Lower-Dose Zinc for Childhood Diarrhea - A Randomized, Multicenter Trial.

BACKGROUND: The World Health Organization recommends 20 mg of zinc per day for 10 to 14 days for children with acute diarrhea; in previous trials, this dosage decreased diarrhea but increased vomiting. METHODS: We randomly assigned 4500 children in India and Tanzania who were 6 to 59 months of age and had acute diarrhea to receive 5 mg, 10 mg, or 20 mg of zinc sulfate for 14 days. The three primary outcomes were a diarrhea duration of more than 5 days and the number of stools (assessed in a noninferiority analysis) and the occurrence of vomiting (assessed in a superiority analysis) within 30 minutes after zinc administration. RESULTS: The percentage of children with diarrhea for more than 5 days was 6.5% in the 20-mg group, 7.7% in the 10-mg group, and 7.2% in the 5-mg group. The difference between the 20-mg and 10-mg groups was 1.2 percentage points (upper boundary of the 98.75% confidence interval [CI], 3.3), and that between the 20-mg and 5-mg groups was 0.7 percentage points (upper boundary of the 98.75% CI, 2.8), both of which were below the noninferiority margin of 4 percentage points. The mean number of diarrheal stools was 10.7 in the 20-mg group, 10.9 in the 10-mg group, and 10.8 in 5-mg group. The difference between the 20-mg and 10-mg groups was 0.3 stools (upper boundary of the 98.75% CI, 1.0), and that between the 20-mg and 5-mg groups was 0.1 stools (upper boundary of the 98.75% CI, 0.8), both of which were below the noninferiority margin (2 stools). Vomiting within 30 minutes after administration occurred in 19.3%, 15.6%, and 13.7% of the patients in the 20-mg, 10-mg, and 5-mg groups, respectively; the risk was significantly lower in the 10-mg group than in the 20-mg group (relative risk, 0.81; 97.5% CI, 0.67 to 0.96) and in the 5-mg group than in the 20-mg group (relative risk, 0.71; 97.5% CI, 0.59 to 0.86). Lower doses were also associated with less vomiting beyond 30 minutes after administration. CONCLUSIONS: Lower doses of zinc had noninferior efficacy for the treatment of diarrhea in children and were associated with less vomiting than the standard 20-mg dose. (Funded by the Bill and Melinda Gates Foundation; ZTDT ClinicalTrials.gov number, NCT03078842.).

Iron status among HIV-infected adults during the first year of antiretroviral therapy in Tanzania.

BACKGROUND: The influence of inflammation on iron status among people living with HIV (PLWHIV) has not been well explored. We evaluated the trajectory of iron status among PLWHIV during the first year of highly active antiretroviral therapy (HAART), compared alternative approaches for inflammation correction, and assessed the associations of iron status with HIV-1 viral load and anthropometric outcomes. METHODS: We conducted a secondary analysis of data from a randomized trial among 400 adults initiating HAART in Tanzania. Ferritin and C-reactive protein (CRP) were measured at baseline, 1, 6 or 12 months. Ferritin was considered in four ways: unadjusted, and adjusted for inflammation using higher cut-off (HC), Thurnham-corrected (TC) and regression-corrected (RC) approaches. For unadjusted, TC and RC ferritin, iron deficiency (ID) was defined using ferritin < 15 µg/L and elevated iron status was defined using ferritin > 150 µg/L among females and > 200 µg/L among males. For HC ferritin, elevated iron status was defined based on serum ferritin > 500 µg/L, while ID was defined using ferritin < 70 µg/L in the presence of inflammation and < 15 µg/L in the absence of inflammation. Regression models evaluated the trajectory of ferritin concentration across categories of baseline characteristics, and assessed the association of iron status with viral and anthropometric outcomes. RESULTS: The prevalence of iron deficiency at HAART initiation was 9% for unadjusted, 17% for HC, 12% for TC and 22% for RC ferritin. The prevalence of elevated iron status was 42% for unadjusted, 18% for HC, 31% for TC, and 15% for RC ferritin. The prevalence of iron deficiency for all three methods increased during the first year of HAART, while the prevalence of elevated iron status decreased. Baseline elevated iron status defined using HC ferritin was associated with a greater risk of HIV-1 viral load > 1000 copies/mL [relative risk (RR) = 4.29, 95% CI: 1.38-13.3] and incidence of being underweight [body mass index (BMI) < 18.5 kg/m2 , hazard ratio (HR) = 3.65, 95% confidence interval (CI): 1.38-9.67]. Neither baseline-elevated iron status defined using TC or RC ferritin nor baseline iron deficiency defined using any of the three methods was associated with HIV-1 viral load or anthropometric outcomes. CONCLUSIONS: Whether and how inflammation correction is done influences findings of studies of iron status among PLWHIV.

