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).

Association of Exposure to Intimate Partner Violence With Maternal Depressive Symptoms and Early Childhood Socioemotional Development Among Mothers and Children in Rural Tanzania.

Importance: Approximately 1 in 4 women experience intimate partner violence (IPV) or nonpartner sexual violence during their lifetime. Mothers exposed to IPV are more likely to experience depressive symptoms and to discipline their children harshly, which may affect their children's socioemotional development; however, there is limited evidence on these outcomes. Objective: To examine the association between IPV, maternal depressive symptoms, harsh child discipline, and child stimulation with child socioemotional development. Design, Setting, and Participants: This study used cross-sectional follow-up data collected from February 19 to October 10, 2014, from a birth cohort of children aged 18 to 36 months who were enrolled in a randomized, double-blind, placebo-controlled trial of neonatal vitamin A supplementation in the Morogoro region of Tanzania. Data analysis occurred between September 10, 2019, and January 20, 2020. Exposures: Lifetime experience of IPV was assessed using an abbreviated module of the Tanzania Demographic and Health Survey, maternal depressive symptoms were assessed with the Patient Health Questionnaire, and data on harsh child discipline and maternal stimulation of their children were collected using modules of the United Nations Children's Fund Multiple Indicator Cluster Survey. Main Outcomes and Measures: Child socioemotional development was measured by the Caregiver-Reported Early Childhood Development Instruments. Results: A total of 981 mother-child dyads were included in the analytic sample; 388 children (39.6%) were between ages 18 and 24 (mean [SD] age, 27.06 [6.08]) months, and 515 (52.5%) were male children. A negative association was observed between maternal report of physical IPV only (mean difference, -0.022; 95% CI, -0.045 to -0.006) and physical and sexual IPV (mean difference, -0.045; 95% CI, -0.077 to -0.013) with child socioemotional scores, but neither was statistically significant after including depressive symptoms in the model, which is consistent with mediation. Furthermore, a negative association was observed between maternal mild to severe depressive symptoms and child socioemotional development, including adjustment for IPV (mean difference, -0.073; 95% CI, -0.103 to -0.043). Harsh disciplinary practices and stimulation were not associated with child socioemotional development after adjusting for IPV, maternal depressive symptoms, and other factors. Conclusions and Relevance: The findings of this study suggest that maternal depressive symptoms may explain the negative association between IPV and child socioemotional development.

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).

Non-inferiority of low-dose compared to standard high-dose calcium supplementation in pregnancy: study protocol for two randomized, parallel group, non-inferiority trials in India and Tanzania.

BACKGROUND: Hypertensive disorders of pregnancy are important causes of maternal morbidity and mortality, as well as preterm birth, the leading cause of death for children under 5 years globally. The World Health Organization currently recommends that pregnant women receive high-dose calcium supplementation (1500-2000 mg elemental calcium) for prevention of preeclampsia in populations with low dietary calcium intake. Trials of low-dose calcium supplementation (< 1000 mg elemental calcium/day) during pregnancy have also shown similar reductions in the risk of preeclampsia; however, no trials to date have directly compared low-dose to the standard high-dose calcium supplementation. Our objective is to assess the non-inferiority of low-dose as compared to standard high-dose calcium supplementation in pregnancy. METHODS/DESIGN: We will conduct two independent trials in Bangalore, India (n = 11,000 pregnancies), and Dar es Salaam, Tanzania (n = 11,000 pregnancies). The trial designs are individually randomized, parallel group, quadruple-blind, non-inferiority trials of low-dose calcium supplementation (500 mg elemental calcium/day) as compared to standard high-dose calcium supplementation (1500 mg elemental calcium/day) among nulliparous pregnant women. Pregnant women will be enrolled in the trial before 20 weeks of gestation and will receive the randomized calcium regimen from randomization until the time of delivery. The co-primary outcomes are (i) preeclampsia and (ii) preterm birth; we will test non-inferiority of the primary outcomes for low-dose as compared to the standard high-dose supplementation regimen in each trial. The trials' secondary outcomes include gestational hypertension, severe features of preeclampsia, pregnancy-related death, third trimester severe anemia, fetal death, stillbirth, low birthweight, small-for-gestational age birth, and infant death. DISCUSSION: The trials will provide causal evidence on the non-inferiority of low-dose as compared to the standard high-dose supplementation in India and Tanzania. A single tablet, low-dose calcium supplementation regimen may improve individual-level adherence, reduce programmatic costs, and ultimately expand implementation of routine calcium supplementation in pregnancy in populations with low dietary calcium intake. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03350516 ; registered on 22 November 2018. Clinical Trials Registry-India identifier: CTRI/2018/02/012119 ; registered on 23 February 2018. Tanzania Medicines and Medical Devices Authority Trials Registry identifier: TFDA0018/CTR/0010/5 ; registered on 20 December 2018.

