Social withdrawal behaviour in Nepalese infants and the relationship with future neurodevelopment; a longitudinal cohort study.

BACKGROUND: Social withdrawal in infants may be a signal of distress and a precursor for non-optimal development. OBJECTIVE: To examine the relationship between infant social withdrawal and neurodevelopment up to 4 years in Nepalese children. METHODS: A total of 597 Nepalese infants 6-11 months old were assessed with the modified Alarm Distress Baby Scale (m-ADBB), and of these, 527 with the Bayley Scales of Infant and Toddler Development 3rd edition (Bayley-III) during early childhood, and the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) and NEPSY-II subtests at 4 years. We examined whether social withdrawal defined by the m-ADBB was associated with neurodevelopmental scores in regression models. RESULTS: Children socially withdrawn in infancy had lower Bayley-III language scores (-2.6 (95% CI -4.5, -0.7)) in early childhood. This association seems to be driven by the expressive communication subscale (-0.7 (95% CI -1.0, -0.3)), but not the receptive communication subscale (-0.2 (95% CI -0.6, 0.1)). There were no differences in the other Bayley-III scores or the WPPSI-IV and NEPSY-II scores at 4 years in children who were socially withdrawn or not. CONCLUSION: Social withdrawal in infancy was reflected in early language development but not cognitive functioning at 4 years.

Sleep characteristics and changes in sleep patterns among infants in Bhaktapur, Nepal.

OBJECTIVE: Sleep undergoes major changes during the first year of life, but the characteristics of sleep among infants in low and middle-income countries are not well documented. This study describes sleep characteristics and changes in sleep patterns in infants at 6 and 12months of age from Bhaktapur, Nepal. METHODS: This was a community-based longitudinal study comprising 735 infants. Sleep characteristics were obtained by interview with the mother using the Brief Infant Sleep Questionnaires. The stability of sleep duration and night awakenings were estimated by logistic regression analysis. RESULTS: Cosleeping in the parent's bed at 6 and 12months of age was almost universal (>97%). At 6months of age, 254 (35%) and at 12months of age, 341 (46%) infants had a total 24-hour sleep duration <12 hours. Night awakenings >3 times per night were common (65%) both at 6 and 12months of age. Infants with frequent nightly awakenings at 6months had increased odds of frequent nightly awakenings at 12months (OR=2.2; 95% CI: 1.6, 2.9). Very few (<3%) mothers reported sleep problems in their infants at 6 and 12months of age. CONCLUSIONS: Cosleeping was almost universal among Nepalese infants, and very few of the mothers reported sleep problems in their infants. Infants at 6 and 12months had similar patterns for both sleep duration and nocturnal awakenings. For infants, there were increased odds of having similar sleep duration and nocturnal awakening at 6 and 12months.

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.

Unmet Diagnostic and Therapeutic Opportunities for Chronic Obstructive Pulmonary Disease in Low- and Middle-Income Countries.

Rationale: Chronic obstructive pulmonary disease (COPD) is a prevalent and burdensome condition in low- and middle-income countries (LMICs). Challenges to better care include more effective diagnosis and access to affordable interventions. There are no previous reports describing therapeutic needs of populations with COPD in LMICs who were identified through screening. Objectives: To describe unmet therapeutic need in screening-detected COPD in LMIC settings. Methods: We compared interventions recommended by the international Global Initiative for Chronic Obstructive Lung Disease COPD strategy document, with that received in 1,000 people with COPD identified by population screening at three LMIC sites in Nepal, Peru, and Uganda. We calculated costs using data on the availability and affordability of medicines. Measurement and Main Results: The greatest unmet need for nonpharmacological interventions was for education and vaccinations (applicable to all), pulmonary rehabilitation (49%), smoking cessation (30%), and advice on biomass smoke exposure (26%). Ninety-five percent of the cases were previously undiagnosed, and few were receiving therapy (4.5% had short-acting ß-agonists). Only three of 47 people (6%) with a previous COPD diagnosis had access to drugs consistent with recommendations. None of those with more severe COPD were accessing appropriate maintenance inhalers. Even when available, maintenance treatments were unaffordable, with 30 days of treatment costing more than a low-skilled worker's daily average wage. Conclusions: We found a significant missed opportunity to reduce the burden of COPD in LMIC settings, with most cases undiagnosed. Although there is unmet need in developing novel therapies, in LMICs where the burden is greatest, better diagnosis combined with access to affordable interventions could translate to immediate benefit.