Associations Between Social Support and Symptoms of Antenatal Depression with Infant Growth and Development Among Mothers Living with HIV in Tanzania.

Children born to mothers living with HIV may experience greater risk of poor growth and development outcomes than their HIV-unexposed peers. Few studies have examined the relationship between maternal depression and social support with infant growth and development in the context of HIV. We conducted a prospective cohort study of 2,298 pregnant women living with HIV in Dar es Salaam, Tanzania, assessing antenatal depression (Hopkins Symptoms Checklist-25) and social support (Duke-UNC Functional Social Support Questionnaire) at 12-27 weeks of gestation. At one-year age, infant anthropometry and caregiver-reported infant development were assessed. Generalized estimating equations were used to assess mean differences (MD) and relative risks (RR) for growth and developmental outcomes. Symptoms consistent with maternal antenatal depression had 67% prevalence and were associated with infant wasting (RR 2.61; 95% confidence interval (CI) 1.03-6.65; z = 2.02; p = 0.04), but no other growth or developmental outcomes. Greater maternal social support was not associated with infant growth outcomes. Greater affective support was associated with better cognitive (MD 0.18; CI 0.01-0.35; z = 2.14; p = 0.03) and motor (MD 0.16; CI 0.01-0.31; z = 2.04; p = 0.04) development scores. Greater instrumental support was associated with better cognitive (MD 0.26; CI 0.10-0.42; z = 3.15; p < 0.01), motor (MD 0.17; CI 0.02-0.33; z = 2.22; p = 0.03), and overall (MD 0.19; CI 0.03-0.35; z = 2.35; p = 0.02) development scores. Depressive symptoms were associated with greater risk of wasting, while social support was associated with better infant development scores. Strategies to improve mental health and social support for mothers living with HIV during the antenatal period may benefit infant growth and development.

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).

Timing of Antiretroviral Therapy: Initiation and Birth Outcomes Among Pregnant Women With Human Immunodeficiency Virus in Tanzania

BACKGROUND: Combination antiretroviral therapy (cART) initiation during pregnancy reduces the risk of perinatal human immunodeficiency virus (HIV) transmission; however, studies have suggested that there may be unintended adverse consequences on birth outcomes for selected cART regimens. METHODS: We analyzed adverse birth outcomes among a prospective cohort of 1307 pregnant women with HIV in Dar es Salaam who initiated cART during the first or second trimester of a singleton pregnancy. Our primary analysis compared birth outcomes by gestational age at cART initiation among these women initiating cART in pregnancy. RESULTS: Among women who initiated cART in pregnancy, there was no relationship of gestational age at cART initiation with the risk of fetal death or stillbirth. However, women who initiated cART before 20 weeks of gestation compared with after 20 weeks had increased risk of preterm birth (risk ratio [RR], 1.30; 95% confidence interval [CI], 1.03-1.67) but decreased risk of small-for-gestational age birth (RR, 0.71; 95% CI, .55-.93). CONCLUSIONS: With increasing use of cART preconception and early in pregnancy, clinicians should be aware of the benefits and potential risks of cART regimens to optimize birth outcomes.

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.

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.

Predominance of PVL-negative community-associated methicillin-resistant Staphylococcus aureus sequence type 8 in newly diagnosed HIV-infected adults, Tanzania.

