Anemia and Iron Supplementation in Relation to Viral Load and Mortality among 70,442 People Living with Human Immunodeficiency Virus in Tanzania.

BACKGROUND: Anemia may be associated with poor clinical outcomes among people living with human immunodeficiency virus (HIV) (PLHIV) despite highly active antiretroviral therapy (HAART). There are concerns that iron supplementation may be unsafe to prevent and treat anemia among PLHIV. OBJECTIVE: The objective of the study was to evaluate the associations of anemia and iron supplementation with mortality and viral load among PLHIV in Tanzania. METHODS: We analyzed data from a cohort of 70,442 nonpregnant adult PLHIV in Tanzania conducted between 2015 and 2019. Regression models evaluated the relationships between anemia severity and iron supplement use with mortality and unsuppressed HIV-1 viral load among all participants and stratified by whether participants were initiating or continuing HAART. RESULTS: Anemia was associated with an increased risk of mortality and unsuppressed viral load for participants who initiated or continued HAART. Iron supplement use was associated with reduced mortality risk but also had a greater risk of an unsuppressed viral load among participants continuing HAART. There was no association of iron supplement use with mortality, and unsuppressed viral load among PLHIV that were initiating HAART. There was a stronger negative association between iron supplement use and the risk of having an unsuppressed viral load among participants with stage III/IV disease compared with stage I/II disease. CONCLUSIONS: Anemia is associated with increased risk of mortality and unsuppressed viral load, but the benefits and safety of iron supplements appear to differ for those initiating compared with continuing ART as well as by HIV disease severity.

Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy.

BACKGROUND: The World Health Organization recommends 1500 to 2000 mg of calcium daily as supplementation, divided into three doses, for pregnant persons in populations with low dietary calcium intake in order to reduce the risk of preeclampsia. The complexity of the dosing scheme, however, has led to implementation barriers. METHODS: We conducted two independent randomized trials of calcium supplementation, in India and Tanzania, to assess the noninferiority of a 500-mg daily dose to a 1500-mg daily dose of calcium supplementation. In each trial, the two primary outcomes were preeclampsia and preterm birth, and the noninferiority margins for the relative risks were 1.54 and 1.16, respectively. RESULTS: A total of 11,000 nulliparous pregnant women were included in each trial. The cumulative incidence of preeclampsia was 3.0% in the 500-mg group and 3.6% in the 1500-mg group in the India trial (relative risk, 0.84; 95% confidence interval [CI], 0.68 to 1.03) and 3.0% and 2.7%, respectively, in the Tanzania trial (relative risk, 1.10; 95% CI, 0.88 to 1.36) - findings consistent with the noninferiority of the lower dose in both trials. The percentage of live births that were preterm was 11.4% in the 500-mg group and 12.8% in the 1500-mg group in the India trial (relative risk, 0.89; 95% CI, 0.80 to 0.98), which was within the noninferiority margin of 1.16; in the Tanzania trial, the respective percentages were 10.4% and 9.7% (relative risk, 1.07; 95% CI, 0.95 to 1.21), which exceeded the noninferiority margin. CONCLUSIONS: In these two trials, low-dose calcium supplementation was noninferior to high-dose calcium supplementation with respect to the risk of preeclampsia. It was noninferior with respect to the risk of preterm live birth in the trial in India but not in the trial in Tanzania. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT03350516; Clinical Trials Registry-India number, CTRI/2018/02/012119; and Tanzania Medicines and Medical Devices Authority Trials Registry number, TFDA0018/CTR/0010/5).

Effects of Zinc Supplementation on Metabolomic Profiles in Tanzanian Infants: A Randomized Trial.