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 reliability and predictive ability of the Test of Infant Motor Performance (TIMP) in a community-based study in Bhaktapur, Nepal.

AIM: In a Nepalese setting, to measure the reliability of the Test of Infant Motor Performance (TIMP) and its ability to predict development scores at 6 months. METHODS: Nepalese infants (n = 705) were assessed by the TIMP when they were 8-12 weeks old and the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III) at 6 months. Inter-rater agreement was expressed by intraclass correlation coefficients (ICCs), the internal consistency by Cronbach's alphas and Pearson correlation coefficients. Predictive ability was estimated in linear regression models. RESULTS: Inter-rater agreement was excellent (ICCs > 0.93). Alphas for the TIMP total scores were 0.76 for infants born to term and 0.72 in those born preterm. Correlation coefficients between TIMP total and Bayley-III subscale-scores ranged from 0.05 to 0.28 for term infants and from 0.15 to 0.43 for preterm infants. Using American norms, 56.3 % had TIMP scores within average and 43.7 % below average range. Bayley-III subscale scores were lower in children with TIMP scores below the average range, with the strongest estimates for Gross motor and Socio-emotional development. INTERPRETATION: The reliability of the TIMP was acceptable, and the TIMP could be a feasible tool to monitor infant motor development in low-resource settings. Properties of the TIMP differed according to gestational age.

The association between household biomass fuel use and leukocyte telomere length among toddlers in Bhaktapur, Nepal.

BACKGROUND: Biomass fuels are still in use for cooking by many households in resource poor countries such as Nepal and is a major source of household air pollution (HAP). Chronic exposure to HAP has been shown to be associated with shorter telomere length in adults. OBJECTIVES: To measure the association between exposure related to household biomass fuel in infancy and leukocyte telomere length (LTL) at 18-23 months of age among 497 children from Bhaktapur, Nepal. METHODS: In a prospective cohort study design, we have collected information on household cooking fuel use and several clinical, anthropometric, demographic, and socioeconomic variables. We estimated the association between biomass fuel use and the relative LTL in multiple linear regression models. RESULTS: Most of the families (78%) reported liquified petroleum gas (LPG) as the primary cooking fuel, and 18.7% used biomass. The mean relative (SD) LTL was 1.03 (0.19). Children living in households using biomass fuel had on average 0.09 (95% CI: 0.05 to 0.13) units shorter LTL than children in households with no biomass fuel use. The observed association was unaltered after adjusting for relevant confounders. The association between LTL and biomass use was strongest among children from households with ≤2 rooms and without separate kitchen. SIGNIFICANCE: Exposure to biomass fuel use in early life might have consequences for longevity, and risk of chronic illnesses reflected in shortening of the telomeres. Our findings support the ongoing effort to reduce exposure to biomass fuel in low-resource settings. IMPACT STATEMENTS: Biomass for cooking is a leading source of household air pollution in low and middle-income countries, contributing to many chronic diseases and premature deaths. Chronic exposure to biomass fuel through oxidative stress and inflammation has been associated with a shortening of the telomeres, a "biological marker" of longevity. This prospective cohort study describes the association between household biomass fuel use and leukocyte telomere length among 497 toddlers. Leukocyte telomere length was significantly shorter among children living in households with biomass fuel than in children from homes where mainly LPG was used for cooking. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT02272842, registered October 21, 2014, Universal Trial Number: U1111-1161-5187 (September 8, 2014).

