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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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Abstract
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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Early-life exposures and cardiovascular disease risk among Ghanaian migrant and home populations: the RODAM study.
Boateng, D, Danquah, I, Said-Mohamed, R, Smeeth, L, Nicolaou, M, Meeks, K, Beune, E, Addo, J, Bahendeka, S, Agyei-Baffour, P, et al
Journal of developmental origins of health and disease. 2020;(3):250-263
Abstract
Early-life environmental and nutritional exposures are considered to contribute to the differences in cardiovascular disease (CVD) burden. Among sub-Saharan African populations, the association between markers of early-life exposures such as leg length and sitting height and CVD risk is yet to be investigated. This study assessed the association between leg length, sitting height, and estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk among Ghanaian-born populations in Europe and Ghana. We constructed sex-specific quintiles for sitting height and leg length for 3250 participants aged 40-70 years (mean age 52 years; men 39.6%; women 60.4%) in the cross-sectional multicenter Research on Diabetes and Obesity among African Migrants study. Ten-year risk of ASCVD was estimated using the Pooled Cohort Equations; risk ≥7.5% was defined as "elevated" CVD risk. Prevalence ratios (PR) were estimated to determine the associations between sitting height, leg length, and estimated 10-year ASCVD risk. For both men and women, mean sitting height and leg length were highest in Europe and lowest in rural Ghana. Sitting height was inversely associated with 10-year ASCVD risk among all women (PR for 1 standard deviation increase of sitting height: 0.75; 95% confidence interval: 0.67, 0.85). Among men, an inverse association between sitting height and 10-year ASCVD risk was significant on adjustment for study site, adult, and parental education but attenuated when further adjusted for height. No association was found between leg length and estimated 10-year ASCVD risk. Early-life and childhood exposures that influence sitting height could be the important determinants of ASCVD risk in this adult population.
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Early Life Experiences and Trajectories of Cognitive Development.
McCormick, BJJ, Caulfield, LE, Richard, SA, Pendergast, L, Seidman, JC, Maphula, A, Koshy, B, Blacy, L, Roshan, R, Nahar, B, et al
Pediatrics. 2020;(3)
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Abstract
BACKGROUND Multiple factors constrain the trajectories of child cognitive development, but the drivers that differentiate the trajectories are unknown. We examine how multiple early life experiences differentiate patterns of cognitive development over the first 5 years of life in low-and middle-income settings. METHODS Cognitive development of 835 children from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) multisite observational cohort study was assessed at 6, 15, 24 (Bayley Scales of Infant and Toddler Development), and 60 months (Wechsler Preschool and Primary Scale of Intelligence). Markers of socioeconomic status, infection, illness, dietary intake and status, anthropometry, and maternal factors were also assessed. Trajectories of development were determined by latent class-mixed models, and factors associated with class membership were examined by discriminant analysis. RESULTS Five trajectory groups of cognitive development are described. The variables that best discriminated between trajectories included presence of stimulating and learning resources in the home, emotional or verbal responsivity of caregiver and the safety of the home environment (especially at 24 and 60 months), proportion of days (0-24 months) for which the child had diarrhea, acute lower respiratory infection, fever or vomiting, maternal reasoning ability, mean nutrient densities of zinc and phytate, and total energy from complementary foods (9-24 months). CONCLUSIONS A supporting and nurturing environment was the variable most strongly differentiating the most and least preferable trajectories of cognitive development. In addition, a higher quality diet promoted cognitive development while prolonged illness was indicative of less favorable patterns of development.
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Growth and metabolic effects of long-term recombinant human growth hormone (rhGH) treatment in short children born small for gestational age: GH-RAST study.
