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Effect of scheduled antimicrobial and nicotinamide treatment on linear growth in children in rural Tanzania: A factorial randomized, double-blind, placebo-controlled trial.
DeBoer, MD, Platts-Mills, JA, Elwood, SE, Scharf, RJ, McDermid, JM, Wanjuhi, AW, Jatosh, S, Katengu, S, Parpia, TC, Rogawski McQuade, ET, et al
PLoS medicine. 2021;(9):e1003617
Abstract
BACKGROUND Stunting among children in low-resource settings is associated with enteric pathogen carriage and micronutrient deficiencies. Our goal was to test whether administration of scheduled antimicrobials and daily nicotinamide improved linear growth in a region with a high prevalence of stunting and enteric pathogen carriage. METHODS AND FINDINGS We performed a randomized, 2 × 2 factorial, double-blind, placebo-controlled trial in the area around Haydom, Tanzania. Mother-child dyads were enrolled by age 14 days and followed with monthly home visits and every 3-month anthropometry assessments through 18 months. Those randomized to the antimicrobial arm received 2 medications (versus corresponding placebos): azithromycin (single dose of 20 mg/kg) at months 6, 9, 12, and 15 and nitazoxanide (3-day course of 100 mg twice daily) at months 12 and 15. Those randomized to nicotinamide arm received daily nicotinamide to the mother (250 mg pills months 0 to 6) and to the child (100 mg sachets months 6 to 18). Primary outcome was length-for-age z-score (LAZ) at 18 months in the modified intention-to-treat group. Between September 5, 2017 and August 31, 2018, 1,188 children were randomized, of whom 1,084 (n = 277 placebo/placebo, 273 antimicrobial/placebo, 274 placebo/nicotinamide, and 260 antimicrobial/nicotinamide) were included in the modified intention-to-treat analysis. The study was suspended for a 3-month period by the Tanzanian National Institute for Medical Research (NIMR) because of concerns related to the timing of laboratory testing and the total number of serious adverse events (SAEs); this resulted in some participants receiving their final study assessment late. There was a high prevalence of stunting overall (533/1,084, 49.2%). Mean 18-month LAZ did not differ between groups for either intervention (mean LAZ with 95% confidence interval [CI]: antimicrobial: -2.05 CI -2.13, -1.96, placebo: -2.05 CI -2.14, -1.97; mean difference: 0.01 CI -0.13, 0.11, p = 0.91; nicotinamide: -2.06 CI -2.13, -1.95, placebo: -2.04 CI -2.14, -1.98, mean difference 0.03 CI -0.15, 0.09, p = 0.66). There was no difference in LAZ for either intervention after adjusting for possible confounders (baseline LAZ, age in days at 18-month measurement, ward, hospital birth, birth month, years of maternal education, socioeconomic status (SES) quartile category, sex, whether the mother was a member of the Datoga tribe, and mother's height). Adverse events (AEs) and SAEs were overall similar between treatment groups for both the nicotinamide and antimicrobial interventions. Key limitations include the absence of laboratory measures of pathogen carriage and nicotinamide metabolism to provide context for the negative findings. CONCLUSIONS In this study, we observed that neither scheduled administration of azithromycin and nitazoxanide nor daily provision of nicotinamide was associated with improved growth in this resource-poor setting with a high force of enteric infections. Further research remains critical to identify interventions toward improved early childhood growth in challenging conditions. TRIAL REGISTRATION ClinicalTrials.gov NCT03268902.
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The Effects of Vitamin D Supplementation During Infancy on Growth During the First 2 Years of Life.