The stability of the Bayley scales in early childhood and its relationship with future intellectual abilities in a low to middle income country.

BACKGROUND: The Bayley Scales of Infant and Toddler Development is widely used worldwide. The objective of the current study was to measure the stability of the Bayley Scales during early childhood and its relationship with intellectual abilities at four years in young Nepalese children. METHODS: In a prospective cohort we used the Bayley 3rd edition to measure early child development in 529 Nepalese children at 6-11, 18-23 and 30-35 months. At four years, we used the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) to measure intellectual abilities. We expressed the stability of the Bayley scores by intraclass correlation coefficients (ICCs) and concordance correlation coefficients (CCCs). The relationship between the Bayley scores and the WPPSI full-scale IQ (FSIQ) at four years was examined in regression models. RESULTS: The ICCs between the Bayley scores across timepoints were 0.01 (95 % CI -0.06, 0.04), 0.19 (95 % CI 0.15, 0.26) and 0.22 (95 % CI 0.17, 0.28) for the Cognitive, Language and Motor composite scores. The CCC for the composite scores ranged from 0.05 to 0.20 between 6 and 11 and 30-35 months and from 0.20 to 0.36 between 18 and 23 and 30-35 months. The Bayley scores at 6-11, 18-23 and 30-35 months explained 3 %, 20 % and 36 % of the variation of the FSIQ. CONCLUSION: The stability of the Bayley scales is poor in early childhood, and its relationship with future intellectual abilities is poor in infancy but improves slightly with age in early childhood. Findings from this large community-based cohort of healthy at-risk children are relevant when measuring early child development worldwide.

Biomass fuel use for cooking in Nepalese families and child cognitive abilities, results from a community-based study.

BACKGROUND: Biomass fuel use for cooking is widespread in low to middle income countries. Studies on the association between biomass fuel use and cognitive abilities in children are limited. OBJECTIVE: To examine the association between biomass fuel use for cooking and cognitive abilities in Nepalese children at 4 years of age. METHODS: In a cohort design we have information on biomass fuel use in the households of 533 children in infancy and cognitive abilities when they were 4 years old from a community-based sample. Cognitive abilities were measured by the Wechsler Preschool and Primary Scale of Intelligence, 4th edition (WPPSI-IV) and the NEPSY-II. We examined the associations between biomass fuel use and scores on the WPPSI-IV Full-Scale IQ (FSIQ) (primary outcome), and WPPSI index and NEPSY-II subtest scores in multiple linear regression models. The associations were also examined in predefined subgroups. RESULTS: Ninety-nine (18.6%) of the families used biomass fuel for cooking. Children in these families had lower mean FSIQ than children in families with no biomass use (83.3 (95%CI 81.7, 85.0) vs. 85.3 (95%CI 84.5, 86.0)), with a mean difference of -2.2 (95%CI -3.9, -0.5) adjusting for demographics and socio-economic status. The association between biomass fuel use and cognitive abilities was strongest in subgroups of children from households with more than three rooms, with separate kitchen and bedroom, and with higher wealth-score. These interactions were significant for number of rooms in the home (p = 0.04), if the household had separate bedroom and kitchen (p = 0.05), and for the wealth-score (p = 0.03). CONCLUSION: Biomass fuel use for cooking in Nepalese families was associated with lower overall cognitive abilities at 4 years. Uncertainties include exposure misclassification and unmeasured confounding. The associations between biomass fuel use and neurodevelopment in children needs further investigation with more precise measurements of the exposure.

The association between biomass fuel use for cooking and linear growth in young children in Bhaktapur, Nepal.

