESULTS: The simulation results are provided in an interactive web application that allows the user to explore and compare the design operating characteristics for a variety of assumptions and design parameters with respect to different outcome definitions. The results for select simulation scenarios are provided in the article. DISCUSSION: Bayesian adaptive designs offer the potential for maximizing the information learned from the data collected through clinical trials. The proposed design enables monitoring and utilizing multiple composite outcomes based on rare events to optimize the trial design operating characteristics.

Growth delay: an alternative measure of population health based on child height distributions.

BACKGROUND: Indicators of child height, such as mean height-for-age Z-scores (HAZ), height-for-age difference (HAD) and stunting prevalence, do not account for differences in population-average bone developmental stage. AIM: Propose a measure of child height that conveys the dependency of linear growth on stage rather than chronological age. SUBJECTS AND METHODS: Using Demographic and Health Surveys (2000-2018; 64 countries), we generated: (1) predicted HAZ at specific ages (HAZ regressed on age); (2) height-age (age at which mean height matches the WHO Growth Standards median); (3) Growth delay (GD), the difference between chronological age and height-age; (4) HAD; and (5) stunting prevalence. Metrics were compared based on secular trends within countries and age-related trajectories within surveys. RESULTS: In the most recent surveys (N = 64), GDs ranged from 1.9 to 19.1 months at 60 months chronological age. Cross-sectionally, HAZ, HAD and GD were perfectly correlated, and showed similar secular trends. However, age-related trajectories differed across metrics. Accumulating GD with age demonstrated growth faltering as slower than expected growth for children of the same height-age. Resumption of growth at the median for height-age was rarely observed. CONCLUSION: GD is a population-level measure of child health that reflects the role of delayed skeletal development in linear growth faltering.

Effect of Correcting the Postnatal Age of Preterm-Born Children on Measures of Associations Between Infant Length-for-Age z Scores and Mid-Childhood Outcomes.

Child growth standards are commonly used to derive age- and sex-standardized anthropometric indices but are often inappropriately applied to preterm-born children (<37 weeks of gestational age (GA)) in epidemiology studies. Using the 2004 Pelotas Birth Cohort, we examined the impact of correcting for GA in the application of child growth standards on the magnitude and direction of associations in 2 a priori-selected exposure-outcome scenarios: infant length-for-age z score (LAZ) and mid-childhood body mass index (scenario A), and infant LAZ and mid-childhood intelligence quotient (scenario B). GA was a confounder that had a strong (scenario A) or weak (scenario B) association with the outcome. Compared with uncorrected postnatal age, using GA-corrected postnatal age attenuated the magnitude of associations, particularly in early infancy, and changed inferences for associations at birth. Although differences in the magnitude of associations were small when GA was weakly associated with the outcome, model fit was meaningfully improved using corrected postnatal age. When estimating population-averaged associations with early childhood growth in studies where preterm- and term-born children are included, incorporating heterogeneity in GA at birth in the age scale used to standardize anthropometric indices postnatally provides a useful strategy to reduce standardization errors.

Vitamin D deficiency enhances expression of autophagy-regulating miR-142-3p in mouse and "involved" IBD patient intestinal tissues.