Vitamin B12 is Low in Milk of Early Postpartum Women in Urban Tanzania, and was not Significantly Increased by High dose Supplementation.

The effect of maternal multivitamin supplementation on breast milk vitamin B12 concentrations has not been examined in Tanzania, where the prevalence of maternal plasma B12 insufficiency is 25.6%. Multivitamins (containing 50 µg vitamin B12) or placebo were provided during pregnancy and in the postpartum period. Breast milk samples were collected at or around six weeks postpartum from 491 participants in a trial of multivitamins (NCT00197548). Linear and logistic regression models were used to examine the effect of supplements on vitamin B12 concentration in milk and its associations with other variables including potential confounders. Median vitamin B12 concentration in breast milk was 206 pmol/L and 70% of women had levels indicating inadequacy (<310 pmol/L). Multivitamin supplements did not significantly reduce the odds of inadequate vitamin B12 in breast milk, suggesting suboptimal absorption. A single unit increase in maternal hemoglobin at six weeks was associated with 18% lower odds of inadequate vitamin B12 in breast milk. Participants with higher BMI at baseline had double the odds of having inadequate vitamin B12 than the reference group (<22 kg/m2). Trials to determine the optimal dose, route, and duration of supplementation to improve maternal B12 status in Sub-Saharan Africa are of utmost importance.

Effects of school-based physical activity and multi-micronutrient supplementation intervention on growth, health and well-being of schoolchildren in three African countries: the KaziAfya cluster randomised controlled trial protocol with a 2 × 2 factorial design.

BACKGROUND: In low- and middle-income countries, infectious diseases remain a key public health issue. Additionally, non-communicable diseases are a rapidly growing public health problem that impose a considerable burden on population health. One way to address this dual disease burden, is to incorporate (lifestyle) health promotion measures within the education sector. In the planned study, we will (i) assess and compare physical activity, physical fitness, micronutrient status, body composition, infections with soil-transmitted helminths, Schistosoma mansoni, malaria, inflammatory and cardiovascular health risk markers, cognitive function, health-related quality of life, and sleep in schoolchildren in Côte d'Ivoire, South Africa and Tanzania. We will (ii) determine the bi- and multivariate associations between these variables and (iii) examine the effects of a school-based health intervention that consists of physical activity, multi-micronutrient supplementation, or both. METHODS: Assuming that no interaction occurs between the two interventions (physical activity and multi-micronutrient supplementation), the study is designed as a cluster-randomised, placebo-controlled trial with a 2 × 2 factorial design. Data will be obtained at three time points: at baseline and at 9 months and 21 months after the baseline assessment. In each country, 1320 primary schoolchildren from grades 1-4 will be recruited. In each school, classes will be randomly assigned to one of four interventions: (i) physical activity; (ii) multi-micronutrient supplementation; (iii) physical activity plus multi-micronutrient supplementation; and (iv) no intervention, which will serve as the control. A placebo product will be given to all children who do not receive multi-micronutrient supplementation. After obtaining written informed consent from the parents/guardians, the children will be subjected to anthropometric, clinical, parasitological and physiological assessments. Additionally, fitness tests will be performed, and children will be invited to wear an accelerometer device for 7 days to objectively assess their physical activity. Children infected with S. mansoni and soil-transmitted helminths will receive deworming drugs according to national policies. Health and nutrition education will be provided to the whole study population independently of the study arm allocation. DISCUSSION: The study builds on the experience and lessons of a previous study conducted in South Africa. It involves three African countries with different social-ecological contexts to investigate whether results are generalisable across the continent. TRIAL REGISTRATION: The study was registered on August 9, 2018, with ISRCTN. https://doi.org/10.1186/ISRCTN29534081.

