The Effect of Vitamin B12 Supplementation on Leukocyte Telomere Length in Mildly Stunted Nepalese Children: A Secondary Outcome of a Randomized Controlled Trial.

BACKGROUND: Vitamin B12 is essential for deoxyribonucleic acid synthesis and genome stability. A deficiency of vitamin B12 is associated with telomere shortening, genomic aging, and increased risk of chronic disease and mortality. OBJECTIVES: The study aims to determine the effect of vitamin B12 supplementation on leukocyte telomere length (LTL) in infants at risk of vitamin B12 deficiency. METHODS: The study was a predefined secondary analysis of a randomized controlled trial enrolling 600 Nepalese infants aged 6 -11 mo, who were supplemented with 2 µg (2-3 recommended daily allowances) vitamin B12 or placebo daily for 1 y. At the end of the study, LTL was measured in 497 participants. Mean LTL was compared between the treatment arms in the full sample and predefined subgroups based on markers of vitamin B12 status, hemoglobin, sex, and growth indices. RESULTS: LTL at end-study did not differ between the vitamin B12 and placebo arm with a standardized mean difference (95% confidence interval) of 0.04 (-0.14, 0.21). There was no effect of vitamin B12 on LTL in any of the subgroups. CONCLUSIONS: Providing daily vitamin B12 for 1 y during infancy in a population at risk of vitamin B12 deficiency does not affect LTL. This trial was registered at clinicaltrials.gov as NCT02272842.

The effect of vitamin B12 supplementation during pregnancy on infant growth and development in Nepal: a community-based, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Vitamin B12 is required for healthy infant growth and development, but low and marginal vitamin B12 status is endemic in low-income and middle-income countries. We aimed to measure the effect of vitamin B12 supplementation from early pregnancy until 6 months post partum on infant growth and neurodevelopment. METHODS: In this community-based, double-blind, placebo-controlled trial, we randomly assigned (1:1) 800 pregnant women (aged 20-40 years) who were up to 15 weeks pregnant-recruited from home visits and outpatient departments at three hospitals in Nepal-to daily supplementation with 50 µg oral vitamin B12 or placebo until 6 months postpartum. Independent scientists generated the list that linked allocation to participants' study identification number. Participants were masked to group assignment and all investigators were masked until data cleaning was completed. The primary outcomes were length-for-age Z score (LAZ) at age 12 months and the cognitive composite score of the Bayley Scales of Infant and Toddler Development (3rd edition) at age 6 months and 12 months. The primary and secondary outcomes, including adverse events, were assessed in the intention-to-treat population, for all participants with available outcome data. This trial is registered with ClinicalTrials.gov, NCT03071666. FINDINGS: 800 eligible pregnant women were enrolled in the trial between March 28, 2017, and Oct 15, 2020, with 400 women randomly assigned to each group. Follow-up was completed on May 18, 2022. At baseline, 569 (71%) of 800 women had plasma vitamin B12 indicating low or marginal status (<221 pmol/L). We found no effect of vitamin B12 on the primary outcomes. The mean LAZ at age 12 months were -0·57 (SD 1·03) in the B12 group and -0·55 (1.03) in the placebo group (366 infants in the vitamin B12 group vs 363 infants in the placebo group) with a mean difference of -0·02 (95% CI -0·16 to 0·13). The mean cognitive composite scores were 97·7 (SD 10·5) in the B12 group and 97·1 (10·2) in the placebo group, with a mean difference of 0·5 (95% CI -0·6 to 1·7) measured in 364 and 361 infants. Stillbirths or infant deaths occurred in three (1%) of 374 women in the vitamin B12 group and nine (2%) of 379 women in the placebo group. INTERPRETATION: Although vitamin B12 deficiency was prevalent in our study population and vitamin B12 supplementation from early pregnancy substantially improved vitamin B12 status, supplementation did not improve infant growth or neurodevelopment. Our findings support the current WHO recommendations of no routine vitamin B12 supplementation during pregnancy. FUNDING: Research Council of Norway.