Vitamin D deficiency is an environmental factor involved in the pathogenesis of inflammatory bowel disease (IBD); however, the mechanisms surrounding its role remain unclear. Previous studies conducted in an intestinal epithelial-specific vitamin D receptor (VDR) knockout model suggest that a lack of vitamin D signaling causes a reduction in intestinal autophagy. A potential link between vitamin D deficiency and dysregulated autophagy is microRNA (miR)-142-3p, which suppresses autophagy. In this study, we found that wild-type C57BL/6 mice fed a vitamin D-deficient diet for 5 wk had increased miR-142-3p expression in ileal tissues compared with mice that were fed a matched control diet. Interestingly, there was no difference in expression of key autophagy markers ATG16L1 and LC3II in the ileum whole tissue. However, Paneth cells of vitamin D-deficient mice were morphologically abnormal and had an accumulation of the autophagy adaptor protein p62, which was not present in the total crypt epithelium. These findings suggest that Paneth cells exhibit early markers of autophagy dysregulation within the intestinal epithelium in response to vitamin D deficiency and enhanced miR-142-3p expression. Finally, we demonstrated that treatment-naïve IBD patients with low levels of vitamin D have an increase in miR-142-3p expression in colonic tissues procured from "involved" areas of the disease. Taken together, our findings demonstrate that insufficient vitamin D levels alter expression of autophagy-regulating miR-142-3p in intestinal tissues of mice and patients with IBD, providing insight into the mechanisms by which vitamin D deficiency modulates IBD pathogenesis.NEW & NOTEWORTHY Vitamin D deficiency has a role in IBD pathogenesis, and although the mechanisms surrounding its role remain unclear, it has been suggested that autophagy dysregulation is involved. Here, we show increased ileal expression of autophagy-suppressing miR-142-3p in mice that were fed a vitamin D-deficient diet and in "involved" colonic biopsies from pediatric IBD patients with low vitamin D. miR-142-3p serves as a potential mechanism mediating vitamin D deficiency and reduced autophagy.

Vitamin D Supplementation in Pregnancy and Lactation and Infant Growth.

BACKGROUND: It is unclear whether maternal vitamin D supplementation during pregnancy and lactation improves fetal and infant growth in regions where vitamin D deficiency is common. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in Bangladesh to assess the effects of weekly prenatal vitamin D supplementation (from 17 to 24 weeks of gestation until birth) and postpartum vitamin D supplementation on the primary outcome of infants' length-for-age z scores at 1 year according to World Health Organization (WHO) child growth standards. One group received neither prenatal nor postpartum vitamin D (placebo group). Three groups received prenatal supplementation only, in doses of 4200 IU (prenatal 4200 group), 16,800 IU (prenatal 16,800 group), and 28,000 IU (prenatal 28,000 group). The fifth group received prenatal supplementation as well as 26 weeks of postpartum supplementation in the amount of 28,000 IU (prenatal and postpartum 28,000 group). RESULTS: Among 1164 infants assessed at 1 year of age (89.5% of 1300 pregnancies), there were no significant differences across groups in the mean (±SD) length-for-age z scores. Scores were as follows: placebo, -0.93±1.05; prenatal 4200, -1.11±1.12; prenatal 16,800, -0.97±0.97; prenatal 28,000, -1.06±1.07; and prenatal and postpartum 28,000, -0.94±1.00 (P=0.23 for a global test of differences across groups). Other anthropometric measures, birth outcomes, and morbidity did not differ significantly across groups. Vitamin D supplementation had expected effects on maternal and infant serum 25-hydroxyvitamin D and calcium concentrations, maternal urinary calcium excretion, and maternal parathyroid hormone concentrations. There were no significant differences in the frequencies of adverse events across groups, with the exception of a higher rate of possible hypercalciuria among the women receiving the highest dose. CONCLUSIONS: In a population with widespread prenatal vitamin D deficiency and fetal and infant growth restriction, maternal vitamin D supplementation from midpregnancy until birth or until 6 months post partum did not improve fetal or infant growth. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT01924013 .).

Basal Vitamin D Status and Supplement Dose Are Primary Contributors to Maternal 25-Hydroxyvitamin D Response to Prenatal and Postpartum Cholecalciferol Supplementation.