BACKGROUND: Provision of zinc supplementation to young children has been associated with reduced infectious morbidity and better growth outcomes. However, the metabolic pathways underlying these outcomes are unclear, and metabolomic data from humans undergoing zinc supplementation, particularly infants, are generally lacking. OBJECTIVES: This study aimed to examine the effect of zinc supplementation on metabolic profiles in Tanzanian infants aged 6 wk and 6 mo. METHODS: Blood samples were collected at age 6 wk and 6 mo from 50 Tanzanian infants who were enrolled in a randomized placebo-controlled trial of zinc supplementation (5 mg oral daily). Metabolomic analysis using an ultrahigh-performance liquid chromatography/tandem mass spectroscopy platform was performed to identify potential metabolomic profiles and biomarkers associated with zinc supplementation. Principal component analysis (PCA) was used to summarize metabolomic data from all samples. Two-way repeated measures analysis of variance with compound symmetry covariance structures were used to compare metabolome levels over time between infants in the 2 treatment arms. RESULTS: In PCA, the samples tended to be more separated by child age (6 wk compared with 6 mo) than by zinc supplementation status. We found that zinc supplementation affected a variety of metabolites associated with amino acid, lipid, nucleotide, and xenobiotic metabolism, including indoleacetate in the tryptophan metabolism pathway; 3-methoxytrosine and 4-hydrxoyphenylphruvate in the tyrosine pathway; eicosanedioate, 2-aminooctanoate, and N-acetyl-2-aminooctanoate in the fatty acid pathway; and N6-succinyladenosine in the purine metabolism pathway. Compared to the relatively small number of metabolites associated with zinc supplements, many infant metabolites changed significantly from age 6 wk to 6 mo. CONCLUSIONS: Zinc supplementation, despite having overall clinical benefits, appears to induce limited metabolomic changes in blood metabolites in young infants. Future larger studies may be warranted to further examine metabolic pathways associated with zinc supplementation. The parent trial was registered at clinicaltrials.gov as NCT00421668.

Antenatal depression and adverse birth outcomes among pregnant women living with HIV in Dar es Salaam, Tanzania.

BACKGROUND: Women who experience antenatal depression may be at increased risk of adverse birth outcomes. Few studies have examined this association among women living with HIV (WHIV). METHODS: We conducted a prospective cohort study of 2298 pregnant WHIV on antiretroviral therapy (ART) in Dar es Salaam, Tanzania, who were participants in a randomized trial of vitamin D3 supplementation. Depressive symptoms were assessed at 12-27 weeks gestation using the Hopkins Symptoms Checklist (HSCL-25). Generalized estimating equations to account for twins were used to assess the relative risks of adverse birth outcomes. RESULTS: Approximately 67 % of the women in our study population reported symptoms consistent with depression. We observed a 4.0 % prevalence of stillbirth and a 25.1 % prevalence of preterm birth. We found that low social support, higher education, and more recent initiation of ART were associated with a greater risk of antenatal depression. There was no association of antenatal depression with risk of fetal loss, stillbirth, low birth weight, birth weight, preterm birth, gestational age at delivery, or small-for-gestational age. LIMITATIONS: Depression was self-reported and only collected at one timepoint in pregnancy. Our findings may not be generalizable to all WHIV. CONCLUSIONS: Our findings illustrate the high risk of both depression and adverse birth outcomes among WHIV and underscore the need for interventions to improve their mental health and the health of their infants; however, the relationship between depression and birth outcomes remains unclear. Further research on this topic is merited, particularly examining the chronicity and timing of depression in pregnancy.

Dietary Iron Intake and HIV-Related Outcomes Among Adults Initiating Antiretroviral Therapy in Tanzania.

OBJECTIVE: Anemia is highly prevalent among people living with HIV (PLWHIV) and is often due to iron deficiency. This study evaluated the relationship of dietary iron intake levels and sources with mortality and clinical outcomes among adults initiating HAART. DESIGN: We conducted a secondary analysis of a multivitamin supplementation trial among 2293 PLWHIV initiating HAART in Dar es Salaam, Tanzania. METHODS: Dietary iron intake was assessed with a food frequency questionnaire at HAART initiation, and participants followed until death or censoring. Total, animal-, and plant-sourced iron were categorized into quartiles. Intake of food groups was categorized into 0-1, 2-3, and ≥4 servings/wk. Cox proportional hazards models estimated hazard ratios for mortality and incident clinical outcomes. RESULTS: There were 175 deaths (8%). Red meat intake was associated with a lower risk of all-cause mortality (HR: 0.54; 95% CI: 0.35 to 0.83), AIDS-related mortality (HR: 0.49; 95% CI: 0.28 to 0.85), and severe anemia (HR: 0.57; 95% CI: 0.35 to 0.91), when intake ≥4 servings/wk, compared with 0-1 servings/wk. Legume intake was a lower risk of associated with all-cause mortality (HR: 0.49; 95% CI: 0.31 to 0.77) and AIDS-related mortality (HR: 0.37; 95% CI: 0.23 to 0.61), when intake ≥4 servings/wk, compared with 0-1 servings/wk. Although total dietary iron and overall plant-sourced iron intake were not associated with the risk of mortality or HIV-related outcomes, the highest quartile of animal-sourced iron intake was associated with a lower risk of all-cause mortality (HR: 0.56; 95% CI: 0.35 to 0.90) and a lower risk of AIDS-related mortality (HR: 0.50; 95% CI: 0.30 to 0.90), compared with the lowest quartile. CONCLUSION: Intake of iron-rich food groups may be associated with a lower risk of mortality and critical HIV-related outcomes among adults initiating HAART. TRIAL REGISTRATION: The parent trial was registered at Clinicaltrials.gov . Identifier: NCT00383669.

