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.

Knowledge, attitudes and practices regarding respirable silica exposure and personal protective equipment use among brick kiln workers in Nepal.

OBJECTIVES: Brick kiln workers in Nepal are a neglected population who are exposed to high respirable silica concentrations, and few use interventions to reduce exposure. We aimed to characterise the prevalence of respiratory personal protective equipment (PPE) use, understand knowledge and attitudes towards kiln dust and respiratory PPE and identify factors associated with respiratory PPE use. METHODS: We conducted a cross-sectional study in Bhaktapur, Nepal. We used simple random selection to identify 10 out of 64 total kilns and stratified random sampling of 30 households to enrol workers aged ≥14 years within selected kilns. Field workers surveyed participants using structured questionnaires. Our primary outcome was to characterise the prevalence of current respiratory PPE use and secondary outcomes were summaries of knowledge, attitudes and practice of PPE use. RESULTS: We surveyed 83 workers (mean age 30.8 years, 77.1% male). Of these, 28.9% reported current respiratory PPE use at work, 3.6% heard of silicosis prior to the survey and 24.1% correctly identified the best respiratory PPE (N95, compared with surgical masks and barrier face coverings) for reducing dust exposure. Respiratory PPE users had higher income (mean monthly household income US$206 vs US$145; p=0.04) and education levels (25% vs 5.1% completed more than primary school; p=0.02) compared with non-users. CONCLUSIONS: Respiratory PPE use was low. Workers had poor knowledge of kiln dust health effects and proper respiratory PPE. We highlight important barriers to PPE use, particularly knowledge gaps, which can guide future investigations to reduce the silicosis burden among brick kiln workers.

Brick kiln pollution and its impact on health: A systematic review and meta-analysis.

Brick kiln emissions adversely affect air pollution and the health of workers and individuals living near the kilns; however, evidence of their impacts remains limited. We conducted a systematic review of brick kiln pollution (emissions, source contributions and personal exposures) and its effects on health. We extracted articles from electronic databases and through manual citation searching. We estimated pooled, sample-size-weighted means and standard deviations for personal exposures by job type; computed mean emission factors and pollutant concentrations by brick kiln design; and meta-analyzed differences in means or proportions for health outcomes between brick kiln workers and controls or for participants living near or far away from kilns. We identified 104 studies; 74 were conducted in South Asia. The most evaluated pollutants were particulate matter (PM; n = 48), sulfur dioxide (SO2; n = 24) and carbon monoxide (CO; n = 22), and the most evaluated health outcomes were respiratory health (n = 34) and musculoskeletal disorders (n = 9). PM and CO emissions were higher among traditional than improved brick kilns. Mean respirable silica exposures were only measured in 4 (4%) studies and were as high as 620 µg/m3, exceeding the NIOSH recommended exposure limit by a factor of over 12. Brick kiln workers had consistently worse lung function, more respiratory symptoms, more musculoskeletal complaints, and more inflammation when compared to unexposed participants across studies; however, most studies had a small sample size and did not fully describe methods used for sampling or data collection. On average, brick kiln workers had worse health outcomes when compared to unexposed controls but study quality supporting the evidence was low. Few studies reported silica concentrations or personal exposures, but the few that did suggest that exposures are high. Further research is needed to better understand the relationship between brick kiln pollution and health among workers, and to evaluate exposure mitigation strategies.

Chronic Obstructive Pulmonary Disease Self-Management in Three Low- and Middle-Income Countries: A Pilot Randomized Trial.