BACKGROUND: Variability in the 25-hydroxyvitamin D [25(OH)D] response to prenatal and postpartum vitamin D supplementation is an important consideration for establishing vitamin D deficiency prevention regimens. OBJECTIVES: We aimed to examine interindividual variation in maternal and infant 25(OH)D following maternal vitamin D supplementation. METHODS: In a randomized trial of maternal vitamin D supplementation (Maternal Vitamin D for Infant Growth Trial), healthy pregnant women (n = 1300) received a prenatal cholecalciferol (vitamin D-3) dose of 0, 4200, 16,800, or 28,000 IU/wk from 17 to 24 wk of gestation followed by placebo to 6 mo postpartum. A fifth group received 28,000 IU cholecalciferol/wk both prenatally and postpartum. In a subset of participants, associations of 25(OH)D with hypothesized explanatory factors were estimated in women at delivery (n = 655) and 6 mo postpartum (n = 566), and in their infants at birth (n = 502) and 6 mo of age (n = 215). Base models included initial 25(OH)D and supplemental vitamin D dose. Multivariable models were extended to include other individual characteristics and specimen-related factors. The model coefficient of determination (R2) was used to express the percentage of total variance explained. RESULTS: Supplemental vitamin D intake and initial 25(OH)D accounted for the majority of variance in maternal 25(OH)D at delivery and postpartum (R2 = 70% and 79%, respectively). Additional characteristics, including BMI, contributed negligibly to remaining variance (<5% increase in R2). Variance in neonatal 25(OH)D was explained mostly by maternal delivery 25(OH)D and prenatal vitamin D intake (R2 = 82%). Variance in 25(OH)D in later infancy could only partly be explained by numerous biological, sociodemographic, and laboratory-related characteristics, including feeding practices (R2 = 43%). CONCLUSIONS: Presupplementation 25(OH)D and vitamin D supplemental dose are the major determinants of the response to maternal prenatal vitamin D intake. Vitamin D dosing regimens to prevent maternal and infant vitamin D deficiency should take into consideration the mean 25(OH)D concentration of the target population.

Antimicrobial Prescribing during Infant Hospital Admissions in a Birth Cohort in Dhaka, Bangladesh.

Empirical antimicrobial use is common in hospitalized infants and may contribute to antimicrobial resistance in low- and middle-income countries. In this observational birth cohort study nested in a randomized controlled trial in Dhaka, Bangladesh, inpatient antimicrobial prescription data were extracted from serious adverse event forms completed for hospitalizations of infants (0-12 months of age). The primary outcome was the proportion of inpatient admissions where systemic antimicrobials were prescribed. Infant and hospitalization-related factors associated with antimicrobial prescriptions were determined. Among 1254 infants, there were 448 admissions to 32 facilities from 2014 to 2016. Antimicrobials were prescribed in 73% of admissions with a mean antimicrobial exposure rate of 0.25 antimicrobials per day of admission [95% confidence intervals (95% CIs): 0.24-0.27]. The most common antibiotics were aminoglycosides (29%), penicillins (26%) and third-generation cephalosporins (25%). In all, 58% of antibiotics were classified as 'access', 38% 'watch' and 1% 'reserve' using the World Health Organization (WHO) Essential Medicines List classification. WHO-recommended antimicrobial regimens were used in 68% of neonatal sepsis and 9% of lower respiratory tract infection (LRTI) admissions. 'Watch' antimicrobials were used in 26% of neonatal sepsis and 76% of LRTI admissions. Compared with private facilities, antimicrobial prescription rates were lower at government [rate ratio (RR) 0.71; 95% CI: 0.61-0.83] and charitable facilities (RR 0.39; 95% CI: 0.28-0.53), after adjustment for household wealth index and parental education. Younger infant age, older maternal age and longer admission were associated with higher prescription rates. These findings highlight the need for paediatric antimicrobial stewardship programs in Bangladesh.

Maternal Food Insecurity is Positively Associated with Postpartum Mental Disorders in Ontario, Canada.

