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Abstract Background HIV infection can cause malabsorption and rapid utilization of nutrients. A randomized trial of multivitamin supplementation among people living with HIV/AIDS (PLWHA) initiating antiretroviral therapy (ART) in Tanzania was stopped early due to increased alanine aminotransferase (ALT) concentrations in the multiple recommended dietary allowances (RDA) multivitamin group. We conducted detailed analysis to assess the effect of multivitamins on ALT elevations and evaluate whether subgroups of PLWHA have greater hepatotoxicity risks associated with the use of high-dose multivitamins. Methods We utilized data from a randomized, double-blind trial conducted in 2006–2009 that assessed the effect of high-dose multivitamins that contained vitamin B complex, vitamin C, and vitamin E at multiple RDA as compared to standard-dose multivitamins containing single RDAs among adults initiating ART in Tanzania. We evaluated the effect of high-dose multivitamins on incident mild/moderate ALT elevations > 40 IU/L, persistent ALT elevations > 40 IU/L (2 + clinic visits), and severe ALT elevations > 200IU/L using Cox proportional hazard models. We then evaluated effect modification by patient characteristics to determine if subgroups of PLWHA experienced different magnitudes of risk for ALT elevations associated with high-dose multivitamins. Results High-dose multivitamins increased the risk of incident mild/moderate ALT elevations > 40 IU/mL as compared to standard-dose multivitamins (hazard ratio (HR): 1.41; 95%CI: 1.26,1.58) as well as incident sustained mild/moderate ALT elevations (HR: 1.19; 95%CI: 1.04,1.36), but there was no overall effect on severe ALT elevations (HR: 1.44; 95% CI: 0.91,2.28). There was no evidence that the effect of high-dose multivitamins on any or sustained mild/moderate ALT elevations was modified by any patient characteristic. However, CD4 T-cell count was found to modify the effect of high-dose multivitamins on severe ALT elevations (p-value for interaction:0.01). Among participants with a baseline CD4 T-cell count ≤ 100 cells/µL, individuals receiving high-dose multivitamins had 3.74 times (95%CI: 1.52–9.17) the risk of incident severe ALT elevations compared to standard-dose multivitamins, while participants with CD4 T-cell counts > 100 cells/µL, appeared to have no effect of high-dose multivitamins on severe ALT elevations (HR:0.92; 95% CI: 0.50,1.67). Conclusions High-dose RDA multivitamin supplementation increased the incidence of any mild to moderate ALT elevations among adults starting ART in Tanzania and the magnitude of the risk does not appear to differ by patient characteristics. However, immunocompromised PLWHA with CD4 T-cell counts

Abstract Calcium supplementation in pregnancy is recommended in contexts with low dietary calcium intake to reduce the risk of pre‐eclampsia and its complications. The World Health Organisation suggested high‐dose calcium supplementation (1500–2000 mg/day), divided into three doses and taken at different times from daily iron‐folic supplements. We conducted a mixed methods evaluation study to assess experiences, acceptability and barriers to high‐dose calcium supplementation from the perspectives of pregnant women and antenatal health care providers at two public health facilities in Dar es Salaam, Tanzania. Descriptive statistics and thematic analysis were used to characterise acceptability, barriers and overall experiences of using high‐dose calcium supplementation. Pregnant women in the cohort were aged 19–41 years, with 32.4% being primiparous. The proportion of pregnant women who liked calcium supplements ‘a lot’ decreased from 50.2% at the first visit to 31.8% at the last antenatal follow‐up visit. Adherence was 71.3% (interquartile range: 50.5%, 89.3%), with only 24.0% of the participants taking 90% or more of the required supplements. Although participants expressed positive attitudes towards using calcium supplements, they also voiced concerns about the large size, side effects, the potential to forget and the burden of taking calcium supplements three times per day. Antenatal health care providers also affirmed the high burden of taking calcium supplements in addition to iron‐folic acid supplements. Participants expressed the acceptability of using calcium supplements during pregnancy, but adherence to three doses per day posed challenges to pregnant women. Reducing the number of calcium supplement doses per day may improve adherence.

Antiretroviral therapy (ART) has improved the survival of people living with HIV (PLHIV) but this success has been accompanied by an increase in noncommunicable diseases. We conducted a prospective cohort study of 4000 adult PLHIV who were initiating ART in Dar es Salaam, Tanzania, to assess weight gain during the first year of treatment and associated sociodemographic and clinical factors. Anthropometric data were collected at ART initiation and monthly follow-up visits. The mean weight gain during the first year of treatment was 2.6 ± 0.3 kg, and the prevalence of overweight or obesity increased from 26.3% at baseline to 40.7%. Female sex, greater household wealth, lower CD4-T-cell counts, higher WHO HIV disease stage, and pulmonary tuberculosis were associated with a greater increase in body mass index ( P < .05). Weight gain following ART initiation was common but was greater among females and PLHIV with advanced HIV or comorbidities.