Objectives: Chronic obstructive pulmonary disease (COPD) disproportionately affects low- and middle-income countries. Health systems are ill prepared to manage the increase in COPD cases. Methods: We performed a pilot effectiveness-implementation randomized field trial of a community health worker (CHW)-supported, 1-year self-management intervention in individuals with COPD grades B-D. The study took place in low-resource settings of Nepal, Peru, and Uganda. The primary outcome was the St. George's Respiratory Questionnaire (SGRQ) score at 1 year. We evaluated differences in moderate to severe exacerbations, all-cause hospitalizations, and the EuroQol score (EQ-5D-3 L) at 12 months. Measurements and Main Results: We randomly assigned 239 participants (119 control arm, 120 intervention arm) with grades B-D COPD to a multicomponent, CHW-supported intervention or standard of care and COPD education. Twenty-five participants (21%) died or were lost to follow-up in the control arm compared with 11 (9%) in the intervention arm. At 12 months, there was no difference in mean total SGRQ score between the intervention and control arms (34.7 vs. 34.0 points; adjusted mean difference, 1.0; 95% confidence interval, -4.2, 6.1; P = 0.71). The intervention arm had a higher proportion of hospitalizations than the control arm (10% vs. 5.2%; adjusted odds ratio, 2.2; 95% confidence interval, 0.8, 7.5; P = 0.15) at 12 months. Conclusions: A CHW-based intervention to support self-management of acute exacerbations of COPD in three resource-poor settings did not result in differences in SGRQ scores at 1 year. Fidelity was high, and intervention engagement was moderate. Although these results cannot differentiate between a failed intervention or implementation, they nonetheless suggest that we need to revisit our strategy. Clinical trial registered with www.clinicaltrials.gov (NCT03359915).

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.

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.

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.

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).

Acute gastroenteritis associated with Rotavirus A among children less than 5 years of age in Nepal.

BACKGROUND: Rotavirus gastroenteritis is a major public health problem in Nepal. This study was conducted to obtain information associated with Rotavirus gastroenteritis and to perform genotyping of Rotavirus A. METHODS: Hospital based cross sectional study was conducted from January to December 2017 among children less than 5 years of age attending Kanti Children's Hospital and Tribhuvan University Teaching Hospital. Rotavirus A antigen detection was performed by Enzyme Linked Immunosorbent Assay (ELISA) using ProSpecT Rotavirus Microplate Assay. Rotavirus A positive strains were further confirmed by genotyping using Reverse-Transcription Polymerase Chain Reaction (RT-PCR). RESULTS: A total of 1074 stool samples were collected, of them 770 were hospitalized, and 304 were non-hospitalized cases. Rotavirus A infection was found in 28% of children with infection rate higher in hospitalized (34%) than in non-hospitalized (14%) children. Rotavirus A detection was higher in male (31%) than in female (24%), but this was statistically not significant (p > 0.05). Rotavirus A positivity was higher in children of age group 0-23 months, this result was statistically not significant (p > 0.05) with higher frequency found in the months of November, December, January, February and March (p < 0.05). On the basis of molecular analysis of Rotavirus A genotyping, G12P[6] (46.39%) was found to be the predominant followed by G1P[8] (35.05%), G3P[8] (7.21%) and G1P[6] (5.15%) while 4.12% was mixed infection and 1.03% was partially typed (p < 0.05). CONCLUSION: Rotavirus A infection occurred throughout the year, but the infection was significantly higher during the month of March. The higher frequency of rotavirus infection was observed among children of age group 0-23 months; however this was not found to be statistically significant. In this study, G12P[6] is predominant genotype observed. The results of genotyping are essential for the introduction of Rotavirus vaccine in Nepal.

Parental height modifies the association between linear growth and neurodevelopment in infancy.

AIM: To estimate the extent to which maternal and paternal height modify the association between length-for-age Z-score (LAZ) and neurodevelopmental outcomes assessed by the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III). METHODS: Baseline data from a clinical trial in 600 Nepalese infants aged six to 11 months with LAZ less than -1 were utilised. The primary exposure was the LAZ score, interaction variables were maternal and paternal height, and the outcomes were Bayley-III cognitive, language and motor scaled scores. Linear regression and generalised additive model (GAM) were used to identify potential interactions. RESULTS: Linear regression analysis stratified by parental height categories showed that association between unit increase in LAZ and cognitive scaled score differed across maternal (normal height: ß 1.16, 95% CI; 0.75, 1.57 and short height: ß 0.67, 95% CI; 0.28, 1.05) and paternal (normal height: ß 1.32, 95% CI; 0.91, 1.72 and short height: ß 0.61, 95% CI; 0.03, 1.18) height categories. Maternal height also modified the association between LAZ and fine motor scaled score. CONCLUSION: The association between LAZ and neurodevelopmental outcomes was attenuated when maternal and paternal height was taken into account. Parental stature should be considered when using LAZ as a proxy for neurodevelopment among infants.