BACKGROUND: Household food insecurity has been associated with pregnancy complications and poorer birth outcomes in the United States and with maternal mental disorders in the United Kingdom, but there has been little investigation of the effects of food insecurity during this life stage in Canada. OBJECTIVES: Our objective was to examine the relationship between the food insecurity status of women during pregnancy and maternal and birth outcomes and health in infancy in Canada. METHODS: We drew on data from 1998 women in Ontario, Canada, whose food insecurity was assessed using the Household Food Security Survey Module on the Canadian Community Health Survey, cycles 2005 to 2011-2012. These records were linked to multiple health administrative databases to identify indications of adverse health outcomes during pregnancy, at birth, and during children's first year of life. We included women who gave birth between 9 months prior and 6 months after their interview date, and for whom infant outcome data were available. Multivariable Poisson regression models were used to compare outcomes by maternal food security status, expressed as adjusted relative risks (aRR) with 95% CIs. RESULTS: While pregnant, 5.6% of women were marginally food insecure and 10.0% were moderately or severely food insecure. Food insecurity was unrelated to pregnancy complications and adverse birth outcomes, but 26.8% of women with moderate or severe food insecurity had treatment for postpartum mental disorders in the 6-month postpartum period, compared to 13.9% of food-secure women (aRR, 1.86; 95% CI, 1.40-2.46). Children born to food-insecure mothers were at elevated risk of being treated in an emergency department in the first year of life (aRR, 1.18; 95% CI, 1.01-1.38). CONCLUSIONS: Maternal food insecurity during pregnancy in Ontario, Canada, is associated with postpartum mental disorders and a greater likelihood of infants being treated in an emergency department.

Genetic characterization of human metapneumovirus identified through community and facility-based surveillance of infants in Dhaka, Bangladesh.

BACKGROUND: Acute respiratory infection (ARI) is a leading cause of morbidity and mortality in children in low and middle-income countries. Human metapneumovirus (hMPV) is one of the most common viral etiological agents for ARIs in children. OBJECTIVES: In this study, we explored the genotypic diversity and the epidemiology of hMPV among infants in Dhaka, Bangladesh. STUDY DESIGN: Between December 2014 and August 2016, a total of 3810 mid-turbinate nasal swab samples were collected from infants (0 to 6 months of age) who met clinical ARI criteria, as a part of a prospective ARI cohort study. hMPV was detected using polymerase chain reaction, and genotyped by sequencing and phylogenetic analysis. RESULTS: hMPV was identified in 206 (5.4%) nasal swab specimens. One-tenth of the hMPV-positive swabs (n = 19) were also positive for other respiratory viruses. hMPV activity peaked in January and September in 2015; however, no seasonal pattern of hMPV infection was detected. Phylogenetic analyses of the N and F gene-fragments revealed that the hMPV strains circulating in Dhaka, Bangladesh, belonged to three genotypes: A2b, A2c, and B1. Genotype A (57%) was the predominant hMPV genotype circulating in Bangladesh during the study period. CONCLUSION: This study describes both the epidemiology of hMPV infection and its genotypic strain diversity in Dhaka, Bangladesh.

Arguments against routine administration of probiotics for NEC prevention.

PURPOSE OF REVIEW: Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among premature neonates. Although randomized trials have shown that probiotics may be efficacious in the prevention of NEC, their use has not been universally adopted in the neonatal intensive care unit (NICU). Caveats regarding routine probiotic supplementation for the prevention of NEC are summarized in this review. RECENT FINDINGS: Accumulating evidence indicates that prophylactic probiotic supplementation in preterm infants can reduce the incidence of NEC. However, substantial knowledge gaps, regulatory issues, and implementation challenges should be addressed before probiotics are introduced as standard of care for all preterm neonates. Limitations of published trial data have made it challenging to define regimens that optimize efficacy and safety in specific patient subgroups. Moreover, the current probiotic market lacks rigorous regulatory oversight, which could raise concerns about the quality and safety of probiotic products. Finally, implementation pitfalls include risks of cross-colonization and resource requirements to monitor and mitigate potential adverse events. SUMMARY: Probiotics have shown promise in the prevention of NEC. However, there is insufficient evidence to guide the selection of optimal regimens. Furthermore, issues related to regulatory and institutional oversight should be addressed before supplementation is routinely implemented in NICUs.

Use and Misuse of Stunting as a Measure of Child Health.