Factors associated with plasma n-3 and n-6 polyunsaturated fatty acid levels in Tanzanian infants.

BACKGROUND/OBJECTIVES: To identify factors associated with plasma polyunsaturated fatty acid (PUFA) levels among 3-month-old Tanzanian infants. SUBJECTS/METHODS: Infants (n = 238) and mothers (n = 193) randomly selected from participants in the neonatal vitamin A supplementation randomized controlled trial. A cross-sectional study of maternal-infant pairs at 3 months postpartum. RESULTS: All infant total, n-3, n-6, and individual PUFA levels were correlated with maternal levels. Infant plasma n-3 PUFA levels were higher when maternal n-3 PUFA levels were higher (mean difference in infant % fatty acid per unit increase in maternal levels ± standard error: 0.79 ± 0.08; P < 0.01). Infant plasma docosahexaenoic acid (DHA) levels were positively associated with maternal DHA levels (0.77 ± 0.09; P < 0.01) but were lower for twin births (-0.55 ± 0.27; P = 0.03). Greater birth weight in kilograms (1.00 ± 0.43; P = 0.02) and higher maternal n-6 PUFA levels (0.20 ± 0.07; P < 0.01) were positively associated with higher infant n-6 PUFA levels, whereas maternal mono-unsaturated fatty acid (MUFA) levels (-0.26 ± 0.08; P < 0.01), maternal mid upper arm circumference (MUAC) (-0.22 ± 0.11; P = 0.04), and male sex (-0.99 ± 0.45; P = 0.03) were associated with lower infant plasma n-6 PUFA levels. Infant plasma arachidonic acid (AA) levels were positively associated with maternal plasma AA levels (0.38 ± 0.09; P < 0.01), but inversely associated with twin births (-1.37 ± 0.67; P = 0.04). CONCLUSIONS: Greater birth weight and higher maternal plasma PUFA levels at 3 months postpartum were significantly associated with higher infant plasma PUFA levels at 3 months age. Twin births, male sex, and higher maternal MUFA levels were associated with lower infant plasma PUFA levels. Nutrition counseling for optimal intake of PUFA-rich foods, to lactating mothers in resource-limited settings may be beneficial for improved infant health.

Factors associated with the decline in under five diarrhea mortality in Tanzania from 1980-2015.

BACKGROUND: Tanzania has made great progress in reducing diarrhea mortality in under- five children. We examined factors associated with the decline and projected the impact of scaling up interventions or reducing risk factors on diarrhea deaths. METHODS: We reviewed economic, health, and diarrhea-related policies, reports and programs implemented during 1980 to 2015. We used the Lives Saved Tool to determine the percentage reduction in diarrhea-specific mortality attributable to changes in coverage of the interventions and risk factors, including direct diarrhea-related interventions, nutrition, and water, sanitation and hygiene (WASH). We projected the number of diarrhea deaths that could be prevented in 2030, assuming near universal coverage of different intervention packages. RESULTS: Diarrhea-specific mortality among under-five children in Tanzania declined by 89% from 35.3 deaths per 1000 live births in 1980 to 3.9 deaths per 1000 live births in 2015. Factors associated with diarrhea-specific under-five mortality reduction included oral rehydration solution (ORS) use, changes in stunting prevalence, vitamin A supplementation, rotavirus vaccine, change in wasting prevalence and change in age-appropriate breastfeeding practices. Universal coverage of direct diarrhea, nutrition and WASH interventions has the potential reduce the diarrhea-specific mortality rate by 90%. CONCLUSIONS: Scaling up of a few key childhood interventions such as ORS and nutrition, and reducing the prevalence of stunting would address the remaining diarrhea-specific under-five mortality by 2030.

Newborn screening for sickle cell disease: an innovative pilot program to improve child survival in Dar es Salaam, Tanzania.