The feasibility of the Ages and Stages Questionnaire for the assessment of child development in a community setting in Nepal.

BACKGROUND: The Ages and Stages Questionnaire Third Edition (ASQ-3) may be a feasible and cost-effective tool to screen children's development in resource poor settings. We have assessed the feasibility of the ASQ-3 "home procedure" when conducted by fieldworkers in a community-based nutritional interventional trial on early child development in Nepal. METHOD: Six hundred children aged 6-11 months at risk of stunting were assessed by trained fieldworkers in their homes by the ASQ-3. Three fieldworkers performed standardization exercises and were double scored with a gold standard during the study period. Intraclass correlations (ICCs) were calculated to measure the interrater agreement. The internal consistency was expressed by standardized Cronbach's alphas. The association between total ASQ score and gestation, low birth weight, and stunted children is presented to give an estimate of the construct validity of the tool. RESULT: Mean scores of the 600 Nepalese children were consistently lower than in the American norm sample. The ICCs from the standardization exercises were initially good to excellent but declined throughout the study period. The standardized alphas for the total score in the different age groups indicate good internal consistency but varied in the subscales. Children who were preterm, children with low birth weight, and children who were stunted scored substantially lower on the total ASQ score than those who were not. CONCLUSION: Although the ASQ-3 "home procedure" is low at cost and easily accessible in a Nepalese context, the tool requires rigorous and stringent training to achieve acceptable interrater agreement. Further adjustment is required to achieve satisfactory internal consistency.

Impact of Timing of Influenza Vaccination in Pregnancy on Transplacental Antibody Transfer, Influenza Incidence, and Birth Outcomes: A Randomized Trial in Rural Nepal.

Background: Maternal influenza vaccination protects mothers and their infants in low resource settings, but little is known about whether the protection varies by gestational age at vaccination. Methods: Women of childbearing age in rural southern Nepal were surveilled for pregnancy, consented and randomized to receive maternal influenza vaccination or placebo, with randomization stratified on gestational age (17-25 or 26-34 weeks). Enrollment occurred in 2 annual cohorts, and vaccinations occurred from April 2011 through September 2013. Results: In sum, 3693 women consented and enrolled, resulting in 3646 live births. Although cord blood antibody titers and the rise in maternal titers were generally greater when women were vaccinated later in pregnancy, this was not statistically significant. The incidence risk ratio (IRR) for maternal influenza in pregnancy through 6 months postpartum was 0.62 (95% confidence interval [CI]: 0.35, 1.10) for those vaccinated 17-25 weeks gestation and 0.89 (95% CI: 0.39, 2.00) for those 26-34 weeks. Infant influenza IRRs were 0.73 (95% CI: 0.51, 1.05) for those whose mothers were vaccinated earlier in gestation, and 0.63 (95% CI: 0.37, 1.08) for those later. Relative risks (RR) for low birthweight were 0.83 (95% CI: 0.71, 0.98) and 0.90 (95% CI: 0.72, 1.12) for 17-25 and 26-34 weeks gestation at vaccination, respectively. IRRs did not differ for small-for-gestational age or preterm. No RRs were statistically different by timing of vaccine receipt. Conclusions: Vaccine efficacy did not vary by gestational age at vaccination, making maternal influenza immunization programs easier to implement where women present for care late in pregnancy. Clinical Trials Registration: NCT01034254.

Burden and Risk Factors for Coronavirus Infections in Infants in Rural Nepal.