The term "stunting" has become pervasive in international nutrition and child health research, program, and policy circles. Although originally intended as a population-level statistical indicator of children's social and economic deprivation, the conventional anthropometric definition of stunting (height-for-age z scores <-2 SD) is now widely used to define chronic malnutrition. Epidemiologists often portray it as a disease, making inferences about the causes of growth faltering based on comparisons between stunted (i.e., undernourished) and nonstunted children. Stunting is commonly used to monitor public health and nutrition program effectiveness alongside calls for the "elimination of stunting." However, there is no biological basis for the -2 SD cutoff to define stunting, making it a poor individual-level classifier of malnutrition or disease. In fact, in many low- and middle-income countries, children above and below the threshold are similarly affected by growth-limiting exposures. We argue that the common use of stunting as an indicator of child linear growth has contributed to unsubstantiated assumptions about the biological mechanisms underlying linear growth impairment in low- and middle-income countries and has led to a systematic underestimation of the burden of linear growth deficits among children in low-resource settings. Moreover, because nutrition-specific short-term public health interventions may result in relatively minor changes in child height, the use of stunting prevalence to monitor health or nutrition program effectiveness may be inappropriate. A more nuanced approach to the application and interpretation of stunting as an indicator in child growth research and public health programming is warranted.

Effect of correcting for gestational age at birth on population prevalence of early childhood undernutrition.

BACKGROUND: Postmenstrual and/or gestational age-corrected age (CA) is required to apply child growth standards to children born preterm (< 37 weeks gestational age). Yet, CA is rarely used in epidemiologic studies in low- and middle-income countries (LMICs), which may bias population estimates of childhood undernutrition. To evaluate the effect of accounting for GA in the application of growth standards, we used GA-specific standards at birth (INTERGROWTH-21st newborn size standards) in conjunction with CA for preterm-born children in the application of World Health Organization Child Growth Standards postnatally (referred to as 'CA' strategy) versus postnatal age for all children, to estimate mean length-for-age (LAZ) and weight-for-age (WAZ) z scores at 0, 3, 12, 24, and 48-months of age in the 2004 Pelotas (Brazil) Birth Cohort. RESULTS: At birth (n = 4066), mean LAZ was higher and the prevalence of stunting (LAZ < -2) was lower using CA versus postnatal age (mean ± SD): - 0.36 ± 1.19 versus - 0.67 ± 1.32; and 8.3 versus 11.6%, respectively. Odds ratio (OR) and population attributable risk (PAR) of stunting due to preterm birth were attenuated and changed inferences using CA versus postnatal age at birth [OR, 95% confidence interval (CI): 1.32 (95% CI 0.95, 1.82) vs 14.7 (95% CI 11.7, 18.4); PAR 3.1 vs 42.9%]; differences in inferences persisted at 3-months. At 12, 24, and 48-months, preterm birth was associated with stunting, but ORs/PARs remained attenuated using CA compared to postnatal age. Findings were similar for weight-for-age z scores. CONCLUSIONS: Population-based epidemiologic studies in LMICs in which GA is unused or unavailable may overestimate the prevalence of early childhood undernutrition and inflate the fraction of undernutrition attributable to preterm birth.

Conditional random slope: A new approach for estimating individual child growth velocity in epidemiological research.

OBJECTIVES: Conditioning child growth measures on baseline accounts for regression to the mean (RTM). Here, we present the "conditional random slope" (CRS) model, based on a linear-mixed effects model that incorporates a baseline-time interaction term that can accommodate multiple data points for a child while also directly accounting for RTM. METHODS: In two birth cohorts, we applied five approaches to estimate child growth velocities from 0 to 12 months to assess the effect of increasing data density (number of measures per child) on the magnitude of RTM of unconditional estimates, and the correlation and concordance between the CRS and four alternative metrics. Further, we demonstrated the differential effect of the choice of velocity metric on the magnitude of the association between infant growth and stunting at 2 years. RESULTS: RTM was minimally attenuated by increasing data density for unconditional growth modeling approaches. CRS and classical conditional models gave nearly identical estimates with two measures per child. Compared to the CRS estimates, unconditional metrics had moderate correlation (r = 0.65-0.91), but poor agreement in the classification of infants with relatively slow growth (kappa = 0.38-0.78). Estimates of the velocity-stunting association were the same for CRS and classical conditional models but differed substantially between conditional versus unconditional metrics. CONCLUSION: The CRS can leverage the flexibility of linear mixed models while addressing RTM in longitudinal analyses.