Difficult-to-treat infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are of concern in people living with HIV infection as they are more vulnerable to infection. We aimed to identify molecular characteristics of MRSA colonizing newly diagnosed HIV-infected adults in Tanzania. Individuals newly diagnosed with HIV infection were recruited in Dar es Salaam, Tanzania, from April 2017 to May 2018, as part of the randomized clinical trial CoTrimResist ( ClinicalTrials.gov identifier: NCT03087890). Nasal/nasopharyngeal isolates of Staphylococcus aureus were susceptibility tested by disk diffusion method, and cefoxitin-resistant isolates were characterized by short-reads whole genome sequencing. Four percent (22/537) of patients carried MRSA in the nose/nasopharynx. MRSA isolates were frequently resistant towards gentamicin (95%), ciprofloxacin (91%), and erythromycin (82%) but less often towards trimethoprim-sulfamethoxazole (9%). Seventy-three percent had inducible clindamycin resistance. Erythromycin-resistant isolates harbored ermC (15/18) and LmrS (3/18) resistance genes. Ciprofloxacin resistance was mediated by mutations of the quinolone resistance-determining region (QRDR) sequence in the gyrA (S84L) and parC (S80Y) genes. All isolates belonged to the CC8 and ST8-SCCmecIV MRSA clone. Ninety-five percent of the MRSA isolates were spa-type t1476, and one exhibited spa-type t064. All isolates were negative for Panton-Valentine leucocidin (PVL) and arginine catabolic mobile element (ACME) type 1. All ST8-SCCmecIV-spa-t1476 MRSA clones from Tanzania were unrelated to the globally successful USA300 clone. Carriage of ST8 MRSA (non-USA300) was common among newly diagnosed HIV-infected adults in Tanzania. Frequent co-resistance to non-beta lactam antibiotics limits therapeutic options when infection occurs.

Depression and Viral Suppression Among Adults Living with HIV in Tanzania.

Limited information is available on the association between depression and viral suppression among people living with HIV (PLH) in sub-Saharan Africa. We conducted a prospective cohort study of 3996 adults initiating antiretroviral therapy (ART) in Dar es Salaam, Tanzania. Log-binomial models were used to assess the association between depression and the risk of an unsuppressed viral load (> 400 copies/mL) after 6 months of ART. Women who had depression at both initiation and after 6 months of treatment had 1.94 times (95% CI 1.22, 3.09; z = 2.78, p < 0.01) the risk of an unsuppressed viral load after 6 months of treatment as compared to women who did not have depression at either time point. Men with the top tertile of depressive symptoms after 6 months of treatment had 1.58 times the risk of an unsuppressed viral load (95% CI 1.04, 2.38; z = 2.15, p = 0.03) as compared to the lowest tertile. Research should be pursued on interventions to prevent and address depression among adults initiating ART to potentially support achievement of viral suppression.

Plasma concentrations of leptin at mid-pregnancy are associated with gestational weight gain among pregnant women in Tanzania: a prospective cohort study.

BACKGROUND: Gestational weight gain (GWG) has critical implications for maternal and child health. Inflammation and angiogenesis are implicated in various aspects of maternal metabolism that may play a role in gestational weight gain. The associations of inflammatory, angiogenic, and metabolic pathways with GWG are yet to be elucidated. This study evaluated associations between a panel of inflammatory, angiogenic, and metabolic proteins measured in mid-pregnancy and gestational weight gain. METHODS: Pregnant women were enrolled from Dar es Salaam, Tanzania, between 2001 and 2004. The participants were enrolled at mid-pregnancy (12 to 27 weeks of gestation) and followed up until delivery. This analysis focused on a cohort of 1002 women who were primigravid, had singleton live births, had longitudinal measures of gestational weight, and whose mid-pregnancy plasma samples underwent analysis for 18 proteins. RESULTS: Higher plasma concentrations of leptin (mean difference in GWG percent adequacy comparing highest with lowest quartiles: 10.24; 95% CI 3.31, 17.16; p-trend = 0.003) and chitinase-3-like protein-1 (CH3L1) (mean difference in GWG percent adequacy comparing highest with lowest quartiles: 7.02; 95% CI 0.31, 13.72; p-trend = 0.007) were associated with greater GWG in a dose-response pattern. Higher leptin concentrations were associated with a lower risk of inadequate GWG (risk ratio comparing highest with lowest quartiles: 0.77; 95% CI 0.65, 0.91; p-trend = 0.001) and a higher risk of excessive GWG (risk ratio comparing highest with lowest quartiles: 1.57; 95% CI 1.03, 2.39; p-trend = 0.03). Higher CH3L1 concentrations were associated with a higher risk of excessive GWG (p-trend = 0.007). The associations of leptin and CH3L1 with inadequate GWG were stronger during the second than the third trimester. The other 16 proteins examined were not significantly associated with GWG. CONCLUSIONS: Mid-pregnancy plasma leptin concentrations may be associated with GWG and have clinical predictive utility in identifying women at a higher risk of inadequate or excessive gestational weight gain.