Background: Knowledge of risk factors for symptomatic human coronavirus (HCoV) infections in children in community settings is limited. We estimated the disease burden and impact of birth-related, maternal, household, and seasonal factors on HCoV infections among children from birth to 6 months old in rural Nepal. Methods: Prospective, active, weekly surveillance for acute respiratory infections (ARIs) was conducted in infants over a period of 3 years during 2 consecutive, population-based randomized trials of maternal influenza immunization. Midnasal swabs were collected for acute respiratory symptoms and tested for HCoV and other viruses by reverse-transcription polymerase chain reaction. Association between HCoV incidence and potential risk factors was modeled using Poisson regression. Results: Overall, 282 of 3505 (8%) infants experienced an HCoV ARI within the first 6 months of life. HCoV incidence overall was 255.6 (95% confidence interval [CI], 227.3-286.5) per 1000 person-years, and was more than twice as high among nonneonates than among neonates (incidence rate ratio [IRR], 2.53; 95% CI, 1.52-4.21). HCoV ARI incidence was also positively associated with the number of children <5 years of age per room in a household (IRR, 1.13; 95% CI, 1.01-1.28). Of the 296 HCoV infections detected, 46% were coinfections with other respiratory viruses. While HCoVs were detected throughout the study period, seasonal variation was also observed, with incidence peaking in 2 winters (December-February) and 1 autumn (September-November). Conclusions: HCoV is associated with a substantial proportion of illnesses among young infants in rural Nepal. There is an increased risk of HCoV infection beyond the first month of life.

Human Metapneumovirus and Other Respiratory Viral Infections during Pregnancy and Birth, Nepal.

Human metapneumovirus (HMPV) is a respiratory virus that can cause severe lower respiratory tract disease and even death, primarily in young children. The incidence and characteristics of HMPV have not been well described in pregnant women. As part of a trial of maternal influenza immunization in rural southern Nepal, we conducted prospective, longitudinal, home-based active surveillance for febrile respiratory illness during pregnancy through 6 months postpartum. During 2011-2014, HMPV was detected in 55 of 3,693 women (16.4 cases/1,000 person-years). Twenty-five women were infected with HMPV during pregnancy, compared with 98 pregnant women who contracted rhinovirus and 7 who contracted respiratory syncytial virus. Women with HMPV during pregnancy had an increased risk of giving birth to infants who were small for gestational age. An intervention to reduce HMPV febrile respiratory illness in pregnant women may have the potential to decrease risk of adverse birth outcomes in developing countries.

Designs of two randomized, community-based trials to assess the impact of influenza immunization during pregnancy on respiratory illness among pregnant women and their infants and reproductive outcomes in rural Nepal.

BACKGROUND: Among the most important causes of illness and death in both pregnant women and their newborn infants are respiratory infections including influenza. Pregnant women in North America have a 4 to 5 fold excess rate of hospitalization compared to non-pregnant women. Rates of infant hospitalization associated with influenza are much higher than in their mothers. Fully half of children hospitalized for influenza in the US are in the age group 0-5 months, a group where no vaccine is licensed. Data on influenza are much fewer in low income countries where the risks of serious morbidity and mortality are much higher. A recent trial in Bangladesh suggested that influenza immunization in pregnant women could have important protective effects against influenza in both mothers and their infants. These trials were designed to provide additional evidence about the effect of influenza vaccination in pregnancy in settings where influenza may circulate for up to ten months/year. METHODS/DESIGN: We conducted a consecutive pair of community-based, placebo-controlled, randomized trials of influenza vaccination of pregnant women in a rural district in southern Nepal. Two trials were conducted to insure, as much as possible, the match of circulating strains with those included in the vaccine. Eligible women included all who were or became pregnant over a one year period. Each trial included a one year cohort of pregnant women who were individually randomized to the influenza vaccine available at the time of their enrollment or placebo. Exclusions included a history of allergy to vaccine components, prior influenza vaccine receipt, and for the second trial, participation in the first trial. Morbidity was assessed on a weekly basis for women throughout pregnancy and through 180 days post-partum. Infants were followed weekly through 180 days. Primary outcomes included: 1) incidence of influenza like illness in women, 2) incidence of laboratory confirmed influenza illness in infants, and 3) birthweight among newborn infants. DISCUSSION: We have presented the design and methods of two randomized trials of influenza immunization of pregnant women. TRIAL REGISTRATION: Clinicaltrials.gov: ( NCT01034254 ).