Hauta-Alus, HH, Holmlund-Suila, EM, Kajantie, E, Rosendahl, J, Valkama, SM, Enlund-Cerullo, M, Andersson, S, Mäkitie, O
The Journal of clinical endocrinology and metabolism. 2021;(3):e1140-e1155
Abstract
CONTEXT The relationship between maternal and infant vitamin D and early childhood growth remains inadequately understood. OBJECTIVE This work aimed to investigate how maternal and child 25-hydroxyvitamin D (25[OH]D) and vitamin D supplementation affect growth during the first 2 years of life. METHODS A randomized, double-blinded, single-center intervention study was conducted from pregnancy until offspring age 2 years. Altogether 812 term-born children with complete data were recruited at a maternity hospital. Children received daily vitamin D3 supplementation of 10 μg (group 10) or 30 μg (group 30) from age 2 weeks to 2 years. Anthropometry and growth rate were measured at age 1 and 2 years. RESULTS Toddlers born to mothers with pregnancy 25(OH)D greater than 125 nmol/L were at 2 years lighter and thinner than the reference group with 25(OH)D of 50 to 74.9 nmol/L (P < .010). Mean 2-year 25(OH)D concentrations were 87 nmol/L in group 10 and 118 nmol/L in group 30 (P < .001). When group 30 was compared with group 10, difference in body size was not statistically significant (P > .053), but group 30 had slower growth in length and head circumference between 6 months and 1 year (P < .047), and more rapid growth in weight and length-adjusted weight between 1 and 2 years (P < .043). Toddlers in the highest quartile of 25(OH)D (> 121 nmol/L) were shorter (mean difference 0.2 SD score [SDS], P = .021), lighter (mean difference 0.4 SDS, P = .001), and thinner (in length-adjusted weight) (mean difference 0.4 SDS, P = .003) compared with the lowest quartile (< 81.2 nmol/L). CONCLUSION Vitamin D and early childhood growth may have an inverse U-shaped relationship.
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Neurodevelopmental Outcomes and Gut Bifidobacteria in Term Infants Fed an Infant Formula Containing High sn-2 Palmitate: A Cluster Randomized Clinical Trial.
Wu, W, Zhao, A, Liu, B, Ye, WH, Su, HW, Li, J, Zhang, YM
Nutrients. 2021;(2)
Abstract
A few studies suggested high stereo-specifically numbered (sn)-2 palmitate in a formula might favor the gut Bifidobacteria of infants. The initial colonization and subsequent development of gut microbiota in early life might be associated with development and later life functions of the central nervous system via the microbiota-gut-brain axis, such as children with autism. This study aims to assess the hypothesized effect of increasing the amount of palmitic acid esterified in the sn-2 position in infant formula on neurodevelopment in healthy full-term infants and to explore the association of this effect with the altered gut Bifidobacteria. One hundred and ninety-nine infants were enrolled in this cluster randomized clinical trial: 66 breast-fed (BF group) and 133 formula-fed infants who were clustered and randomly assigned to receive formula containing high sn-2 palmitate (sn-2 group, n = 66) or low sn-2 palmitate (control group, n = 67), where 46.3% and 10.3% of the palmitic acid (PA) was sn-2-palmitate, respectively. Infants' neurodevelopmental outcomes were measured by the Ages and Stages Questionnaire, third edition (ASQ-3). Stool samples were collected for the analysis of Bifidobacteria (Trial registration number: ChiCTR1800014479). At week 16, the risk of scoring close to the threshold for fine motor skills (reference: scoring above the typical development threshold) was significantly lower in the sn-2 group than the control group after adjustment for the maternal education level (p = 0.036) but did not differ significantly versus the BF group (p = 0.513). At week 16 and week 24, the sn-2 group (week 16: 15.7% and week 24: 15.6%) had a significantly higher relative abundance of fecal Bifidobacteria than the control group (week 16: 6.6%, p = 0.001 and week 24:11.2%, p = 0.028) and did not differ from the BF group (week 16: 14.4%, p = 0.674 and week 24: 14.9%, p = 0.749). At week 16, a higher relative abundance of Bifidobacteria was associated with the decreased odds of only one domain scoring close to the threshold in the formula-fed infants group (odds ratio (OR), 95% confidence interval (CI): 0.947 (0.901-0.996)). Elevating the sn-2 palmitate level in the formula improved infants' development of fine motor skills, and the beneficial effects of high sn-2 palmitate on infant neurodevelopment was associated with the increased gut Bifidobacteria level.