BACKGROUND: Sickle cell disease (SCD) is a recognized cause of childhood mortality. Tanzania has the fifth highest incidence of SCD (with an estimated 11 000 SCD annual births) worldwide. Although newborn screening (NBS) for SCD and comprehensive healthcare have been shown to reduce under-5 mortality by up to 94% in high-income countries such as the USA, no country in Africa has maintained NBS for SCD as a national health program. The aims of this program were to establish and evaluate NBS-SCD as a health intervention in Tanzania and to determine the birth prevalence of SCD. METHODS: Muhimbili University of Health and Allied Sciences conducted NBS for SCD from January 2015 to November 2016. Dried blood spot samples were collected and tested for SCD using isoelectric focusing. RESULTS: Screening was conducted on 3981 newborns. Thirty-one (0.8%) babies had SCD, 505 (12.6%) had sickle cell trait and 26 (0.7%) had other hemoglobinopathies. Twenty-eight (90.3%) of the 31 newborns with SCD were enrolled for comprehensive healthcare. CONCLUSIONS: This is the first report on NBS as a health program for SCD in Tanzania. The SCD birth prevalence of 8 per 1000 births is of public health significance. It is therefore important to conduct NBS for SCD with enrollment into a comprehensive care program.

Determinants of delayed or incomplete diphtheria-tetanus-pertussis vaccination in parallel urban and rural birth cohorts of 30,956 infants in Tanzania.

BACKGROUND: Delayed vaccination increases the time infants are at risk for acquiring vaccine-preventable diseases. Factors associated with incomplete vaccination are relatively well characterized in resource-limited settings; however, few studies have assessed immunization timeliness. METHODS: We conducted a prospective cohort study examining Diphtheria-Tetanus-Pertussis (DTP) vaccination timing among newborns enrolled in a Neonatal Vitamin A supplementation trial (NEOVITA) conducted in urban Dar es Salaam (n = 11,189) and rural Morogoro Region (n = 19,767), Tanzania. We used log-binomial models to assess the relationship of demographic, socioeconomic, healthcare access, and birth characteristics with late or incomplete DTP1 and DTP3 immunization. RESULTS: The proportion of infants with either delayed or incomplete vaccination was similar in Dar es Salaam (DTP1 11.5% and DTP3 16.0%) and Morogoro (DTP1 9.2% and DTP3 17.3%); however, the determinants of delayed or incomplete vaccination as well as their magnitude of association differed by setting. Both maternal and paternal education were more strongly associated with vaccination status in rural Morogoro region as compared to Dar es Salaam (p-values for heterogeneity < 0.05). Infants in Morogoro who had fathers and mothers with no education had 36% (95% CI: 22-52%) and 22% (95% CI: 10-34%) increased risk of delayed or incomplete DTP3 vaccination as compared to those with primary school education, respectively. In Dar es Salaam, mothers who attended their first antenatal care (ANC) visit in the 3rd trimester had 1.55 (95% CI: 1.36-1.78) times the risk of delayed or not received vaccination as compared to those with a 2nd trimester booking, while there was no relationship in Morogoro. In rural Morogoro, infants born at home had 17% (95% CI: 8-27%) increased risk for delayed or no receipt of DTP3 vaccination. In both settings, younger maternal age and poorer households were at increased risk for delayed or incomplete vaccination. CONCLUSION: We found some risk factors for delayed and incomplete vaccination were shared between urban and rural Tanzania; however, we found several context-specific risk factors as well as determinants that differed in their magnitude of risk between contexts. Immunization programs should be tailored to address context-specific barriers and enablers to improve timely and complete vaccination.

Micronutrient Deficiencies among Breastfeeding Infants in Tanzania.