Designs of two randomized, community-based trials to assess the impact of alternative cookstove installation on respiratory illness among young children and reproductive outcomes in rural Nepal.

BACKGROUND: Acute lower respiratory infections (ALRI) are a leading cause of death among children. Low birthweight is prevalent in South Asia and associated with increased risks of mortality, and morbidity, high levels of indoor household air pollution caused by open burning of biomass fuels are common and associated with high rates of ALRI and low birthweight. Alternative stove designs that burn biomass fuel more efficiently have been proposed as one method for reducing these high exposures and lowering rates of these disorders. We designed two randomized trials to test this hypothesis. METHODS/DESIGN: We conducted a pair of community-based, randomized trials of alternative cookstove installation in a rural district in southern Nepal. Phase one was a cluster randomized, modified step-wedge design using an alternative biomass stove with a chimney. A pre-installation period of morbidity assessment and household environmental assessment was conducted for six months in all households. This was followed by a one year step-wedge phase with 12 monthly steps for clusters of households to receive the alternative stove. The timing of alternative stove introduction was randomized. This step-wedge phase was followed in all households by another six month follow-up phase. Eligibility criteria for phase one included household informed consent, the presence of a married woman of reproductive age (15-30 yrs) or a child < 36 months. Children were followed until 36 months of age or the end of the trial. Pregnancies were identified and followed until completion or end of the trial. Phase two was an individually randomized trial of the same alternative biomass stove versus liquid propane gas stove in a subset of households that participated in phase one. Follow-up for phase two was 12 months following stove installation. Eligibility criteria included the same components as phase one except children were only enrolled for morbidity follow-up if they were less than 24 months.The primary outcomes included: incidence of ALRI in children and birthweight. DISCUSSION: We presented the design and methods of two randomized trials of alternative cookstoves on rates of ALRI and birthweight. TRIAL REGISTRATION: Clinicaltrials.gov (NCT00786877, Nov. 5, 2008).

Impact of topical applications of sunflower seed oil on neonatal mortality and morbidity in southern Nepal: a community-based, cluster-randomised trial.

INTRODUCTION: Hospital-based studies have demonstrated topical applications of sunflower seed oil (SSO) to skin of preterm infants can reduce nosocomial infections and improve survival. In South Asia, replacing traditional mustard with SSO might have similar benefits. METHODS: 340 communities in Sarlahi, Nepal were randomised to use mustard oil (MO) or SSO for community practice of daily newborn massage. Women were provided oil in late pregnancy and the first month post partum, and visited daily through the first week of life to encourage massage practice. A separate data collection team visited on days 1, 3, 7, 10, 14, 21 and 28 to record vital status and assess serious bacterial infection. RESULTS: Between November 2010 and January 2017, we enrolled 39 479 pregnancies. 32 114 live births were analysed. Neonatal mortality rates (NMRs) were 31.8/1000 (520 deaths, 16 327 births) and 30.5/1000 (478 deaths, 15 676 births) in control and intervention, respectively (relative risk (RR)=0.95, 95% CI: 0.84, 1.08). Among preterm births, NMR was 90.4/1000 (229 deaths, 2533 births) and 79.2/1000 (188 deaths, 2373 births) in control and intervention, respectively (RR=0.88; 95% CI: 0.74, 1.05). Among preterm births <34 weeks, the RR was 0.83 (95% CI: 0.67, 1.02). No statistically significant differences were observed in incidence of serious bacterial infection. CONCLUSIONS: We did not find any neonatal mortality or morbidity benefit of using SSO instead of MO as emollient therapy in the early neonatal period. Further studies examining whether very preterm babies may benefit are warranted. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT01177111).

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).

Persistence of immunity following a single dose of inactivated poliovirus vaccine: a phase 4, open label, non-randomised clinical trial.

