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).

Vitamin D and Zinc Supplementation to Improve Treatment Outcomes among COVID-19 Patients in India: Results from a Double-Blind Randomized Placebo-Controlled Trial.

Background: There remains a need to identify low-cost interventions to improve coronavirus disease 2019 (COVID-19) outcomes. Vitamin D and zinc play a role in respiratory infections and could hold value as part of therapeutic regimens. Objectives: To determine the effect of vitamin D or zinc supplementation on recovery from COVID-19. Methods: We conducted a double-blind, randomly assigned 2 x 2 factorial placebo-controlled trial with 1:1:1:1 allocation ratio, enrolling nonpregnant adults with COVID-19 from hospitals in Mumbai and Pune, India (NCT04641195). Participants (N = 181) were randomly assigned to vitamin D3 (180,000 IU bolus, then 2000 IU daily), zinc (40 mg daily), vitamin D3 and zinc, or placebo, for 8 wk. Participants were followed until 8 wk. The primary outcome was time to resolution of fever, cough, and shortness of breath. Secondary outcomes were duration of individual symptoms; need for assisted ventilation; duration of hospital stay; all-cause mortality; and blood biomarkers, including nutritional, inflammatory, and immunological markers. Results: We observed no effect of vitamin D or zinc supplementation on time to resolution of all 3 symptoms [vitamin D hazard ratio (HR): 0.92; 95% confidence interval (95% CI): 0.66, 1.30; P = 0.650; zinc HR: 0.94; 95% CI: 0.67, 1.33; P = 0.745)]. Neither vitamin D nor zinc supplementation was associated with secondary outcomes, except for increased endline serum vitamin D with vitamin D supplementation [median (interquartile range) difference between endline and baseline for vitamin D: 5.3 ng/mL (-2.3 to 13.7); for no vitamin D: -1.4 ng/mL (-5.6 to 3.9); P = 0.003]. We observed nonsignificant increases in serum zinc at endline following zinc supplementation. There was no evidence of interaction between vitamin D and zinc supplementation, no effect of either on hypercalcemia, and no adverse events. Conclusions: Results suggest that neither vitamin D nor zinc supplementation improves COVID-19 treatment outcomes in this population. However, much larger-scale evidence, particularly from populations with vitamin D or zinc deficiency and severe infection, is required to corroborate our findings. This trial was registered at ClinicalTrials.gov and the Clinical Trials Registry of India as NCT04641195 and CTRI/2021/04/032593 respectively.

Associations of Diet Quality, Socioeconomic Factors, and Nutritional Status with Gestational Weight Gain among Pregnant Women in Dar es Salaam, Tanzania.

Background: Gestational weight gain (GWG) is a modifiable factor associated with maternal and child health outcomes, but the relationship between diet quality and GWG has not been evaluated using metrics validated for low-income and middle-income countries (LMICs). Objective: This study aimed to investigate relationships between diet quality, socioeconomic characteristics, and GWG adequacy using the novel Global Diet Quality Score (GDQS), the first diet quality indicator validated for use across LMIC. Methods: Weights of pregnant women enrolled between 12 and 27 wk of gestation (N = 7577) were recorded in Dar es Salaam, Tanzania, from 2001 to 2005 during a prenatal micronutrient supplementation trial. GWG adequacy was the ratio of measured GWG to Institute of Medicine-recommended GWG, categorized into severely inadequate (<70%), inadequate (70 to <90%), adequate (90 to <125%), or excessive (≥125%). Dietary data were collected using 24-h recalls. Multinomial logit models were used to estimate relationships between GDQS tercile, macronutrient intake, nutritional status, and socioeconomic characteristics and GWG. Results: GDQS scores in the second [relative risk (RR): 0.82; 95% confidence interval (CI): 0.70, 0.97] tercile were associated with lower risk of inadequate weight gain than those in the first tercile. Increased protein intake was associated with higher risk of severely inadequate GWG (RR: 1.06; 95% CI: 1.02, 1.09). Nutritional status and socioeconomic factors were associated with GWG: underweight prepregnancy BMI (in kg/m2) with a higher risk of severely inadequate GWG (RR: 1.49; 95% CI: 1.12, 1.99), overweight or obese BMI with a higher risk of excessive GWG (RR: 6.80; 95% CI: 5.34, 8.66), and a higher education (RR: 0.61; 95% CI: 0.42, 0.89), wealth (RR: 0.68; 95% CI: 0.48, 0.80), and height (RR: 0.96; 95% CI: 0.95, 0.98) with a lower risk of severely inadequate GWG. Conclusions: Dietary indicators showed few associations with GWG. However, stronger relationships were revealed between GWG, nutritional status, and several socioeconomic factors.This trial was registered at clinicaltrials.gov as NCT00197548.