Nutritious Supplemental Foods for Pregnant Women from Food Insecure Settings: Types, Nutritional Composition, and Relationships to Health Outcomes.

There is growing evidence that the provision of nutritious supplemental foods to undernourished pregnant women can improve maternal and infant outcomes. However, comparing and synthesizing the evidence base is complicated by differences in interventions and products and the use of ambiguous terminology. We aimed to define 2 common types of nutritious supplemental foods used in pregnancy, balanced energy-protein (BEP) supplements and lipid-based nutrient supplements (LNS), and to review the evidence supporting each via a narrative review of systematic reviews and meta-analyses (SRMAs). Information about the nutritional composition of the food supplements and their effects on maternal and infant outcomes was abstracted. Five SRMAs (n = 20 trials) evaluated the effect of BEP compared with no BEP/control (comparison group commonly received iron and folic acid [IFA]). BEP foods/products ranged in calories (118-1017 kcals), protein (3-50 g), fat (6-57 g), and micronutrient content. Overall, maternal BEP improved birth weight and reduced the risk of stillbirth and small for gestational age when compared with no BEP/control in pregnancy. Three SRMAs (n = 5 trials) evaluated the effect of LNS compared with IFA or multiple micronutrients (MMNs). The LNS interventions comprised small- and large-quantity LNS that ranged in calories (118-746 kcals), protein (3-21 g), fat (10-53 g), and micronutrient content. LNS compared with IFA increased pregnancy duration, birth weight, and birth length and reduced the risk of small for gestational age and infant stunting; however, no beneficial effect of LNS was identified when compared with MMN. Despite heterogeneity in the nutritional composition of BEP supplements, the evidence suggests that in nutritionally at-risk populations, these products may improve birth outcomes in pregnant women. The evidence is limited but promising when LNS is compared with IFA in improving maternal and infant outcomes. Overall, BEP, compared with MMN or LNS, are key areas that have not been studied and deserve attention.

Analysis of Postdischarge Interventions for Children Treated for Moderate or Severe Wasting, Growth Faltering or Failure, or Edema: A Systematic Review.

Importance: Children treated for acute malnutrition remain at increased risk of relapse, infection, and mortality after programmatic recovery. Global guidelines for the management of acute malnutrition currently provide no recommendations to sustain recovery following treatment discharge. Objective: To inform guideline development by evaluating the evidence on postdischarge interventions to improve outcomes within 6 months after discharge. Evidence Review: In this systematic review, 8 databases were searched from inception through December 2021 and included randomized and quasi-experimental studies investigating interventions delivered after discharge from nutritional treatment for children aged 0 to 59 months. Outcomes were relapse, deterioration to severe wasting, readmission, sustained recovery, anthropometry, all-cause mortality, and morbidity within 6 months after discharge. The risk of bias was assessed using Cochrane tools, and the certainty of the evidence was evaluated with the GRADE approach. Findings: Of 7124 records identified, 8 studies, conducted in 7 countries between 2003 and 2019 with 5965 participants, were included. The study interventions included antibiotic prophylaxis (n = 1), zinc supplementation (n = 1), food supplementation (n = 2), psychosocial stimulation (n = 3), unconditional cash transfers (n = 1), and an integrated biomedical, food supplementation, and malaria prevention package (n = 1). Risk of bias was moderate or high for half the studies. Only unconditional cash transfers were associated with reduced relapse, while the integrated package was associated with improved sustained recovery. Zinc supplementation, food supplementation, psychosocial stimulation, and unconditional cash transfers were associated with improvements in postdischarge anthropometry, while zinc supplementation was associated with reductions in multiple postdischarge morbidities. Conclusions and Relevance: In this systematic review of postdischarge interventions to reduce relapse and improve other postdischarge outcomes among children treated for acute malnutrition, evidence was limited. Biomedical, cash, and integrated interventions showed promise in improving certain postdischarge outcomes for children treated for moderate or severe acute malnutrition in single studies. Further evidence on the efficacy, effectiveness, and operational feasibility of postdischarge interventions in other contexts is needed to inform global guidance development.

