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).

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.

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

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

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.

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.

Iron supplementation and paediatric HIV disease progression: a cohort study among children receiving routine HIV care in Dar es Salaam, Tanzania.

BACKGROUND: Anaemia is common among HIV-infected children and iron supplementation is prescribed routinely for the prevention and management of anaemia among children. Limited evidence suggests iron supplementation may have adverse effects among HIV-infected populations. We aimed to estimate the effect of iron supplement use on mortality, disease progression and haematological outcomes among HIV-infected children in Dar es Salaam, Tanzania. METHODS: A prospective cohort study was conducted among HIV-infected children (aged 0-14 years) receiving antiretroviral treatment or supportive care between October 2004 and September 2014. Clinical data were recorded on morbidity and vital status, haematological status and prescriptions at each clinical visit. Cox proportional hazards models adjusted for time-varying covariates were used to estimate the association of time-varying iron supplementation on the hazard rate of mortality, HIV disease stage progression, tuberculosis incidence and anaemia and microcytosis persistence. RESULTS: In all, 4229 children were observed during 149 260 clinic visits for a mean follow-up of 2.9 years. After adjustment for time-varying clinical covariates, time-varying iron supplementation was associated with a 2.87 times higher hazard rate of mortality (95% CI: 1.70, 4.87) and a 1.48 times higher hazard rate of HIV disease stage progression (95% CI: 1.10, 1.98). Iron supplementation was also associated with a lower rate of anaemia persistence (HR = 0.47; 95% CI: 0.37, 0.61). No differences in the association between iron supplementation and clinical outcomes were observed by antiretroviral therapy or anaemia status. CONCLUSIONS: Iron supplementation may increase the risk of HIV disease stage progression and mortality among HIV-infected children, while reducing the risk of anaemia.

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.

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

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

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

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

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.

Impact of scaling up prenatal nutrition interventions on human capital outcomes in low- and middle-income countries: a modeling analysis.

BACKGROUND: Prenatal nutrition interventions can lead to improved birth outcomes, which in turn are associated with better education and human capital outcomes later in life. OBJECTIVE: We estimated the impact of scaling up iron-folic acid (IFA), calcium, multiple micronutrient (MMS), and balanced energy protein (BEP) supplementation for pregnant women, on human capital outcomes in low- and middle-income countries (LMIC). METHODS: We used mathematical modeling with proportional reductions in adverse birth outcomes to estimate the potential gains in school years and lifetime income due to scaling up each prenatal nutrition intervention. Estimates of intervention effects on birth outcomes were derived from meta-analyses of randomized trials. Estimates of the associations between birth outcomes and schooling and lifetime income were derived from de novo meta-analyses of observational studies. RESULTS: Across 132 LMIC, scaling up prenatal nutrition interventions to 90% coverage was estimated to increase school years and lifetime income per birth cohort by: 2.28 million y (95% uncertainty intervals (UI): -0.44, 6.26) and $8.26 billion (95% UI: -1.60, 22.4) for IFA; 4.08 million y (95% UI: 0.12, 9.68) and $18.9 billion (95% UI: 0.59, 44.6) for calcium; 5.02 million y (95% UI: 1.07, 11.0) and $18.1 billion (95% UI: 3.88, 39.1) for MMS; and 0.53 million y (95% UI: -0.49, 1.70) and $1.34 billion (95% UI: -1.10, 3.10 billion) for BEP supplementation. South Asia and Sub-Saharan Africa tended to have the largest estimated regional gains in school years for scaling up each intervention due to the large population size and high burden of poor birth outcomes. Absolute income benefits for each intervention were estimated to be the largest in Latin America, where returns to education and incomes are higher relative to other regions. CONCLUSION: Increasing coverage of prenatal nutrition interventions in LMIC may lead to substantial gains in schooling and lifetime income. Decision makers should consider the potential long-term human capital returns of investments in maternal nutrition.

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.

Prenatal vitamin D supplementation and infant vitamin D status in Bangladesh.