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Association of Infant Physical Development and Rapid Growth With Pubertal Onset Among Girls in Rural China.
Wei, J, Liu, S, Cheng, Y, Yang, W, Zhu, Z, Zeng, L
JAMA network open. 2021;(5):e216831
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IMPORTANCE Whether physical development and rapid growth during the first 2 years of life are associated with puberty onset in girls remains unclear. OBJECTIVE To examine the associations of infant physical development and rapid growth with the timing of puberty onset in girls. DESIGN, SETTING, AND PARTICIPANTS This prospective birth cohort study included girls whose mothers had participated in a randomized, double-blind cluster trial of micronutrient supplementation with a daily capsule of folic acid, iron and folic acid, or multiple micronutrients during pregnancy. A total of 547 singleton girls in rural western China who were born after 2004 were followed up at 3, 6, 12, and 24 months of age and were eligible for long-term follow-up. Of these, 294 adolescent girls (aged 10-12 years), representing 53.7% of the total sample, were included in the follow-up interview that was conducted from June 1 through December 31, 2016. Data analyses were conducted from November 1, 2019, to May 30, 2020. EXPOSURES Infant weight and length were assessed at birth and 3, 6, 12, and 24 months of age. Rapid growth, defined as a weight-for-age or length-for-age z score increase of greater than 0.67, was calculated during 5 periods: birth to 3 months, birth to 6 months, 6 to 12 months, 12 to 24 months, and birth to 24 months of age. MAIN OUTCOMES AND MEASURES Puberty stage was assessed using the standardized Tanner staging system. Onset of puberty was defined as attaining Tanner stage 2 of breast development or pubic hair growth, and the corresponding age at follow-up was recorded. RESULTS Of 294 girls included in the analysis (mean [SD] age, 11.25 [0.57] years), the median age of puberty onset was 11 (interquartile range, 10-11) years. A significant association with puberty onset was found for infancy weight-for-age z score at 12 months of age (adjusted hazard ratio [HR], 1.20; 95% CI, 1.01-1.44) and rapid weight gain from birth to 24 months of age (adjusted HR, 1.40; 95% CI, 1.01-1.93) and birth to 3 months of age (adjusted HR, 1.39; 95% CI, 1.02-1.91). However, length-related indicators during early life were not associated with adolescent puberty onset. CONCLUSIONS AND RELEVANCE This study found that a higher weight-for-age z score and rapid weight gain during infancy, particularly from birth to 3 months of age, were associated with an increased likelihood of puberty onset in girls. These findings suggest that weight-related indicators may serve as proxies of puberty onset among adolescent girls.
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Infant growth during the first year of life following a pregnancy lifestyle intervention in routine care-Findings from the cluster-randomised GeliS trial.
Hoffmann, J, Günther, J, Stecher, L, Spies, M, Geyer, K, Raab, R, Meyer, D, Rauh, K, Hauner, H
Pediatric obesity. 2021;(2):e12705
Abstract
BACKGROUND Lifestyle interventions in pregnancy may influence postpartum development and obesity risk in offspring. The impact of lifestyle interventions as health system-based approaches is unclear. OBJECTIVE To evaluate the effect of an antenatal lifestyle intervention conducted as public health approach on infant development and feeding practices. METHODS We followed offspring born to women participating in the cluster-randomised GeliS trial who received usual care (CG) or repeated lifestyle counselling (IG). We collected data on offspring development and complementary feeding until the 12th month postpartum. RESULTS Of the 1998 mother-child pairs, 1783 completed the follow-up. Mean infant weight at 12 months was comparable between groups (IG: 9497.9 ± 1137.0 g; CG: 9433.4 ± 1055.2 g; P = .177). There was no significant evidence of differences in sex- and age-adjusted z-scores or in the odds of offspring being overweight. More infants in the IG received whole-grain products compared to the CG (95.6% vs. 90.8%; P = .003). Despite small differences in the timing of introducing solid foods, there were no further significant differences in the pattern of complementary feeding. CONCLUSIONS The antenatal lifestyle intervention embedded in routine care did not substantially influence infant anthropometrics and is thus unlikely to impact future development.