BACKGROUND: There are still many people in the world who prepare their meals on open fires or stoves using solid fuels from biomass, especially in low-and middle-income countries. Although biomass cooking fuels have been associated with adverse health impacts and diseases, the association with child linear growth remains unclear. OBJECTIVES: In a cohort design, we aimed to describe the association between the use of biomass cooking fuels and linear growth in children aged 18-23 months living in the urban and peri-urban community of Bhaktapur, situated in the Kathmandu valley in Nepal. METHODS: Caretakers of 600 marginally stunted children aged 6-11 months were interviewed about their source of cooking fuel and other socio-demographic characteristics at enrolment into a randomized controlled trial. Children's body length was measured when children were 18-23 months old. In linear regression models, we estimated the association between the use of biomass fuel and length-for-age Z-scores (LAZ), adjusted for relevant confounders. We repeated these analyses in pre-defined sub-groups and different percentiles of LAZ using quantile regression models. RESULTS: Among study participants, 101 (18%) used biomass as cooking fuel. The association between biomass fuel and LAZ was not statistically significant in the full sample (adjusted regression coefficient: -0.14, 95% CI: -0.28, 0.00). The association was stronger in some of the sub-groups and in the lower tail of the LAZ distribution (those who are stunted), but neither reached statistical significance. DISCUSSION: Children from households in poor, urban neighborhoods in Nepal which used biomass fuel for cooking were on average slightly shorter than other children, although the association only approached statistical significance. As this was an observational study, residual confounding cannot be excluded. Further studies are needed to confirm these associations, in particular those seen in certain sub-groups.

Discriminative Accuracy of Chronic Obstructive Pulmonary Disease Screening Instruments in 3 Low- and Middle-Income Country Settings.

Importance: Most of the global morbidity and mortality in chronic obstructive pulmonary disease (COPD) occurs in low- and middle-income countries (LMICs), with significant economic effects. Objective: To assess the discriminative accuracy of 3 instruments using questionnaires and peak expiratory flow (PEF) to screen for COPD in 3 LMIC settings. Design, Setting, and Participants: A cross-sectional analysis of discriminative accuracy, conducted between January 2018 and March 2020 in semiurban Bhaktapur, Nepal; urban Lima, Peru; and rural Nakaseke, Uganda, using a random age- and sex-stratified sample of the population 40 years or older. Exposures: Three screening tools, the COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE; range, 0-6; high risk indicated by a score of 5 or more or score 2-5 with low PEF [<250 L/min for females and <350 L/min for males]), the COPD in LMICs Assessment questionnaire (COLA-6; range, 0-5; high risk indicated by a score of 4 or more), and the Lung Function Questionnaire (LFQ; range, 0-25; high risk indicated by a score of 18 or less) were assessed against a reference standard diagnosis of COPD using quality-assured postbronchodilator spirometry. CAPTURE and COLA-6 include a measure of PEF. Main Outcomes and Measures: The primary outcome was discriminative accuracy of the tools in identifying COPD as measured by area under receiver operating characteristic curves (AUCs) with 95% CIs. Secondary outcomes included sensitivity, specificity, positive predictive value, and negative predictive value. Results: Among 10 709 adults who consented to participate in the study (mean age, 56.3 years (SD, 11.7); 50% female), 35% had ever smoked, and 30% were currently exposed to biomass smoke. The unweighted prevalence of COPD at the 3 sites was 18.2% (642/3534 participants) in Nepal, 2.7% (97/3550) in Peru, and 7.4% (264/3580) in Uganda. Among 1000 COPD cases, 49.3% had clinically important disease (Global Initiative for Chronic Obstructive Lung Disease classification B-D), 16.4% had severe or very severe airflow obstruction (forced expiratory volume in 1 second <50% predicted), and 95.3% of cases were previously undiagnosed. The AUC for the screening instruments ranged from 0.717 (95% CI, 0.677-0.774) for LFQ in Peru to 0.791 (95% CI, 0.770-0.809) for COLA-6 in Nepal. The sensitivity ranged from 34.8% (95% CI, 25.3%-45.2%) for COLA-6 in Nepal to 64.2% (95% CI, 60.3%-67.9%) for CAPTURE in Nepal. The mean time to administer the instruments was 7.6 minutes (SD 1.11), and data completeness was 99.5%. Conclusions and Relevance: This study demonstrated that screening instruments for COPD were feasible to administer in 3 low- and middle-income settings. Further research is needed to assess instrument performance in other low- and middle-income settings and to determine whether implementation is associated with improved clinical outcomes.