Assessing environmental enteric dysfunction via multiplex assay and its relation to growth and development among HIV-exposed uninfected Tanzanian infants.

BACKGROUND: Environmental enteric dysfunction (EED) may contribute to poor growth and development in young children. While validated EED biomarkers are currently lacking, multiplex assays are able to capture multiple domains of the condition. The purpose of this exploratory study was to examine the relationship between biomarkers of EED and subsequent growth and development among Tanzanian HIV-exposed uninfected (HEU) infants. METHODOLOGY: We enrolled 467 infants of mothers living with HIV who had participated in a trial of vitamin D3 supplementation during pregnancy. Infant serum samples collected at 6 weeks (n = 365) and 6 months (n = 266) were analyzed for anti-flagellin and anti-lipopolysaccharide (LPS) IgA and IgG via ELISA as well as the 11-plex Micronutrient and EED Assessment Tool (MEEDAT), which incorporates two biomarkers of EED [intestinal fatty acid-binding protein (I-FABP) and soluble CD14 (sCD14)]. Outcomes were 12-month growth [length-for-age z-score (LAZ), weight-for-length z-score (WLZ), and weight-for-age z-score (WAZ)] and development [Caregiver Reported Early Development Instruments (CREDI) z-scores] and were assessed using linear regression. FINDINGS: In primary analyses, higher quartiles of 6-month anti-LPS IgG concentrations were significantly associated with lower LAZ at 12 months (ptrend = 0.040). In secondary analyses, higher log2-transformed 6-week anti-flagellin IgA and 6-month anti-LPS IgA concentrations were significantly associated with lower LAZ at 12 months. No associations were observed between I-FABP or sCD14 and infant growth. However, higher log2-transformed 6-week sCD14 concentrations were significantly associated with lower overall CREDI z-scores, while higher log2-transformed 6-month I-FABP concentrations were significantly associated with higher overall CREDI z-scores. CONCLUSIONS: Unlike anti-flagellin and anti-LPS Igs, MEEDAT's biomarkers of EED (I-FABP and sCD14) were not associated with subsequent linear growth among HEU infants in Tanzania. The relationship between EED and infant development warrants further study.

Effects of antenatal micronutrient supplementation regimens on adolescent emotional and behavioral problems: A 14-year follow-up of a double-blind, cluster-randomized controlled trial.

BACKGROUND & AIMS: Antenatal multiple micronutrient supplementation has been shown to have beneficial effects on birth outcomes and may improve child development. However, whether there is an effect of antenatal micronutrient supplementation strategies on offspring socioemotional outcomes remains unknown. We aimed to examine the effect of antenatal folic acid (FA), iron-folic acid (IFA), and multiple micronutrient (MMN) supplementation on adolescent emotional and behavioral outcomes. METHODS: We conducted a double-blind, cluster-randomized trial of antenatal micronutrient supplementation in rural western China between 2002 and 2006. Pregnant females were randomized by village to receive either daily (i) 400 µg FA, (ii) IFA containing 60 mg iron and 400 µg FA or (iii) MMN supplementation containing 30 mg iron, 400 µg FA plus 13 additional vitamins and minerals. A 14-year follow-up of their offspring was conducted in 2016. Adolescents were administered the locally adapted Youth Self-Report-2001 (YSR-2001) which produced internalizing, externalizing, and total behavior problem scores. We applied generalized estimating equations to assess the effect of the randomized regimens on YSR-2001 scores and explored the potential effect modification by household wealth and initial timing and duration of supplementation. RESULTS: A total of 1920 adolescents were included in the analysis, 1130 (58.9%) were male, and the mean (SD) age was 11.8 (0.78) years. Adolescents in IFA group had lower total (mean difference (MD): -2.89; 95% CI -5.73, -0.04) and externalizing (MD: -0.97; 95% CI -1.79, -0.15) problem scores as compared to those in FA group. There was no effect of MMN on behavior problem scores as compared to IFA and FA alone. Although, in effect modification analyses, MMN appeared to have greater beneficial effects in wealthier households than IFA and FA alone. CONCLUSIONS: Iron supplementation during pregnancy reduced adolescent emotional and behavioral problem scores which provides additional support for expanding coverage of iron-containing prenatal supplements in resource-limited settings. TRIAL REGISTRATION: isrctn. org Identifier: ISRCTN08850194.