Labarta, JI, de Arriba, A, Ferrer, M, Loranca, M, Martos, JM, Rodríguez, A, Samaniego, ML, Sánchez-Cenizo, L
Journal of pediatric endocrinology & metabolism : JPEM. 2020;(7):923-932
Abstract
Objectives To study the efficacy and influence on metabolism of recombinant human growth hormone (rhGH) treatment in short children born small for gestational age (SGA). Methods Retrospective, observational, multicenter study in 305 short children born SGA, treated with rhGH during a mean ± SD of 5.03 ± 1.73 years at a mean ± SD dose of 37 ± 8 μg/kg/day. Auxological and metabolic assessment including glucose and lipids profile were collected. Results Mean ± SD age at the start of treatment was 7.11 ± 2.78 years. Height and weight improved significantly until the end of treatment from mean -2.72 (CI95%: -2.81 to -2.63) standard deviation score (SDS) to -1.16 (CI95%: -1.44 to -0.88) SDS and from -1.62 (CI95%: -1.69 to -1.55) SDS to -0.94 (CI95%: -1.14 to -0.74) SDS respectively. Mean height gain was 1.27 (CI95%: 0.99-1.54) SDS. Prepubertal patients showed higher height gain than pubertal children (mean [CI95%] = 1.44 [CI95%: 1.14-1.74] vs. 0.73 [CI95%: 0.22-1.24], p=0.02). Height gain SDS during treatment negatively correlated with chronological age (CA) and bone age (BA) delay and positively correlated with duration of treatment, height gain during first year of treatment, years on prepubertal treatment and height SDS from target height (TH). Glucose, insulin, and triglycerides increased significantly but remained within the normal range. Total and LDL-cholesterol decreased significantly, and HDL-cholesterol remained unchanged. Conclusions rhGH treatment in short SGA children effectively normalized height in most of the patients and showed a safe metabolic profile. Children who benefit the most are those with greater height SDS distance from TH, BA delay, longer duration of treatment and prepubertal treatment initiation.
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Growth, stool consistency and bone mineral content in healthy term infants fed sn-2-palmitate-enriched starter infant formula: A randomized, double-blind, multicentre clinical trial.
Béghin, L, Marchandise, X, Lien, E, Bricout, M, Bernet, JP, Lienhardt, JF, Jeannerot, F, Menet, V, Requillart, JC, Marx, J, et al
Clinical nutrition (Edinburgh, Scotland). 2019;(3):1023-1030
Abstract
BACKGROUND Palmitate in breast milk is predominantly located in the triacylglycerol sn-2 position, while infant formulae contain palmitate predominantly in the sn-1 and sn-3 positions. During digestion, palmitate in the sn-1 and sn-3 positions is hydrolyzed to free palmitic acid that can subsequently complex with calcium to form insoluble soaps; this may partially explain why formula-fed infants have harder stools than breast-fed infants. METHODS This large (n = 488) randomized, double-blind, multicentre trial investigated whether increasing the sn-2 palmitate content of infant formula improves stool consistency and bone mineral content (measured by dual-energy x-ray absorptiometry), without affecting growth or health. From ∼1 week to 4 months of age, infants were exclusively fed one of three formulae: i) control formula (CF; 16% of total palmitate at sn-2; n = 162), (ii) experimental formula 1 (EF1; 43% of total palmitate at sn-2; n = 166) or (iii) experimental formula 2 (EF2; 51% of total palmitate at sn-2; n = 160). RESULTS Intention-to-treat analysis showed softer stools in both EF groups (vs. CF) at ages 2 weeks and 1 and 2 months (p ≤ 0.01), but not 3 and 4 months. At 4 months, all groups had similar growth outcomes while bone mineral content was significantly higher in EF1 (p = 0.0012) and EF2 (p = 0.0002) compared with CF. Comparison of reported adverse events up to 12 months revealed no differences among groups. All 3 infant formulae exhibited equally good digestive tolerance. CONCLUSIONS Formulae enriched in sn-2 palmitate fed in early infancy are safe, improve stool consistency (from 2 weeks to 2 months) and increase bone mineral content (at 4 months).
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Hydrolyzed Formula With Reduced Protein Content Supports Adequate Growth: A Randomized Controlled Noninferiority Trial.