Effects of prenatal nutritional supplements on gestational weight gain in low- and middle-income countries: a meta-analysis of individual participant data.

BACKGROUND: Gestational weight gain (GWG) below or above the Institute of Medicine (IOM) recommendations has been associated with adverse perinatal outcomes. Few studies have examined the effect of prenatal nutrient supplementations on GWG in low- and middle-income countries (LMICs). OBJECTIVES: We aimed to investigate the effects of multiple micronutrient supplements (MMSs) and small-quantity lipid-based nutrient supplements (LNSs) on GWG in LMICs. METHODS: A 2-stage meta-analysis of individual participant data was conducted to examine the effects of MMSs (45,507 women from 14 trials) and small-quantity LNSs (6237 women from 4 trials) on GWG compared with iron and folic acid supplements only. Percentage adequacy of GWG and total weight gain at delivery were calculated according to the IOM 2009 guidelines. Binary outcomes included severely inadequate (percentage adequacy <70%), inadequate (<90%), and excessive (>125%) GWG. Results from individual trials were pooled using fixed-effects inverse-variance models. Heterogeneity was examined using I2, stratified analysis, and meta-regression. RESULTS: MMSs resulted in a greater percentage adequacy of GWG [weighted mean difference (WMD): 0.86%; 95% CI: 0.28%, 1.44%; P < 0.01] and higher GWG at delivery (WMD: 209 g; 95% CI: 139, 280 g; P < 0.01) than among those in the control arm. Women who received MMSs had a 2.9% reduced risk of severely inadequate GWG (RR: 0.971; 95% CI: 0.956, 0.987; P < 0.01). No association was found between small-quantity LNSs and GWG percentage adequacy (WMD: 1.51%; 95% CI: -0.38%, 3.40%; P = 0.21). Neither MMSs nor small-quantity LNSs were associated with excessive GWG. CONCLUSIONS: Maternal MMSs were associated with greater GWG percentage adequacy and total GWG at delivery than was iron and folic acid only. This finding is consistent with previous results on birth outcomes and will inform policy development and local recommendations of switching routine prenatal iron and folic acid supplements to MMSs.

Randomised trial to determine the effect of vitamin D and zinc supplementation for improving treatment outcomes among patients with COVID-19 in India: trial protocol.

INTRODUCTION: Presently, there are few population-level strategies to address SARS-CoV-2 infection except preventive measures such as vaccination. Micronutrient deficiency, particularly vitamin D and zinc deficiency, has been associated with dysregulated host responses, and may play an important role in COVID-19. METHODS AND ANALYSIS: We have designed a 2×2 factorial, randomised, double-blind, multi-centre placebo-controlled trial to evaluate the effect of vitamin D and zinc on COVID-19 outcomes in Maharashtra, India. COVID-19 positive individuals are recruited from hospitals in Mumbai and Pune. Participants are provided (1) vitamin D3 bolus (180 000 IU) maintained by daily dose of 2000 IU and/or (2) zinc gluconate (40 mg daily), versus placebo for 8 weeks. Participants undergo a detailed assessment at baseline and at 8 weeks, and are monitored daily in hospital or every 3 days after leaving the hospital to assess symptoms and other clinical measures. A final follow-up telephone call occurs 12 weeks post-enrolment to assess long-term outcomes. The primary outcome of the study is to time to recovery, defined as time to resolution of all of fever, cough and shortness of breath. Secondary outcomes include: duration of hospital stay, all-cause mortality, necessity of assisted ventilation, change in blood biomarker levels and individual symptoms duration. Participant recruitment commenced on April 2021. ETHICS AND DISSEMINATION: Ethical approval was obtained from institutional ethical committees of all participating institutions. The study findings will be presented in peer-reviewed medical journals. TRIAL REGISTRATION NUMBERS: NCT04641195, CTRI/2021/04/032593, HMSC (GOI)-2021-0060.

