Micronutrient Supplementation Before and During 1st Pregnancy to Improve Birth Outcomes (JiVitA-5) (JiVitA-5)

The purpose of this cluster-randomized trial is to evaluate the efficacy of daily, multiple micronutrient (MM) supplement versus identical placebo use among nulligravid, recently married women, starting preconceptionally through the 1st trimester of pregnancy, in reducing low birth weight and other adverse pregnancy outcomes in rural Bangladesh.

Study Overview

• Status: Terminated
• Conditions: Preterm Birth; Birth Weight; Miscarriage; Small-for-gestational Age
• Intervention / Treatment: Dietary supplement: Multiple micronutrient supplement; Drug: Placebo Oral Tablet

Detailed Description

Micronutrient deficiencies are common among women of reproductive age in rural South Asia, including Bangladesh. Antenatal multiple micronutrient (MM) supplementation, usually starting toward the end of the 1st trimester, has been shown to reduce low birth weight in many cultures. In northern Bangladesh, where the current study will be conducted, MM versus iron-folic acid supplementation has been shown to extend gestational age, thereby reducing risks of preterm birth 15% and low birth weight by 12%, and reduce risk of stillbirth by 11% (West KP et al. JAMA 2014), and to reduce risk of micronutrient deficiencies (Schulze KJ et al J Nutr 2019). Since it is plausible that women of reproductive age conceive in a state of lower micronutrient nutriture, it remains unknown the degree to which MM supplementation, starting preconceptionally through the 1st trimester (covering the periconceptional and embryonic period) can benefit pregnancy outcome. Further, there is concern that newlywed, nulligravid women in rural South Asia are at high risk, and may be at particular health and pregnancy risks due to micronutrient deficiencies resulting from dietary inadequacy.

The investigators propose to conduct a double-masked, cluster-randomized, placebo-controlled trial among recently married women in 18 rural unions of Gaibandha District, Bangladesh, that will provide a daily tablet containing either (a) a MM formulation containing a US Institute of Medicine (IOM) Recommended Dietary Allowance (RDA) for pregnancy for 15 essential vitamins and minerals (and closely approximates the UNIMAP formula), or (b) a placebo tablet of identical appearance containing no micronutrients, during a period extending from at least one-month prior to last menstrual period through the 1st trimester of pregnancy (~12 weeks' gestation). The study area will comprise 566 rural clusters (sectors) each with 250-400 households, serving as units of randomization. Consenting, recently married women will be detected through routine community surveillance and start to receive coded, double-masked supplements, resupplied during monthly home visits. Participating women will receive coded supplements for daily consumption until the end of the trial or until determined to be pregnant. On detection of pregnancy by a history of amenorrhea confirmed by urine test, irrespective of randomized allocation, all women will be switched to receive an open-labeled MM supplement, expected to occur toward the end of the 1st trimester, which will continue through 3 months post-partum. This switch is in response to previous positive effects shown on pregnancy outcomes with a MM supplement starting at the end of the 1st trimester.

Participating married women will be periodically interviewed for socioeconomic, morbidity, dietary and lifestyle risk factors and assessed by anthropometry. Pregnancies will be followed for miscarriage, abortion, live birth and still birth outcomes. Newborn anthropometry will be assessed to determine birth weight and size. Infants and mothers will be eligible for additional breast feeding, dietary, morbidity and growth assessments at 8 days, and 1, 3 and 6 months after delivery. Participating women resident in a predefined subset of the study area (n~68 sectors) will receive enhanced assessments, including blood draw in the end of the 1st trimester for subsequent laboratory assessment of micronutrient status, and body composition, among other measures.

• Study Type: Interventional
• Enrollment (Actual): 9859
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Bangladesh
  • Gaibandha Distict
    • Gaibandha, Gaibandha Distict, Bangladesh, 5700
      • JiVitA Project Office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Resident of 566 rural sectors (clusters) in Gaibandha district
• Recently-married woman
• Nulligravid

Exclusion Criteria:

• Women with a history of previous pregnancy
• Women who refuse consent for participation