Abstract Aim To synthesize available evidence on the association between change in linear growth (height for age z score, HAZ) beyond the first two years of life with later child neurodevelopment outcomes in Low- and middle-income countries (LMICs). Methods We searched PubMed, Web of Science, and EMBASE for cohort studies on the association between change in HAZ after age two and neurodevelopment outcomes in middle or late childhood. Data extraction was done independently by two reviewers. Results A total of 21 studies, that included 64,562 children from 13 LMICs were identified. Each unit increase in change in HAZ above two years is associated with a + 0.01 increase (N = 8 studies, 27,393 children) in the cognitive scores at 3.5 to 12 years of age and a + 0.05-standard deviation (SD) increase (95% CI 0.02 to 0.08, N = 3 studies, 17,830 children) in the language score at 5 to 15 years of age. No significant association of change in HAZ with motor (standardized mean difference (SMD) 0.04; 95% CI: -0.10, 0.18, N = 1 study, 966 children) or socio-emotional scores (SMD 0.00; 95% CI: -0.02, 0.01, N = 4 studies, 14,616 participants) was observed. Conclusion Changes in HAZ after the first two years of life appear to have a small or no association with child neurodevelopment outcomes in LMICs.

Objective: To explore the relationship of undernutrition and the short duration of breastfeeding with child development of children 0–66 months of age residing in Ceará, Brazil. Methods: The authors of the present study utilized population-based data from children enrolled in the Study on Maternal and Child Health in Ceará, Brazil (PESMIC). Children's development was assessed with the Ages and Stages Questionnaire third version, validated in Brazil. Undernutrition was accessed through anthropometric measures obtained by trained staff. Breastfeeding information was obtained through the mothers' report and confirmed in the child's governmental booklet. The authors used logistic regressions adjusted for sample clusters used in PESMIC design in a theoretical model for known determinants of child development following the World Health Organization nurturing framework. Results: A total of 3,566 children were enrolled in the sixth PESMIC study and had their development assessed. The authors found that 8.2%, 3.0%, 2.1%, and 3.6% of children were stunted, underweight, or wasted, at the time of the interview, respectively. All studied factors were associated with a higher prevalence of child development impairment in at least one of the assessed domains. Underweight was the factor with the strongest effect, with an adjusted odds ratio (AOR) of 4,14 (2,26–7,58), p

Abstract Background Hypertensive disorders of pregnancy are important causes of maternal morbidity and mortality, as well as preterm birth, the leading cause of death for children under 5 years globally. The World Health Organization currently recommends that pregnant women receive high-dose calcium supplementation (1500–2000 mg elemental calcium) for prevention of preeclampsia in populations with low dietary calcium intake. Trials of low-dose calcium supplementation (

Globally, increasing rates of facility-based childbirth enable early intervention for small vulnerable newborns. We describe health system-level inputs, current feeding, and discharge practices for moderately low birthweight (MLBW) infants (1500-10% less than their birthweight; 18.8% of infants were discharged with weights below facility-specific policy [1800g in India, 1500g in Malawi, and 2000g in Tanzania]. Based on descriptive analysis, we found constraints in health system inputs which have the potential to hinder high quality care for MLBW infants. Targeted LBW-specific lactation support, discharge at appropriate weight, and access to feeding alternatives would position MLBW for successful feeding and growth post-discharge.

Infants need to receive care in environments that limit their exposure to pathogens. Inadequate water, sanitation, and hygiene (WASH) environments and suboptimal infection prevention and control practices in healthcare settings contribute to the burden of healthcare-associated infections, which are particularly high in low-income settings. Specific research is needed to understand infant feeding preparation in healthcare settings, a task involving multiple behaviors that can introduce pathogens and negatively impact health. To understand feeding preparation practices and potential risks, and to inform strategies for improvement, we assessed facility WASH environments and observed infant feeding preparation practices across 12 facilities in India, Malawi, and Tanzania serving newborn infants. Research was embedded within the Low Birthweight Infant Feeding Exploration (LIFE) observational cohort study, which documented feeding practices and growth patterns to inform feeding interventions. We assessed WASH-related environments and feeding policies of all 12 facilities involved in the LIFE study. Additionally, we used a guidance-informed tool to carry out 27 feeding preparation observations across 9 facilities, enabling assessment of 270 total behaviors. All facilities had ‘improved’ water and sanitation services. Only 50% had written procedures for preparing expressed breastmilk; 50% had written procedures for cleaning, drying, and storage of infant feeding implements; and 33% had written procedures for preparing infant formula. Among 270 behaviors assessed across the 27 feeding preparation observations, 46 (17.0%) practices were carried out sub-optimally, including preparers not handwashing prior to preparation, and cleaning, drying, and storing of feeding implements in ways that do not effectively prevent contamination. While further research is needed to improve assessment tools and to identify specific microbial risks of the suboptimal behaviors identified, the evidence generated is sufficient to justify investment in developing guidance and programing to strengthen infant feeding preparation practices to ensure optimal newborn health.