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Group-based parenting interventions to promote child development in rural Kenya: a multi-arm, cluster-randomised community effectiveness trial.
Luoto, JE, Lopez Garcia, I, Aboud, FE, Singla, DR, Fernald, LCH, Pitchik, HO, Saya, UY, Otieno, R, Alu, E
The Lancet. Global health. 2021;(3):e309-e319
Abstract
BACKGROUND Early childhood development (ECD) programmes can help address early disadvantages for the 43% of children younger than 5 years in low-income and middle-income countries who have compromised development. We aimed to test the effectiveness of two group-based delivery models for an integrated ECD responsive stimulation and nutrition education intervention using Kenya's network of community health volunteers. METHODS We implemented a multi-arm, cluster-randomised community effectiveness trial in three rural subcounties across 60 villages (clusters) in western Kenya. Eligible participants were mothers or female primary caregivers aged 15 years or older with children aged 6-24 months at enrolment. If married or in established relationships, fathers or male caregivers aged 18 years or older were also eligible. Villages were randomly assigned (1:1:1) to one of three groups: group-only delivery with 16 fortnightly sessions; mixed delivery combining 12 group sessions with four home visits; and a comparison group. Villages in the intervention groups were randomly assigned (1:1) to invite or not invite fathers and male caregivers to participate. Households were surveyed at baseline and immediately post-intervention. Assessors were masked. Primary outcomes were child cognitive and language development (score on the Bayley Scales of Infant Development third edition), socioemotional development (score on the Wolke scale), and parental stimulation (Home Observation for Measurement of the Environment inventory). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03548558. FINDINGS Between Oct 1 and Nov 12, 2018, 1152 mother-child dyads were enrolled and randomly assigned (n=376 group-only intervention, n=400 mixed-delivery intervention, n=376 comparison group). At the 11-month endline survey (Aug 5-Oct 31, 2019), 1070 households were assessed for the primary outcomes (n=346 group only, n=373 mixed delivery, n=351 comparison). Children in group-only villages had higher cognitive (effect size 0·52 SD [95% CI 0·21-0·83]), receptive language (0·42 SD [0·08-0·77]), and socioemotional scores (0·23 SD [0·03-0·44]) than children in comparison villages at endline. Children in mixed-delivery villages had higher cognitive (0·34 SD [0·05-0·62]) and socioemotional scores (0·22 SD [0·05-0·38]) than children in comparison villages; there was no difference in language scores. Parental stimulation also improved for group-only (0·80 SD [0·49-1·11]) and mixed-delivery villages (0·77 SD [0·49-1·05]) compared with the villages in the comparison group. Including fathers in the intervention had no measurable effect on any of the primary outcomes. INTERPRETATION Parenting interventions delivered by trained community health volunteers in mother-child groups can effectively promote child development in low-resource settings and have great potential for scalability. FUNDING Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health.
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Infant Formula with Added Bovine Milk Fat Globule Membrane and Modified Iron Supports Growth and Normal Iron Status at One Year of Age: A Randomized Controlled Trial.
Hedrick, J, Yeiser, M, Harris, CL, Wampler, JL, London, HE, Patterson, AC, Wu, SS
Nutrients. 2021;(12)
Abstract
Inclusion of bovine-derived milk fat globule membrane (bMFGM) or bMFGM components in infant formulas (IFs) may support healthy brain development. This double-blind, prospective trial evaluated growth, tolerance, and iron status in infants receiving added bMFGM and modified protein, iron, and arachidonic acid (ARA) concentrations in IF. Healthy term infants were randomized to: control (marketed, routine cow's milk-based IF/100 kcal: 2.1 g protein, 1.8 mg iron, 34 mg ARA) or INV-MFGM (investigational cow's milk-based IF/100 kcal: 1.9 g protein, 1.2 mg iron, 25 mg ARA and whey protein-lipid concentrate, 5 g/L (source of bMFGM)). Anthropometrics, stool characteristics, fussiness, and gassiness through day 365 and blood markers of iron status at day 365 were evaluated. The primary outcome was rate of weight gain from 14-120 days of age. Of 373 infants enrolled (control: 191, INV-MFGM: 182), 275 completed the study (control: 141; INV-MFGM: 134). No group differences in growth rate (g/day) from day 14-120 or study discontinuation were detected. Few group differences in growth or parent-reported fussiness, gassiness, or stool characteristics were detected. No group differences were detected in hemoglobin, hematocrit, or incidence of anemia. In healthy term infants, bMFGM and modified protein, iron, and ARA concentrations in a cow's milk-based IF were well-tolerated, associated with adequate growth throughout the first year of life, and supported normal iron status at one year of age.