Gestational weight gain during the second and third trimesters and adverse pregnancy outcomes, results from a prospective pregnancy cohort in urban Tanzania.

BACKGROUND: Appropriate gestational weight gain (GWG) is important for optimal pregnancy outcomes. This study prospectively evaluated the associations between GWG during the second and third trimesters of pregnancy and adverse pregnancy outcomes in an urban Tanzanian pregnancy cohort. METHODS: We used data from a randomized clinical trial conducted among pregnant women recruited by 27 weeks of gestation in Dar es Salaam, Tanzania (N = 1230). Women's gestational weight was measured at baseline and at monthly antenatal visits. Weekly GWG rate during the second and third trimesters was calculated and characterized as inadequate, adequate, or excessive, in conjunction with measured or imputed early-pregnancy BMI status according to the 2009 Institute of Medicine (IOM) GWG guidelines. We used multivariable Poisson regression with a sandwich variance estimator to calculate risk ratios (RR) for associations of GWG with low birth weight, preterm birth, small for gestational age (SGA), and large for gestational age (LGA). Degree of appropriate GWG defined using additional metrics (i.e., percentage of adequacy, z-score) and potential effect modification by maternal BMI were additionally evaluated. RESULTS: According to the IOM guidelines, 517 (42.0%), 270 (22.0%), and 443 (36.0%) women were characterized as having inadequate, adequate, and excessive GWG, respectively. Overall, compared to women with adequate GWG, women with inadequate GWG had a lower risk of LGA births (RR = 0.54, 95% CI: 0.36-0.80) and a higher risk of SGA births (RR = 1.32, 95% CI: 0.95-1.81). Women with inadequate GWG as defined by percentage of GWG adequacy had a higher risk of LBW (OR = 1.93, 95% CI: 1.03-3.63). In stratified analyses by early-pregnancy BMI, excessive GWG among women with normal BMI was associated with a higher risk of preterm birth (RR = 1.59, 95% CI: 1.03-2.44). CONCLUSIONS: A comparatively high percentage of excessive GWG was observed among healthy pregnant women in Tanzania. Both inadequate and excessive GWGs were associated with elevated risks of poor pregnancy outcomes. Future studies among diverse SSA populations are warranted to confirm our findings, and clinical recommendations on optimal GWG should be developed to promote healthy GWG in SSA settings. TRIAL REGISTRATION: This trial was registered as "Prenatal Iron Supplements: Safety and Efficacy in Tanzania" (NCT01119612; http://clinicaltrials.gov/show/NCT01119612 ).

Pregnancy is a critical lifetime event for both mother and the offspring, with implications in short-term and long-term health consequences. Gestational weight gain (GWG) is an important modifiable factor for pregnancy outcomes related to infant body size and weight and prematurity. Countries in sub-Saharan Africa (SSA) have long had poor rates of insufficient GWG and pregnancy complications associated with insufficient GWG. Nevertheless, some SSA countries are experiencing economic transitions accompanied with changes in lifestyle and nutrition, which might impact pregnancy experiences, including GWG and pregnancy outcomes. This study aimed to characterize recent GWG patterns and the associations of both inadequate and excessive GWG with adverse pregnancy outcomes, using an urban pregnancy cohort in Tanzania. This study found that 42.0%. 22.0%, and 36.0% of women had insufficient, adequate, and excessive GWG, respectively. Insufficient GWG was associated with higher risks of small infant size and low infant body weight, and excessive GWG was associated with higher risk of preterm birth, particularly among women with body mass index 18.5­25.0 kg/m². Results from the present study highlight that both insufficient and excessive GWG are of potential public health concerns in urban centers of SSA, concerning upward trends in obesity and possibly obesity-related pregnancy consequences. Local public health practitioners should continue to advocate longitudinal GWG monitoring and care among African pregnant women, and optimal GWG with feasible and effective clinical guidelines should be developed to prevent both over- and under-gaining of maternal weight during pregnancy.