Ahrens, B, Hellmuth, C, Haiden, N, Olbertz, D, Hamelmann, E, Vusurovic, M, Fleddermann, M, Roehle, R, Knoll, A, Koletzko, B, et al
Journal of pediatric gastroenterology and nutrition. 2018;(5):822-830
Abstract
OBJECTIVE A high protein content of nonhydrolyzed infant formula exceeding metabolic requirements can induce rapid weight gain and obesity. Hydrolyzed formula with too low protein (LP) content may result in inadequate growth. The aim of this study was to investigate noninferiority of partial and extensively hydrolyzed formulas (pHF, eHF) with lower hydrolyzed protein content than conventionally, regularly used formulas, with or without synbiotics for normal growth of healthy term infants. METHODS In an European multi-center, parallel, prospective, controlled, double-blind trial, 402 formula-fed infants were randomly assigned to four groups: LP-formulas (1.9 g protein/100 kcal) as pHF with or without synbiotics, LP-eHF formula with synbiotics, or regular protein eHF (2.3 g protein/100 kcal). One hundred and one breast-fed infants served as observational reference group. As primary endpoint, noninferiority of daily weight gain during the first 4 months of life was investigated comparing the LP-group to a regular protein eHF group. RESULTS A comparison of daily weight gain in infants receiving LPpHF (2.15 g/day CI -0.18 to inf.) with infants receiving regular protein eHF showed noninferior weight gain (-3.5 g/day margin; per protocol [PP] population). Noninferiority was also confirmed for the other tested LP formulas. Likewise, analysis of metabolic parameters and plasma amino acid concentrations demonstrated a safe and balanced nutritional composition. Energetic efficiency for growth (weight) was slightly higher in LPeHF and synbiotics compared with LPpHF and synbiotics. CONCLUSIONS All tested hydrolyzed LP formulas allowed normal weight gain without being inferior to regular protein eHF in the first 4 months of life. This trial was registered at clinicaltrials.gov, NCT01143233.
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Effect of haemodiafiltration vs conventional haemodialysis on growth and cardiovascular outcomes in children - the HDF, heart and height (3H) study.
Shroff, R, Bayazit, A, Stefanidis, CJ, Askiti, V, Azukaitis, K, Canpolat, N, Agbas, A, Anarat, A, Aoun, B, Bakkaloglu, S, et al
BMC nephrology. 2018;(1):199
Abstract
BACKGROUND Cardiovascular disease is prevalent in children on dialysis and accounts for almost 30% of all deaths. Randomised trials in adults suggest that haemodiafiltration (HDF) with high convection volumes is associated with reduced cardiovascular mortality compared to high-flux haemodialysis (HD); however paediatric data are scarce. We designed the haemodiafiltration, heart and height (3H) study to test the hypothesis that children on HDF have an improved cardiovascular risk profile, growth and nutritional status and quality of life, compared to those on conventional HD. We performed a non-randomised parallel-arm intervention study within the International Paediatric Haemodialysis Network Registry comparing children on HDF and conventional HD to determine annualised change in cardiovascular end-points and growth. Here we present the 3H study design and baseline characteristics of the study population. METHODS 190 children were screened and 177 (106 on HD and 71 on HDF) recruited from 28 centres in 10 countries. There was no difference in age, underlying diagnosis, comorbidities, previous dialysis therapy, dialysis vintage, residual renal function, type of vascular access or blood flow between HD and HDF groups. High flux dialysers were used in 63% of HD patients and ultra-pure water was available in 52%. HDF patients achieved a median convection volume of 13.3 L/m2; this was associated with the blood flow rate only ((p = 0.0004, r = 0.42) and independent of access type (p = 0.38). DISCUSSION This is the largest study on dialysis outcomes in children that involves deep phenotyping across a wide range of cardiovascular, anthropometric, nutritional and health-related quality of life measures, to test the hypothesis that HDF leads to improved cardiovascular and growth outcomes compared to conventional HD. TRIAL REGISTRATION ClinicalTrials.gov: NCT02063776 . The trial was prospectively registered on the 14 Feb 2014.