The effect of vitamin B12-supplementation on actigraphy measured sleep pattern; a randomized control trial.

BACKGROUND: Vitamin B12 deficiency is common worldwide and has been associated with poor sleep. The effect of vitamin B12 supplementation on sleep in infants is not known. AIMS: To measure the effect of daily supplementation of vitamin B12 for one year on sleep in infants at risk of deficiency. METHODS: This was an individually randomized double-blind placebo-controlled trial in 600 infants in low-to middle-income neighborhoods in Bhaktapur, Nepal of daily supplementation of vitamin B12 for one year. Infants were included if they were 6-11 month year-old and with a length-for-age less than one z-score. Sleep was a predefined, secondary outcome, and was measured by actigraphy including sleep duration at night and total sleep duration (day and night), sleep onset latency (SOL), and wake after sleep onset (WASO). The effect of vitamin B12 on sleep was additionally assessed in predefined subgroups defined by stunting, underweight, vitamin B12 status, low birthweight, anemia and exclusive breastfeeding for 3 months. RESULTS: There was no effect of vitamin B12 supplementation on sleep duration at night, total sleep duration, or WASO. There was a small significant negative effect for SOL. None of the included subgroup analyses revealed effect modification on any of the sleep outcomes. CONCLUSION: Overall, vitamin B12 supplementation did not have an effect on sleep in infants or for high-risk subgroups, with the exception of a small negative effect for SOL. The present study does not support vitamin B12 supplementation to improve sleep in infants. TRIAL REGISTRATION: clinicaltrials.gov: NCT02272842. UNIVERSAL TRIAL NUMBER: U1111-1161-5187.

Impact of the COVID-19 pandemic on daily life and worry among mothers in Bhaktapur, Nepal.

The COVID-19 pandemic has affected many aspects of daily life worldwide, but the impact may be higher for impoverished populations. The main aim of this study is to describe the impact of the COVID-19 pandemic on different aspects of daily life in mothers in Nepal. We included 493 mothers of children aged 54-71 months participating in a randomized controlled trial on vitamin B12 supplementation. Mothers answered questions regarding the exposure and impact of the pandemic on their daily lives, and pandemic-related worries and sleep problems. We examined the extent to which worry, and sleep problems differed between mothers according to their exposure to COVID-19, socioeconomic status, and previous symptoms of depression. The mean age (SD) of the mothers was 32.3 (4.6) years and 54% had education below the secondary level. Of the mothers, 5.4% had either been exposed to someone who had tested positive or who had a family member with COVID-19. One-third of the participants responded that the pandemic had affected their economic situation, employment, and family life to a great deal. Both mothers and fathers with educational levels above 10 years or households with higher socioeconomic status had significantly higher average worry scores (maternal p = 0.020 and paternal p = 0.005). Mothers with a history of symptoms of depression had significantly more worry-related sleep problems during the pandemic (p = 0.020) than those without a history of depressive symptoms. Our study underlines the negative impact of the COVID-19 pandemic on diverse aspects of everyday life of mothers in Nepal.

Cobalamin and folate status in women during early pregnancy in Bhaktapur, Nepal.