Background Perinatal women living with HIV (PWLH) have a greater risk of depression compared to other women; however, there are limited specialized mental health services available to them. We aimed to determine whether a stepped-care intervention facilitated by trained lay providers can improve mental health outcomes postpartum for PWLH. Methods and findings Healthy Options is a cluster-randomized controlled study conducted in 16 government-managed antenatal care clinics that provided HIV care for pregnant women in urban Tanzania. Recruitment occurred from May 2015 through April 2016, with the final round of data collection completed in October 2017. Participants included a consecutive sample of pregnant women under 30 weeks of gestation, living with HIV and depression, and attending the study clinics. Control sites received enhanced usual care for depression (EUDC). Intervention sites received EUDC plus the Healthy Options intervention, which includes prenatal group sessions of problem-solving therapy (PST) plus cognitive behavioral therapy (CBT) sessions for individuals showing depressive symptoms at 6 weeks postdelivery. We assessed depressive symptoms comparable to major depressive disorder (MDD) using the Patient Health Questionnaire-9 (PHQ-9) with a locally validated cutoff at 9 months and 6 weeks postpartum. The primary time point is 9 months postpartum. We examined differences in outcomes using an intent-to-treat analysis with a complete case approach, meaning those with data at the relevant time point were included in the analysis. We used generalized estimating equations accounting for clustering. Of 818 women screened using the PHQ-9, 742 were determined eligible and enrolled (395 intervention; 347 control); 649 women (87.5%) participated in the first follow-up and 641 women (86.4%) in the second. A majority (270, 74.6%) of women in the intervention arm attended 5 or more PST sessions. Women enrolled in Healthy Options demonstrated a 67% (RR 0.33; 95% CI: 0.22, 0.51; p-value: Conclusions The Healthy Options intervention did not demonstrate reduction in depressive symptoms at 9 months postpartum, the primary outcome. Significant reductions were seen in depression symptoms at 6 weeks postpartum, the secondary outcome. Stepped-care interventions may be relevant for improving outcomes in the critical early postpartum window. Trial registration Clinical Trial registration number (closed to new participants) NCT02039973 Elysia Larson and colleagues report the results of a cluster-randomized trial from Tanzania which investigates the impact of a peer-facilitated psychological intervention for perinatal women living with HIV and depression. Author summary Why was this study done? Depression during the pregnancy and postpartum periods is common, particularly among women living with HIV. In many resource-limited areas, availability of specialized mental health services is inadequate. Models of effective lay health worker-facilitated psychological interventions are needed to fill the care gap. What did the researchers do and find? A cluster-randomized controlled trial was conducted in 16 government-managed health clinics in urban Tanzania to examine the impact of a community-based health worker (CBHW)-led group intervention on symptoms of depression in the postpartum period. The stepped-care intervention included problem-solving therapy (PST) provided to all enrolled participants during pregnancy plus cognitive behavioral therapy (CBT) provided to participants who still showed symptoms of depression postpartum. At 9 months postpartum, the intervention group did not have a significant reduction in depressive symptoms compared to the enhanced control group. There was a 67% reduction in the likelihood of symptoms of depression at 6 weeks postpartum in the intervention group compared to the control group. What do these findings mean? The stepped-care model tested here was not effective in reducing symptoms of depression at 9 months postpartum, but was at 6 weeks postpartum. Additional interventions in the postpartum period need to be explored to significantly reduce symptoms of depression among pregnant women living with HIV in the longer term.

Abstract Background Wasting and stunting, physical growth manifestations of child undernutrition, have historically been considered separately with distinct interventions at the program, policy, and financing levels despite similar risk factors, overlapping burdens and multiplicative risk of death when the conditions are concurrent. The aim of this study was to elucidate shared risk factors and the temporal relationship between wasting and stunting among children under 2 years of age in rural Niger. Methods From August 2014 to December 2019, anthropometric data were collected every 4 weeks from 6 to 8 weeks to 24 months of age for 6567 children comprising 139,529 visits in Madarounfa, Niger. Children were defined as wasted if they had a weight-for-length Z-score

Abstract Background The Sustainable Development Goals (SDGs) highlight the importance of investments in early childhood care and education (ECCE) and youth development. Given Pakistan’s large young population, and gender and urban-rural inequalities in access to education, training, and employment, such investments offer opportunities. LEAPS is a youth-led ECCE program that trains female youth, 18–24 years, as Community Youth Leaders (CYLs) to deliver high-quality ECCE for children, 3.5–5.5 years, in rural Sindh, Pakistan. Methods We use a stepped wedge cluster-randomized trial to evaluate implementation of LEAPS. Ninety-nine clusters will be randomized to receive the intervention in one of three 7-month steps (33 clusters/step). The primary outcome is children’s school readiness (indexed by the total score on the International Development and Early Learning Assessment (IDELA)). Secondary child outcomes are children’s IDELA domain scores and executive functions. Data are collected in cross-sectional surveys of 1089 children (11 children/cluster from 99 clusters) aged 4.5–5.5 years at four timepoints (baseline and at the end of each step). Additionally, we will enroll three non-randomized youth participant open cohorts, one per step (33 CYLs: 66 comparison youth per cohort; 99:198 in total). Youth cohorts will be assessed at enrollment and every 7 months thereafter to measure secondary outcomes of youth personal and professional development, depressive symptoms, and executive functions. A non-randomized school cohort of 330 LEAPS students (10 students/cluster from 33 clusters) will also be enrolled and assessed during Step 1 after intervention rollout and at endline. The quality of the learning environment will be assessed in each LEAPS ECCE center and in a comparison center at two timepoints midway following rollout and at endline. A concurrent mixed-methods implementation evaluation will assess program fidelity and quality, and the extent to which a technical support strategy is successful in strengthening systems for program expansion. A cost evaluation will assess cost per beneficiary. Data collection for implementation and cost evaluations will occur in Step 3. Discussion Youth-led models for ECCE offer a promising approach to support young children and youth. This study will contribute to the evidence as a means to promote sustainable human development across multiple SDG targets. Trial registration ClinicalTrials.gov NCT03764436 . Registered on December 5, 2018.