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Effects of an antenatal dietary intervention in overweight and obese women on 6 month infant outcomes: follow-up from the LIMIT randomised trial.
Dodd, JM, McPhee, AJ, Deussen, AR, Louise, J, Yelland, LN, Owens, JA, Robinson, JS
International journal of obesity (2005). 2018;(7):1326-1335
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Abstract
BACKGROUND The immediate impact of providing an antenatal dietary intervention during pregnancy has been extensively studied, but little is known of the effects beyond the neonatal period. Our objective was to evaluate the effect of an antenatal dietary intervention in overweight or obese women on infant outcomes 6 months after birth. METHODS We conducted a follow up study of infants born to women who participated in the LIMIT trial during pregnancy. Live-born infants at 6-months of age, and whose mother provided consent to ongoing follow-up were eligible. The primary follow-up study endpoint was the incidence of infant BMI z-score ≥90th centile for infant sex and age. Secondary study outcomes included a range of infant anthropometric measures, neurodevelopment, general health, and infant feeding. Analyses used intention to treat principles according to the treatment group allocated in pregnancy. Missing data were imputed and analyses adjusted for maternal early pregnancy BMI, parity, study centre, socioeconomic status, age, and smoking status. Outcome assessors were blinded to the allocated treatment group. RESULTS A total of 1754 infants were assessed at age 6 months (Lifestyle Advice n = 869; Standard Care n = 885), representing 82.1% of the eligible sample (n = 2136). There were no statistically significant differences in the incidence of infant BMI z-score ≥90th centile for infants born to women in the Lifestyle Advice group, compared with the Standard Care group (Lifestyle Advice 233 (21.71%) vs. Standard Care 233 (21.90%); adjusted relative risk (aRR) 0.99; 95% confidence interval 0.82 to 1.18; p = 0.88). There were no other effects on infant growth, adiposity, or neurodevelopment. CONCLUSION Providing pregnant women who were overweight or obese with an antenatal dietary and lifestyle intervention did not alter 6-month infant growth and adiposity. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426).
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Impact of maternal nutritional supplementation in conjunction with a breastfeeding support program during the last trimester to 12 weeks postpartum on breastfeeding practices and child development at 30 months old.
Zhang, Z, Tran, NT, Nguyen, TS, Nguyen, LT, Berde, Y, Tey, SL, Low, YL, Huynh, DTT
PloS one. 2018;(7):e0200519
Abstract
BACKGROUND Maternal nutrition during pregnancy and breastfeeding is important for the healthy growth and development of the fetus and infant. PURPOSE This study aimed to evaluate the long-term effects of a maternal milk supplementation (MMS) in conjunction with a breastfeeding support program on breastfeeding practices including duration of any breastfeeding and exclusive breastfeeding and child neurodevelopment outcomes at 30 months old. METHODS We followed up the offspring of 204 Vietnamese women who completed a randomized controlled trial where the intervention group received MMS with a breastfeeding support program from the last trimester to 12 weeks postpartum while the control group received standard care. At 30 months postpartum, information on child feeding practices was collected and child neurodevelopment was assessed by the Bayley Scales of Infant and Toddler Development (Bayley-III). RESULTS There was no significant difference in the duration of any breastfeeding (ABF) from birth between the groups. However, the intervention group had longer exclusive breastfeeding (EBF) duration (p = 0.0172), higher EBF rate at 6 months (p = 0.0093) and lower risk of discontinuing EBF (p = 0.0071) than the control. Children in the intervention group had significantly higher Bayley-III composite scores in the domains of cognitive (p = 0.0498) and motor (p = 0.0422) functions, as well as a tendency toward better social-emotional behavior (p = 0.0513) than children in the control group. The association between maternal intervention and child development was attenuated after further adjustment for birth weight but not EBF duration, suggesting that improvements in child development may be partially attributed to the benefits of prenatal nutrition supplementation on birth outcomes. CONCLUSIONS MMS with breastfeeding support during late pregnancy and early postpartum significantly improved EBF practices. The intervention was also associated with improvements in neurodevelopment in children at 30 months old.