The effect of infant vitamin B12 supplementation on neurodevelopment: a follow-up of a randomised placebo-controlled trial in Nepal.

The most critical period for brain development is before a child's second birthday. Standardised tests measuring neurodevelopment are more reliable when administered after this period. Severe vitamin B12 deficiency affects brain development and function. In a randomised, double-blind, placebo-controlled trial in 600 Nepalese infants (6-11 months at enrolment), we found no effect of 2 µg vitamin B12 daily for a year on neurodevelopment. The primary objective of the current study was to measure the effect of the intervention on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) full scale intelligence quotient (FSIQ). We measured the effect on the Bayley Scales of Infant and Toddler Development 3rd edition at age 30-35 months (n 555). At age 42-47 months (n 533), we used the WPPSI-IV and subtests from the Neuropsychological Assessment, 2nd edition (NEPSY-II). We also used the FSIQ to estimate subgroup specific effects. The mean (sd) WPPSI-IV FSIQ in the vitamin B12 group was 84·4 (8·4) and 85·0 (8·6) in the placebo group (mean difference -0·5 (95 % CI -1·97, 0·94), P = 0·48). There were no effect of the vitamin B12 on any of the other neurodevelopmental outcomes and no beneficial effect in any of the subgroups. In conclusion, providing 2 µg of vitamin B12 for a year in infants at risk of vitamin B12 deficiency does not improve preschool cognitive function.

The effects of vitamin B12 supplementation in pregnancy and postpartum on growth and neurodevelopment in early childhood: Study Protocol for a Randomized Placebo Controlled Trial.

INTRODUCTION: Vitamin B12 is crucial for normal cell division and differentiation, and necessary for the development and myelination of the central nervous system. Pregnant mothers in resource poor settings are at risk for poor vitamin B12 status. Poor vitamin B12 status in infancy is linked to poor growth and neurodevelopment. Brain development starts from conception, and pregnancy is a period of rapid growth and development for the brain. METHODS AND ANALYSIS: The study is an individually randomised double-blind placebo controlled trial in 800 pregnant Nepalese women randomised in a 1:1 ratio. A daily dose of 50 µg of vitamin B12 or placebo is given to women from early pregnancy, not later than week 15, until 6 months after birth. Weekly visits are conducted in order to record compliance, growth and morbidity. The primary outcomes are scores on the cognitive, language and motor subscales of the Bayley Scales of Infant and Toddler Development, Third Edition, measured at 6 and 12 months of age, and growth (length and weight) measured at 6 and 12 months of age. ETHICS AND DISSEMINATION: National Health and Research Council, Nepal (NHRC 253/2016) and Regional Committee for Medical and Health Research Ethics of Western Norway (2016/1620/REK vest) have approved the study. Investigators who have contributed to the conceptualising, conducting, as well as being involved in the data analyses and manuscript writing will be eligible for authorship and be responsible to share outcomes with different stakeholders through publications and workshops. The results from this study may support new dietary guidelines for Nepalese and possibly South Asian pregnant women that can lead to improved pregnancy outcomes, neurodevelopment and cognitive functioning in children. TRIAL REGISTRATION NUMBER: Universal Trial Number: U1111-1183-4093. TRIAL REGISTRATION: clinicaltrials.gov: NCT03071666. Protocol date: version 1.2, 1 June 2017.

Zinc as an adjunct treatment for reducing case fatality due to clinical severe infection in young infants: study protocol for a randomized controlled trial.