BACKGROUND: The polio eradication endgame required the withdrawal of Sabin type 2 from the oral poliovirus vaccine and introduction of one or more dose of inactivated poliovirus vaccine (IPV) into routine immunisation schedules. However, the duration of single-dose IPV immunity is unknown. We aimed to address this deficiency. METHODS: In this phase 4, open-label, non-randomised clinical trial, we assessed single-dose IPV immunity. Two groups of infants or children were screened: the first group had previously received IPV at 14 weeks of age or older (previous IPV group; age >2 years); the second had not previously received IPV (no previous IPV group; age 7-12 months). At enrolment, all participants received an IPV dose. Children in the no previous IPV group received a second IPV dose at day 30. Blood was collected three times in each group: on days 0, 7, and 30 in the previous IPV group and on days 0, 30, and 37 in the no previous IPV group. Poliovirus antibody was measured by microneutralisation assay. Immunity was defined as the presence of a detectable antibody or a rapid anamnestic response (ie, priming). We used the χ2 to compare proportions and the Mann-Whitney U test to assess continuous variables. To assess safety, vaccinees were observed for 30 min, caregivers for each participating child reported adverse events after each follow-up visit and were questioned during each follow-up visit regarding any adverse events during the intervening period. Adverse events were recorded and graded according to the severity of clinical symptoms. The study is registered with ClinicalTrials.gov, NCT03723837. FINDINGS: From Nov 18, 2018, to July 31, 2019, 502 participants enrolled in the study, 458 (255 [65%] boys and 203 [44%] girls) were included in the per protocol analysis: 234 (93%) in the previous IPV group and 224 (90%) in the no previous IPV group. In the previous IPV group, 28 months after one IPV dose 233 (>99%) of 234 children had persistence of poliovirus type 2 immunity (100 [43%] of 234 children were seropositive; 133 [99%] of 134 were seronegative and primed). In the no previous IPV group, 30 days after one IPV dose all 224 (100%) children who were type 2 poliovirus naive had seroconverted (223 [>99%] children) or were primed (one [<1%]). No adverse events were deemed attributable to study interventions. INTERPRETATION: A single IPV dose administered at 14 weeks of age or older is highly immunogenic and induces nearly universal type 2 immunity (seroconversion and priming), with immunity persisting for at least 28 months. The polio eradication initiative should prioritise first IPV dose administration to mitigate the paralytic burden caused by poliovirus type 2. FUNDING: WHO and Rotary International.

Optimising DTwP-containing vaccine infant immunisation schedules (OptImms) - a protocol for two parallel, open-label, randomised controlled trials.

BACKGROUND: Universal immunisation is the cornerstone of preventive medicine for children, The World Health Organisation (WHO) recommends diphtheria-tetanus-pertussis (DTP) vaccine administered at 6, 10 and 14 weeks of age as part of routine immunisation. However, globally, more than 17 unique DTP-containing vaccine schedules are in use. New vaccines for other diseases continue to be introduced into the infant immunisation schedule, resulting in an increasingly crowded schedule. The OptImms trial will assess whether antibody titres against pertussis and other antigens in childhood can be maintained whilst adjusting the current Expanded Programme on Immunisation (EPI) schedule to provide space for the introduction of new vaccines. METHODS: The OptImms studies are two randomised, five-arm, non-inferiority clinical trials in Nepal and Uganda. Infants aged 6 weeks will be randomised to one of five primary vaccination schedules based on age at first DTwP-vaccination (6 versus 8 weeks of age), number of doses in the DTwP priming series (two versus three), and spacing of priming series vaccinations (4 versus 8 weeks). Additionally, participants will be randomised to receive their DTwP booster at 9 or 12 months of age. A further sub-study will compare the co-administration of typhoid vaccine with other routine vaccines at one year of age. The primary outcome is anti-pertussis toxin IgG antibodies measured at the time of the booster dose. Secondary outcomes include antibodies against other vaccine antigens in the primary schedule and their safety. DISCUSSION: These data will provide key data to inform policy decisions on streamlining vaccination schedules in childhood. TRIAL REGISTRATIONS: ISRCTN12240140 (Nepa1, 7th January 2021) and ISRCTN6036654 (Uganda, 17th February 2021).