OBJECTIVE: To determine the effect of prenatal maternal vitamin D supplementation on infant vitamin D status in a tropical region where vitamin D supplementation is not routine. DESIGN: A prospective observational follow-up of a randomized trial. SETTING: Maternal-child health facility in Dhaka, Bangladesh (23°N). SUBJECTS: Infants born to pregnant women (n 160) randomized to receive 875 µg (35 000 IU) cholecalciferol (vitamin D3) per week (VD) or placebo (PL) during the third trimester were followed from birth until 6 months of age (n 115). Infant serum 25-hydroxyvitamin D concentration (25(OH)D) was measured at <1, 2, 4 and 6 months of age. RESULTS: Mean infant 25(OH)D was higher in the VD v. PL group at <1 month of age (mean (sd): 80 (20) nmol/l v. 22 (18) nmol/l; P<0·001), but the difference was attenuated by 2 months (52 (19) nmol/l v. 40 (23) nmol/l; P=0·05). Groups were similar at 4 months (P=0·40) and 6 months (n 72; P=0·26). In the PL group, mean infant 25(OH)D increased to 78 (95 % CI 67, 88) nmol/l by 6 months of age (n 34). 25(OH)D was higher with infant formula-feeding and higher in summer v. winter. CONCLUSIONS: Prenatal third-trimester vitamin D supplementation (875 µg (35 000 IU)/week) significantly ameliorated infant vitamin D status during the neonatal period when the risk of vitamin D deficiency is greatest. Further research is warranted to determine factors that contribute to the rise in 25(OH)D during the first 6 months of life among breast-fed infants in this setting.

Effect of weekly high-dose vitamin D3 supplementation on serum cholecalciferol concentrations in pregnant women.

Vitamin D status is conventionally defined by the serum concentration of 25-hydroxyvitamin D. However, it has been proposed that the serum cholecalciferol concentration (D3) also determines functional vitamin D sufficiency. The objective of this study was to describe the effect of weekly high-dose vitamin D3 supplementation on inter-dose serum D3 in pregnant women. We conducted a sub-study of a completed randomized double-blind placebo-controlled trial of vitamin D3 (35,000 IU/week) supplementation in late pregnancy (AViDD trial) in Dhaka, Bangladesh. This study included pregnant women enrolled at 26-29 weeks gestation who fully adhered to the prenatal supplement intervention for ≥8 consecutive weeks and for whom serum samples were available for D3 analysis (n=65). Serum D3 was uniformly low at enrolment. Mean D3 increased and was maximal at 1 day after vitamin D dose administration (152.09nmol/L, SD 25.11nmol/L) and remained significantly higher in VitD vs. Pl at 7 days (29.59nmol/L vs. 1.92nmol/L, p=0.007). Daily average of the group mean D3 during the week following dosing was 66.97nmol/L in VitD versus 2.13nmol/L in Pl. In conclusion, serum D3 remained significantly elevated throughout the week following ≥8 consecutive weekly doses of 35,000 IU D3 in pregnant women. However, the clinically significant minimum threshold of serum D3 remains to be established.

Prenatal vitamin D3 supplementation suppresses LL-37 peptide expression in ex vivo activated neonatal macrophages but not their killing capacity.

Vitamin D has regulatory effects on innate immunity. In the present study, we aimed to assess the effect of prenatal vitamin D3 (vitD3) supplementation on neonatal innate immunity in a randomised, placebo-controlled trial by evaluating cathelicidin (LL-37) expression and the killing capacity of macrophages. Healthy pregnant women (n 129) attending a clinic in Dhaka were randomised to receive either a weekly oral dose of 0·875 mg vitD3 or placebo starting from 26 weeks of gestation up to delivery. Serum, plasma and monocyte-derived macrophages (MDM) were obtained from the cord blood. 25-Hydroxyvitamin D (25(OH)D) concentration was measured in serum. MDM were stimulated with or without Toll-like-receptor 4 ligand (TLR4L). Innate immune function was assessed by measuring LL-37 peptide levels in the culture supernatant of MDM by ELISA, LL-37 transcript levels by quantitative PCR, and ex vivo bactericidal capacity of MDM. VitD3 supplementation did not increase LL-37 peptide levels in plasma or in the extracellular fluid of macrophages with or without TLR4L induction. However, stimulated intracellular LL-37 expression (ratio of stimulated:unstimulated MDM) was significantly reduced in the vitamin D group v. placebo (P=0·02). Multivariate-adjusted analyses showed that intracellular LL-37 peptide concentration from stimulated MDM was inversely associated with 25(OH)D concentration in serum (P=0·03). TLR4L stimulation increased the bactericidal capacity of MDM compared with the unstimulated ones (P=0·01); however, there was no difference in killing capacity between the two groups. A weekly dose of 0·875 mg vitD3 to healthy pregnant women suppressed the intracellular LL-37 peptide stores of activated macrophages, but did not significantly affect the ex vivo bactericidal capacity of cord blood MDM.

Vitamin D and fetal-neonatal calcium homeostasis: findings from a randomized controlled trial of high-dose antenatal vitamin D supplementation.