The effect of iron supplementation on maternal iron deficiency anemia does not differ by baseline anemia type among Tanzanian pregnant women without severe iron deficiency anemia.

PURPOSE: Whether anemia type modifies the risk of pregnancy and newborn outcomes and the effectiveness of iron supplementation is unclear. We examined the association of iron deficiency anemia (IDA) and non-iron deficiency anemia (NIDA) on the risks of these outcomes and the extent to which anemia type modifies the impact of prenatal iron supplementation. METHODS: This was a secondary analysis of a placebo-controlled trial of iron supplementation among 1450 HIV-negative women in Tanzania. Eligibility criteria included gestational age < 27 weeks, hemoglobin > 85 g/L, and ferritin > 12 µg/L. Individuals were categorized as non-anemia, IDA or NIDA using hemoglobin, ferritin and CRP. Analyses were conducted using regression models and likelihood ratio tests. RESULTS: Compared to the non-anemia group, delivery hemoglobin was lower by 15 g/L (95% CI 10.9, 19.3) in the baseline IDA group, and 7.3 g/L (95% CI 3.1, 11.5) in the baseline NIDA group. The RRs of anemia severity, iron deficiency, placental malaria, stillbirths, perinatal mortality, birthweight, and preterm birth were not different among women in the baseline NIDA group (vs. non-anemia) compared to the baseline IDA group (vs. non-anemia). The difference in the mean delivery hemoglobin for iron supplementation and placebo arms was 8 g/L (95% CI 6, 11) in the non-anemia group, 7 g/L (95% CI 2, 13) in the NIDA group, and 16 g/L (95% CI 10, 22) in the IDA group. CONCLUSION: Iron supplementation is effective even among pregnant women with NIDA. TRIAL REGISTRATION: NCT01119612 (May 7, 2010).

Effect of Oral Iron Supplementation on Cognitive Function among Children and Adolescents in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis.

BACKGROUND: There is abundant evidence showing that iron deficiency is closely linked with delayed brain development, worse school performance, and behavioral abnormalities. However, evidence on the impact of iron supplementation among children and adolescents in low- and middle-income countries (LMICs) has been inconsistent. This study aims to examine the effect of oral iron supplementation on cognitive function among children and adolescents in LMICs. METHODS: A systematic review and meta-analysis was conducted to examine the impact of iron supplementation on cognitive function (including intelligence, attention, short-term memory, long-term memory, and school performance) among children and adolescents aged 5 to 19. We searched PubMed, Embase, Web of Science, CINAHL, and references of related articles published from the inception of the databases to 1 May 2022. Random-effects pooled standardized mean difference (SMD) with 95% confidence intervals (CIs) were calculated to estimate the effect of iron supplementation on cognitive function. We also investigated the heterogeneity of the effects using subgroup and meta-regression analyses. This review was registered with PROSPERO (CRD42020179064). RESULTS: Nine studies with 1196 individual participants from five countries were identified and included. Iron had a positive impact on intelligence test scores among children and adolescents (SMD = 0.47, 95% confidence interval [CI]: 0.10, 0.83). Meta-regression showed that the intelligence test scores improved with increasing the iron supplement dose (odds ratio [CI] = 1.02, 95% CI: 1.00, 1.04). There were no significant effects on attention, short-term memory, long-term memory, or school performance. CONCLUSIONS: Oral iron intake can improve the intelligence test scores of children and adolescents in LMICs and should be considered for future nutritional interventions.

Evaluation of multiple micronutrient supplementation and medium-quantity lipid-based nutrient supplementation in pregnancy on child development in rural Niger: A secondary analysis of a cluster randomized controlled trial.

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 <0.001). Children whose mothers received LNS also had earlier achievement of sitting alone (hazard ratio [HR]: 1.57; 95% CI: 1.10 to 2.24; p = 0.01) and walking alone (1.52; 95% CI: 1.14 to 2.03; p = 0.004) as compared to IFA, but there was no effect on time to achievement of other motor milestones. A limitation of our study is that we assessed child development up to 2 years of age, and, therefore, we may have not captured effects that are easier to detect or emerge at older ages. 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.

Non-specific effects of BCG and DTP vaccination on infant mortality: An analysis of birth cohorts in Ghana and Tanzania.