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Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings: A Randomized Clinical Trial.
, , Ahmed, T, Chisti, MJ, Rahman, MW, Alam, T, Ahmed, D, Parvin, I, Kabir, MF, Sazawal, S, Dhingra, P, et al
JAMA network open. 2021;(12):e2136726
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IMPORTANCE World Health Organization (WHO) guidelines do not recommend routine antibiotic use for children with acute watery diarrhea. However, recent studies suggest that a significant proportion of such episodes have a bacterial cause and are associated with mortality and growth impairment, especially among children at high risk of diarrhea-associated mortality. Expanding antibiotic use among dehydrated or undernourished children may reduce diarrhea-associated mortality and improve growth. OBJECTIVE To determine whether the addition of azithromycin to standard case management of acute nonbloody watery diarrhea for children aged 2 to 23 months who are dehydrated or undernourished could reduce mortality and improve linear growth. DESIGN, SETTING, AND PARTICIPANTS The Antibiotics for Children with Diarrhea (ABCD) trial was a multicountry, randomized, double-blind, clinical trial among 8266 high-risk children aged 2 to 23 months presenting with acute nonbloody diarrhea. Participants were recruited between July 1, 2017, and July 10, 2019, from 36 outpatient hospital departments or community health centers in a mixture of urban and rural settings in Bangladesh, India, Kenya, Malawi, Mali, Pakistan, and Tanzania. Each participant was followed up for 180 days. Primary analysis included all randomized participants by intention to treat. INTERVENTIONS Enrolled children were randomly assigned to receive either oral azithromycin, 10 mg/kg, or placebo once daily for 3 days in addition to standard WHO case management protocols for the management of acute watery diarrhea. MAIN OUTCOMES AND MEASURES Primary outcomes included all-cause mortality up to 180 days after enrollment and linear growth faltering 90 days after enrollment. RESULTS A total of 8266 children (4463 boys [54.0%]; mean [SD] age, 11.6 [5.3] months) were randomized. A total of 20 of 4133 children in the azithromycin group (0.5%) and 28 of 4135 children in the placebo group (0.7%) died (relative risk, 0.72; 95% CI, 0.40-1.27). The mean (SD) change in length-for-age z scores 90 days after enrollment was -0.16 (0.59) in the azithromycin group and -0.19 (0.60) in the placebo group (risk difference, 0.03; 95% CI, 0.01-0.06). Overall mortality was much lower than anticipated, and the trial was stopped for futility at the prespecified interim analysis. CONCLUSIONS AND RELEVANCE The study did not detect a survival benefit for children from the addition of azithromycin to standard WHO case management of acute watery diarrhea in low-resource settings. There was a small reduction in linear growth faltering in the azithromycin group, although the magnitude of this effect was not likely to be clinically significant. In low-resource settings, expansion of antibiotic use is not warranted. Adherence to current WHO case management protocols for watery diarrhea remains appropriate and should be encouraged. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03130114.
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Consequences of using chronological age versus corrected age when testing cognitive and motor development in infancy and intelligence quotient at school age for children born preterm.