BACKGROUND: There is current interest in the maternal-fetal effects of antenatal vitamin D supplementation, yet little data regarding vitamin D's role in neonatal calcium homeostasis. We determined to assess the effect of high-dose antenatal vitamin D supplementation on fetal and neonatal calcium concentrations. METHODS: In a double-blinded, placebo-controlled trial in Bangladesh, 160 pregnant women were randomized to oral vitamin D3 (35,000 IU/wk) or placebo from 26 to 29 wk of gestation. RESULTS: Total serum calcium (Ca) was higher in cord blood of those supplemented vs. placebo (2.66 ± 0.1 vs. 2.61 ± 0.2 mmol/l; P = 0.04), but the difference in albumin-adjusted calcium was not statistically significant. Change in Ca concentration from birth to day 3 of life was attenuated by vitamin D (-0.10 ± 0.17) compared with placebo (-0.22 ± 0.18 mmol/l; P = 0.02). Maternal 25-hydroxyvitamin D (25(OH)D) (P = 0.04) and cord 25(OH)D (P < 0.01) were associated with day 3 infant Ca, suggesting that the effect of supplementation was mediated by change in maternal-infant vitamin D status. Six infants in each of the supplemented and placebo groups had transient hypercalcemia/hypercalcuria; in all the hypercalcemia/hypercalcuria was asymptomatic, spontaneously resolved, and unassociated with nephrocalcinosis at 1 mo of life. CONCLUSION: High-dose antenatal third-trimester vitamin D supplementation attenuated the early postnatal calcium nadir, without increasing the risk of postnatal hypercalcemia.

Maternal-fetal-infant dynamics of the C3-epimer of 25-hydroxyvitamin D.

BACKGROUND: Poor vitamin D status (i.e. low serum 25-hydroxyvitamin D (25(OH)D)) has been associated with adverse clinical outcomes during pregnancy and childhood. However, the interpretation of serum 25(OH)D levels may be complicated by the presence of the C3-epimer of 25(OH)D. We aimed to quantify C3-epi-25(OH)D3 in pregnant women and fetuses, to explore the relationship of the C3-epimer between maternal and cord samples, and to establish whether infant C3-epimer abundance is explained by prenatal formation. METHODS: In a sub-study of a randomized trial of prenatal vitamin D3, 25(OH)D3 and C3-epi-25(OH)D3 were quantified by LC-MS/MS in 71 sets of mother-fetus-infant serum samples, including maternal delivery specimens, cord blood, and infant specimens acquired at 3-28 weeks of age. RESULTS: Without supplementation, median concentrations of C3-epi-25(OH)D3 were higher in infants (6.80 nmol/L) than mothers (0.45 nmol/L) and cord blood (0 nmol/L). However, there was substantial variation such that C3-epi-25(OH)D3 accounted for up to 11% (maternal), 14% (cord), and 25% (infant) of the total 25(OH)D3. Supplemental vitamin D3 significantly increased maternal-fetal C3-epi-25(OH)D3, and was a preferential source of C3-epi-25(OH)D3 compared to basal vitamin D, possibly due to C3-epi-cholecalciferol in the supplement. Multivariate regression did not suggest transplacental transfer of C3-epi-25(OH)D3, but rather indicated its generation within the fetal-placental unit from maternally-derived 25(OH)D3. Neither maternal nor fetal C3-epi-25(OH)D3 is accounted for the relatively high concentrations of infant C3-epi-25(OH)D3, suggesting rapid postnatal generation. CONCLUSIONS: C3-epi-25(OH)D3 is present in some pregnant women and fetuses, but does not appear to be efficiently transferred transplacentally. High C3-epimer concentrations in infancy are probably due to postnatal formation rather than fetal stores.

Maternal vitamin D3 supplementation during the third trimester of pregnancy: effects on infant growth in a longitudinal follow-up study in Bangladesh.

OBJECTIVE: To estimate the effects of prenatal vitamin D supplementation on infant growth in Dhaka, Bangladesh. STUDY DESIGN: Longitudinal follow-up of infants born at term or late preterm (≥34 weeks) to participants in a randomized double-blind trial of maternal third-trimester vitamin D3 (35 000 IU/wk; vitamin D ) vs placebo. Anthropometry was performed at birth, 1, 2, 4, 6, 9, and 12 months of age. The primary analysis (n = 145 overall; n = 134 at 1 year) was a comparison of mean length-for-age z-score (LAZ) based on World Health Organization standards. RESULTS: LAZ was similar between groups at birth, but 0.44 (95% CI, 0.06-0.82) higher in vitamin D vs placebo at 1 year, corresponding to a sex-adjusted increase of 1.1 cm (95% CI, 0.06-2.0). Mean change in LAZ from birth to 1 month was significantly greater in vitamin D (0.53 per month) vs placebo (0.19 per month; P = .004); but there was no significant divergence thereafter. In longitudinal (repeated-measures) analysis, average LAZ during infancy was 0.41 higher in vitamin D vs placebo (95% CI, 0.11-0.71, P = .01). Stunting was less common in vitamin D (17% of infants were ever stunted) vs placebo (31%; P = .049). Other anthropometric indices were similar between groups. CONCLUSIONS: Maternal vitamin D3 supplementation (35 000 IU/wk) during the third trimester of pregnancy enhanced early postnatal linear growth in a cohort of infants in Bangladesh.