Summary: Background: Environmental enteric dysfunction (EED) may contribute to adverse birth outcomes in low-resource settings. We examined the associations of EED biomarkers with birth outcomes in pregnant women living with human immunodeficiency virus in Dar es Salaam, Tanzania. Methods: We performed a cohort study of 706 HIV-infected pregnant women. Maternal serum samples collected at 32 weeks gestation were analyzed for markers of EED (anti-flagellin and anti-LPS immunoglobulins, intestinal fatty acid-binding protein [I-FABP] and soluble CD14), systemic inflammation (C-reactive protein and α1-acid glycoprotein [AGP]), and growth hormone resistance (insulin-like growth factor 1 [IGF-1] and fibroblast growth factor 21 [FGF21]. Associations of biomarkers categorized into quartiles with birth outcomes (birthweight, gestational duration, birthweight-for-gestational age, and stillbirth) were assessed using linear and log-binomial regression models adjusted for multiple sociodemographic and clinical variables. Findings: Maternal EED biomarkers were not significantly associated with birthweight, gestation duration, or birthweight-for-gestational age. However, higher quintiles of I-FABP concentrations were associated with greater risk of stillbirth (ptrend=0·02). Higher AGP was associated with lower birthweight and was associated with increased risk of small-for-gestational age births. Higher IGF-1 was associated with higher birthweight and birthweight-for-gestational age while higher FGF21 was associated with shorter gestation and higher risk of preterm birth. Interpretation: Maternal biomarkers of EED, systemic inflammation, and growth hormones were differentially associated with birth outcomes. Biomarkers of EED may be useful to identify pregnant women at risk of adverse birth outcomes, but further research is needed to confirm these findings and elucidate biological mechanisms. Funding: National Institutes of Health.

Abstract Background The first 1000 days of life are a critical period when the foundations of child development and growth are established. Few studies in Latin America have examined the relationship of birth outcomes and neonatal care factors with development outcomes in young children. We aimed to assess the association between pregnancy and neonatal factors with children’s developmental scores in a cross-sectional, population-based study of children in Ceará, Brazil. Methods Population-based, cross-sectional study of children aged 0–66 months (0–5.5 years) living in Ceará, Brazil. We examined the relationship of pregnancy (iron and folic acid supplementation, smoking and alcohol consumption) and neonatal (low birth weight (LBW) gestational age, neonatal care interventions, and breastfeeding in the first hour) factors with child development. Children’s development was assessed with the Ages and Stages Questionnaire (ASQ-BR). We used multivariate generalized linear models that accounted for clustering sampling to evaluate the relationship of pregnancy and neonatal factors with development domain scores. Findings A total of 3566 children were enrolled. Among pregnancy factors, children whose mothers did not receive folic acid supplementation during pregnancy had lower fine motor and problem-solving scores (p-values