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

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

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

BACKGROUND: Observational studies suggest that vitamin D deficiency among people living with HIV is associated with a greater risk of disease progression and death. Low levels of vitamin D in pregnancy are also associated with poor fetal and infant growth. Therefore, vitamin D supplementation may improve clinical outcomes for pregnant women living with HIV and improve fetal and postnatal growth for their infants. METHODS AND FINDINGS: We conducted a randomized, triple-blind, placebo-controlled trial of vitamin D3 supplementation among pregnant and lactating women living with HIV in Dar es Salaam, Tanzania (ClinicalTrials.gov NCT02305927). Participants were randomized with 1:1 allocation stratified by study clinic to receive either daily 3,000 IU vitamin D3 supplements or matching placebo supplements from the second trimester of pregnancy (12-27 weeks) until 1 year postpartum. The primary outcomes were (i) maternal HIV progression or death, (ii) small-for-gestational-age (SGA) live births (<10th percentile), and (iii) infant stunting at 1 year of age (length-for-age z-score < -2). We also examined the effect of vitamin D3 supplementation on secondary maternal and infant health outcomes, maternal and infant serum 25-hydroxyvitamin D (25[OH]D) concentrations, and maternal hypercalcemia. An intent-to-treat analysis was used as the primary analytic approach. We enrolled 2,300 pregnant women between June 15, 2015, and April 17, 2018, and follow-up of mothers and infants was completed on October 20, 2019. There were 1,148 pregnant women randomly assigned to the vitamin D3 group, and 1,152 to the placebo group. The proportion of mothers lost to follow-up at 1 year postpartum was 6.6% in the vitamin D3 group (83 of 1,148) and 6.6% in the placebo group (76 of 1,152). The proportion of children lost to follow-up at 1 year of age was 5.5% in the vitamin D3 group (59 of 1,074 live births) and 5.2% in the placebo group (57 of 1,093 live births). There was no difference in the risk of maternal HIV progression or death, with 166 events during 1,461 person-years of follow-up in the vitamin D3 group and 141 events during 1,469 person-years of follow-up in the placebo group (hazard ratio 1.21, 95% CI 0.97 to 1.52, p = 0.09). There was no difference in the risk of SGA birth between the vitamin D3 (229 SGA births among 1,070 live births) and placebo groups (236 SGA births among 1,091 live births) (relative risk 1.03, 95% CI 0.87 to 1.22, p = 0.70). There was also no difference in the risk of infant stunting at 1 year of age between the vitamin D3 (407 events among 867 infants) and placebo groups (413 events among 873 infants) (relative risk 1.00, 95% CI 0.92 to 1.10, p = 0.95). In terms of adverse events, no cases of maternal hypercalcemia were identified. One hypersensitivity reaction to the trial supplements occurred for a pregnant woman in the placebo group. A limitation of our study is that our findings may not be generalizable to HIV-negative pregnant women or contexts where severe vitamin D deficiency is prevalent. CONCLUSIONS: The trial findings do not support routine vitamin D supplementation for pregnant and lactating women living with HIV in Tanzania. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02305927.

Associations between Gestational Weight Gain Adequacy and Neonatal Outcomes in Tanzania.

