Derivation and Internal Validation of a Novel Risk Assessment Tool to Identify Infants and Young Children at Risk for Post-Discharge Mortality in Dar es Salaam, Tanzania and Monrovia, Liberia.

OBJECTIVE: To derive and validate internally a novel risk assessment tool to identify young children at risk for all-cause mortality ≤60 days of discharge from hospitals in sub-Saharan Africa. STUDY DESIGN: We performed a prospective observational cohort study of children aged 1-59 months discharged from Muhimbili National Hospital in Dar es Salaam, Tanzania and John F. Kennedy Medical Center in Monrovia, Liberia (2019 to 2022). Caregivers received telephone calls up to 60 days after discharge to ascertain participant vital status. We collected socioeconomic, demographic, clinical, and anthropometric data during hospitalization. Candidate variables with P<0.20 in bivariate analyses were included in a multivariable logistic regression model with best subset selection to identify risk factors for the outcome. We internally validated our tool using bootstrapping with 500 repetitions. RESULTS: There were 1,933 young children enrolled in the study. The median (interquartile range) age was 11 (4, 23) months and 58.7% were male. In total, 67 (3.5%) died during follow-up. Ten variables contributed to our tool (total possible score 82). Cancer (adjusted odds ratio [aOR] 10.6, 95% CI 2.58, 34.6), pedal edema (aOR 6.94, 95% CI 1.69, 22.6), and leaving against medical advice (aOR 6.46, 95% CI 2.46, 15.3) were most predictive of post-discharge mortality. Our risk assessment tool demonstrated good discriminatory value (optimism corrected area under the receiver operating characteristic curve 0.77), high precision, and sufficient calibration. CONCLUSIONS: After validation, this tool may be used to identify young children at risk for post-discharge mortality to direct resources for follow-up of high-risk children.

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.

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.

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.

Gestational Age, Birth Weight, and Neurocognitive Development in Adolescents in Tanzania.

OBJECTIVES: To investigate the association between gestational age, birthweight, and birthweight adjusted for gestational age, with domains of neurocognitive development and behavioral problems in adolescents in Tanzania. STUDY DESIGN: Data from a long-term follow-up of adolescents aged 11-15 years born to women previously enrolled in a randomized controlled trial of prenatal multiple micronutrient supplementation in Dar es Salaam, Tanzania, were used. A battery of neurodevelopmental tests were administered to measure adolescent general intelligence, executive function, and behavioral problems. The INTERGROWTH-21st newborn anthropometric standards were used to derive birthweight for gestational age z-scores. We assessed the shape of relationships using restricted cubic splines and estimated the associations of gestational age, birthweight, and birthweight for gestational age z-score with adolescent development using multivariable linear regressions. RESULTS: Among adolescents studied (n = 421), higher gestational age (per week), birthweight (per 100 grams), and birthweight for gestational age z-score (per SD) were linearly associated with higher intelligence score (adjusted standardized mean difference, 0.05 SD [95% CI, 0.01-0.09], 0.04 SD [95% CI, 0.02-0.06], and 0.09 SD [95% CI, 0.01-0.17], respectively). Birthweight and birthweight for gestational age z-score, but not gestational age, were also associated with improved executive function. Low birthweight (<2500 g) was associated with lower intelligence and executive function scores. Associations between birthweight and executive function were stronger among adolescents born to women with higher education. CONCLUSIONS: The duration of gestation and birthweight were positively associated with adolescent neurodevelopment in Tanzania. These findings suggest that interventions to improve birth outcomes may also benefit adolescent cognitive function.

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.

Delayed Breastfeeding Initiation Is Associated with Infant Morbidity.