Genetic Determinants of Resistance among ESBL-Producing Enterobacteriaceae in Community and Hospital Settings in East, Central, and Southern Africa: A Systematic Review and Meta-Analysis of Prevalence.

BACKGROUND: The world prevalence of community and hospital-acquired extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae is increasing tremendously. Bacteria harboring ESBLs are currently the number one critical pathogens posing a major threat to human health. OBJECTIVE: To provide a summary of molecular evidence on the prevalence of ESBL-producing Enterobacteriaceae (ESBL-E) and associated genes at community and hospital settings in East, Central, and Southern African countries. METHODS: We conducted a systematic literature search on PubMed and Google Scholar databases for the available molecular studies on ESBL-E in hospitals and community settings in East, Central, and Sothern Africa (ECSA). Published studies in English language involving gene characterization of ESBLs from human samples in hospital and community settings were included in the review, inception to November 2019. A random effect meta-analysis was performed to estimate the prevalence of ESBL-E. RESULTS: A total of 27 studies involving molecular characterization of resistance genes from 20,225 ESBL-E isolates were included in the analysis. Seventy-four percent of all studies were hospital based, 15% were based in community settings, and others were done in both hospital and community settings. Of all the studies, 63% reported E. coli as the dominant isolate among ESBL-E recovered from clinical samples and Klebsiella pneumoniae was reported dominant isolates in 33% of all studies. A random pooled prevalence of ESBL-E was 38% (95% CI = 24-53%), highest in Congo, 92% (95% CI = 90-94%), and lowest in Zimbabwe, 14% (95% CI = 9-20%). Prevalence was higher in hospital settings 41% (95% CI = 23-58%) compared to community settings 34% (95% CI = 8-60%). ESBL genes detected from clinical isolates with ESBL-E phenotypes in ECSA were those of Ambler molecular class A [1] that belongs to both functional groups 2be and 2d of Bush and Jacob classification of 2010 [2]. Majority of studies (n = 22, 81.5%) reported predominance of blaCTX-M gene among isolates, particularly CTX-M-15. Predictors of ESBL-E included increased age, hospital admissions, previous use of antibiotics, and paramedical use of herbs. CONCLUSION: Few studies have been conducted at a molecular level to understand the genetic basis of increased resistance among members of ESBL-E in ECSA. Limited molecular studies in the ECSA region leave a gap in estimating the burden and risk posed by the carriage of ESBL genes in these countries. We found a high prevalence of ESBL-E most carrying CTX-M enzyme in ECSA with a greater variation between countries. This could be an important call for combined (regional or global) efforts to combat the problem of antimicrobial resistance (AMR) in the region. Antibiotic use and hospital admission increased the carriage of ESBL-E, while poor people contributed little to the increase of AMR due to lack of access and failure to meet the cost of healthcare compared to high income individuals.

Impaired Hematological Status Increases the Risk of Mortality among HIV-Infected Adults Initiating Antiretroviral Therapy in Tanzania.

BACKGROUND: Hematological status may predict HIV disease progression and mortality among adults initiating highly active antiretroviral therapy (HAART). OBJECTIVES: We aimed to examine the relation of anemia and iron status at HAART initiation with survival and morbidity outcomes. METHODS: We conducted a case-cohort study of 570 HIV-infected adults initiating HAART who were enrolled in a trial of multivitamins in Tanzania. Hemoglobin, serum ferritin, and hepcidin concentrations were assessed at HAART initiation and participants were followed up monthly. We adjusted serum ferritin for inflammation using a regression correction method to characterize hematological status. Cox proportional hazards models were used to estimate HRs for mortality and incident clinical outcomes. RESULTS: We found an 83% prevalence of anemia, 15% prevalence of iron deficiency anemia, and 66% prevalence of anemia of chronic diseases (ACD). The prevalence of elevated iron was 33% and 19% had iron deficiency (ID). After multivariate adjustment, severe anemia (HR: 2.57; 95% CI: 1.49, 4.45) and ACD (HR: 4.71; 95% CI: 2.91, 7.62) were associated with increased risk of mortality as compared with nonanemic participants. In addition, both ID (HR: 2.65; 95% CI: 1.08, 7.78) and elevated iron (HR: 2.83; 95% CI: 2.10, 3.82) were associated with increased risk of mortality as compared with normal iron concentrations. Severe anemia and elevated iron concentrations were associated with incident wasting and >10% weight loss (P values <0.05). CONCLUSIONS: Anemia and both ID and elevated iron were associated with increased mortality among HIV-infected adults initiating HAART. Safety and efficacy studies including anemia etiology, timing of HAART initiation, and dose of iron supplementation among HIV patients appear warranted.This trial was registered at clinicaltrials.gov as NCT00383669.

