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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Birth Weight, Miscarriage, Small-for-gestational Age, Preterm Birth

Intervention / Treatment
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* Dietary Supplement: Multiple micronutrient supplement
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 45 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
Interventional Model Description: Cluster-randomized, placebo-controlled concurrent intervention trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multiple micronutrient supplement<br>Daily micronutrient supplement | Dietary Supplement: Multiple micronutrient supplement<br>* 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).<br>|
| Placebo Comparator: Placebo<br>Daily identifcal placebo tablet | Drug: Placebo Oral Tablet<br>* Preconception to 12-weeks gestation: identical tablet<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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preconceptional multiple micronutrient supplementation, periconceptional multiple micronutrient supplementation, pregnancy outcomes, adolescent pregnancy, Bangladesh