Background It is estimated that over 250 million children under 5 years of age in low- and middle-income countries (LMICs) do not reach their full developmental potential. Poor maternal diet, anemia, and micronutrient deficiencies during pregnancy are associated with suboptimal neurodevelopmental outcomes in children. However, the effect of prenatal macronutrient and micronutrient supplementation on child development in LMIC settings remains unclear due to limited evidence from randomized trials. Methods and findings We conducted a 3-arm cluster-randomized trial (n = 53 clusters) that evaluated the efficacy of (1) prenatal multiple micronutrient supplementation (MMS; n = 18 clusters) and (2) lipid-based nutrient supplementation (LNS; n = 18 clusters) as compared to (3) routine iron–folic acid (IFA) supplementation (n = 17 clusters) among pregnant women in the rural district of Madarounfa, Niger, from March 2015 to August 2019 (ClinicalTrials.gov identifier NCT02145000). Children were followed until 2 years of age, and the Bayley Scales of Infant and Toddler Development III (BSID-III) were administered to children every 3 months from 6 to 24 months of age. Maternal report of WHO gross motor milestone achievement was assessed monthly from 3 to 24 months of age. An intention-to-treat analysis was followed. Child BSID-III data were available for 559, 492, and 581 singleton children in the MMS, LNS, and IFA groups, respectively. Child WHO motor milestone data were available for 691, 781, and 753 singleton children in the MMS, LNS, and IFA groups, respectively. Prenatal MMS had no effect on child BSID-III cognitive (standardized mean difference [SMD]: 0.21; 95% CI: −0.20, 0.62; p = 0.32), language (SMD: 0.16; 95% CI: −0.30, 0.61; p = 0.50) or motor scores (SMD: 0.18; 95% CI: −0.39, 0.74; p = 0.54) or on time to achievement of the WHO gross motor milestones as compared to IFA. Prenatal LNS had no effect on child BSID-III cognitive (SMD: 0.17; 95% CI: −0.15, 0.49; p = 0.29), language (SMD: 0.11; 95% CI: −0.22, 0.44; p = 0.53) or motor scores (SMD: −0.04; 95% CI: −0.46, 0.37; p = 0.85) at the 24-month endline visit as compared to IFA. However, the trajectory of BSID-III cognitive scores during the first 2 years of life differed between the groups with children in the LNS group having higher cognitive scores at 18 and 21 months (approximately 0.35 SD) as compared to the IFA group (p-value for difference in trajectory Conclusions There was no benefit of prenatal MMS on child development outcomes up to 2 years of age as compared to IFA. There was evidence of an apparent positive effect of prenatal LNS on cognitive development trajectory and time to achievement of selected gross motor milestones. Trial registration ClinicalTrials.gov NCT02145000. Christopher R. Sudfeld and colleagues evaluate the benefit of multiple micronutrient supplementation and medium‐quantity lipid‐based nutrient supplementation in pregnancy on child development in rural Niger. Author summary Why was this study done? It is estimated that over 250 million children under 5 years of age do not reach their developmental potential in low- and middle-income country (LMIC) settings. Observational studies suggest that poor diet, anemia, and micronutrient deficiencies in pregnancy are associated with poor child development outcomes; however, the effect of macronutrient and micronutrient supplementation in pregnancy on child development outcomes remains inconclusive due to a limited number of randomized trials that have assessed developmental outcomes. What did the researchers do and find? We conducted a cluster-randomized controlled trial of prenatal multiple micronutrient supplementation (MMS) and lipid-based nutrient supplementation (LNS) as compared to routine iron–folic acid (IFA) supplementation among pregnant women in rural Niger and evaluated the effect on child development outcomes during the first 2 years of life. There was no benefit of prenatal MMS on child Bayley Scales of Infant and Toddler Development III (BSID-III) scores or on time to achievement of motor milestones as compared to IFA. There was no effect of prenatal LNS on BSID-III scores at 24 months of age as compared to IFA; however, the trajectory of child development differed between groups, with children in the prenatal LNS group having higher cognitive scores at 18 and 21 months of age as compared to IFA. Children whose mothers received prenatal LNS also had earlier achievement of sitting alone and walking alone as compared to children whose mothers received prenatal IFA. What do these findings mean? Prenatal supplementation with LNS appeared to support the achievement of selected motor milestones and improve cognitive development trajectory; however, there was no evidence of benefit of MMS over routine IFA on developmental outcomes in the context of rural Niger. Nevertheless, the apparent beneficial effects of prenatal LNS were limited, and, therefore, integrated interventions that consider maternal and child nutritional support along with parenting interventions and other components to support an enabling environment may provide larger effects on child development outcomes.

Abstract Background Evidence on anemia and associated factors among young adolescent girls and boys in rural western China is limited. Methods We used data from a follow-up study of adolescents (10–14 years) born to women who participated in a randomized trial of antenatal micronutrient supplementation in western China. Anemia was defined by World Health Organization standards. Logistic regression was used to examine the factors associated with anemia. Results The overall prevalence of anemia was 11.7% (178/1517). Female adolescents were 1.73 (95% CI 1.21, 2.48) times more likely to have anemia as compared to males. Adolescents whose mothers had completed high school were 0.35 (95% CI 0.13, 0.93) times less likely to be anemic, compared to those of whom had

Abstract Objective A recent trial of vitamin B12 supplementation among Indian children 6–30 months found no effect on the incidence of diarrhea and respiratory infections. These results differ with studies in adults that showed improvement of the immune response following treatment with vitamin B12. We sought to determine how the adequacy of vitamin B12 concentrations in breast milk could act as immune modulator and protect against the incidence of diarrhea and respiratory infections of children up to 18 months in urban Tanzania. Results A prospective cohort study was undertaken to determine the association of breast milk vitamin B12 concentration with the incidence of acute respiratory infection and diarrhea among infants in urban Tanzania. A random sample of 491 women enrolled in a trial of multivitamins provided milk for B12 analysis at or around 6 weeks postpartum. Of 491 women, 345 had breast milk vitamin B12 inadequacy (