The demand for cobalamin (vitamin B12) and folate is increased during pregnancy, and deficiency during pregnancy may lead to complications and adverse outcomes. Yet, the status of these micronutrients is unknown in many populations. We assessed the concentration of cobalamin, folate and their functional biomarkers, total homocysteine (tHcy) and methylmalonic acid (MMA), in 561 pregnant women enrolled in a community-based randomised controlled trial in Bhaktapur, Nepal. Plasma concentrations of cobalamin, folate, tHcy and MMA were measured and a combined indicator of vitamin B12 status (3cB12) was calculated. We report mean or median concentrations and the prevalence of deficiency according to commonly used cut-offs, and assessed their association with indicators of socio-economic status, and maternal and dietary characteristics by linear regression. Among the women at gestational week less than 15, deficiencies of cobalamin and folate were seen in 24 and 1 %, respectively. Being a vegetarian was associated with lower plasma cobalamin, and a higher socio-economic status was associated with a better micronutrient status. We conclude that cobalamin deficiency defined by commonly used cut-offs was common in Nepalese women in early pregnancy. In contrast, folate deficiency was rare. As there is no consensus on cut-off points for vitamin B12 deficiency during pregnancy, future studies are needed to assess the potential functional consequences of these low values.

Characteristics associated with the transition to partial breastfeeding prior to 6 months of age: Data from seven sites in a birth cohort study.

The WHO recommends exclusive breastfeeding for the first 6 months of life. However, the transition of the infants' diet to partial breastfeeding with the addition of animal milks and/or solids typically occurs earlier than this. Here, we explored factors associated with the timing of an early transition to partial breastfeeding across seven sites of a birth cohort study in which twice weekly information on infant feeding practices was collected. Infant (size, sex, illness and temperament), maternal (age, education, parity and depressive symptoms), breastfeeding initiation practices (time of initiation, colostrum and pre-lacteal feeding) and household factors (food security, crowding, assets, income and resources) were considered. Three consecutive caregiver reports of feeding animal milks and/or solids (over a 10-day period) were characterized as a transition to partial breastfeeding, and Cox proportional hazard models with time (in days) to partial breastfeeding were used to evaluate associations with both fixed and time-varying characteristics. Overall, 1470 infants were included in this analysis. Median age of transition to partial breastfeeding ranged from 59 days (South Africa and Tanzania) to 178 days (Bangladesh). Overall, higher weight-for-length z-scores were associated with later transitions to partial breastfeeding, as were food insecurity, and infant cough in the past 30 days. Maternal depressive symptoms (evaluated amongst 1227 infants from six sites) were associated with an earlier transition to partial breastfeeding. Relative thinness or heaviness within each site was related to breastfeeding transitions, as opposed to absolute z-scores. Further research is needed to understand relationships between local perceptions of infant body size and decisions about breastfeeding.

One-Carbon Metabolism in Nepalese Infant-Mother Pairs and Child Cognition at 5 Years Old.

BACKGROUND: One-carbon metabolism (OCM) refers to the transfer of methyl groups central to DNA methylation and histone modification. Insufficient access to methyl donors and B-vitamin cofactors affects epigenetic maintenance and stability, and when occurring in early life may impact future health and neurodevelopment. OBJECTIVE: The objective of this study was to examine the relative associations between one-carbon metabolites in Nepalese mother-infant pairs and child cognition measured at 5 y of age. METHODS: This is a cross-sectional study from Bhaktapur, Nepal, in a population at high risk of subclinical B-vitamin deficiencies and cumulative infection burden. Venous blood samples from 500 mother-infant pairs were collected when the infants were 2 to 12 mo old, and metabolite concentrations measured by microbiological assays and GC-tandem MS. We re-enrolled 321 of these children at 5 y and assessed cognition by the Ages and Stages Questionnaire, 3rd edition, and subtests from the Developmental Neuropsychological Assessment, 2nd edition (NEPSY-II). The associations of the independent metabolites or unobserved metabolic phenotypes (identified by latent class analysis) with the cognitive outcomes were estimated by seemingly unrelated regression. We explored direct and indirect relations between the OCM pathway and the cognitive outcomes using path analysis. RESULTS: Infant cystathionine concentration was inversely associated with 4 cognitive outcomes (standardized ßs ranging from -0.22 to -0.11, P values from <0.001 to 0.034). Infants with a metabolic phenotype indicating impaired OCM and low vitamin B-12 status had poorer cognitive outcomes compared with infants with normal OCM activity and adequate vitamin B-12 status (standardized ßs ranging from -0.80 to -0.40, P < 0.001 and 0.05). In the path analysis, we found several OCM biomarkers were associated with affect recognition through infant plasma cystathionine. CONCLUSIONS: Elevated plasma cystathionine during infancy reflects a metabolic phenotype of impaired OCM and low vitamin B-12 status and is associated with poorer cognitive function when the children are 5 y old.