Infant mortality accounts for the majority of child deaths in Tanzania, and malnutrition is an important underlying cause. The objectives of this cross-sectional study were to describe the micronutrient status of infants in Tanzania and assess predictors of infant micronutrient deficiency. We analyzed serum vitamin D, vitamin B12, folate, and ferritin levels from 446 infants at two weeks of age, 408 infants at three months of age, and 427 mothers three months post-partum. We used log-Poisson regression to estimate relative risk of being deficient in vitamin D and vitamin B12 for infants in each age group. The prevalence of vitamin D and vitamin B12 deficiency decreased from 60% and 30% at two weeks to 9% and 13% at three months respectively. Yet, the prevalence of insufficiency at three months was 49% for vitamin D and 17% for vitamin B12. Predictors of infant vitamin D deficiency were low birthweight, urban residence, maternal education, and maternal vitamin D status. Maternal vitamin B12 status was the main predictor for infant vitamin B12 deficiency. The majority of infants had sufficient levels of folate or ferritin. Further research is necessary to examine the potential benefits of improving infants' nutritional status through vitamin D and B12 supplements.

Magnitude and factors associated with nonadherence to antiepileptic drug treatment in Africa: A cross-sectional multisite study.

Objectives: The epilepsy treatment gap is large in low- and middle-income countries, but the reasons behind nonadherence to treatment with antiepileptic drugs (AEDs) across African countries remain unclear. We investigated the extent to which AEDs are not taken and associated factors in people with active convulsive epilepsy (ACE) identified in cross-sectional studies conducted in five African countries. Methods: We approached 2,192 people with a confirmed diagnosis of ACE for consent to give blood voluntarily. Participants were asked if they were taking AEDs, and plasma drug concentrations were measured using a fluorescence polarization immunoassay analyzer. Information about possible risk factors was collected using questionnaire-based clinical interviews. We determined factors associated with nonadherence to AED treatment in children and adults, as measured by detectable and optimal levels, using multilevel logistic regression. Results: In 1,303 samples assayed (43.7% were children), AEDs were detected in 482, but only 287 had optimal levels. Of the 1,303 samples, 532 (40.8%) were from people who had reported they were on AEDs. The overall prevalence of nonadherence to treatment was 63.1% (95% confidence interval [CI] 60.5-65.6%) as measured by detectable AED levels and 79.1% (95% CI 73.3-84.3%) as measured by optimal AED levels; self-reported nonadherence was 65.1% (95% CI 45.0-79.5%). Nonadherence was significantly (p < 0.001) more common among the children than among adults for optimal and detectable levels of AEDs, as was the self-reported nonadherence. In children, lack of previous hospitalization and learning difficulties were independently associated with nonadherence to treatment. In adults, history of delivery at home, absence of burn marks, and not seeking traditional medicine were independently associated with the nonadherence to AED treatment. Significance: Only about 20% of people with epilepsy benefit fully from antiepileptic drugs in sub-Saharan Africa, according to optimum AEDs levels. Children taking AEDs should be supervised to promote compliance.

Dietary iron and calcium intakes during pregnancy are associated with lower risk of prematurity, stillbirth and neonatal mortality among women in Tanzania.

OBJECTIVE: Prematurity, stillbirth and other adverse birth outcomes remain major concerns in resource-limited settings. Poor dietary intake of micronutrients during pregnancy has been associated with increased risk of adverse outcomes. We determined the relationships between dietary Fe and Ca intakes during pregnancy and risks of adverse birth outcomes among HIV-negative women. DESIGN: Women's diet was assessed through repeated 24 h diet recalls in pregnancy. Mean intakes of total Fe, Fe from animal sources and Ca during pregnancy were examined in relation to adverse birth outcomes and neonatal mortality. Women were prescribed daily Fe supplements as per standard perinatal care. SETTING: Dar es Salaam, Tanzania. SUBJECTS: A cohort of 7634 pregnant women. RESULTS: Median (interquartile range) daily dietary intake of total Fe, animal Fe and Ca was 11·9 (9·3-14·7), 0·5 (0-1·1) and 383·9 (187·4-741·2) mg, respectively. Total Fe intake was significantly associated with reduced risk of stillbirth (trend over quartiles, P=0·010). Animal Fe intake was significantly associated with reduced risk of preterm birth and extreme preterm birth. Animal Fe intake was inversely related to neonatal mortality risk; compared with women in the lowest intake quartile, those in the top quartile were 0·51 times as likely to have neonatal death (95 % CI 0·33, 0·77). Higher Ca intake was associated with reduced risk of preterm birth (relative risk; 95 % CI: 0·76; 0·65, 0·88) and extreme preterm birth (0·63; 0·47, 0·86). Women in the highest Ca intake quartile had reduced risk of neonatal mortality (0·59; 0·37, 0·92). CONCLUSIONS: Daily dietary Fe and Ca intakes among pregnant women are very low. Improvement of women's diet quality during gestation is likely to improve the risks of adverse birth outcomes.

