JiVitA-3: Antenatal Micronutrient Supplementation and Infant Survival

• Sponsor: Johns Hopkins Bloomberg School of Public Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT00860470
• Collaborator: Bill and Melinda Gates Foundation (Other), United States Agency for International Development (USAID) (U.S. Fed), Mahidol University (Other), Johns Hopkins University (Other), Beximco Pharmaceuticals Ltd. (Industry), DSM Nutritional Products, Inc. (Industry)
• Enrollment: 44,567
• Locations: 2
• Arms: 2
• Duration (Months): 56
• Patients Per Site: 22283.5
• Patients Per Site Per Month: 397.8

Study Details

Study Description

Brief Summary

The purpose of this community-based randomized trial is to examine whether a daily antenatal and postnatal multiple micronutrient supplement given to women will enhance newborn and infant survival and health and other birth outcomes in a rural setting in northwestern Bangladesh.

Condition or Disease	Intervention/Treatment	Phase
Infant Mortality; Preterm Birth; Low Birth Weight; Neonatal Mortality; Perinatal Mortality	Dietary Supplement: Iron (27 mg) - folic acid (600 ug); Dietary Supplement: Multiple micronutrient	Phase 3

Detailed Description

Maternal deficiency in multiple essential micronutrients is likely to be a major public health problem in low-income countries. Supplementing mothers with certain individual micronutrients has been shown to confer health benefits, although the evidence is not clear for multiple micronutrients. We aim to test, in a cluster-randomized, double-masked, controlled trial whether giving a daily multiple micronutrient supplement (similar in composition to the UNICEF antenatal supplement) will enhance infant survival and birth outcomes such as birth weight and gestational duration in a rural population in Bangladesh. Over the duration of 2-3 years a community-surveillance in the northwestern, rural Districts of Gaibandha and Southern Rangpur, the trial plans to identify and recruit 45,000 pregnant women based on 5-weekly histories of amenorrhea confirmed by urine-testing, and supplement them with either a multiple micronutrient supplement or an iron-folic acid supplement (as the standard of care control for pregnancy) and monitor pregnancy health, birth outcomes and vital status and health of liveborn infants through 6 months of age. In a ~3% sub-sample of mothers, additional measures of nutritional and health status will be evaluated in the 1st and 3rd trimesters of pregnancy, and at 3 months postpartum (with infants), that include anthropometric and body composition (bioelectrical impedance) assessment, collection of biospecimens (eg, phlebotomy and breast milk sampling for micronutrient and other analyte concentration determinations), and other clinical assessments. The trial will generate evidence from which to examine the safety and efficacy of an antenatal through postnatal maternal micronutrient supplement intervention in order to inform and guide antenatal nutrition policies and programs in South Asia.

Study Design

• Study Type: Interventional
• Actual Enrollment: 44567 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Antenatal Multiple Micronutrient Supplementation to Improve Infant Survival and Health in Bangladesh
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Sep 1, 2012
• Actual Study Completion Date: Sep 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Iron (27 mg) and folic acid (600 ug)	Dietary Supplement: Iron (27 mg) - folic acid (600 ug); Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.; Other Names: iron-folate
Experimental: 2 Multiple micronutrient	Dietary Supplement: Multiple micronutrient; Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.; Other Names: one-a-day multivitamin antenatal micronutrient

Outcome Measures

Primary Outcome Measures

1. Infant Mortality Through 6 mo of Age [Dec 2014]

   Risk of Infant Mortality to Age 6 months (180 days)

Secondary Outcome Measures

1. Neonatal Mortality [Dec 2014]

   Risk of neonatal Mortality (28 days of life)

2. Post-neonatal Mortality [Dec 2014]

   Risk of Post-neonatal Mortality (29th -180th day of life)

3. Still Birth Rates [December 2014]

   Risk of Still birth

4. Preterm Birth [December 2014]

   Risk of being born before 37 weeks of gestation

5. Extremely Pre-term [December 2014]

   Risk of birth before 28 weeks gestation

6. Very Pre-term [December 2014]

   Risk of birth between 28 and 32 weeks of gestation

7. Moderate to Late Preterm [December 2014]

   Risk of birth between 32 and 37 weeks gestation

8. Low Birth Weight [December 2014]

   Birth weight below 2500g

9. Small for Gestation Age [December 2014]

   Small for Gestational Age defined as birth weight <10th percentile of a standard reference (Alexander GR, Himes JH, Kaufman RB, et al. Obstet Gynecol. 1996;87(2):163-68).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 45 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Pregnant and consents to participate

Exclusion Criteria:

• Not interviewed for consent within 12 consecutive weeks after being ascertained as pregnant by urine testing

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins School of Public Health	Baltimore	Maryland	United States	21205
2	JiVitA Project Office	Rangpur	Gaibandha District	Bangladesh

Sponsors and Collaborators

• Johns Hopkins Bloomberg School of Public Health
• Bill and Melinda Gates Foundation
• United States Agency for International Development (USAID)
• Mahidol University
• Johns Hopkins University
• Beximco Pharmaceuticals Ltd.
• DSM Nutritional Products, Inc.