OBJECTIVE: To assess the relationship between breastfeeding initiation time and postneonatal mortality, morbidity, and growth through 24 months in a cohort of Tanzanian infants. STUDY DESIGN: We included 4203 infants from 2 trials of micronutrient supplementation. We used Cox proportional hazards models or general estimating equations to estimate relative risks. RESULTS: A total of 13% of infants initiated breastfeeding >1 hour after birth (n = 536). There was no association between breastfeeding initiation time and risk of all-cause or cause-specific mortality, nor infant growth failure, from 6 weeks to 2 years of age. However, delayed breastfeeding was associated with an increased risk of several common infectious morbidities in early infancy, including upper respiratory infection symptoms and vomiting. Compared with those who initiated breastfeeding within the first hour of birth, delayed breastfeeding initiation was associated with an 11% increased risk of cough (relative risk 1.11, 95% CI 1.02-1.21) and a 48% increased risk of difficulty breathing (relative risk 1.48, 95% CI 1.09-2.01) during the first 6 months. Delayed initiation was associated with a greater risk of difficulty breathing from 6 to 12 months of age, but it was not associated with risk of any other morbidity during this time, nor any morbidity between 12 and 24 months. CONCLUSION: Delayed breastfeeding initiation is associated with an increased risk of infant morbidity during the first 6 months of life. Early breastfeeding initiation, along with exclusive and prolonged breastfeeding, should be prioritized and promoted in efforts to improve child health.

High Burden of Morbidity and Mortality but Not Growth Failure in Infants Exposed to but Uninfected with Human Immunodeficiency Virus in Tanzania.

OBJECTIVE: To compare health and growth outcomes in children infected with HIV, children exposed to but uninfected with HIV, and children unexposed to HIV. STUDY DESIGN: Our cohort included 3554 Tanzanian children enrolled in 2 trials of micronutrient supplementation. Among infants born to mothers infected with HIV, 264 were infected with HIV and 2088 were exposed to but uninfected at 6 weeks of age. An additional 1202 infants were unexposed to HIV. Infants were followed until 18 months of age, death, or loss to follow-up. Morbidity and growth were assessed at monthly nurse visits. RESULTS: Compared with unexposed infants, hazard ratios (95% CI) for all-cause mortality in infants infected with HIV and infants who were exposed to but uninfected with HIV were 28.99 (14.83-56.66) and 2.79 (1.41-5.53), respectively, after adjusting for demographic and nutritional covariates. Compared with infants unexposed to HIV, infants infected with HIV also had a significantly greater risk of all measured morbidities, while infants who were exposed to but uninfected with HIV were significantly more likely to suffer from cough, fever, unscheduled outpatient visits, and hospitalizations. Infants infected with HIV also were more likely to experience stunting, wasting, and underweight at baseline and during follow-up. Infants exposed to but uninfected with HIV were more likely to be underweight at baseline (adjusted relative risk, 2.05; 95% CI, 1.45-2.89), but on average, experienced slower declines in height-for-age z-score, weight-for-age z-score, and weight-for-height z-score as well as a lower rate of stunting over follow-up, compared with unexposed infants. CONCLUSION: In addition to preventing and treating HIV infection in infants, prevention-of-mother-to-child-transmission of HIV and child health services should also target children exposed to but uninfected with HIV to improve health outcomes in this vulnerable population. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00197730 and NCT00421668.

Infant Nutritional Status and Markers of Environmental Enteric Dysfunction are Associated with Midchildhood Anthropometry and Blood Pressure in Tanzania.

OBJECTIVE: To assess whether growth and biomarkers of environmental enteric dysfunction in infancy are related to health outcomes in midchildhood in Tanzania. STUDY DESIGN: Children who participated in 2 randomized trials of micronutrient supplements in infancy were followed up in midchildhood (4.6-9.8 years of age). Anthropometry was measured at age 6 and 52 weeks in both trials, and blood samples were available from children at 6 weeks and 6 months from 1 trial. Linear regression was used for height-for-age z-score, body mass index-for-age z-score, and weight for age z-score, and blood pressure analyses; log-binomial models were used to estimate risk of overweight, obesity, and stunting in midchildhood. RESULTS: One hundred thirteen children were followed-up. Length-for-age z-score at 6 weeks and delta length-for-age z-score from 6 to 52 weeks were associated independently and positively with height-for-age z-score and inversely associated with stunting in midchildhood. Delta weight-for-length and weight-for-age z-score were also positively associated with midchildhood height-for-age z-score. The 6-week and delta weight-for-length z-scores were associated independently and positively with midchildhood body mass index-for-age z-score and overweight, as was the 6-week and delta weight-for-age z-score. Delta length-for-age z-score was also associated with an increased risk of overweight in midchildhood. Body mass index-for-age z-score in midchildhood was associated positively with systolic blood pressure. Serum anti-flagellin IgA concentration at 6 weeks was also associated with increased blood pressure in midchildhood. CONCLUSIONS: Anthropometry at 6 weeks and growth in infancy independently predict size in midchildhood, while anti-flagellin IgA, a biomarker of environmental enteric dysfunction, in early infancy is associated with increased blood pressure in midchildhood. Interventions in early life should focus on optimizing linear growth while minimizing excess weight gain and environmental enteric dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00197730 and NCT00421668.