Prenatal Zinc and Vitamin A Reduce the Benefit of Iron on Maternal Hematologic and Micronutrient Status at Delivery in Tanzania.

BACKGROUND: Zinc and vitamin A supplementation have both been shown to affect iron status, hemoglobin (Hb) concentration, and anemia in animal and human studies. However, evidence on their combined use in pregnancy, in the context of iron-folic acid (IFA) supplementation, remains limited. OBJECTIVE: This study determined the effects of prenatal zinc, vitamin A, and iron supplementation on maternal hematologic and micronutrient status at delivery in Tanzania. METHODS: We analyzed 2 large randomized controlled trials, using generalized estimating equations, and examined the effect of daily zinc (25 mg) and vitamin A (2500 IU) supplementation starting in the first trimester of pregnancy compared with placebo (n = 2500), and separately evaluated the safety and efficacy of daily iron (60 mg) supplementation among iron-replete pregnant women (n = 1500). Blood samples from baseline and delivery were tested for Hb, serum ferritin, soluble transferrin receptor, plasma zinc, and zinc protoporphyrin. RESULTS: Zinc and vitamin A supplementation were associated with lower Hb concentrations at delivery of  -0.26 g/dL (95% CI: -0.50, -0.02 g/dL) and -0.25 g/dL (95% CI: -0.49, -0.01 g/dL), respectively. Vitamin A increased mean ferritin concentrations at delivery (14.3 µg/L, 95% CI: 1.84, 29.11 µg/L), but was associated with increased risk of severe anemia (RR: 1.41; 95% CI: 1.06, 1.88). Among women who were iron replete at baseline, iron supplementation reduced the risk of iron depletion at delivery by 47% (RR: 0.53; 95% CI: 0.43, 0.65). There was no effect of zinc or iron supplements on plasma zinc concentrations. CONCLUSIONS: Our findings support existing WHO guidelines on prenatal iron, vitamin A, and zinc supplementation among pregnant women. In this setting, scaling uptake of prenatal iron supplements is warranted, but prenatal zinc and vitamin A supplementation did not benefit maternal hematologic status at delivery. In settings where vitamin A deficiency is endemic, the efficacy and safety of the WHO recommended prenatal vitamin A supplementation require further evaluation.

Factors associated with sub-microscopic placental malaria and its association with adverse pregnancy outcomes among HIV-negative women in Dar es Salaam, Tanzania: a cohort study.

BACKGROUND: Malaria infection during pregnancy has negative health consequences for both mothers and offspring. Sub-microscopic malaria infection during pregnancy is common in most African countries. We sought to identify factors associated with sub-microscopic placental malaria, and its association with adverse pregnancy outcomes among HIV-negative pregnant women in Dar es Salaam, Tanzania. METHODS: We recruited a cohort of pregnant women during their first trimester and assessed for the occurrence of placental malaria and pregnancy outcomes. The follow-up was done monthly from recruitment until delivery. Histopathology placental malaria positive results were defined as the presence of malaria pigment or parasitized erythrocytes on the slide (histology-positive (HP)), and the sub-microscopic placental infection was defined as positive Plasmodium falciparum DNA by polymerase chain reaction (DNA PCR) amplification in a negative histopathology test. Adverse pregnancy outcomes investigated included low birth weight (birth weight below 2.5 kg), prematurity (live birth below 37 weeks), and small-for-gestational-age (SGA) (live born with a birth weight below 10th percentile for gestational age and sex). Weighted baseline category logit, log-binomial, and log-Poisson models were used to assess factors associated with placental malaria, and its association with adverse pregnancy outcomes. RESULTS: Among 1115 women who had histopathology and DNA PCR performed, 93 (8%) had HP placental infection, and 136 (12%) had the sub-microscopic placental infection. The risk of sub-microscopic placental malaria was greater in women who did not use mosquito prevention methods such as bed nets, fumigation, or mosquito coils (odds ratio (OR) = 1.75; 95% confidence interval (CI): 1.05-2.92; P = 0.03) and in women who were anemic (OR = 1.59; 95% CI: 1.20-2.11; P = 0.001). Women who were underweight had reduced odds of sub-microscopic placental malaria infection (OR = 0.33; 95% CI: 0.17-0.62; P = 0.001). Women who were overweight/obese had 1.48 times higher the odds of HP placental malaria compared to normal weight (OR = 1.48; 95% CI: 1.03-2.11; P = 0.03). HP placental malaria infection was associated with an increased risk of SGA births (RR = 1.30, 95% CI: 0.98-1.72, P = 0.07). In contrast, the sub-microscopic infection was associated with a reduced risk of SGA births (RR = 0.61, 95% CI: 0.43-0.88, P = 0.01). Placental malaria was not associated with low birth weight or prematurity. CONCLUSION: Malaria prevention methods and maternal nutrition status during early pregnancy were important predictors of sub-microscopic placental malaria. More research is needed to understand sub-microscopic placental malaria and the possible mechanisms mediating the association between placental malaria and SGA.

