Maternal Vitamin D for Infant Growth (MDIG) Trial (MDIG)

Randomized Placebo-controlled Trial of Maternal Vitamin D Supplementation During Pregnancy and Lactation to Improve Infant Linear Growth in Dhaka, Bangladesh.

The primary aims of this study are: 1) to determine whether maternal prenatal vitamin D3 supplementation (4200 IU/week, 16,800 IU/week, or 28,000 IU/week) versus placebo increases or decreases infant length at 1 year of age, and 2) to determine whether maternal postpartum vitamin D3 supplementation (28,000 IU/week) versus placebo increases or decreases length at 1 year of age among infants born to women who received vitamin D 28,000 U/week during pregnancy. Infants enrolled in the study will be followed for 2 years to document the persistence of any observed effects measured at 1 year of age. This study aims to enroll 1300 pregnant women in the 2nd trimester at a maternity hospital in Dhaka. Participants will be randomized to one of three doses of vitamin D3 (4200 IU/week, 16,800 IU/week, or 28,000 IU/week) or placebo throughout pregnancy. Women in the 28,000 IU/week group will be additionally randomized to either placebo or a continuation of 28,000 IU/week for 6 months postpartum. In addition to linear length, the trial will include analyses of inflammatory and hormonal determinants of infant growth, epigenetic phenomena that affect vitamin D metabolism, and diarrheal and respiratory morbidity in the infants.

Study Overview

• Status: Completed
• Conditions: Pregnancy
• Intervention / Treatment: Dietary supplement: Placebo; Dietary supplement: Vitamin D3 (cholecalciferol)

• Study Type: Interventional
• Enrollment (Actual): 1300
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bangladesh
  • Dhaka, Bangladesh
    • International Centre for Diarrhoeal Disease Research, Bangladesh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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.

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Group A; Prenatal Period 0 IU; Postpartum Period 0 IU (placebo) Overall:The Prenatal Period will start at enrolment (17-24 weeks gestation) and last until delivery. The Postpartum Period will last from delivery until 6 months postpartum.	Dietary supplement: Placebo; This product will be identical in appearance, taste and texture to the experimental formulation but will not include any vitamin D3.
Experimental: Group B; Prenatal Period 4,200 IU/week of vitamin D3 (=600 IU/d); Postpartum Period 0 IU/week (placebo)	Dietary supplement: Placebo; This product will be identical in appearance, taste and texture to the experimental formulation but will not include any vitamin D3.; Dietary supplement: Vitamin D3 (cholecalciferol); The intervention is an oral tablet containing vitamin D3 (cholecalciferol). This vitamin D supplement will be provided in the form of small tablets (approximately 10 mm diameter) and will be custom- manufactured by Toronto Institute for Pharmaceutical Technology (TIPT) in Toronto, Ontario, Canada. Each weekly dose will consist of a single tablet. Across trial groups, the tablets will only vary with respect to the vitamin D3 dose, as described above.
Experimental: Group C; Prenatal Period 16,800 IU/week of vitamin D3 (=2,400 IU/d); Postpartum Period 0 IU/week (placebo)	Dietary supplement: Placebo; This product will be identical in appearance, taste and texture to the experimental formulation but will not include any vitamin D3.; Dietary supplement: Vitamin D3 (cholecalciferol); The intervention is an oral tablet containing vitamin D3 (cholecalciferol). This vitamin D supplement will be provided in the form of small tablets (approximately 10 mm diameter) and will be custom- manufactured by Toronto Institute for Pharmaceutical Technology (TIPT) in Toronto, Ontario, Canada. Each weekly dose will consist of a single tablet. Across trial groups, the tablets will only vary with respect to the vitamin D3 dose, as described above.
Experimental: Group D; Prenatal Period 28,000 IU/week of vitamin D3 (=4,000 IU/d); Postpartum Period 0 IU/week (placebo)	Dietary supplement: Placebo; This product will be identical in appearance, taste and texture to the experimental formulation but will not include any vitamin D3.; Dietary supplement: Vitamin D3 (cholecalciferol); The intervention is an oral tablet containing vitamin D3 (cholecalciferol). This vitamin D supplement will be provided in the form of small tablets (approximately 10 mm diameter) and will be custom- manufactured by Toronto Institute for Pharmaceutical Technology (TIPT) in Toronto, Ontario, Canada. Each weekly dose will consist of a single tablet. Across trial groups, the tablets will only vary with respect to the vitamin D3 dose, as described above.
Experimental: Group E; Prenatal Period 28,000 IU/week of vitamin D3 (=4,000 IU/d); Postpartum Period 28,000 IU/week(=4,000 IU/d)	Dietary supplement: Vitamin D3 (cholecalciferol); The intervention is an oral tablet containing vitamin D3 (cholecalciferol). This vitamin D supplement will be provided in the form of small tablets (approximately 10 mm diameter) and will be custom- manufactured by Toronto Institute for Pharmaceutical Technology (TIPT) in Toronto, Ontario, Canada. Each weekly dose will consist of a single tablet. Across trial groups, the tablets will only vary with respect to the vitamin D3 dose, as described above.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infant Length-for-Age Z-Scores with Prenatal Supplementation		1 year of age
Infant Length-for-Age Z-Scores with Postpartum Supplementation	A separate analysis will be performed to assess the effect of continuation of 28,000 IU/week postpartum supplementation versus placebo (postpartum) among participants randomized to 28,000 IU/week prenatal.	1 year of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum calcium	Maternal serum calcium will be measured during pregnancy as a primary biochemical safety parameter and post partum.	17 weeks gestation to birth (prenatal) and over 2 years postpartum