The effect of neonatal vitamin A supplementation on morbidity and mortality at 12 months: a randomized trial.

Background: : Neonatal vitamin A supplementation (NVAS) is an intervention hypothesized to reduce infant morbidity and mortality. The objective of this study was to assess the efficacy of neonatal vitamin A supplementation in reducing infant morbidity and mortality and assess potential sources of heterogeneity of the effect of NVAS. Methods: : We completed an individually randomized, double-blind, placebo-controlled trial in Tanzania. Infants were randomized within 3 days of birth to a single dose of vitamin A (50 000 IU) or placebo. We assessed infants at 1 and 3 days after supplementation, as well as 1, 3, 6 and 12 months after supplementation. We included all live births in the analysis and used relative risks (RR) and 95% confidence intervals (CI) to assess the risks of mortality and hospitalization by 12 months. We used general estimating equations to assess the incidence of morbidities during infancy. Results: : A total of 31 999 infants were enrolled in the study between August 2010 and March 2013. At 12 months, vitamin A did not reduce all-cause infant mortality (RR 1.04; 95% CI 0.92-1.16), nor affect hospitalization (RR 1.09; 95% CI 0.97-1.22) or all-cause morbidity (RR 1.00; 95% CI 0.96-1.05). Postpartum maternal vitamin A supplementation modified the effect of neonatal vitamin A supplementation on mortality at 12 months ( P -value, test for interaction = 0.04). Among infants born to women who received a mega-dose of vitamin A after delivery, NVAS appeared to increase the risk of death (RR 1.12; 95% CI 0.98-1.29), whereas the risk of death among infants born to women who did not receive a mega-dose was reduced (RR 0.86; 95% CI 0.70-1.06). We noted no modification of the effect of NVAS by infant gender, birthweight or maternal HIV status. Conclusion: : NVAS did not affect the risk of death or incidence of common childhood morbidities. However, this study sheds light on potential sources of heterogeneity of the effect of neonatal vitamin A supplementation which should be further examined in a pooled analysis of all NVAS trials.

Risk factors for small-for-gestational-age and preterm births among 19,269 Tanzanian newborns.

BACKGROUND: Few studies have differentiated risk factors for term-small for gestational age (SGA), preterm-appropriate for gestational age (AGA), and preterm-SGA, despite evidence of varying risk of child mortality and poor developmental outcomes. METHODS: We analyzed birth outcome data from singleton infants, who were enrolled in a large randomized, double-blind, placebo-controlled trial of neonatal vitamin A supplementation conducted in Tanzania. SGA was defined as birth weight <10th percentile for gestation age and sex using INTERGROWTH standards and preterm birth as delivery at <37 complete weeks of gestation. Risk factors for term-SGA, preterm-AGA, and preterm-SGA were examined independently using log-binomial regression. RESULTS: Among 19,269 singleton Tanzanian newborns included in this analysis, 68.3 % were term-AGA, 15.8 % term-SGA, 15.5 % preterm-AGA, and 0.3 % preterm-SGA. In multivariate analyses, significant risk factors for term-SGA included maternal age <20 years, starting antenatal care (ANC) in the 3(rd) trimester, short maternal stature, being firstborn, and male sex (all p < 0.05). Independent risk factors for preterm-AGA were maternal age <25 years, short maternal stature, firstborns, and decreased wealth (all p < 0.05). In addition, receiving ANC services in the 1(st) trimester significantly reduced the risk of preterm-AGA (p = 0.01). Significant risk factors for preterm-SGA included maternal age >30 years, being firstborn, and short maternal stature which appeared to carry a particularly strong risk (all p < 0.05). CONCLUSION: Over 30 % of newborns in this large urban and rural cohort of Tanzanian newborns were born preterm and/or SGA. Interventions to promote early attendance to ANC services, reduce unintended young pregnancies, increased maternal height, and reduce poverty may significantly decrease the burden of SGA and preterm birth in sub-Saharan Africa. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) - ACTRN12610000636055 , registered on 3(rd) August 2010.