Vitamin D Deficiency Is Not Associated With Growth or the Incidence of Common Morbidities Among Tanzanian Infants.

OBJECTIVE: The objective of this study was to examine risk factors for vitamin D deficiency and determine the association of vitamin D status with child growth and incidence of common morbidities among Tanzanian infants. METHODS: A prospective cohort of 581 Tanzanian infants born to human immunodeficiency virus (HIV)-uninfected mothers had serum 25-hydroxyvitamin D assessed at 6 weeks and 6 months of age. Infants were seen at monthly clinic visits for growth monitoring until 18 months of age. Physicians examined infants every 3 months or when an illness was noted to document morbidities. RESULTS: The prevalence of vitamin D deficiency (<20 ng/mL) declined from 76.4% at 6 weeks of age to 21.2% at 6 months. Infants who were exclusively breastfed at 6 weeks of age had 2.05 (95% confidence interval 1.11-3.79; P = 0.02) times the risk of vitamin D deficiency as compared formula-fed infants. After multivariate adjustment, there was no association of vitamin D status at 6 weeks or 6 months with the incidence of stunting, wasting, or underweight. There was also no association of low vitamin D with the incidence of diarrhea, upper respiratory infection, acute lower respiratory tract infection, or malaria. CONCLUSIONS: Vitamin D deficiency is common during early infancy, particularly among exclusively breastfed infants; however, these observational data suggest it may not be an important contributor to morbidity and growth among the general population of Tanzanian infants. Future studies of vitamin D among high-risk infants, including those with low birthweight and exposed to HIV, may be warranted.

Vitamin D Levels in Malnourished Children under 5 Years in a Tertiary Care Center at Muhimbili National Hospital, Dar es Salaam, Tanzania-A Cross-sectional Study.

Objective: : To evaluate vitamin D levels/deficiency among malnourished children <5 years admitted at a tertiary care center, the Muhimbili National Hospital, Dar es Salaam, Tanzania. Children with malnutrition may have co-existing vitamin D deficiency (VDD), which may be severe. Methods: : Serum vitamin D and alkaline phosphatase were evaluated, and X-ray of the wrist was carried out on 134 children. Results: : VDD was found in 41 of 134 children (30.6%). The mean vitamin D level was 74.8 nmol/l. The mean alkaline phosphatase level was 176.6 U/l. Sixty-four (48%) children were found to have severe stunting, of whom 20 (31.2%) were vitamin D deficient. Marasmic children had higher odds of VDD compared with other forms of malnutrition. Conclusion: : The high prevalence of VDD in malnourished children underlines the need for active surveillance and aggressive management.

Nutritional status and complementary feeding among HIV-exposed infants: a prospective cohort study.

Complementary feeding is crucial for improving child survival and promoting growth and development, particularly among HIV-exposed children who have higher risk of morbidity and mortality than their un-exposed peers. This prospective study employed an infant and child feeding index (ICFI) to measure complementary feeding and determine its association with nutritional status among 2092 HIV-exposed infants followed from 6 to 24 months of age in Dar es Salaam, Tanzania. The ICFI measured both quality and quantity of complementary feeding, including current breastfeeding status, food consistency, dietary diversity scores (DDS), food group frequency score, and meal frequency. The ICFI score ranged from 0 to 9; the median score was 6 (Inter-Quartile Range, IQR= 4-7). After adjusting for potential confounders, high ICFI scores were associated with reduced risk of stunting (high vs. low tertile hazard ratio, HR: 0.72; 95% confidence interval, CI: 0.57, 0.91; P< 0.01) and underweight (high vs. low tertile HR: 0.79; 95% CI: 0.61, 1.02; P= 0.07). Low DDS were associated with higher risk of stunting (low vs. high tertile HR: 1.59; 95% CI: 1.23, 2.07; P< 0.01) and underweight (low vs. high tertile HR: 1.48; 95% CI: 1.12, 1.96; P= 0.01). In this setting, high DDS and ICFI scores were protective of stunting and underweight. We recommend for nutrition programs in low-income countries to emphasize educating HIV-exposed children's caregivers on the importance of dietary diversity and optimal complementary feeding to improve nutritional status in this important subpopulation.

