Effect of Maternal Vitamin D3 Supplementation on Iron Status During Pregnancy and Early Infancy

Study Overview
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Brief Summary
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This is a secondary-use study based on previously-collected data and blood samples from a previously completed double-blind, dose-ranging trial of maternal prenatal and postpartum vitamin D supplementation in Dhaka, Bangladesh (NCT01924013). The aim of this sub-study is to examine the effect of vitamin D supplementation on iron status during pregnancy and early infancy.

Detailed Description
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The risk of both low iron and vitamin D status have been recognized as public health concerns among pregnant women and young children, with high rates of deficiency in low-and middle-income countries. Through its involvement in regulation of the hepcidin-ferroportin axis, as well as its potential to increase the expression of the erythropoietin receptor, vitamin D has been suggested as a modulator of iron homeostasis. Vitamin D supplementation may therefore represent a candidate facilitator for the management of iron deficiency, yet few intervention trials have directly assessed the effect of vitamin D supplementation on biomarkers of iron status. To examine the effect of vitamin D supplementation on iron status during pregnancy and early infancy, data and blood samples will be drawn from a completed double-blind, dose-ranging trial of maternal prenatal and postpartum vitamin D supplementation. Women at 17-24 weeks' gestation were randomized to 1 of 5 dose groups comprising a prenatal; postpartum regimen of placebo; placebo, 4200;0, 16800;0, 28000;0 or 28000;28000 IU vitamin D3/week until 26 weeks postpartum. Enrolment (n=1300) was completed in September 2015, and all infants were delivered by February 2016. The MDIG trial was primarily designed to determine the effect of maternal vitamin D on infant length at 12 months of age (with follow-up continuing until infants reached 24 months of age; completed in March 2018). Analyses of serum ferritin and related iron biomarkers (serum iron, transferrin, soluble transferrin receptor, hepcidin), and inflammatory makers (e.g. CRP), will be conducted using previously collected stored blood samples. Linear regression models will be used to assess the effect of vitamin D supplementation on the biomarkers of interest among pregnant women and their infants at 6 months of age. To examine the potential dose-response relation between prenatal vitamin D treatment dose (i.e., across all 4 assigned prenatal vitamin D doses by combining the 2 high-dose prenatal vitamin D treatment groups) and the biomarker of interest, linear regression models will be fitted using the assigned prenatal vitamin D treatment group as the categorical exposure variable and the specified biomarker as the (continuous) outcome variable. Data will be reported as mean differences (or mean % differences, if applicable) and 95% CIs. To explore potential effects of prenatal only versus prenatal plus postpartum vitamin D supplementation on Hb and ferritin concentrations among infants at 6 months of age, a similar dose-response analysis will be conducted across all 5 treatment groups (i.e., disaggregation of the 2 high-dose prenatal vitamin D groups), for which the investigators will regress the biomarker (Hb as a continuous variable) on the vitamin D treatment group assigned during the prenatal and postpartum periods (as a categorical variable). Differences in each supplementation group will therefore be compared to the placebo group, and expressed as mean differences (or geometric means, or mean % differences, if applicable) and 95% CIs. Given the influence of inflammation on serum ferritin concentrations, secondary analyses will include inflammatory markers (e.g. CRP) as covariates to test the role of inflammation in mediating the association between the vitamin D intervention and serum ferritin concentrations.

Official Title
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Effect of Maternal Vitamin D3 Supplementation on Iron Status During Pregnancy and Early Infancy