INTRODUCTION: Gestational weight gain (GWG) is associated with fetal and newborn health; however, data from sub-Saharan Africa are limited. METHODS: We used data from a prenatal micronutrient supplementation trial among a cohort of human immunodeficiency virus-negative pregnant women in Dar es Salaam, Tanzania to estimate the relationships between GWG and neonatal outcomes. GWG adequacy was defined as the ratio of the total observed weight gain over the recommended weight gain based on the Institute of Medicine body mass index-specific guidelines. Neonatal outcomes assessed were stillbirth, perinatal death, preterm birth, low birthweight, macrosomia, small-for-gestational age (SGA), large-for-gestational age (LGA), stunting at birth, and microcephaly. Modified Poisson regressions with robust standard error were used to estimate the relative risk of newborn outcomes as a function of GWG adequacy. RESULTS: Of 7,561 women included in this study, 51% had severely inadequate (<70%) or inadequate GWG (70 to <90%), 31% had adequate GWG (90 to <125%), and 18% had excessive GWG (≥125%). Compared to adequate GWG, severely inadequate GWG was associated with a higher risk of low birthweight, SGA, stunting at birth, and microcephaly, whereas excessive GWG was associated with a higher risk of LGA and macrosomia. CONCLUSION: Interventions to support optimal GWG are needed and may contribute to preventing adverse neonatal outcomes.

Coffee Intake of Colorectal Cancer Patients and Prognosis According to Histopathologic Lymphocytic Reaction and T-Cell Infiltrates.

Given previous biologic evidence of immunomodulatory effects of coffee, we hypothesized that the association between coffee intake of colorectal cancer patients and survival differs by immune responses. Using a molecular pathologic epidemiology database of 4465 incident colorectal cancer cases, including 1262 cases with molecular data, in the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association between coffee intake of colorectal cancer patients and survival in strata of levels of histopathologic lymphocytic reaction and T-cell infiltrates in tumor tissue. We did not observe a significant association of coffee intake with colorectal cancer-specific mortality (multivariable-adjusted hazard ratio [HR] for 1-cup increase of coffee intake per day, 0.93; 95% CI, 0.84 to 1.03). Although statistical significance was not reached at the stringent level (α=.005), the association of coffee intake with colorectal cancer-specific mortality differed by Crohn disease-like lymphoid reaction (Pinteraction=.007). Coffee intake was associated with lower colorectal cancer-specific mortality in patients with high Crohn disease-like reaction (multivariable HR for 1-cup increase of coffee intake per day, 0.55; 95% CI, 0.37 to 0.81; Ptrend=.002) but not in patients with intermediate Crohn disease-like reaction (the corresponding HR, 1.02; 95% CI, 0.72 to 1.44) or negative/low Crohn disease-like reaction (the corresponding HR, 0.95; 95% CI, 0.83 to 1.07). The associations of coffee intake with colorectal cancer-specific mortality did not significantly differ by levels of other lymphocytic reaction or any T-cell subset (Pinteraction>.18). There is suggestive evidence for differential prognostic effects of coffee intake by Crohn disease-like lymphoid reaction in colorectal cancer.

Multivitamin Supplementation Is Associated with Greater Adequacy of Gestational Weight Gain among Pregnant Women in Tanzania.

BACKGROUND: Gestational weight gain (GWG) is a modifiable risk factor associated with adverse birth outcomes. Studies have shown that the provision of multiple micronutrient supplements to pregnant women reduces the risk of low birth weight. However, the effect of multiple micronutrient supplements on GWG has been understudied. OBJECTIVES: We examined the effect of daily supplementation of pregnant women with multivitamins on GWG in relation to the GWG recommendation by the Institute of Medicine (IOM). METHODS: Pregnant women with gestational age between 12 and 27 wk were randomly assigned to receive daily multivitamins or placebo until delivery. Weight was measured at enrollment and every follow-up visit. Percentage adequacy of GWG was calculated as actual GWG divided by the recommended GWG according to the IOM recommendation. Binary outcomes included severely inadequate (<70%), inadequate (<90%), and excessive GWG (≥125%). The analysis included 7573 women with singleton pregnancies. Multiple linear regression models were used to examine the association between multivitamin supplementation and percentage adequacy of GWG, and log-binomial models were used for binary outcomes. RESULTS: The mean percentage adequacy of GWG was 96.7% in the multivitamin arm and 94.4% in the placebo arm, with a mean difference of 2.3% (95% CI: 0.3%, 4.2%; P = 0.022). Compared with women in the placebo arm, those who received multivitamins had a lower risk of severely inadequate GWG (RR: 0.90; 95% CI: 0.83, 0.97; P = 0.008) and inadequate GWG (RR: 0.95; 95% CI: 0.91, 0.99; P = 0.018). No significant difference was found in excessive GWG. CONCLUSIONS: Multivitamin supplementation increased GWG and reduced the risk of severely inadequate and inadequate GWG among pregnant women in Tanzania. Together with previously reported beneficial effects of the supplements on birth outcomes in low- and middle-income countries, our findings support scaling up the use of prenatal supplements that include multivitamins in addition to iron and folic acid.This trial was registered at clinicaltrials.gov as NCT00197548.