Predictors of Hospitalization During the First Year of Life among 31999 Tanzanian Infants.

OBJECTIVE: This study explored the risk factors for infant hospitalization in urban and peri-urban/rural Tanzania. METHODS: We conducted a prospective cohort study examining predictors of hospitalization during the first year of life among infants enrolled at birth in a large randomized controlled trial of neonatal vitamin A supplementation conducted in urban Dar es Salaam (n = 11,895) and peri-urban/rural Morogoro region (n = 20,104) in Tanzania. Demographic, socioeconomic, environmental and birth outcome predictors of hospitalization were assessed using proportional hazard models. RESULTS: The rate of hospitalization was highest during the neonatal period in both Dar es Salaam (102/10,000 neonatal-months) and Morogoro region (78/10,000 neonatal-months). Hospitalization declined with increased age and was lowest for infants 6-12 months of age in both Dar es Salaam (11/10,000 infant-months) and Morogoro region (16/10,000 infant-months). In both Dar es Salaam and Morogoro region, older maternal age, male sex, low birth weight and being small for gestational age were significant predictors of higher risk of hospitalization (p < 0.05). Increased wealth and having a flush toilet were significantly associated with an increased risk of hospitalization in Morogoro region only (p < 0.05). CONCLUSIONS: This study determined high rates of neonatal hospitalization in Tanzania. Interventions to increase birth size may decrease risk of hospitalization. Equity in access to hospitals for poor rural families in Tanzania requires attention.

Multivitamin and iron supplementation to prevent periconceptional anemia in rural tanzanian women: a randomized, controlled trial.

OBJECTIVE: Women's nutritional status during conception and early pregnancy can influence maternal and infant outcomes. This study examined the efficacy of pre-pregnancy supplementation with iron and multivitamins to reduce the prevalence of anemia during the periconceptional period among rural Tanzanian women and adolescent girls. DESIGN: A double-blind, randomized controlled trial was conducted in which participants were individually randomized to receive daily oral supplements of folic acid alone, folic acid and iron, or folic acid, iron, and vitamins A, B-complex, C, and E at approximately single recommended dietary allowance (RDA) doses for six months. SETTING: Rural Rufiji District, Tanzania. SUBJECTS: Non-pregnant women and adolescent girls aged 15-29 years (n = 802). RESULTS: The study arms were comparable in demographic and socioeconomic characteristics, food security, nutritional status, pregnancy history, and compliance with the regimen (p>0.05). In total, 561 participants (70%) completed the study and were included in the intention-to-treat analysis. Hemoglobin levels were not different across treatments (median: 11.1 g/dL, Q1-Q3: 10.0-12.4 g/dL, p = 0.65). However, compared with the folic acid arm (28%), there was a significant reduction in the risk of hypochromic microcytic anemia in the folic acid and iron arm (17%, RR: 0.61, 95% CI: 0.42-0.90, p = 0.01) and the folic acid, iron, and multivitamin arm (19%, RR: 0.66, 95% CI: 0.45-0.96, p = 0.03). Inverse probability of treatment weighting (IPTW) to adjust for potential selection bias due to loss to follow-up did not materially change these results. The effect of the regimens was not modified by frequency of household meat consumption, baseline underweight status, parity, breastfeeding status, or level of compliance (in all cases, p for interaction>0.2). CONCLUSIONS: Daily oral supplementation with iron and folic acid among women and adolescents prior to pregnancy reduces risk of anemia. The potential benefits of supplementation on the risk of periconceptional anemia and adverse pregnancy outcomes warrant investigation in larger studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01183572.