Conditions
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Pregnancy

Intervention / Treatment
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* Dietary Supplement: Placebo
* Dietary Supplement: Vitamin D3 (cholecalciferol)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged 18 years and above. Gestational age of 17 to 24 completed weeks estimated based on recalled last menstrual period (LMP) and/or ultrasound. Intends to permanently reside in the trial catchment area for at least 18 months MDIG trial participants with availability of at least one measurement of the biomarkers of interest (serum ferritin, circulating hepcidin, transferrin, soluble transferrin receptor, serum iron and/or whole-blood Hb). Exclusion Criteria: History of medical conditions that may predispose the participant to vitamin D sensitivity, altered vitamin D metabolism and/or hypercalcemia, or history of renal calculi. High-risk pregnancy based on one or more of the following findings by point-of-care testing: - Severe anemia: hemoglobin <70 g/L assessed by Hemocue. - Moderate-severe proteinuria: ≥ 300 mg/dl (3+ or 4+) based on urine dipstick. - Hypertension: systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg. - Multiple gestation, major congenital anomaly, or severe oligohydramnios based on maternal history and/or ultrasound. - Unwillingness to stop taking non-study vitamin D or calcium supplements or a multivitamin with calcium and/or vitamin D. - Currently prescribed vitamin D supplements as part of a physician's treatment plan for vitamin D deficiency. - Previous participation in the same study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group A (Placebo)<br>Prenatal Period 0 IU/week (17-24 weeks gestation - delivery) ; Postpartum Period 0 IU/week (delivery-6 months postpartum) | Dietary Supplement: Placebo<br>* This product is identical in appearance, taste and texture to the experimental formulation but does not include any vitamin D3.<br>|
| Experimental: Group B (4200:0 IU/week)<br>Prenatal Period 4200 IU/week (17-24 weeks gestation - delivery) ; Postpartum Period 0 IU/week (delivery-6 months postpartum) | Dietary Supplement: Placebo<br>* This product is identical in appearance, taste and texture to the experimental formulation but does not include any vitamin D3.<br>Dietary Supplement: Vitamin D3 (cholecalciferol)<br>* The intervention is an oral tablet containing vitamin D3 (cholecalciferol). Each weekly dose consists of a single tablet. Vitamin D3 content of the dose depends on the intervention group.<br>|
| Experimental: 16800:0 IU/week<br>Prenatal Period 16800 IU/week (17-24 weeks gestation - delivery) ; Postpartum Period 0 IU/week (delivery-6 months postpartum) | Dietary Supplement: Placebo<br>* This product is identical in appearance, taste and texture to the experimental formulation but does not include any vitamin D3.<br>Dietary Supplement: Vitamin D3 (cholecalciferol)<br>* The intervention is an oral tablet containing vitamin D3 (cholecalciferol). Each weekly dose consists of a single tablet. Vitamin D3 content of the dose depends on the intervention group.<br>|
| Experimental: 28000:0 IU/week<br>Prenatal Period 28000 IU/week (17-24 weeks gestation - delivery) ; Postpartum Period 0 IU/week (delivery-6 months postpartum) | Dietary Supplement: Placebo<br>* This product is identical in appearance, taste and texture to the experimental formulation but does not include any vitamin D3.<br>Dietary Supplement: Vitamin D3 (cholecalciferol)<br>* The intervention is an oral tablet containing vitamin D3 (cholecalciferol). Each weekly dose consists of a single tablet. Vitamin D3 content of the dose depends on the intervention group.<br>|
| Experimental: 28000:28000 IU/week<br>Prenatal Period 28000 IU/week (17-24 weeks gestation - delivery) ; Postpartum Period 28000 IU/week (delivery-6 months postpartum) | Dietary Supplement: Vitamin D3 (cholecalciferol)<br>* The intervention is an oral tablet containing vitamin D3 (cholecalciferol). Each weekly dose consists of a single tablet. Vitamin D3 content of the dose depends on the intervention group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal serum ferritin concentration at delivery | Maternal serum ferritin concentration at delivery | Delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal transferrin saturation at delivery | Maternal transferrin saturation at delivery | Delivery | 
| Maternal soluble transferrin receptor at delivery | Maternal soluble transferrin receptor at delivery | Delivery | 
| Maternal circulating hepcidin at delivery | Maternal circulating hepcidin at delivery | Delivery | 
| Infant whole-blood Hb concentration | Infant whole-blood Hb concentration at 6 months of age | 6 months of age | 
| Infant ferritin concentration | Infant ferritin concentration at 6 months of age | 6 months of age | 
| Maternal total iron binding capacity at delivery | Maternal total iron binding capacity at delivery | Delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Maternal Nutrition, Vitamin D, Iron Status, Iron Deficiency