Background Observational studies suggest that vitamin D deficiency among people living with HIV is associated with a greater risk of disease progression and death. Low levels of vitamin D in pregnancy are also associated with poor fetal and infant growth. Therefore, vitamin D supplementation may improve clinical outcomes for pregnant women living with HIV and improve fetal and postnatal growth for their infants. Methods and findings We conducted a randomized, triple-blind, placebo-controlled trial of vitamin D3 supplementation among pregnant and lactating women living with HIV in Dar es Salaam, Tanzania (ClinicalTrials.gov NCT02305927). Participants were randomized with 1:1 allocation stratified by study clinic to receive either daily 3,000 IU vitamin D3 supplements or matching placebo supplements from the second trimester of pregnancy (12–27 weeks) until 1 year postpartum. The primary outcomes were (i) maternal HIV progression or death, (ii) small-for-gestational-age (SGA) live births (Conclusions The trial findings do not support routine vitamin D supplementation for pregnant and lactating women living with HIV in Tanzania. Trial registration ClinicalTrials.gov Identifier: NCT02305927. Christopher R. Sudfeld and colleagues, investigate the impact of vitamin D supplementation on clinical outcomes for pregnant women living with HIV, and growth outcomes for their infants. Author summary Why was this study done? Observational studies have found that vitamin D deficiency among people living with HIV is associated with an increased risk of HIV disease progression and death. Low levels of vitamin D in pregnancy are also associated with adverse birth outcomes and poor infant growth. What did the researchers do and find? We conducted a randomized controlled trial of maternal vitamin D3 supplementation during pregnancy and lactation and found no effect on the primary trial outcomes of maternal HIV progression or death, small-for-gestational-age (SGA) live births, and infant stunting (length-for-age z-score < −2) at 1 year of age. There was no effect on most secondary outcomes; however, we found that vitamin D supplementation decreased the risk of death for mothers and increased the risk of preterm birth. Maternal vitamin D supplementation increased maternal serum 25-hydroxyvitamin D (25[OH]D) concentrations throughout follow-up and increased infant 25(OH)D at 6 weeks and 6 months of age, but not at 12 months of age. What do these findings mean? The trial findings are not in support of routine vitamin D supplementation for pregnant and lactating women living with HIV. The mixed findings on the secondary outcomes of maternal death and preterm birth should be interpreted with caution and require replication in other randomized trials.

Abstract This study examined whether child diet and mother–child interactions mediated the effects of a responsive stimulation and nutrition intervention delivered from 2009 to 2012 to 1324 children aged 0–24 months living in rural Pakistan. Results showed that the intervention improved children's cognitive, language and motor development through child diet and mother–child interactions. Although the intervention did not improve child growth or socio‐emotional development, we observed positive indirect effects on child growth via child diet and on socio‐emotional development via both child diet and mother–child interactions. In addition, child diet emerged as a shared mechanism to improve both child growth and development, whereas mother–child interactions emerged as a distinct mechanism to improve child development. Nevertheless, our results suggest the two mechanisms were mutually reinforcing and that interventions leveraging both mechanisms are likely to be more effective at improving child outcomes than interventions leveraging only one of these mechanisms.

Maternal educational attainment has been identified as relevant to several child health and development outcomes. This study aimed to evaluate the association of sociodemographic and maternal education factors with child development in families living below the poverty line. A cross-sectional study was conducted through telephone contact from May to July 2021 in Ceará, a state in Northeastern Brazil. The study population comprised families with children up to six years of age participating in the cash transfer program “Mais infância”. The families selected to participate in this program must have a monthly per capita income of less than US$16.50. The Ages and Stages Questionnaire version 3 was applied to assess the children’s development status. The mothers reported maternal educational attainment as the highest grade and or degree obtained. The final weighted and adjusted model showed that maternal schooling was associated with the risk of delay in all domains except for the fine motor domain. The risk of delay in at least one domain was 2.5-fold higher in mothers with a lower level of schooling (95% CI: 1.6–3.9). The findings of this study suggest that mothers with higher educational attainment have children with better child development outcomes.

While the global contributions of adverse birth outcomes to child morbidity and mortality is relatively well documented, the potential long-term schooling and economic consequences of adverse birth outcomes has not been estimated. We sought to quantify the potential schooling and lifetime income gains associated with reducing the excess prevalence of adverse birth outcomes in 121 low- and middle-income countries. We used a linear deterministic model to estimate the potential gains in schooling and lifetime income that may be achieved by attaining theoretical minimum prevalence of low birthweight, preterm birth and small-for-gestational age births at the national, regional, and global levels. We estimated that potential total gains across the 121 countries from reducing low birthweight to the theoretical minimum were 20.3 million school years (95% CI: 6.0,34.8) and US$ 68.8 billion (95% CI: 20.3,117.9) in lifetime income gains per birth cohort. As for preterm birth, we estimated gains of 9.8 million school years (95% CI: 1.5,18.4) and US$ 41.9 billion (95% CI: 6.1,80.9) in lifetime income. The potential gains from small-for-gestational age were 39.5 million (95% CI: 19.1,60.3) school years and US$113.6 billion (95% CI: 55.5,174.2) in lifetime income gained. In summary, reducing the excess prevalence of low birthweight, preterm birth or small-for-gestational age births in low- and middle-income countries may lead to substantial long-term human capital gains in addition to benefits on child mortality, growth, and development as well as on risk of non-communicable diseases in adults and other consequences across the life course.