BACKGROUND: An estimated 2.7 of the 5.9 million deaths in children under 5 years of age occur in the neonatal period. Severe infections contribute to almost a quarter of these deaths. Mortality due to severe infections in developing country settings is substantial despite antibiotic therapy. Effective interventions that can be added to standard therapy for severe infections are required to reduce case fatality. METHODS/DESIGN: This is a double-blind randomized placebo-controlled parallel group superiority trial to investigate the effect of zinc administered orally as an adjunct to standard therapy to infants aged 3 days up to 2 months (59 days) hospitalized with clinical severe infection, that will be undertaken in seven hospitals in Delhi, India and Kathmandu, Nepal. In a 1:1 ratio, we will randomly assign young infants to receive 10 mg of elemental zinc or placebo orally in addition to the standard therapy for a total of 14 days. The primary outcomes hospital case fatality, which is death due to any cause and at any time after enrolment while hospitalized for the illness episode, and extended case fatality, which encompasses the period until 12 weeks after enrolment. DISCUSSION: A previous study showed a beneficial effect of zinc in reducing the risk of treatment failure, as well as a non-significant effect on case fatality. This study was not powered to detect an effect on case fatality, which this current study is. If the results are consistent with this earlier trial, we would have provided strong evidence for recommending zinc as an adjunct to standard therapy for clinical severe infection in young infants. TRIAL REGISTRATION: Universal Trial Number: U1111-1187-6479, Clinical Trials Registry - India: CTRI/2017/02/007966 : Registered on February 27, 2017.

The effect of vitamin B12 supplementation in Nepalese infants on growth and development: study protocol for a randomized controlled trial.

BACKGROUND: Vitamin B12 deficiency is one of the most common micronutrient deficiencies and is associated with poor cognitive development and growth. Vitamin B12 is crucial for normal cell division and differentiation, and it is necessary for the development and myelination of the central nervous system. The aim of the present study is to measure the effect of daily supplementation of vitamin B12 on the neurodevelopment and growth of young children in Nepal. METHODS/DESIGN: We are conducting an individually randomized, double-blind, placebo-controlled trial with 600 marginally stunted children 6-11 months old (length for age less than -1 z-score). Children are randomized to receive a lipid-based paste containing vitamin B12 or placebo daily for 12 months. The main outcomes are changes in growth (z-scores) and in neurodevelopment measured by the Bayley Scales of Infant and Toddler Development, Third Edition, from baseline until the end of the study. DISCUSSION: If vitamin B12 supplementation benefits early child development and growth, this will have consequences for dietary recommendations for malnourished children worldwide. TRIAL REGISTRATIONS: ClinicalTrials.gov Identifier: NCT02272842 . Registered on 21 October 2014. Universal Trial Number: U1111-1161-5187. Registered on 8 September 2014.

Predictors of duration and treatment failure of severe pneumonia in hospitalized young Nepalese children.

BACKGROUND: Pneumonia in young children is still the most frequent cause of death in developing countries. We aimed to identify predictors for recovery and treatment failure in children hospitalized with severe pneumonia. METHODS: We enrolled 610 Nepalese children, aged 2 - 35 months from February 2006 to June 2008. Study participants were provided with standard treatment for pneumonia and followed up until discharge. Three multiple regression models representing clinical variables, clinical and radiological combined and all variables, including C-reactive protein (CRP) and viral etiology were used to assess the associations. RESULTS: The median age of study participants was 6 months with 493 (82%) infants and 367 (61%) males. The median time (IQR) till recovery was 49 (31, 87) hours and treatment failure was experienced by 209 (35%) of the children. Younger age, hypoxia on admission and radiographic pneumonia were independent predictors for both prolonged recovery and risk of treatment failure. While wasting and presence of any danger sign also predicted slower recovery, Parainfluenza type 1 isolated from the nasopharynx was associated with earlier resolution of illness. Gender, being breastfed, stunting, high fever, elevated CRP, presence of other viruses and supplementation with oral zinc did not show any significant association with these outcomes. CONCLUSION: Age, hypoxia and consolidation on chest radiograph were significant predictors for time till recovery and treatment failure in children with severe pneumonia. While chest radiograph is not always needed, detection and treatment of hypoxia is a crucial step to guide the management of hospitalized children with pneumonia.