Effects of vitamin B12 supplementation on neurodevelopment and growth in Nepalese Infants: A randomized controlled trial.

BACKGROUND: Vitamin B12 deficiency is common and affects cell division and differentiation, erythropoiesis, and the central nervous system. Several observational studies have demonstrated associations between biomarkers of vitamin B12 status with growth, neurodevelopment, and anemia. The objective of this study was to measure the effects of daily supplementation of vitamin B12 for 1 year on neurodevelopment, growth, and hemoglobin concentration in infants at risk of deficiency. METHODS AND FINDINGS: This is a community-based, individually randomized, double-blind placebo-controlled trial conducted in low- to middle-income neighborhoods in Bhaktapur, Nepal. We enrolled 600 marginally stunted, 6- to 11-month-old infants between April 2015 and February 2017. Children were randomized in a 1:1 ratio to 2 µg of vitamin B12, corresponding to approximately 2 to 3 recommended daily allowances (RDAs) or a placebo daily for 12 months. Both groups were also given 15 other vitamins and minerals at around 1 RDA. The primary outcomes were neurodevelopment measured by the Bayley Scales of Infant and Toddler Development 3rd ed. (Bayley-III), attained growth, and hemoglobin concentration. Secondary outcomes included the metabolic response measured by plasma total homocysteine (tHcy) and methylmalonic acid (MMA). A total of 16 children (2.7%) in the vitamin B12 group and 10 children (1.7%) in the placebo group were lost to follow-up. Of note, 94% of the scheduled daily doses of vitamin B12 or placebo were reported to have been consumed (in part or completely). In this study, we observed that there were no effects of the intervention on the Bayley-III scores, growth, or hemoglobin concentration. Children in both groups grew on an average 12.5 cm (SD: 1.8), and the mean difference was 0.20 cm (95% confidence interval (CI): -0.23 to 0.63, P = 0.354). Furthermore, at the end of the study, the mean difference in hemoglobin concentration was 0.02 g/dL (95% CI: -1.33 to 1.37, P = 0.978), and the difference in the cognitive scaled scores was 0.16 (95% CI: -0.54 to 0.87, P = 0.648). The tHcy and MMA concentrations were 23% (95% CI: 17 to 30, P < 0.001) and 30% (95% CI: 15 to 46, P < 0.001) higher in the placebo group than in the vitamin B12 group, respectively. We observed 43 adverse events in 36 children, and these events were not associated with the intervention. In addition, 20 in the vitamin B12 group and 16 in the placebo group were hospitalized during the supplementation period. Important limitations of the study are that the strict inclusion criteria could limit the external validity and that the period of vitamin B12 supplementation might not have covered a critical window for infant growth or brain development. CONCLUSIONS: In this study, we observed that vitamin B12 supplementation in young children at risk of vitamin B12 deficiency resulted in an improved metabolic response but did not affect neurodevelopment, growth, or hemoglobin concentration. Our results do not support widespread vitamin B12 supplementation in marginalized infants from low-income countries. TRIAL REGISTRATION: ClinicalTrials.gov NCT02272842 Universal Trial Number: U1111-1161-5187 (September 8, 2014) Trial Protocol: Original trial protocol: PMID: 28431557 (reference [18]; study protocols and plan of analysis included as Supporting information).

Prevalence of Underweight, Overweight, and Obesity in Adults in Bhaktapur, Nepal in 2015-2017.