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.

Total Vitamin D Intake and Risks of Early-Onset Colorectal Cancer and Precursors.

BACKGROUND & AIMS: Vitamin D has been implicated in colorectal cancer (CRC) pathogenesis, but it remains unknown whether total vitamin D intake is associated with early-onset CRC and precursors diagnosed before age 50. METHODS: We prospectively examined the association between total vitamin D intake and risks of early-onset CRC and precursors among women enrolled in the Nurses' Health Study II. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset CRC were estimated with Cox proportional hazards model. Multivariable-adjusted odds ratios (ORs) and 95% CIs for early-onset conventional adenoma and serrated polyp were estimated with logistic regression model. RESULTS: We documented 111 incident cases of early-onset CRC during 1,250,560 person-years of follow-up (1991 to 2015). Higher total vitamin D intake was significantly associated with a reduced risk of early-onset CRC (HR for ≥450 IU/day vs <300 IU/day, 0.49; 95% CI, 0.26-0.93; P for trend = .01). The HR per 400 IU/day increase was 0.46 (95% CI, 0.26-0.83). The inverse association was significant and appeared more evident for dietary sources of vitamin D (HR per 400 IU/day increase, 0.34; 95% CI, 0.15-0.79) than supplemental vitamin D (HR per 400 IU/day increase, 0.77; 95% CI, 0.37-1.62). For CRC precursors, the ORs per 400 IU/day increase were 0.76 (95% CI, 0.65-0.88) for conventional adenoma (n = 1,439) and 0.85 (95% CI, 0.75-0.97) for serrated polyp (n = 1,878). CONCLUSIONS: In a cohort of younger women, higher total vitamin D intake was associated with decreased risks of early-onset CRC and precursors.

Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies.

BACKGROUND: Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes. OBJECTIVE: To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status. METHOD: We pooled the individual-level data of over 1 million women who were followed for a maximum of 8-20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models. RESULTS: Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d). CONCLUSION: Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.

Maternal dietary diversity and dietary quality scores in relation to adverse birth outcomes in Tanzanian women.

BACKGROUND: Preterm birth (PTB), small for gestational age (SGA), and low birth weight (LBW) are risk factors for morbidity and mortality among infants. High-quality maternal diets during pregnancy may protect against these adverse birth outcomes. OBJECTIVES: The aim of this study was to prospectively examine the association of maternal dietary diversity and quality during pregnancy with birth outcomes among women in Dar es Salaam, Tanzania. METHODS: We analyzed data from 7553 HIV-negative pregnant women enrolled in a multivitamin trial at 12-27 weeks of gestation. Dietary intake was assessed using 24-h dietary recalls. Dietary diversity scores (DDS; range: 0-10) were computed as the number of food groups consumed by women, using FAO's Minimum Dietary Diversity for Women index. The Prime Diet Quality Score (PDQS; range: 0-42) assessed maternal diet quality based on consumption of 21 healthy and unhealthy food groups. Log binomial regression methods were used to assess associations of DDS and PDQS with PTB, SGA, LBW, and fetal loss. RESULTS: In the previous 24 h, 99.9% of all women had consumed cereal and staples, 57.9% meats, 4.7% eggs, and 0.5% nuts and seeds. Median DDS was 3.0 (IQR: 2.5-3.5). For the PDQS, all women consumed ≥4 servings/wk of green leafy vegetables and refined grains. Higher DDS was associated with lower risk of SGA (RR highest compared with lowest quintile: 0.74; 95% CI: 0.62, 0.89). Higher PDQS was associated with lower risk of PTB (RR highest compared with lowest quintile: 0.55; 95% CI: 0.46, 0.66), LBW (RR: 0.53; 95% CI: 0.40, 0.70), and fetal loss (RR: 0.53; 95% CI, 0.34, 0.82). CONCLUSIONS: PDQS was inversely associated with PTB, LBW, and fetal loss, and DDS was inversely associated with SGA. These findings suggest that in addition to dietary diversity, diet quality should be considered as important in understanding dietary risk factors for poor birth outcomes.This trial was registered at clinicaltrials.gov as NCT00197548.