Oral zinc and common childhood infections--An update.

Zinc is an essential micronutrient important for growth and for normal function of the immune system. Many children in developing countries have inadequate zinc nutrition. Routine zinc supplementation reduces the risk of respiratory infections and diarrhea, the two leading causes of morbidity and mortality in young children worldwide. In childhood diarrhea oral zinc also reduces illness duration and risk of persistent episodes. Oral zinc is therefore recommended for the treatment of acute diarrhea in young children. The results from the studies that have measured the therapeutic effect of zinc on acute respiratory infections, however, are conflicting. Moreover, the results of therapeutic zinc for childhood malaria also are so far not promising.This paper gives a brief outline of the current evidence from clinical trials on therapeutic effect of oral zinc on childhood respiratory infections, pneumonia and malaria and also of new evidence of the effect on serious bacterial illness in young infants.

A randomized controlled trial of zinc as adjuvant therapy for severe pneumonia in young children.

BACKGROUND AND OBJECTIVE: Diarrhea and pneumonia are the leading causes of illness and death in children <5 years of age. Zinc supplementation is effective for treatment of acute diarrhea and can prevent pneumonia. In this trial, we measured the efficacy of zinc when given to children hospitalized and treated with antibiotics for severe pneumonia. METHODS: We enrolled 610 children aged 2 to 35 months who presented with severe pneumonia defined by the World Health Organization as cough and/or difficult breathing combined with lower chest indrawing. All children received standard antibiotic treatment and were randomized to receive zinc (10 mg in 2- to 11-month-olds and 20 mg in older children) or placebo daily for up to 14 days. The primary outcome was time to cessation of severe pneumonia. RESULTS: Zinc recipients recovered marginally faster, but this difference was not statistically significant (hazard ratio = 1.10, 95% CI 0.94-1.30). Similarly, the risk of treatment failure was slightly but not significantly lower in those who received zinc (risk ratio = 0.88 95% CI 0.71-1.10). CONCLUSIONS: Adjunct treatment with zinc reduced the time to cessation of severe pneumonia and the risk of treatment failure only marginally, if at all, in hospitalized children.

Two weeks of zinc administration to Nepalese children with pneumonia does not reduce the incidence of pneumonia or diarrhea during the next six months.

Diarrhea and pneumonia are the 2 main causes of death in children under 5 y of age. Short courses of zinc administration are now recommended for treatment of childhood diarrhea and some studies have also shown its beneficial effect on treatment of pneumonia. The objective of our study was to assess the efficacy of zinc administration (10 mg/d for children 2-11 mo and 20 mg/d for >or= 12 mo of age) for 14 d on preventing diarrheal and respiratory illnesses for 6 mo of follow-up. This was a randomized, double-blind, placebo-controlled trial in children 2-35 mo of age with community-acquired pneumonia. The number of illness episodes and time until the first episode of various illnesses were compared between the 2 study groups. After 14 d of zinc supplementation, plasma zinc was significantly higher in the group receiving zinc. However, this difference was not detectable at 1 and 2.5 mo after the end of zinc administration. Of 2628 enrolled cases, a total of 2599 (99%) were available for assessment after the completion of zinc supplementation. The number of hospital visits and the median number of days until the first episode of pneumonia, diarrhea, and dysentery was similar in the 2 groups. The hazard ratios (95% CI) were 1.02 (0.92, 1.14) for nonsevere pneumonia, 1.11 (0.72, 1.73) for severe pneumonia, 1.07 (0.91, 1.26) for diarrhea, and 0.96 (0.69, 1.34) for dysentery. A short course of zinc supplementation given during an episode of pneumonia did not prevent diarrheal or respiratory illness over the next 6 mo.

A randomized controlled trial of the effect of zinc as adjuvant therapy in children 2-35 mo of age with severe or nonsevere pneumonia in Bhaktapur, Nepal.