Abstract Background Perinatal women accessing prevention of mother-to-child transmission of HIV (PMTCT) services are at an increased risk of depression; however, in Tanzania there is limited access to services provided by mental health professionals. This paper presents a protocol and baseline characteristics for a study evaluating a psychosocial support group intervention facilitated by lay community-based health workers (CBHWs) for perinatal women living with HIV and depression in Dar es Salaam. Methods A cluster randomized controlled trial (RCT) is conducted comparing: 1) a psychosocial support group intervention; and 2) improved standard of mental health care. The study is implemented in reproductive and child health (RCH) centers providing PMTCT services. Baseline characteristics are presented by comparing sociodemographic characteristics and primary as well as secondary outcomes for the trial for intervention and control groups. The trial is registered under clinicaltrials.gov (NCT02039973). Results Among 742 women enrolled, baseline characteristics were comparable for intervention and control groups, although more women in the control group had completed secondary school (25.2% versus 18.2%). Overall, findings suggest that the population is highly vulnerable with over 45% demonstrating food insecurity and 17% reporting intimate partner violence in the past 6 months. Conclusions Baseline characteristics for the cluster RCT were comparable for intervention and control groups. The trial will examine the effectiveness of a psychosocial support group intervention for the treatment of depression among women living with HIV accessing PMTCT services. A reduction in the burden of depression in this vulnerable population has implications in the short-term for improved HIV-related outcomes and for potential long-term effects on child growth and development. Trial registration The trial is registered under clinicaltrials.gov (NCT02039973). Retrospectively registered on January 20, 2014.

Abstract Background Anemia remains a public health challenge in Ethiopia, affecting an estimated 56% of children under age 5 years, 23% of women of reproductive age and 18% of adult men. However, anemia etiology and the relative contribution of underlying risk factors for anemia remains unclear and has hindered implementation of anemia control programs. Methods/design Anemia Etiology in Ethiopia (AnemEE) is a population-based cross-sectional survey of six regions of Ethiopia that includes children, women of reproductive age, and men from regionally representative households. The survey will include detailed assessment of anemia, iron, inflammatory and nutritional biomarkers, diet, comorbidities, and other factors. The objectives of AnemEE are 1) to generate evidence for decision-making on the etiology of anemia in Ethiopia among men, women and children and 2) to simulate the potential effect of iron fortification and other interventions on the prevalence of anemia and risk of iron overload. Discussion AnemEE will provide the most comprehensive evaluation of anemia etiology in Ethiopia to date due to its detailed assessment of diet, biomarkers, infections and other risk factors in a population-based sample. By generating evidence and simulating potential interventions, AnemEE will inform the development of high-impact anemia control programs and policies. Trial registration ClinicalTrials.gov, NCT04002466. Registered on 28 June 2019. Retrospectively registered.

Abstract Background Child health, nutrition, and responsive stimulation interventions have been developed to improve child survival, growth and development outcomes in low- and middle-income countries. Nevertheless, research on integrated implementation approaches to deliver and promote uptake of these interventions is needed, particularly in sub-Saharan Africa. Methods/design We will conduct a cluster-randomized controlled trial of a supply-side community health worker (CHW) delivered child health, nutrition, and responsive stimulation intervention alone and in combination with a demand-side conditional cash transfer (CCT) intervention to promote antenatal care and child growth monitoring attendance in rural Morogoro region, Tanzania. Twelve village clusters will be randomly assigned to one of the three trial arms: (1) CHW, (2) CHW + CCT, or (3) Control. Mothers (or another primary caregiver) residing in study villages are eligible for trial enrollment if they are currently pregnant or have a child

Abstract Background Delayed vaccination increases the time infants are at risk for acquiring vaccine-preventable diseases. Factors associated with incomplete vaccination are relatively well characterized in resource-limited settings; however, few studies have assessed immunization timeliness. Methods We conducted a prospective cohort study examining Diphtheria-Tetanus-Pertussis (DTP) vaccination timing among newborns enrolled in a Neonatal Vitamin A supplementation trial (NEOVITA) conducted in urban Dar es Salaam (n = 11,189) and rural Morogoro Region (n = 19,767), Tanzania. We used log-binomial models to assess the relationship of demographic, socioeconomic, healthcare access, and birth characteristics with late or incomplete DTP1 and DTP3 immunization. Results The proportion of infants with either delayed or incomplete vaccination was similar in Dar es Salaam (DTP1 11.5% and DTP3 16.0%) and Morogoro (DTP1 9.2% and DTP3 17.3%); however, the determinants of delayed or incomplete vaccination as well as their magnitude of association differed by setting. Both maternal and paternal education were more strongly associated with vaccination status in rural Morogoro region as compared to Dar es Salaam (p-values for heterogeneity