The effect of daily zinc and/or multivitamin supplements on early childhood development in Tanzania: results from a randomized controlled trial.

Impaired childhood development has lifelong consequences for educational attainment and wage-earning potential. Micronutrient supplements have the potential to improve development. The objective of this study was to determine the effect of daily zinc and/or multivitamin (vitamins C, E and B-complex) supplements on development among Tanzanian infants. In this randomized, 2 × 2 factorial, double-blind trial, 2400 infants were randomized to zinc (Zn), multivitamins (MV), zinc and multivitamins (Zn + MV) or placebo at 6 weeks of age. At approximately 15 months, a sub-sample of 247 children underwent developmental assessment using the cognitive, language (receptive and expressive) and motor (fine and gross) scales of the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III). Mean BSID-III scores were compared using univariate and multivariate linear regression models adjusted for child's sex, post-conceptual age and test administrator. Logistic regressions were used to assess odds of low developmental scores. We did not detect a significant difference in mean BSID-III scores in any of the five domains in univariate or multivariate models comparing each of the four treatment groups. We also did not detect a significant difference in mean BSID-III scores when comparing children who received zinc supplements versus those who did not, or in comparisons of children who received multivitamin supplements versus those who did not. There was no significant difference in odds of a low BSID-III score in any of the five domains in treatment arms either. Because neither daily zinc nor multivitamin (vitamins B-complex, C and E) supplementation led to improvements in any of the developmental domains assessed using the BSID-III, we recommend pursuing alternative interventions to promote early childhood development in vulnerable populations. © 2016 John Wiley & Sons Ltd.

Maternal Antiretroviral Therapy Is Associated with Lower Risk of Diarrhea in Early Childhood.

OBJECTIVES: To identify risk factors, including maternal antiretroviral therapy (ART), for diarrhea in Tanzanian children exposed to HIV during the first 2 years of life. STUDY DESIGN: Using generalized estimating equations, we analyzed data from a cohort of 2387 Tanzanian children exposed to HIV from age 6 weeks to 2 years, as well as data from their mothers, to determine risk factors for diarrhea in children. Mothers recorded diarrhea in a diary and reported results at visits scheduled every four weeks. RESULTS: Body mass index was ≥18.5 in 95.6% of mothers. World Health Organization HIV stage was 1/2 for 1255 (87.8%) mothers. ART was received by 24.3% of mothers, most initiating ART during pregnancy. At baseline (6 weeks of age) 264 (11.3%) children were infected with HIV. In children whose mothers received ART, the relative risk of diarrhea in children was 0.79 (95% CI 0.68-0.92), after we adjusted for multiple factors, including child HIV status and exclusive breastfeeding duration. Exclusive breastfeeding (relative risk 0.67, 95% CI 0.56-0.80) also was protective. CONCLUSION: Our results provide additional support to increase ART coverage for all pregnant mothers, to control clinical HIV progression, reduce perinatal HIV infection, but also to reduce the risk of a major cause of death and morbidity in young children worldwide. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00197730.

Exclusive Breast-feeding Protects against Mother-to-Child Transmission of HIV-1 through 12 Months of Age in Tanzania.

The jury on transmission of HIV through breast-feeding is still on. Data from a clinical trial in children born to HIV-positive mothers were evaluated with respect to their relationship to mother-to-child transmission. A total of 1629 infants who were not infected at age 6 weeks, had HIV results available at 12 months and who were breast-fed were included in this study. Exclusive breast feeding (EBF) rates declined from 85% at 2 months to < 30% by 4 months. EBF was associated with a sustained and significant reduction in HIV infection. With every incremental month of EBF, HIV infection was reduced by 16% [multivariable (risk ratio) RR: 0.84, CI: 0.72-0.98, p = 0.03] from enrollment to 6 months of age and by 18% (multivariable RR: 0.82, CI: 0.72-0.94, p = 0.005) from enrollment to 12 months of age. EBF significantly reduces the risk of vertical HIV transmission through 12 months of age.