BACKGROUND: Pneumonia is a leading cause of illness and death in young children. Interventions to improve case management of pneumonia are needed. OBJECTIVE: Our objective was to measure the effect of zinc supplementation in children with pneumonia in a population in which zinc deficiency is common. DESIGN: In a double-blind, placebo-controlled clinical trial, children aged 2-35 mo with severe (n = 149) or nonsevere (n = 2479) pneumonia defined according to criteria established by the World Health Organization were randomly assigned to receive zinc (10 mg for children aged 2-11 mo, 20 mg for children aged > or =12 mo) or placebo daily for 14 d as an adjuvant to antibiotics. The primary outcomes were treatment failure, defined as a need for change in antibiotics or hospitalization, and time to recovery from pneumonia. RESULTS: One of 5 children did not respond adequately to antibiotic treatment; the odds ratios between zinc and placebo groups for treatment failure were 0.95 (95% CI: 0.78, 1.2) for nonsevere pneumonia and 0.97 (95% CI: 0.42, 2.2) for severe pneumonia. There was no difference in time to recovery between zinc and placebo groups for nonsevere (median: 2 d; hazard ratio: 1.0; 95% CI: 0.96, 1.1) or severe (median: 4 d; hazard ratio: 1.1; 95% CI: 0.79, 1.5) pneumonia. Regurgitation or vomiting < or =15 min after supplementation was observed more frequently among children in the zinc group than among those in the placebo group during the supplementation period (37% compared with 13%; odds ratio: 0.25; 95% CI: 0.20, 0.30). CONCLUSION: Adjuvant treatment with zinc neither reduced the risk of treatment failure nor accelerated recovery in episodes of nonsevere or severe pneumonia. This trial was registered at clinicaltrials.gov as NCT00148733.

RNA viruses in community-acquired childhood pneumonia in semi-urban Nepal; a cross-sectional study.

BACKGROUND: Pneumonia is among the main causes of illness and death in children <5 years of age. There is a need to better describe the epidemiology of viral community-acquired pneumonia (CAP) in developing countries. METHODS: From July 2004 to June 2007, we examined nasopharyngeal aspirates (NPA) from 2,230 cases of pneumonia (World Health Organization criteria) in children 2 to 35 months old recruited in a randomized trial of zinc supplementation at a field clinic in Bhaktapur, Nepal. The specimens were examined for respiratory syncytial virus (RSV), influenza virus type A (InfA) and B (InfB), parainfluenza virus types 1, 2 and 3 (PIV1, PIV2, and PIV3), and human metapneumovirus (hMPV) using a multiplex reverse transcriptase polymerase chain reaction (PCR) assay. RESULTS: We identified 919 virus isolates in 887 (40.0%) of the 2,219 NPA specimens with a valid PCR result, of which 334 (15.1%) yielded RSV, 164 (7.4%) InfA, 129 (5.8%) PIV3, 98 (4.4%) PIV1, 93 (4.2%) hMPV, 84 (3.8%) InfB, and 17 (0.8%) PIV2. CAP occurred in an epidemic pattern with substantial temporal variation during the three years of study. The largest peaks of pneumonia occurrence coincided with peaks of RSV infection, which occurred in epidemics during the rainy season and in winter. The monthly number of RSV infections was positively correlated with relative humidity (rs = 0.40, P = 0.01), but not with temperature or rainfall. An hMPV epidemic occurred during one of the three winter seasons and the monthly number of hMPV cases was also associated with relative humidity (rs = 0.55, P = 0.0005). CONCLUSION: Respiratory RNA viruses were detected from NPA in 40% of CAP cases in our study. The most commonly isolated viruses were RSV, InfA, and PIV3. RSV infections contributed substantially to the observed CAP epidemics. The occurrence of viral CAP in this community seemed to reflect more or less overlapping micro-epidemics with several respiratory viruses, highlighting the challenges of developing and implementing effective public health control measures.