Parenting practices have been identified as a key determinant of children’s developmental outcomes. The aim of this study was to evaluate the association of parenting practices with child development in a cross-sectional population-based study in a low-income state in northeastern Brazil. The study included data on 3566 caregiver–child pairs, and the children were aged 0–66 months. Positive parenting behaviors (PPBs) were conceptualized in areas of interactive play, social development, and speech and language interactions. Child development was evaluated using the Brazilian Ages and Stages Questionnaire. Linear regression analysis was used to assess the relationships. We found that a greater number of PPBs was associated with better child development domain scores. Among infants < 1 year, each additional PPB was associated with a 0.32 standardized mean difference (SMD) greater communication (95% CI: 0.24–0.41) and 0.38 SMD greater problem-solving scores (95% CI: 0.24–0.52). Among children aged 4–6 years old, each additional PPB was associated with improved communication (SMD: 0.22; 95% CI: 0.13–0.32), problem solving (SMD: 0.21; 95% CI: 0.10–0.32) and personal–social domain scores (SMD: 0.26; 95% CI: 0.17–0.36). Our findings indicate that PPB were robustly associated with better outcomes across developmental domains among Brazilian children. Programs and interventions that support PPB can contribute to improvements in development outcomes.

Abstract Background Vitamin D has significant immunomodulatory effects on both adaptive and innate immune responses. Observational studies indicate that adults infected with HIV with low vitamin D status may be at increased risk of mortality, pulmonary tuberculosis, and HIV disease progression. Growing observational evidence also suggests that low vitamin D status in pregnancy may increase the risk of adverse birth and infant health outcomes. As a result, antiretroviral therapy (ART) adjunct vitamin D3 supplementation may improve the health of HIV-infected pregnant women and their children. Methods/design The Trial of Vitamins-5 (ToV5) is an individually randomized, double-blind, placebo-controlled trial of maternal vitamin D3 (cholecalciferol) supplementation conducted among 2300 HIV-infected pregnant women receiving triple-drug ART under Option B+ in Dar es Salaam, Tanzania. HIV-infected pregnant women of 12–27 weeks gestation are randomized to either: 1) 3000 IU vitamin D3 taken daily from randomization in pregnancy until trial discharge at 12 months postpartum; or 2) a matching placebo regimen. Maternal participants are followed-up at monthly clinic visits during pregnancy, at delivery, and then with their children at monthly postpartum clinic visits. The primary efficacy outcomes of the trial are: 1) maternal HIV disease progression or death; 2) risk of small-for-gestational age (SGA) births; and 3) risk of infant stunting at 1 year of age. The primary safety outcome of the trial is incident maternal hypercalcemia. Secondary outcomes include a range of clinical and biological maternal and child health outcomes. Discussion The ToV5 will provide causal evidence on the effect of vitamin D3 supplementation on HIV progression and death, SGA births, and infant stunting at 1 year of age. The results of the trial are likely generalizable to HIV-infected pregnant women and their children in similar resource-limited settings utilizing the Option B+ approach. Trial registration ClinicalTrials.gov identifier: NCT02305927 . Registered on 29 October 2014.

Introduction: Serum alanine aminotransferase (ALT) elevations are common among HIV-infected patients on combination antiretroviral therapy (cART). Approach: We conducted a prospective cohort study of 3023 HIV-infected Tanzanian adults initiating cART. We assessed risk factors for mild/moderate ALT elevations >40 IU/L and severe ALT elevations >200 IU/L. Results: We found that over a median follow-up of 32.5 months (interquartile range: 19.4-41.5), 44.8% of participants had at least 1 incident ALT elevation >40 IU/L of which 50.1% were persistent elevations. Risk factors for incident ALT elevation >40 IU/L included male sex, CD4 count 200 IU/L ( P values:

Background Vitamin D may play an important role in later-life physical and cognitive health. Vitamin D status is standardly assessed in serum and plasma; however, collection, transport, and storage costs make large epidemiologic studies challenging. We assessed the agreement of 25-hydroxyvitamin D 3 (25(OH)D 3) quantification from dried blood spots (DBS) as compared to standard plasma assessment among older Indian adults. Methods A total of 58 adults over 45 years of age who resided in Pune, India were enrolled in the study from July 2020 to June 2021. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to assess 25(OH)D 3 concentrations in paired plasma and DBS samples. Results Plasma and DBS 25(OH)D 3 concentrations were highly correlated (Pearson’s correlation = 0.976). The median 25(OH)D 3 concentration of the study population assessed by plasma was 14.6 ng/mL (Q1=12.0, Q3= 18.1) while the median concentration assessed in DBS was 12.8 ng/mL (Q1=11.0, Q3= 16.6). 25(OH)D 3 concentrations measured from DBS were on average 6% (95% CI: 2-13%) lower than concentrations assessed by plasma across the observed 25(OH)D 3 distribution. Conclusions We found good agreement between 25(OH)D 3 quantification between DBS and plasma and our findings indicate that DBS can be used in epidemiologic studies of vitamin D among Indian adults.