Active Tuberculosis in HIV-Exposed Tanzanian Children up to 2 years of Age: Early-Life Nutrition, Multivitamin Supplementation and Other Potential Risk Factors.

BACKGROUND: Over half a million children worldwide develop active tuberculosis (TB) each year. Early-life nutritional exposures have rarely been examined in relation to pediatric TB among HIV-exposed children. We therefore investigated independent associations of early-life nutritional exposures with active TB among HIV-exposed children up to 2 years of age. METHODS: Participants were children from a randomized controlled multivitamin supplementation trial conducted in Dar es Salaam, Tanzania, from August 2004 to May 2008, who received daily multivitamin supplements or placebo for 24 months. RESULTS: Lower mean corpuscular volumes [relative risks (RR): 0.48, 95% confidence interval (CI): 0.27, 0.87] and higher birth weights (RR: 0.61, 95% CI: 0.37, 0.99) were protective against active TB, whereas multivitamin supplementation was not associated with TB risk (RR: 0.87, 95% CI: 0.65, 1.16). CONCLUSIONS: Knowledge of nutrition-related risk and protective factors for TB in HIV-exposed children could enhance preventive and case-finding activities in this population, contributing to efforts to reduce the global TB burden.

Daily Zinc but Not Multivitamin Supplementation Reduces Diarrhea and Upper Respiratory Infections in Tanzanian Infants: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Although various micronutrient regimens have been shown to prevent and treat common infectious diseases in children, the effects of daily multivitamin (MV) and/or zinc supplementation have not been widely evaluated in young African infants. OBJECTIVE: The objective was to determine whether daily supplementation of HIV-unexposed Tanzanian infants with MVs or zinc reduces the risk of infectious morbidity compared with placebo. METHODS: In a 2 × 2 factorial, double-blind, randomized controlled trial, 2400 infants who were 6 wk of age and born to HIV-negative mothers in a low-malaria setting were randomly assigned to receive daily oral supplementation of MVs (vitamin B complex and vitamins C and E), zinc, zinc + MVs, or placebo for 18 mo. Morbidity was assessed by study nurses at monthly visits and by physicians every 3 mo and/or when the child was acutely ill. RESULTS: No significant differences were found in the percentage of nurse visits during which diarrhea, cough, or any other symptom were reported throughout the previous month when receiving either zinc or MVs. However, physician diagnoses of all types of diarrhea (RR = 0.88; 95% CI: 0.81, 0.96; P = 0.003), dysentery (RR = 0.84; 95% CI: 0.74, 0.95; P = 0.006), and acute upper respiratory infection (RR = 0.92; 95% CI: 0.88, 0.97; P = 0.0005) were significantly lower for infants supplemented with zinc than for those who did not receive zinc. Among the 2360 infants for whom vital status was obtained, there was a nonsignificant increase in all-cause mortality among infants who received zinc (HR = 1.80; 95% CI: 0.98, 3.31; P = 0.06) compared with those who did not receive zinc. MVs did not alter the rates of any recorded physician diagnoses or mortality. Neither zinc nor MVs reduced hospitalizations or unscheduled outpatient visits. CONCLUSIONS: Daily zinc supplementation of Tanzanian infants beginning at the age of 6 wk may lower the burden of diarrhea and acute upper respiratory infections, but provision of MVs using the regimen in this trial did not confer additional benefit. This trial was registered at clinicaltrials.gov as NCT00421668.

Vitamin D status is associated with mortality, morbidity, and growth failure among a prospective cohort of HIV-infected and HIV-exposed Tanzanian infants.