Aflatoxin exposure in utero and birth and growth outcomes in Tanzania.

Some evidence suggests that aflatoxin may contribute to the high prevalence of stunting observed in low-income countries. Whereas several studies have been conducted in West Africa, fewer exist in East Africa and even fewer in nonagricultural contexts. We analyzed serum samples from 400 iron-replete, nonanemic pregnant women from a cohort in Dar es Salaam, Tanzania to determine the extent and magnitude of exposure to aflatoxin and to study the relationship between levels of aflatoxin exposure in utero and infant birth and growth outcomes. Ninety-nine percent of women had detectable concentrations of aflatoxin B1-lysine (AFB1-lysine), with a median level of 1.4-pg/mg albumin, indicating a much lower level compared to studies of rural populations in sub-Saharan Africa. Our results do not show a statistically significant relationship between AFB1-lysine levels and birth weight, small for gestational age, or prematurity. We observe a small statistically significant reduction in gestational age at delivery (0.47 weeks; 95% CI: -0.86, -0.07) as the natural log of AFB1-lysine levels increases by 1 unit of pg/mg of albumin, after controlling for potential confounders. Among a nonrandom set of infants who had measurements for placental weight, haemoglobin at delivery, and follow-up z-score measurements, we find no association between aflatoxin plasma concentrations and these variables. These findings suggest a high prevalence of chronic low-level exposure to aflatoxin, though its effect on birth outcomes in this population remains unclear. Our research adds to a growing body of literature finding mixed associations between aflatoxins on pregnancy outcomes and child growth.

Vitamin D status and risk of incident tuberculosis disease: A nested case-control study, systematic review, and individual-participant data meta-analysis.

BACKGROUND: Few studies have evaluated the association between preexisting vitamin D deficiency and incident tuberculosis (TB). We assessed the impact of baseline vitamins D levels on TB disease risk. METHODS AND FINDINGS: We assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6,751 HIV-negative household contacts of TB patients enrolled between September 1, 2009, and August 29, 2012, in Lima, Peru. We screened for TB disease at 2, 6, and 12 months after enrollment. We defined cases as household contacts who developed TB disease at least 15 days after enrollment of the index patient. For each case, we randomly selected four controls from among contacts who did not develop TB disease, matching on gender and year of age. We also conducted a one-stage individual-participant data (IPD) meta-analysis searching PubMed and Embase to identify prospective studies of vitamin D and TB disease until June 8, 2019. We included studies that assessed vitamin D before TB diagnosis. In the primary analysis, we defined vitamin D deficiency as 25-(OH)D < 50 nmol/L, insufficiency as 50-75 nmol/L, and sufficiency as >75nmol/L. We estimated the association between baseline vitamin D status and incident TB using conditional logistic regression in the Lima cohort and generalized linear mixed models in the meta-analysis. We further defined severe vitamin D deficiency as 25-(OH)D < 25 nmol/L and performed stratified analyses by HIV status in the IPD meta-analysis. In the Lima cohort, we analyzed 180 cases and 709 matched controls. The adjusted odds ratio (aOR) for TB risk among participants with baseline vitamin D deficiency compared to sufficient vitamin D was 1.63 (95% CI 0.75-3.52; p = 0.22). We included seven published studies in the meta-analysis and analyzed 3,544 participants. In the pooled analysis, the aOR was 1.48 (95% CI 1.04-2.10; p = 0.03). The aOR for severe vitamin D deficiency was 2.05 (95% CI 0.87-4.87; p trend for decreasing 25-(OH)D levels from sufficient vitamin D to severe deficiency = 0.02). Among 1,576 HIV-positive patients, vitamin D deficiency conferred a 2-fold (aOR 2.18, 95% CI 1.22-3.90; p = 0.01) increased risk of TB, and the aOR for severe vitamin D deficiency compared to sufficient vitamin D was 4.28 (95% CI 0.85-21.45; p = 0.08). Our Lima cohort study is limited by the short duration of follow-up, and the IPD meta-analysis is limited by the number of possible confounding covariates available across all studies. CONCLUSION: Our findings suggest vitamin D predicts TB disease risk in a dose-dependent manner and that the risk of TB disease is highest among HIV-positive individuals with severe vitamin D deficiency. Randomized control trials are needed to evaluate the possible role of vitamin D supplementation on reducing TB disease risk.