Efficacy of vitamin D3 supplementation for the prevention of pulmonary tuberculosis and mortality in HIV: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Observational data suggest that low vitamin D status is associated with an increased incidence of pulmonary tuberculosis and mortality among people living with HIV. The primary aims of this study were to assess the effect of vitamin D3 supplementation on the risk of mortality and incidence of pulmonary tuberculosis among adults initiating antiretroviral therapy (ART). METHODS: This was a randomised, double-blind, placebo-controlled trial of vitamin D3 supplementation among adults living with HIV who initiated ART and had serum 25-hydroxyvitamin D concentrations of less than 30 ng/mL at four large HIV care and treatment centres in Dar es Salaam, Tanzania. Patients were excluded if they were younger than 18 years, pregnant at the time of randomisation, or were enrolled in any other clinical trial. Patients were randomly assigned 1:1 to receive either weekly oral 50 000 IU vitamin D3 supplements (cholecalciferol) for the first month of ART followed by daily 2000 IU vitamin D3 supplements or a matching weekly and daily placebo regimen. The randomisation list was computer-generated by a non-study statistician with sequence blocks of ten that were stratified by study clinic. Complete allocation concealment was ensured and patients, field team, and investigators were masked to group assignment. The trial follow-up duration was 1 year and the primary efficacy outcomes were death and incident pulmonary tuberculosis. An intention-to-treat analysis was followed for all-cause mortality; participants diagnosed with or receiving treatment for pulmonary tuberculosis at randomisation, or suspected to have tuberculosis at randomisation and who later had that diagnosis confirmed, were excluded from analyses of pulmonary tuberculosis incidence. Safety was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT01798680, and is completed. FINDINGS: Between Feb 24, 2014, and Feb 24, 2017, 6250 adults initiating ART had serum 25-hydroxyvitamin D screening, 4000 of whom were enrolled in the trial and followed up for 1 year (follow-up of all participants was completed on March 7, 2018). 2001 patients were randomly assigned to the vitamin D3 supplementation group, and 1999 to the placebo group. 415 deaths were recorded: 211 in the vitamin D3 group and 204 in the placebo group. Among all randomly assigned participants, there was no overall effect of vitamin D3 supplementation on the risk of mortality (hazard ratio [HR] 1·04, 95% CI 0·85-1·25; p=0·73). There was also no difference in the overall incidence of pulmonary tuberculosis between the vitamin D3 (50 events in 1812 patients analysed) and placebo groups (64 events in 1827 patients; HR 0·78, 0·54-1·13; p=0·19). The vitamin D3 regimen did not increase the risk of hypercalcaemia (three events in the vitamin D3 group and two events in the placebo group; relative risk 1·25, 95% CI 0·43-3·66; Fisher's exact p=1·00). 101 hospital admissions were reported in the vitamin D3 group and 94 in the placebo group (incidence rate ratio 1·06, 95% CI 0·80-1·41; p=0·66). INTERPRETATION: Additional research is needed before vitamin D3 supplementation should be considered for implementation in HIV care and treatment programmes for the prevention of pulmonary tuberculosis or mortality. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases.

Calcium Intake and Survival after Colorectal Cancer Diagnosis.