Randomized placebo-controlled trial of high-dose prenatal third-trimester vitamin D3 supplementation in Bangladesh: the AViDD trial.

BACKGROUND: Antenatal vitamin D status may be associated with the risk of adverse pregnancy and neonatal outcomes; however, the benefits of vitamin D supplementation during pregnancy remain unknown. METHODS: We conducted a double-blind placebo-controlled randomized trial to evaluate the effect of high-dose prenatal 3rd trimester vitamin D3 supplementation on maternal and neonatal (cord blood) serum 25-hydroxyvitamin D (25(OH)D) concentration (primary biochemical efficacy outcome) and maternal serum calcium concentration (primary safety measure). Eligibility criteria were pregnant women aged 18 to <35 years, at 26 to 29 weeks gestation, and residing in Dhaka, Bangladesh. 160 women were randomized by 1:1 allocation to one of two parallel intervention groups; placebo (n = 80) or 35,000 IU/week of vitamin D3 (n = 80) until delivery. All participants, study personnel and study investigators were blind to treatment allocation. RESULTS: Mean maternal 25(OH)D concentration was similar in the vitamin D and placebo groups at baseline (45 vs. 44 nmol/L; p = 0.66), but was significantly higher in the vitamin D group vs. placebo group among mothers at delivery (134 vs. 38 nmol/L; p < 0.001) and newborns (cord blood: 103 vs. 39; p < 0.001). In the vitamin D group, 95% of neonates and 100% of mothers attained 25(OH)D >50 nmol/L, versus 21% mothers and 19% of neonates in the placebo group. No participants met criteria for hypercalcemia, there were no known supplement-related adverse events, and major pregnancy outcomes were similar between groups. CONCLUSIONS: Antenatal 3rd-trimester vitamin D3 supplementation (35,000 IU/week) significantly raised maternal and cord serum 25(OH)D concentrations above 50 nmol/L in almost all participants without inducing hypercalcemia or other observed safety concerns. Doses up to 35,000 IU/week may be cautiously used in further research aimed at establishing the clinical effects and safety of vitamin D3 supplementation in pregnancy. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov (NCT01126528).

A systematic review of the application and utility of geographical information systems for exploring disease-disease relationships in paediatric global health research: the case of anaemia and malaria.

Malaria and anaemia are important health problems among children globally. Iron deficiency anaemia may offer protection against malaria infection and iron supplementation may increase the risk of malaria-related hospitalization and mortality. The nature and mechanism of these relationships, however, remain largely unresolved, resulting in concern and uncertainty around policies for non-selective iron supplementation in malaria endemic areas. Use of geographical information systems (GIS) to investigate this disease-disease interaction could contribute important new information for developing safe and effective anaemia and malaria interventions. To assess the current state of knowledge we conducted a systematic review of peer-reviewed and grey literature. Our primary objective was to qualitatively assess the application and utility of geographical concepts or spatial analyses in paediatric global health research. The secondary objective was to identify geographical factors that may be associated with anaemia and malaria prevalence or incidence among children 0-5 years of age living in low- and middle-income countries. Evaluation tools for assessing the quality of geographical data could not be found in the peer-reviewed or grey literature, and thus adapted versions of the STROBE (Strengthening The Reporting of Observational Studies in Epidemiology) and GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methods were used to create reporting, and overall evidence quality scoring systems. Among the 20 included studies, we found that both malaria and anaemia were more prevalent in rural communities compared to urban areas. Geographical factors associated with malaria prevalence included regional transmission stability, and proximity to a mosquito breeding area. The prevalence of anaemia tended to vary inversely with greater or poorer access to community services such as piped water. Techniques for investigating geographic relationships ranged from simple descriptive mapping of spatial distribution patterns, to more complex statistical models that incorporated environmental factors such as seasonal temperature and rain fall. Including GIS in paediatric global health research may be an effective approach to explore relationships between childhood diseases and contribute key evidence for safe implementation of anaemia control programs in malaria endemic areas. Further, GIS presentation of ecological health data could provide an efficient means of translating this knowledge to lay audiences.