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Multiple micronutrient supplement; Daily micronutrient supplement	Dietary supplement: Multiple micronutrient supplement; Preconception to 12-weeks gestation: daily (coded) multiple micronutrient supplement containing 15-nutrients (vitamins and minerals) providing an approximate recommended dietary allowance for pregnant women, approximating the UNICEF UNIMAP formulation (UN micronutrient preparation).
Placebo Comparator: Placebo; Daily identifcal placebo tablet	Drug: Placebo Oral Tablet; Preconception to 12-weeks gestation: identical tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preterm Birth - number of live-births occurring earlier than 37 weeks gestation among all live-births (with known gestational age)	Pregnancies ending in a live birth less than 37 weeks' gestation	up to 38 weeks of gestation
Miscarriage - number of spontaneous abortions occurring earlier than 24 weeks gestation among all pregnancies (with known gestational age)	Pregnancies ending as a spontaneous abortion less than 24 weeks' gestation	up to 24 weeks gestation
Small for Gestational Age - number of live-born neonates weighing less than the 10th centile of birth weight for gestational age and sex among all live-births (with known gestational age and birth weight)	Infants weighing less than the 10th centile of birth weight for gestational age and sex	up to 72 hours after live birth
Low Birth Weight - number of live-born neonates weighing less than 2500 g at birth among all live-births (with known birth weight)	Infants weighing less than 2500 g at birth	Measured from time of live birth through 72 hours after birth

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anemia in Pregnant Women	Hemoglobin in whole blood, less than a cutoff of 110 g/L	Measured at 12 weeks gestation
Iron Status	Distribution of plasma ferritin, ng/mL	Measured at 12 weeks gestation
Vitamin A Status	Distribution of plasma retinol, micromoles/L	Measured at 12 weeks gestation
Vitamin E Status	Distribution of plasma alpha-tocopherol, micromoles/L	Measured at 12 weeks gestation
Folate Status	Distribution of total plasma folate, nmol/L	Measured at 12 weeks gestation
Vitamin B12 Status	Distribution of total plasma cobalamin, pmol/L	Measured at 12 weeks gestation
Selenium Status	Distribution of total plasma selenium, ng/mL	Measured at 12 weeks gestation

Collaborators and Investigators

• Sponsor: Johns Hopkins Bloomberg School of Public Health
• Collaborators: JiVitA Project, Gaibandha, Bangladesh
• Investigators: Principal Investigator: Keith P West, Jr., DrPH, Johns Hopkins Bloomberg School of Public Health

Publications and helpful links

General Publications

• West KP Jr, Shamim AA, Mehra S, Labrique AB, Ali H, Shaikh S, Klemm RD, Wu LS, Mitra M, Haque R, Hanif AA, Massie AB, Merrill RD, Schulze KJ, Christian P. Effect of maternal multiple micronutrient vs iron-folic acid supplementation on infant mortality and adverse birth outcomes in rural Bangladesh: the JiVitA-3 randomized trial. JAMA. 2014 Dec 24-31;312(24):2649-58. doi: 10.1001/jama.2014.16819.
• Sugimoto JD, Labrique AB, Ahmad S, Rashid M, Klemm RD, Christian P, West KP Jr. Development and management of a geographic information system for health research in a developing-country setting: a case study from Bangladesh. J Health Popul Nutr. 2007 Dec;25(4):436-47.
• Gernand AD, Schulze KJ, Stewart CP, West KP Jr, Christian P. Micronutrient deficiencies in pregnancy worldwide: health effects and prevention. Nat Rev Endocrinol. 2016 May;12(5):274-89. doi: 10.1038/nrendo.2016.37. Epub 2016 Apr 1.
• Labrique AB, Christian P, Klemm RD, Rashid M, Shamim AA, Massie A, Schulze K, Hackman A, West KP Jr. A cluster-randomized, placebo-controlled, maternal vitamin A or beta-carotene supplementation trial in Bangladesh: design and methods. Trials. 2011 Apr 21;12:102. doi: 10.1186/1745-6215-12-102.

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2019
• Primary Completion (Actual): November 30, 2020
• Study Completion (Actual): May 29, 2021

Study Registration Dates

• First Submitted: April 11, 2019
• First Submitted That Met QC Criteria: April 18, 2019
• First Posted (Actual): April 19, 2019

Study Record Updates

• Last Update Posted (Actual): June 4, 2021
• Last Update Submitted That Met QC Criteria: June 1, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Bangladesh; preconceptional multiple micronutrient supplementation; periconceptional multiple micronutrient supplementation; pregnancy outcomes; adolescent pregnancy
• Additional Relevant MeSH Terms: Body Weight; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Birth Weight; Abortion, Spontaneous; Physiological Effects of Drugs; Micronutrients; Trace Elements
• Other Study ID Numbers: IRB 7841

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: To be delineated
• IPD Sharing Time Frame: Not later than 4 years after completion of data collection in the field
• IPD Sharing Access Criteria: To be delineated
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No