Effect of neonatal vitamin A supplementation on mortality in infants in Tanzania (Neovita): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Supplementation of vitamin A in children aged 6-59 months improves child survival and is implemented as global policy. Studies of the efficacy of supplementation of infants in the neonatal period have inconsistent results. We aimed to assess the efficacy of oral supplementation with vitamin A given to infants in the first 3 days of life to reduce mortality between supplementation and 180 days (6 months). METHODS: We did an individually randomised, double-blind, placebo-controlled trial of infants born in the Morogoro and Dar es Salaam regions of Tanzania. Women were identified during antenatal clinic visits or in the labour wards of public health facilities in Dar es Salaam. In Kilombero, Ulanga, and Kilosa districts, women were seen at home as part of the health and demographic surveillance system. Newborn infants were eligible for randomisation if they were able to feed orally and if the family intended to stay in the study area for at least 6 months. We randomly assigned infants to receive one dose of 50,000 IU of vitamin A or placebo in the first 3 days after birth. Infants were randomly assigned in blocks of 20, and investigators, participants' families, and data analysis teams were masked to treatment assignment. We assessed infants on day 1 and day 3 after dosing, as well as at 1, 3, 6, and 12 months after birth. The primary endpoint was mortality at 6 months, assessed by field interviews. The primary analysis included only children who were not lost to follow-up. This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number ACTRN12610000636055. FINDINGS: Between Aug 26, 2010, and March 3, 2013, 31,999 newborn babies were randomly assigned to receive vitamin A (n=15,995) or placebo (n=16,004; 15,428 and 15,464 included in analysis of mortality at 6 months, respectively). We did not find any evidence for a beneficial effect of vitamin A supplementation on mortality in infants at 6 months (26 deaths per 1000 livebirths in vitamin A vs 24 deaths per 1000 livebirths in placebo group; risk ratio 1·10, 95% CI 0·95-1·26; p=0·193). There was no evidence of a differential effect for vitamin A supplementation on mortality by sex; risk ratio for mortality at 6 months for boys was 1·08 (0·90-1·29) and for girls was 1·12 (0·91-1·39). There was also no evidence of adverse effects of supplementation within 3 days of dosing. INTERPRETATION: Neonatal vitamin A supplementation did not result in any immediate adverse events, but had no beneficial effect on survival in infants in Tanzania. These results strengthen the evidence against a global policy recommendation for neonatal vitamin A supplementation. FUNDING: Bill & Melinda Gates Foundation to WHO.

Efficacy of early neonatal vitamin A supplementation in reducing mortality during infancy in Ghana, India and Tanzania: study protocol for a randomized controlled trial.

BACKGROUND: Vitamin A supplementation of 6-59 month old children is currently recommended by the World Health Organization based on evidence that it reduces mortality. There has been considerable interest in determining the benefits of neonatal vitamin A supplementation, but the results of existing trials are conflicting. A technical consultation convened by WHO pointed to the need for larger scale studies in Asia and Africa to inform global policy on the use of neonatal vitamin A supplementation. Three trials were therefore initiated in Ghana, India and Tanzania to determine if vitamin A supplementation (50,000 IU) given to neonates once orally on the day of birth or within the next two days will reduce mortality in the period from supplementation to 6 months of age compared to placebo. METHODS/DESIGN: The trials are individually randomized, double masked, and placebo controlled. The required sample size is 40,200 in India and 32,000 each in Ghana and Tanzania. The study participants are neonates who fulfil age eligibility, whose families are likely to stay in the study area for the next 6 months, who are able to feed orally, and whose parent(s) provide informed written consent to participate in the study. Neonates randomized to the intervention group receive 50,000 IU vitamin A and the ones randomized to the control group receive placebo at the time of enrollment. Mortality and morbidity information are collected through periodic home visits by a study worker during infancy. The primary outcome of the study is mortality from supplementation to 6 months of age. The secondary outcome of the study is mortality from supplementation to 12 months of age. The three studies will be analysed independent of each other. Subgroup analysis will be carried out to determine the effect by birth weight, sex, and timing of DTP vaccine, socioeconomic groups and maternal large-dose vitamin A supplementation. DISCUSSION: The three ongoing studies are the largest studies evaluating the efficacy of vitamin A supplementation to neonates. Policy formulation will be based on the results of efficacy of the intervention from the ongoing randomized controlled trials combined with results of previous studies.