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stunting (LAZ < -2 SD below the median) at 1 and 2 years of age.		1-2 years
Attained length and LAZ at 2 years of age.		2 years postnatal
Birth weight, low birth weight %, small-for-gestational age %		Birth
Preterm birth %		Birth
Stillbirth %	Prenatal period	17 weeks gestation to 39 weeks
Maternal, perinatal, neonatal and infant severe morbidity and mortality	During intervention phase (prenatal and first 6 months postpartum)	From 17 weeks gestation to 6 months postpartum
Infant acute respiratory infections and diarrhea	first 6 months postnatal	6 months postpartum
Biomarker concentrations (specific hormones, nutrients, environmental contaminants, and inflammatory markers potentially involved in the mediation or modification of the effect of vitamin D on infant stunting).	Prenatal and first 2 years postnatal	17 weeks gestation to 2 years postpartum
Epigenetic patterns of genes involved in vitamin D metabolism.		Birth

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Collaborators: Bill and Melinda Gates Foundation; International Centre for Diarrhoeal Disease Research, Bangladesh; Shimantik
• Investigators: Principal Investigator: Daniel Roth, MD, The Hospital for Sick Children

Publications and helpful links

General Publications

• Pell LG, Ohuma EO, Yonemitsu C, Loutet MG, Ahmed T, Mahmud AA, Azad MB, Bode L, Roth DE. The Human-Milk Oligosaccharide Profile of Lactating Women in Dhaka, Bangladesh. Curr Dev Nutr. 2021 Nov 13;5(12):nzab137. doi: 10.1093/cdn/nzab137. eCollection 2021 Dec.
• O'Callaghan KM, Shanta SS, Fariha F, Harrington J, Mahmud AA, Emdin AL, Gernand AD, Ahmed T, Abrams SA, Moore DR, Roth DE. Effect of maternal prenatal and postpartum vitamin D supplementation on offspring bone mass and muscle strength in early childhood: follow-up of a randomized controlled trial. Am J Clin Nutr. 2022 Mar 4;115(3):770-780. doi: 10.1093/ajcn/nqab396.
• Jukic AMZ, Zuchniak A, Qamar H, Ahmed T, Mahmud AA, Roth DE. Vitamin D Treatment during Pregnancy and Maternal and Neonatal Cord Blood Metal Concentrations at Delivery: Results of a Randomized Controlled Trial in Bangladesh. Environ Health Perspect. 2020 Nov;128(11):117007. doi: 10.1289/EHP7265. Epub 2020 Nov 23.
• Subramanian A, Korsiak J, Murphy KE, Al Mahmud A, Roth DE, Gernand AD. Effect of vitamin D supplementation during pregnancy on mid-to-late gestational blood pressure in a randomized controlled trial in Bangladesh. J Hypertens. 2021 Jan;39(1):135-142. doi: 10.1097/HJH.0000000000002609.
• Jeong JH, Korsiak J, Papp E, Shi J, Gernand AD, Al Mahmud A, Roth DE. Determinants of Vitamin D Status of Women of Reproductive Age in Dhaka, Bangladesh: Insights from Husband-Wife Comparisons. Curr Dev Nutr. 2019 Oct 7;3(11):nzz112. doi: 10.1093/cdn/nzz112. eCollection 2019 Nov.
• Roth DE, Morris SK, Zlotkin S, Gernand AD, Ahmed T, Shanta SS, Papp E, Korsiak J, Shi J, Islam MM, Jahan I, Keya FK, Willan AR, Weksberg R, Mohsin M, Rahman QS, Shah PS, Murphy KE, Stimec J, Pell LG, Qamar H, Al Mahmud A. Vitamin D Supplementation in Pregnancy and Lactation and Infant Growth. N Engl J Med. 2018 Aug 9;379(6):535-546. doi: 10.1056/NEJMoa1800927. Erratum In: N Engl J Med. 2021 Oct 28;385(18):1728.
• Roth DE, Gernand AD, Morris SK, Pezzack B, Islam MM, Dimitris MC, Shanta SS, Zlotkin SH, Willan AR, Ahmed T, Shah PS, Murphy KE, Weksberg R, Choufani S, Shah R, Al Mahmud A. Maternal vitamin D supplementation during pregnancy and lactation to promote infant growth in Dhaka, Bangladesh (MDIG trial): study protocol for a randomized controlled trial. Trials. 2015 Jul 14;16:300. doi: 10.1186/s13063-015-0825-8.

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): March 1, 2018

Study Registration Dates

• First Submitted: August 13, 2013
• First Submitted That Met QC Criteria: August 14, 2013
• First Posted (Estimate): August 16, 2013

Study Record Updates

• Last Update Posted (Actual): August 31, 2018
• Last Update Submitted That Met QC Criteria: August 29, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Vitamin D; Pregnancy; Bangladesh; Infant Growth
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: 1000039072