PURPOSE: Although evidence suggests an inverse association between calcium intake and colorectal cancer incidence, the influence of calcium on survival after colorectal cancer diagnosis remains unclear.Experimental Design: We prospectively assessed the association of postdiagnostic calcium intake with colorectal cancer-specific and overall mortality among 1,660 nonmetastatic colorectal cancer patients within the Nurses' Health Study and the Health Professionals Follow-up Study. Patients completed a validated food frequency questionnaire between 6 months and 4 years after diagnosis and were followed up for death. Multivariable hazard ratios (HRs) and 95% confidence intervals (95% CI) were calculated using Cox proportional hazards regression. RESULTS: Comparing the highest with the lowest quartile intake of postdiagnostic total calcium, the multivariable HRs were 0.56 (95% CI, 0.32-0.96; P trend = 0.04) for colorectal cancer-specific mortality and 0.80 (95% CI, 0.59-1.09; P trend = 0.11) for all-cause mortality. Postdiagnostic supplemental calcium intake was also inversely associated with colorectal cancer-specific mortality (HR, 0.67; 95% CI, 0.42-1.06; P trend = 0.047) and all-cause mortality (HR, 0.71; 95% CI, 0.54-0.94; P trend = 0.008), although these inverse associations were primarily observed in women. In addition, calcium from diet or dairy sources was associated with lower risk in men. CONCLUSIONS: Higher calcium intake after the diagnosis may be associated with a lower risk of death among patients with colorectal cancer. If confirmed, these findings may provide support for the nutritional recommendations of maintaining sufficient calcium intake among colorectal cancer survivors.

Effect of maternal vitamin D3 supplementation on maternal health, birth outcomes, and infant growth among HIV-infected Tanzanian pregnant women: study protocol for a randomized controlled trial.

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

Efficacy of vitamin D3 supplementation in reducing incidence of pulmonary tuberculosis and mortality among HIV-infected Tanzanian adults initiating antiretroviral therapy: study protocol for a randomized controlled trial.

BACKGROUND: HIV-infected adults initiating antiretroviral therapy (ART) in sub-Saharan Africa continue to experience high rates of morbidity and mortality during the initial months of treatment. Observational studies in high-income and resource-limited settings indicate that HIV-infected adults with low vitamin D levels may be at increased risk of mortality, HIV disease progression, and incidence of pulmonary tuberculosis (TB). As a result, vitamin D3 supplementation may improve survival and treatment outcomes for HIV-infected adults initiating ART. METHODS/DESIGN: The Trial of Vitamins-4 (ToV4) is an individually randomized, double-blind, placebo-controlled trial of vitamin D3 (cholecalciferol) supplementation conducted among 4000 HIV-infected adults with low vitamin D levels [25-hydroxyvitamin D (25(OH)D) <30 ng/mL] initiating ART in Dar es Salaam, Tanzania. The two primary aims of the trial are to determine the effect of a vitamin D3 supplementation regimen on incidence of (1) mortality and (2) pulmonary TB as compared to a matching placebo regimen. The primary safety outcome of the study is incident hypercalcemia. The investigational vitamin D3 regimen consists of oral supplements containing 50,000 IU vitamin D3 taken under direct observation at randomization and once a week for 3 weeks (four doses) followed by daily oral supplements containing 2000 IU vitamin D3 taken at home from the fourth week until trial discharge at 1 year post ART initiation. Trial participants are followed up at weekly clinic visits during the first month of ART and at monthly clinic visits thereafter until trial discharge at 1 year post ART initiation. Secondary aims of the trial are to examine the effect of the vitamin D3 regimen on CD4 T cell reconstitution, incidence of non-TB comorbidities, body mass index (BMI), depression and anxiety, physical activity, bone health, and immunologic biomarkers. DISCUSSION: The ToV4 will provide causal evidence on the effect of vitamin D3 supplementation on incidence of pulmonary TB and mortality among HIV-infected Tanzanian adults initiating ART. The trial will also give insight to whether vitamin D3 supplementation trials for the prevention of pulmonary TB should be pursued in HIV-uninfected populations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01798680 . Registered on 21 February 2013.

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.