Prenatal vitamin D supplementation and infant vitamin D status in Bangladesh.

OBJECTIVE: To determine the effect of prenatal maternal vitamin D supplementation on infant vitamin D status in a tropical region where vitamin D supplementation is not routine. DESIGN: A prospective observational follow-up of a randomized trial. SETTING: Maternal-child health facility in Dhaka, Bangladesh (23°N). SUBJECTS: Infants born to pregnant women (n 160) randomized to receive 875 µg (35 000 IU) cholecalciferol (vitamin D3) per week (VD) or placebo (PL) during the third trimester were followed from birth until 6 months of age (n 115). Infant serum 25-hydroxyvitamin D concentration (25(OH)D) was measured at <1, 2, 4 and 6 months of age. RESULTS: Mean infant 25(OH)D was higher in the VD v. PL group at <1 month of age (mean (sd): 80 (20) nmol/l v. 22 (18) nmol/l; P<0·001), but the difference was attenuated by 2 months (52 (19) nmol/l v. 40 (23) nmol/l; P=0·05). Groups were similar at 4 months (P=0·40) and 6 months (n 72; P=0·26). In the PL group, mean infant 25(OH)D increased to 78 (95 % CI 67, 88) nmol/l by 6 months of age (n 34). 25(OH)D was higher with infant formula-feeding and higher in summer v. winter. CONCLUSIONS: Prenatal third-trimester vitamin D supplementation (875 µg (35 000 IU)/week) significantly ameliorated infant vitamin D status during the neonatal period when the risk of vitamin D deficiency is greatest. Further research is warranted to determine factors that contribute to the rise in 25(OH)D during the first 6 months of life among breast-fed infants in this setting.

Prenatal high-dose vitamin D3 supplementation has balanced effects on cord blood Th1 and Th2 responses.

BACKGROUND: Antenatal vitamin D3 (vitD3) supplementation significantly increases maternal and neonatal 25-hydroxyvitamin D3 (25(OH)D3) concentration, yet the effect of an improvement in maternal-fetal vitamin D status on the neonatal immune response is unclear. METHOD: To assess the effect of prenatal vitD3 supplementation on cord blood T cell function, healthy pregnant Bangladeshi women (n = 160) were randomized to receive either oral 35,000 IU/week vitD3 or placebo from 26 to 29 weeks of gestation to delivery. In a subset of participants (n = 80), cord blood mononuclear cells (CBMC) were cultured, non-adherent lymphocytes were isolated to assess T cell cytokine responses to phytohemagglutinin (PHA) and anti-CD3/anti-CD28 (iCD3/iCD28), measured by multiplex assay. In 12 participants, lymphocyte gene expression profiles were analyzed by PCR array. RESULT: In supplemented group, increased concentrations of IL-10 (P < 0.000) and TNF-α (P = 0.05) with iCD3/iCD28 stimulation and IFN-γ (p = 0.05) with PHA stimulation were obtained compared to placebo group. No differences in the gene expression profile were noted between the two groups. However, PHA stimulation significantly induced the expression of genes encoding Th1 and Th2 cytokines and down-regulated a number of genes involved in T-cell development, proliferation and differentiation of B cells, signal transduction pathway, transcriptional regulation and pattern recognition receptors (PRRs) in the vitamin D group (vitD group). CONCLUSION: Third-trimester high-dose vitD3 supplementation in healthy pregnant women had balanced effects on biomarkers of cord blood Th1 and Th2 responses. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01126528 ).