Markers of Systemic Inflammation and Environmental Enteric Dysfunction Are Not Reduced by Zinc or Multivitamins in Tanzanian Infants: A Randomized, Placebo-Controlled Trial.

OBJECTIVE: To examine whether daily zinc and/or multivitamin supplementation reduce biomarkers of environmental enteric dysfunction (EED), systemic inflammation, or markers of growth in a sample of infants from Dar es Salaam, Tanzania. STUDY DESIGN: Subgroup analysis of infants participating in a randomized, double-blind, placebo-controlled trial received daily oral supplementation of zinc, multivitamins, zinc + multivitamins, or placebo for 18 months starting at 6 weeks of age. EED (anti-flagellin and anti-lipopolysaccharide immunoglobulins), systemic inflammation (C-reactive protein and alpha-1-acid glycoprotein), and growth biomarkers (insulin-like growth factor-1 and insulin-like growth factor binding protein-3) were measured via enzyme-linked immunosorbent assay in a subsample of 590 infants at 6 weeks and 6 months of age. EED biomarkers also were measured in 162 infants at 12 months of age. RESULTS: With the exception of anti-lipopolysaccharide IgG concentrations, which were significantly greater in infants who received multivitamins compared with those who did not (1.41 ± 0.61 vs 1.26 ± 0.65, P = .006), and insulin-like growth factor binding protein-3 concentrations, which were significantly lower in children who received zinc compared with those who did not (981.13 ± 297.59 vs 1019.10 ± 333.01, P = .03), at 6 months of age, we did not observe any significant treatment effects of zinc or multivitamins on EED, systemic inflammation, or growth biomarkers. CONCLUSIONS: Neither zinc nor multivitamin supplementation ameliorated markers of EED or systemic inflammation during infancy. Other interventions should be prioritized for future trials. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00421668.

Nutritional, Socioeconomic, and Delivery Characteristics Are Associated with Neurodevelopment in Tanzanian Children.

OBJECTIVES: To evaluate the hypothesis that various maternal, socioeconomic, delivery, and infant nutritional characteristics are associated with early childhood development in young Tanzanian children. STUDY DESIGN: We performed a prospective cohort study among 206 HIV-exposed, uninfected and 247 HIV-unexposed Tanzanian infants who had been enrolled in 2 separate micronutrient trials (NCT00197730 and NCT00421668). Trained nurses administered culturally modified Bayley Scales of Infant and Toddler Development, 3rd edition (BSID-III), to evaluate cognitive, motor, and language development at 15 months of age. This analysis explored predictors of BSID-III z-scores using multivariable linear regression. RESULTS: Among maternal determinants, we found that low maternal height predicted all BSID-III domains in HIV-unexposed children; low maternal education predicted lower cognitive (standardized mean difference, -0.41; 95% CI, -0.74 to -0.08) and lower gross motor scores (standardized mean difference, -0.32; 95% CI, -0.61 to -0.04) in HIV-exposed children. Among delivery characteristics, facility delivery predicted higher cognitive scores (standardized mean difference, 1.36; 95% CI, 0.26-2.46); and oxytocin administration predicted lower fine motor scores (standardized mean difference, -0.48; 95% CI, -0.87 to -0.09) in HIV-exposed children. Higher length-for-age z-scores at 6 weeks of age predicted better cognitive (standardized mean difference, 0.15; 95% CI, 0.01-0.29) and expressive language scores (standardized mean difference, 0.16; 95% CI, 0.02-0.29) at 15 months in HIV-exposed infants. CONCLUSIONS: This hypothesis-generating study found significant associations between nutritional status and health of the mother and child, and maternal educational attainment, with direct measures of early childhood development at 15 months of age. In addition, several aspects of delivery (facility birth and oxytocin administration) were associated with early childhood development. Future intervention trials should focus on modifiable maternal, infant, and obstetric factors to strengthen the evidence base concerning early childhood development. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00197730 and NCT00421668.