Gould, JF, Fuss, BG, Roberts, RM, Collins, CT, Makrides, M
PloS one. 2021;(9):e0256824
Abstract
BACKGROUND Children born preterm (<37 weeks' gestation) have an increased risk of poor neurodevelopment, including lower intelligence quotient (IQ) scores compared with their term-born counterparts. OBJECTIVE To explore the differences in psychometric scores for cognition and motor skills when they are age-standardized according to chronological age instead of corrected age for children born preterm. METHODS We assessed = 554 children born <33 weeks' gestation with the Bayley Scales of Infant Development, 2nd edition (mental and motor scores) at 18 months and the Weschler Abbreviated Scale of Intelligence (IQ score) at seven years of age. Scores were standardized according to chronological age and corrected age and differences between mean chronological and corrected scores were compared, along with the proportion of children whose scores could be classified as impaired. RESULTS When scores were standardized according to chronological age instead of corrected age there was a large significant difference of 17.3 points on the mental scale (79.5 vs. 96.8, respectively) and 11.8 points on the motor scale (84.8 vs. 96.6, respectively) at 18 months. By seven years, the difference in IQ scores remained, although of a smaller magnitude at 1.9 points between mean chronological and corrected age scoring (97.2 vs. 99.1, respectively). CONCLUSION Consistent with previous literature, outcome assessments for preterm infants consistently differed according to use of chronological or corrected age to standardized scores. Cognitive scores were impacted more severely than motor scores, and differences were more substantial in early childhood than later in childhood. For clinical purposes, correction for preterm birth is only likely to have an impact during early childhood, however assessments for research purposes should continue to correct into childhood to account for the persistent bias due to preterm birth.
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Maternal FADS2 single nucleotide polymorphism modified the impact of prenatal docosahexaenoic acid (DHA) supplementation on child neurodevelopment at 5 years: Follow-up of a randomized clinical trial.
Gonzalez Casanova, I, Schoen, M, Tandon, S, Stein, AD, Barraza Villarreal, A, DiGirolamo, AM, Demmelmair, H, Ramirez Silva, I, Feregrino, RG, Rzehak, P, et al
Clinical nutrition (Edinburgh, Scotland). 2021;(10):5339-5345
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BACKGROUND Variability in the FADS2 gene, which codifies the Delta-6 Desaturases and modulates the conversion of essential n-3 and n-6 fatty acids into long-chain polyunsaturated fatty acids, might modify the impact of prenatal supplementation with n-3 docosahexaenoic acid (DHA) on neurodevelopment. OBJECTIVE To assess if maternal FADS2 single nucleotide polymorphisms (SNPs) modified the effect of prenatal DHA on offspring development at 5 years. DESIGN We conducted a post-hoc interaction analysis of the POSGRAD randomized controlled trial (NCT00646360) of prenatal supplementation with algal-DHA where 1094 pregnant women originally randomized to 400 mg/day of preformed algal DHA or a placebo from gestation week 18-22 through delivery. In this analysis, we included offspring with information on maternal genotype and neurodevelopment at 5 years (DHA = 316; Control = 306) and used generalized linear models to assess interactions between FADS2 SNPs rs174602 or rs174575 and prenatal DHA on neurodevelopment at 5 years measured with McCarthy Scales of Children's Abilities (MSCA). RESULTS Maternal and offspring characteristics were similar between groups. At baseline, mean (±standard deviation) maternal age was 26 ± 5 years and schooling was 12 ± 4 years. Forty-six percent (46%) of the children were female. Maternal minor allele frequencies were 0.37 and 0.33 for SNPs rs174602 and rs174575, respectively. There were significant variations by SNP rs174602 and intervention group (p for interactions <0.05) where children in the intervention group had higher MSCA scores on the quantitative (DHA: mean ± SEM = 22.6 ± 0.9 vs. Control = 19.1 ± 0.9, mean difference (Δ) = 3.45; p = 0.01) and memory (DHA = 27.9 ± 1.1 vs. Control = 23.7 ± 1.1, Δ = 4.26; p = 0.02) scales only among offspring of TT (minor allele homozygotes). CONCLUSIONS Maternal FADS2 SNP rs174602 modified the effect of prenatal DHA on cognitive development at 5 years. Variations in the genetic make-up of target populations could be an important factor to consider for prenatal DHA supplementation interventions.