BACKGROUND: Vaccines may induce non-specific effects on survival and health outcomes, in addition to protection against targeted pathogens or disease. Observational evidence suggests that infant Baccillus Calmette-Guérin (BCG) vaccination may provide non-specific survival benefits, while diphtheria-tetanus-pertussis (DTP) vaccination may increase the risk of mortality. Non-specific vaccine effects have been hypothesized to modify the effect of neonatal vitamin A supplementation (NVAS) on mortality. METHODS: 22,955 newborns in Ghana and 31,999 newborns in Tanzania were enrolled in two parallel, randomized, double-blind, placebo-controlled trials of neonatal vitamin A supplementation from 2010 to 2014 and followed until 1-year of age. Cox proportional hazard models were used to estimate associations of BCG and DTP vaccination with infant survival. RESULTS: BCG vaccination was associated with a decreased risk of infant mortality after controlling for confounders in both countries (Ghana adjusted hazard ratio (aHR): 0.51, 95% CI: 0.38-0.68; Tanzania aHR: 0.08, 95% CI: 0.07-0.10). Receiving a DTP vaccination was associated with a decreased risk of death (Ghana aHR: 0.39, 95% CI: 0.26-0.59; Tanzania aHR: 0.19, 95% CI: 0.16-0.22). There was no evidence of interaction between BCG or DTP vaccination status and infant sex or NVAS. CONCLUSION: We demonstrated that BCG and DTP vaccination were associated with decreased risk of infant mortality in Ghana and Tanzania with no evidence of interaction between DTP or BCG vaccination, NVAS, and infant sex. Our study supports global recommendations on BCG and DTP vaccination and programmatic efforts to ensure all children have access to timely vaccination. CLINICAL TRIALS REGISTRATION: Ghana (Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000582055) and Tanzania (ANZCTR: ACTRN12610000636055).

Cholecalciferol Supplementation Does Not Affect the Risk of HIV Progression, Viral Suppression, Comorbidities, Weight Loss, and Depression among Tanzanian Adults Initiating Antiretroviral Therapy: Secondary Outcomes of a Randomized Trial.

BACKGROUND: Observational studies suggest that blood concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with morbidity, viral suppression, and mortality among adults living with HIV. OBJECTIVES: We evaluated the effect of cholecalciferol (vitamin D3) supplementation on the risk of HIV disease progression, HIV-1 viral suppression, comorbidities, weight change, and depression among HIV-infected individuals that were initiating antiretroviral therapy (ART) in Dar es Salaam, Tanzania. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of vitamin D3 supplementation among 4000 HIV-infected adult men and nonpregnant women initiating ART with insufficient serum 25(OH)D concentrations (<30 ng/mL). Participants were randomly assigned to receive either weekly 50,000-IU doses for 4 wk followed by daily 2000 IU vitamin D3 until 1 y or a matching placebo regimen given in weekly followed by daily doses until 1 y. Participants were followed up at weekly visits for the first month followed by monthly visits thereafter. We conducted intent-to-treat analyses to assess the effect of vitamin D3 supplementation on the secondary trial outcomes of HIV progression or death, viral suppression, comorbidities, change in BMI, >10% weight loss, incident wasting, and depression. RESULTS: During follow-up, 345 participants (17.2%) in the vitamin D3 group and 371 participants (18.6%) in the placebo group experienced HIV disease progression or death and there was no difference in risk between groups (RR: 0.91; 95% CI: 0.79, 1.06). Vitamin D3 supplementation did not affect the risk of an unsuppressed HIV-1 viral load (>1000 copies/mL) after 6 mo (RR: 1.10; 95% CI: 0.87, 1.41) and there was also no effect on change in BMI, risk of >10% weight loss, wasting, comorbidities, and depression (P values >0.05). CONCLUSIONS: Vitamin D supplementation did not affect the risk of HIV progression, viral suppression, common morbidities, weight-related indicators, or depression among adults initiating ART in Tanzania.This trial was registered at clinicaltrials.gov as NCT01798680.

Vitamin D3 supplementation during pregnancy and lactation for women living with HIV in Tanzania: A randomized controlled trial.