Association of vitamin D and diarrhoea in children aged less than five years at Muhimbili national hospital, Dar es Salaam: an unmatched case control study.

BACKGROUND: There has been a growing interest in the non-skeletal roles of vitamin D particularly its immune-modulatory properties which has been shown to influence the susceptibility and severity to infections. There is insufficient data globally on the association between Vitamin D levels and Diarrhoea in children. The objective of the study was to determine the association between vitamin D levels and diarrhoea in children aged less than five years. METHODS: Hospital based unmatched case-control study was carried out at MNH between September 2015 and January 2016. Cases were defined as patients with diarrhoea, Sick controls were patients who did not have diarrhoea but were admitted for other illnesses and Healthy controls were children who had neither diarrhoea nor other co-morbid conditions. Structured questionnaires were used to capture the demographic data and anthropometric measurements. Blood samples of study participants were tested for serum vitamin D levels and grouped as vitamin D sufficient, insufficient or deficient (VDD). SPSSv.20 was used to carry out the Statistical analysis. Binary logistic regression, Mann-Whitney and Kruskal-Wallis tests were used, a p-value≤ 0.05 was considered to be statistically significant. RESULTS: A total of 188 children under five were recruited in the study at the ratio of 1 case: 3 controls, of these 47 were Cases, 94 were Sick controls and remaining 47 were Healthy controls. The mean age was 17.01 ± 14.8 months. The mean vitamin D level was 51.18 ± 21.97 nmol/l. Majority of the participants 101 (53.7%) were vitamin D deficient, 64 (34%) were insufficient and 23 (12.2%) had sufficient vitamin D levels. Sick controls were 3.2 times more likely to be VDD compared to cases [95% CI 0.14-0.69; p = 0.0015] and 5.03 times when compared to Healthy controls [95% CI 2.22-11.55; p = 0.000]. Severe acute malnutrition (SAM) was independently associated with diarrhoea (95% CI: 1.26-5.39, p 0.01). CONCLUSIONS: High prevalence of vitamin D deficiency was found in the children under five years studied. Vitamin D levels was not found to be specifically associated with diarrhoea in children under five years of age.

Markers of Environmental Enteric Dysfunction Are Associated With Neurodevelopmental Outcomes in Tanzanian Children.

BACKGROUND: Chronic exposure to enteropathogens may result in environmental enteric dysfunction (EED), a subclinical condition associated with poor child growth. Growth faltering is strongly associated with poor neurodevelopment, and occurs during sensitive periods of postnatal brain development. We investigated the role of novel EED biomarkers, systemic inflammation, and micronutrient status on neurodevelopment in Tanzanian children. METHODS: Non-stunted subjects with 6-week and 6-month blood samples and neurodevelopmental measures (n = 107) were included in this study. Samples were tested for biomarkers of gastrointestinal function (citrulline, antibodies to lipopolysaccharide, and flagellin), micronutrient status (iron, retinol binding protein [RBP], and vitamin D), systemic inflammation (C-reactive protein [CRP] and alpha-1-acid glycoprotein), and growth (insulin-like growth factor and insulin-like growth factor binding protein 3). RESULTS: Cognitive scores at 15 months were associated with higher concentrations of 6-month anti-lipopolysaccharide IgG (ß = 1.95, P = 0.02), anti-flagellin IgA (ß = 2.41, P = 0.04), and IgG (ß = 2.99, P = 0.009). Higher receptive language scores were positively associated with anti-flagellin IgG (ß = 0.95, P = 0.05), and receptive language and gross motor scores were positively associated with citrulline at 6 months (ß = 0.09, P = 0.02; ß = 0.10, P = 0.03, respectively). Gross motor scores were positively associated with RBP at 6 months (ß = 1.70, P = 0.03). Markers of systemic inflammation were not significantly associated with neurodevelopment. CONCLUSIONS: Plasma citrulline, a marker of gastrointestinal mucosal surface area, and vitamin A status were associated with higher gross motor development scores. Novel markers for EED, but not inflammation, were positively associated with cognitive scores, suggesting a possible mechanistic pathway involving immune response and neuroprotection.