BACKGROUND: Vitamin D is a potent immunomodulator, but its impact on morbidity and mortality among infants remains unclear. OBJECTIVE: The objective of the study was to prospectively assess the association of vitamin D status with mortality, morbidity, and growth during the first 2 y of life. METHODS: A prospective cohort of 253 HIV-infected and 948 HIV-exposed Tanzanian infants enrolled in a randomized trial of multivitamins (not including vitamin D) was studied. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured at 5-7 wk of age and infants were followed at monthly clinic visits until 24 mo. Physicians performed a clinical exam every 3 mo or when an illness was noted. RESULTS: Serum 25(OH)D concentrations were (means ± SDs) 18.6 ± 10.3 ng/mL and 18.1 ± 9.2 ng/mL for HIV-infected and HIV-exposed infants, respectively. Unexpectedly, serum 25(OH)D concentrations ≥30 ng/mL were significantly associated with higher mortality as compared to the 20-29.9 ng/mL reference for HIV-infected (HR: 2.47; 95% CI: 1.13, 5.44; P = 0.02) and HIV-exposed (HR: 4.00; 95% CI: 1.67, 9.58; P < 0.01) infants after multivariate adjustment. We found no statistically significant association between 25(OH)D concentrations <10 ng/mL and mortality for HIV-infected (HR: 1.43; 95% CI: 0.74, 2.78; P = 0.29) and HIV-exposed (HR: 1.56; 95% CI: 0.60, 4.03; P = 0.36) infants. Among HIV-exposed infants, 25(OH)D concentrations ≥30 ng/mL were significantly associated with clinical [incidence ratio rate (IRR): 1.34; 95% CI: 1.06,1.70; P = 0.02] and confirmed (IRR: 1.71; 95% CI: 1.71; 1.15, 2.54; P < 0.01) malaria diagnoses, whereas concentrations of <10 ng/mL were associated with oral candidiasis (IRR: 1.47; 95% CI: 1.00-2.15; P = 0.046) and wasting (HR: 1.71; 95% CI: 1.20, 2.43; P < 0.01). CONCLUSION: The observational design of this study does not allow for causal interpretation; however, the results indicate a strong need for additional studies of vitamin D among HIV-infected and -exposed children, particularly in malaria-endemic settings. The parent trial was registered at clinicaltrials.gov as NCT00197730.

Genetic relatedness and risk factor analysis of ampicillin-resistant and high-level gentamicin-resistant enterococci causing bloodstream infections in Tanzanian children.

BACKGROUND: While enterococci resistant to multiple antimicrobials are spreading in hospitals worldwide, causing urinary tract, wound and bloodstream infections, there is little published data on these infections from Africa. METHODS: We assessed the prevalence, susceptibility patterns, clinical outcome and genetic relatedness of enterococcal isolates causing bloodstream infections in children in a tertiary hospital in Tanzania, as part of a prospective cohort study of bloodstream infections among 1828 febrile children admitted consecutively from August 2001 to August 2002. RESULTS: Enterococcal bacteraemia was identified in 2.1% (39/1828) of admissions, and in 15.3% (39/255) of cases of culture-confirmed bloodstream infections. The case-fatality rate in children with Enterococcus faecalis septicaemia (28.6%, 4/14) was not significantly different from those with Enterococcus faecium septicaemia (6.7%, 1/15, p = 0.12). E. faecium isolates commonly had combined ampicillin-resistance and high-level gentamicin resistance (HLGR), (9/17), while E. faecalis frequently displayed HLGR (6/15), but were ampicillin susceptible. None of the tested enterococcal isolates displayed vancomycin resistance by Etest or PCR for vanA and vanB genes. Multi-locus sequence-typing (MLST) showed that the majority of E. faecium (7/12) belonged to the hospital associated Bayesian Analysis of Population Structure (BAPS) group 3-3. Pulsed-field gel electrophoresis (PFGE) indicated close genetic relationship particularly among E. faecium isolates, but also among E. faecalis isolates. There was also correlation between BAPS group and PFGE results. Risk factors for enterococcal bloodstream infection in univariate analysis were hospital-acquired infection and clinical diagnosis of sepsis with unknown focus. In multivariate analysis, neonates in general were relatively protected from enterococcal infection, while both prematurity and clinical sepsis were risk factors. Malnutrition was a risk factor for enterococcal bloodstream infection among HIV negative children. CONCLUSION: This is the first study to describe bloodstream infections caused by ampicillin-resistant HLGR E. faecium and HLGR E. faecalis in Tanzania. The isolates of E. faecium and E. faecalis, respectively, showed high degrees of relatedness by genotyping using PFGE. The commonly used treatment regimens at the hospital are insufficient for infections caused by these microbes. The study results call for increased access to microbiological diagnostics to guide rational antibiotic use in Tanzania.