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 (<10th percentile), and (iii) infant stunting at 1 year of age (length-for-age z-score < -2). We also examined the effect of vitamin D3 supplementation on secondary maternal and infant health outcomes, maternal and infant serum 25-hydroxyvitamin D (25[OH]D) concentrations, and maternal hypercalcemia. An intent-to-treat analysis was used as the primary analytic approach. We enrolled 2,300 pregnant women between June 15, 2015, and April 17, 2018, and follow-up of mothers and infants was completed on October 20, 2019. There were 1,148 pregnant women randomly assigned to the vitamin D3 group, and 1,152 to the placebo group. The proportion of mothers lost to follow-up at 1 year postpartum was 6.6% in the vitamin D3 group (83 of 1,148) and 6.6% in the placebo group (76 of 1,152). The proportion of children lost to follow-up at 1 year of age was 5.5% in the vitamin D3 group (59 of 1,074 live births) and 5.2% in the placebo group (57 of 1,093 live births). There was no difference in the risk of maternal HIV progression or death, with 166 events during 1,461 person-years of follow-up in the vitamin D3 group and 141 events during 1,469 person-years of follow-up in the placebo group (hazard ratio 1.21, 95% CI 0.97 to 1.52, p = 0.09). There was no difference in the risk of SGA birth between the vitamin D3 (229 SGA births among 1,070 live births) and placebo groups (236 SGA births among 1,091 live births) (relative risk 1.03, 95% CI 0.87 to 1.22, p = 0.70). There was also no difference in the risk of infant stunting at 1 year of age between the vitamin D3 (407 events among 867 infants) and placebo groups (413 events among 873 infants) (relative risk 1.00, 95% CI 0.92 to 1.10, p = 0.95). In terms of adverse events, no cases of maternal hypercalcemia were identified. One hypersensitivity reaction to the trial supplements occurred for a pregnant woman in the placebo group. A limitation of our study is that our findings may not be generalizable to HIV-negative pregnant women or contexts where severe vitamin D deficiency is prevalent. 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.

Calcium supplementation for the prevention of hypertensive disorders of pregnancy: current evidence and programmatic considerations.

Most low- and middle-income countries present suboptimal intakes of calcium during pregnancy and high rates of mortality due to maternal hypertensive disorders. Calcium supplementation during pregnancy is known to reduce the risk of these disorders and associated complications, including preeclampsia, maternal morbidity, and preterm birth, and is, therefore, a recommended intervention for pregnant women in populations with low dietary calcium intake (e.g., where ≥25% of individuals in the population have intakes less than 800 mg calcium/day). However, this intervention is not widely implemented in part due to cost and logistical issues related to the large dose and burdensome dosing schedule (three to four 500-mg doses/day). WHO recommends 1.5-2 g/day but limited evidence suggests that less than 1 g/day may be sufficient and ongoing trials with low-dose calcium supplementation (500 mg/day) may point a path toward simplifying supplementation regimens. Calcium carbonate is likely to be the most cost-effective choice, and it is not necessary to counsel women to take calcium supplements separately from iron-containing supplements. In populations at highest risk for preeclampsia, a combination of calcium supplementation and food-based approaches, such as food fortification with calcium, may be required to improve calcium intakes before pregnancy and in early gestation.

Prenatal supplementation with multiple micronutrient supplements or medium-quantity lipid-based nutrient supplements has limited effects on child growth up to 24 months in rural Niger: a secondary analysis of a cluster randomized trial.

BACKGROUND: Prenatal multiple micronutrient supplementation (MMS) and lipid-based nutrient supplementation (LNS) can improve birth outcomes relative to iron-folic acid supplementation (IFA); however, effects on child postnatal growth remain unclear. OBJECTIVES: The aim was to compare the effect of prenatal MMS, medium-quantity LNS (MQ-LNS), and IFA on child growth up to 2 y of age. METHODS: We conducted a cluster randomized controlled trial of prenatal nutritional supplementation in Madarounfa, Niger. Villages were randomly assigned for pregnant women to receive IFA (17 villages, 1105 women), MMS (18 villages, 1083 women) or MQ-LNS (18 villages, 1144 women). Pregnant women received nutritional supplements weekly until delivery, and children were followed up monthly from 6-8 wk to 24 mo of age. We assessed the effect of prenatal MMS and MQ-LNS compared with IFA and the effect of prenatal MMS compared with MQ-LNS on child length-for-age z scores (LAZ), weight-for-age z scores (WAZ), and weight-for-length z scores (WLZ) at 24 mo of age using generalized linear models. In secondary analyses, we used mixed-effects models to assess the trajectories of anthropometric z scores longitudinally from 6-8 wk to 24 mo. RESULTS: Compared with IFA, MMS and MQ-LNS had no effect on child LAZ, WAZ, or WLZ at 24 mo of age (P > 0.05). Children in the MQ-LNS arm had significantly higher mid-upper arm circumference at 24 mo than children in the MMS arm: mean difference 0.50 cm (95% CI 0.10, 0.91 cm). WAZ and WLZ trajectories were more negative in the MQ-LNS arm compared with IFA and MMS, with lower z scores from 14 to 20 mo of age. However, WAZ and WLZ trajectories converged after 20 mo of age, and there were no differences by 24 mo of age. CONCLUSIONS: Prenatal MMS and MQ-LNS had limited effect on anthropometric measures of child growth up to 24 mo of age as compared with IFA in rural Niger.