Introduction: There is an increase in the double burden of malnutrition globally, with a particular rise documented in Asia. In Nepal, undernutrition has been prevalent for decades. Today, however, the incidence of overweight and obesity (OWOB) in the country has increased substantially. There is a need to conduct local studies reporting on the concurrent burden of both underweight and OWOB across adult populations. This study addresses this need by describing the distribution of body mass index (BMI) in a defined population of adults living in the peri-urban community of Bhaktapur, Nepal. Material and methods: For this cross-sectional analysis, we used data that were available from 600 women and 445 men whose children were enrolled in an individually randomized, double-blind, placebo-controlled trial assessing the effect of daily vitamin B12 supplementation. Upon enrolment of their 6-11-month old children, mothers and fathers were interviewed about their socio-demographic details. In addition, their weight and height were measured by trained field workers. Each parent's BMI was calculated as the ratio of body weight (in kg) and height squared (in m), expressed as kg/m2, and categorized according to the WHO recommendation. We used linear and multinomial logistic regression models to assess associations between the BMI of the mothers and fathers, and their baseline characteristics. Results: The mean BMI was 23.7 kg/m2 for both the mothers and fathers with a standard deviation (SD) of 3.6 and 3.7, respectively. The proportion categorized as underweight, overweight, and obese was also similar in the two groups with around 5% being underweight, 30% being overweight and 5% being obese. Age was positively associated with BMI in both groups. Those categorized as daily wage earner had a lower mean BMI than those in other occupational groups. Conclusion: Our results contribute to documenting the burden of both under- and overnutrition in a selected group of young adults living in a peri-urban community in Nepal. As Nepal is undergoing an improvement in its economic situation, as well as a nutrition transition, it is important to provide sufficient information to enable timely action, and evidence-based decision-making to prevent a further increase in Nepal's growing double burden of malnutrition.

The Feasibility of the Full and Modified Versions of the Alarm Distress Baby Scale (ADBB) and the Prevalence of Social Withdrawal in Infants in Nepal.

BACKGROUND: Sustained social withdrawal in infancy may have organic and nonorganic causes and could hinder normal development. The Alarm Distress Baby (ADBB) scale is a widely validated screening tool of social withdrawal in children 2-24 months. The aim of the current study was to evaluate the full and modified ADBB in Nepalese infants in a community-based study. METHODS: We enrolled 600 infants who were video recorded during a pediatric examination. The 36 infants first enrolled were scored by an expert rater, and the subsequent 64 infants were scored by two trained staff with the full ADBB scale. Of the 600 enrolled infants, 597 videos (including the 100 infants scored with the full ADBB) were scored with the modified ADBB (m-ADBB) scale by the trained staff, with 7% double scoring. We measured the interrater agreement and psychometric properties of both scales. RESULTS: In the 64 infants scored with the full ADBB by two raters, the concordance correlation coefficients (CCCs) indicated poor interrater agreement. For the m-ADBB, the CCCs were better indicating acceptable agreement between raters. The greatest lower bound (GLB) for reliability coefficient for the full ADBB scored by an expert rater indicated good internal consistency, whereas the GLB coefficient for the m-ADBB indicated poorer internal consistency. The Spearman correlation coefficient between the total scores of the two versions was 0.82 (P < 0.001). Among the infants scored with the full ADBB, 25% had a score above cutoff (≥5). Scored with the m-ADBB in the full sample, 11.4% of the infants had a score above the suggested cutoff (≥2). In both versions, children achieved high scores on vocalization. CONCLUSION: Our findings suggest that the m-ADBB is an acceptable approach to achieve adequate interrater agreement in a large community-based study in Nepal. Results indicate high prevalence of social withdrawal in this population. There are, however, uncertainties on the internal consistency of the scales in this setting, and the validity of the scales needs to be investigated further. More effective training strategies for administration and additional cultural-specific instructions could be important measures to explore before implementing the scale further in this setting.