Postnatal Stature Does Not Largely Mediate the Relation between Adverse Birth Outcomes and Cognitive Development in Mid-Childhood and Early Adolescence in Rural Western China.

BACKGROUND: Preterm birth and fetal growth restriction are associated with linear growth faltering and suboptimal cognitive development in childhood. OBJECTIVES: We aimed to investigate whether and to what extent the associations between adverse birth outcomes and cognitive development in mid-childhood and early adolescence are mediated by postnatal stature. METHODS: We used data from a prospective birth cohort of children born to women who participated in a large cluster-randomized trial of antenatal micronutrient supplementation in rural western China. Children were followed up for anthropometric assessments at 6, 12, and 24 mo of age and in mid-childhood (7-9 y). Cognitive development was assessed in mid-childhood (n = 669) and early adolescence (n = 735; 10-12 y) using the Wechsler Intelligence Scale for Children-IV. We conducted a causal mediation analysis to evaluate the proportion of the association of low birth weight (LBW; <2500 g), small-for-gestational age (SGA; <10th percentile), and preterm birth (<37 weeks of gestation) with cognitive development in mid-childhood and early adolescence that was mediated by postnatal length/height-for-age and -sex z score (LAZ/HAZ) during the first 2 y of life and in mid-childhood. RESULTS: LBW and SGA, but not preterm birth, were associated with lower cognitive test scores in mid-childhood and early adolescence. The proportion of the total association of SGA with adolescent cognitive development that was mediated by LAZ/HAZ at 6, 12, and 24 mo of age and in mid-childhood was 25%, 32%, 32%, and 27%, respectively. The corresponding proportions for LBW were 25%, 32%, 16%, and 24%, respectively. CONCLUSIONS: The association of LBW and SGA with cognitive development in mid-childhood and adolescence is not largely mediated by postnatal stature during the first 2 y of life. Postnatal interventions that address the antecedent causes of poor child growth and development, rather than early childhood growth alone, are more likely to mitigate the risk of suboptimal development among SGA and LBW children. This trial was registered at www.isrctn.com as ISRCTN08850194.

School readiness among children born to women living with HIV in Dar es Salaam, Tanzania: a cohort study protocol.

INTRODUCTION: Children who are born to women living with HIV are at a greater risk of suboptimal neurodevelopment; however, evidence from sub-Saharan Africa is limited and functional developmental outcomes are rarely assessed in this vulnerable population. The School Readiness among HIV-Exposed Children (SRHEC) cohort study aims to assess the school readiness of preschool aged children born to women living with HIV and to identify the biological, environmental and social factors that contribute to school readiness in this population. METHODS AND ANALYSIS: The SRHEC cohort is an observational follow-up study of children born to HIV-infected pregnant women who were previously enrolled in a maternal vitamin D supplementation randomised, placebo-controlled trial in Dar es Salaam, Tanzania. This parent trial enrolled 2300 pregnant women and followed mothers and infants up to 1-year postpartum. Mother/caregiver and child pairs will be eligible for the SRHEC follow-up study if the child is between 3 and 6.5 years of age at assessment, and the mother/caregiver provides informed consent. The International Development and Early Learning Assessment tool will be used to assess children's school readiness, including their early literacy, early numeracy, motor, socialemotional, and executive function skills. Data on maternal and child health and nutritional status (eg, anthropometry, blood pressure and diet) will be collected using standardised instruments and survey-based questionnaires. Data on maternal/caregiver depression and anxiety, maternal exposure to intimate partner violence, and HIV-related stigma will also be collected. Generalised linear and logistic regressions will be used to assess the relationship between child school readiness and biological, social, environmental factors. ETHICS AND DISSEMINATION: This study received ethical clearance from the Tanzanian National Institute of Medical Research, the Muhimbili University of Health and Allied Sciences, and the Harvard T.H. Chan School of Public Health. We will disseminate our results in the form of scientific conference presentations and peer-reviewed publications.