Investigators

• Principal Investigator: Keith P West, Jr., Johns Hopkins Bloomberg School of Public Health
• Principal Investigator: Parul Christian, Johns Hopkins Bloomberg School of Public Health

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Basic description of the JiVitA project, location and individuals

Publications

• Christian P, Darmstadt GL, Wu L, Khatry SK, Leclerq SC, Katz J, West KP Jr, Adhikari RK. The effect of maternal micronutrient supplementation on early neonatal morbidity in rural Nepal: a randomised, controlled, community trial. Arch Dis Child. 2008 Aug;93(8):660-4. doi: 10.1136/adc.2006.114009.
• Christian P, Jiang T, Khatry SK, LeClerq SC, Shrestha SR, West KP Jr. Antenatal supplementation with micronutrients and biochemical indicators of status and subclinical infection in rural Nepal. Am J Clin Nutr. 2006 Apr;83(4):788-94.
• Christian P, Khatry SK, Katz J, Pradhan EK, LeClerq SC, Shrestha SR, Adhikari RK, Sommer A, West KP Jr. Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal: double blind randomised community trial. BMJ. 2003 Mar 15;326(7389):571.
• Christian P, Osrin D, Manandhar DS, Khatry SK, de L Costello AM, West KP Jr. Antenatal micronutrient supplements in Nepal. Lancet. 2005 Aug 27-Sep 2;366(9487):711-2.
• Christian P, Shrestha J, LeClerq SC, Khatry SK, Jiang T, Wagner T, Katz J, West KP Jr. Supplementation with micronutrients in addition to iron and folic acid does not further improve the hematologic status of pregnant women in rural Nepal. J Nutr. 2003 Nov;133(11):3492-8.
• Christian P, West KP, Khatry SK, Leclerq SC, Pradhan EK, Katz J, Shrestha SR, Sommer A. Effects of maternal micronutrient supplementation on fetal loss and infant mortality: a cluster-randomized trial in Nepal. Am J Clin Nutr. 2003 Dec;78(6):1194-202.
• Christian P. Micronutrients and reproductive health issues: an international perspective. J Nutr. 2003 Jun;133(6):1969S-1973S. Review.
• Jiang T, Christian P, Khatry SK, Wu L, West KP Jr. Micronutrient deficiencies in early pregnancy are common, concurrent, and vary by season among rural Nepali pregnant women. J Nutr. 2005 May;135(5):1106-12.
• Katz J, Christian P, Dominici F, Zeger SL. Treatment effects of maternal micronutrient supplementation vary by percentiles of the birth weight distribution in rural Nepal. J Nutr. 2006 May;136(5):1389-94.
• Katz J, West KP Jr, Khatry SK, Christian P, LeClerq SC, Pradhan EK, Shrestha SR. Risk factors for early infant mortality in Sarlahi district, Nepal. Bull World Health Organ. 2003;81(10):717-25. Epub 2003 Nov 25.
• Shankar AH, Genton B, Baisor M, Paino J, Tamja S, Adiguma T, Wu L, Rare L, Bannon D, Tielsch JM, West KP Jr, Alpers MP. The influence of zinc supplementation on morbidity due to Plasmodium falciparum: a randomized trial in preschool children in Papua New Guinea. Am J Trop Med Hyg. 2000 Jun;62(6):663-9.
• West KP Jr, Christian P. Antenatal micronutrients in undernourished people. Lancet. 2008 Feb 9;371(9611):452-4. doi: 10.1016/S0140-6736(08)60214-7.

• Responsible Party: Keith P. West, Professor, Johns Hopkins Bloomberg School of Public Health
• ClinicalTrials.gov Identifier: NCT00860470
• Other Study ID Numbers: JHU_IRB 570
• First Posted: Mar 12, 2009
• Last Update Posted: May 27, 2015
• Last Verified: May 1, 2015

• Keywords provided by Keith P. West, Professor, Johns Hopkins Bloomberg School of Public Health: micronutrients; deficiency; pregnancy; birth outcomes; infant mortality; neonatal mortality; malnutrition; antenatal
• Additional relevant MeSH terms: Premature Birth; Perinatal Death; Birth Weight; Infant Death; Iron; Trace Elements; Folic Acid; Micronutrients

Study Results

Participant Flow

Recruitment Details	Enumeration of women began in December 2007, and active recruitment of pregnant women into the trail began in January 2008. Women were enrolled into the trial by community workers from the projects who visited them at home.

Arm/Group Title	Iron and Folate	Multiple Micronutrient
Arm/Group Description	Iron (27 mg) and folic acid (600 ug) Iron (27 mg) - folic acid (600 ug): Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.	Multiple micronutrient: Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.
Period Title: Overall Study
STARTED	22162	22405
COMPLETED	22114	22346
NOT COMPLETED	48	59

Baseline Characteristics

Arm/Group Title	Iron and Folate	Multiple Micronutrient	Total
Arm/Group Description	Iron (27 mg) and folic acid (600 ug) Iron (27 mg) - folic acid (600 ug): Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.	Multiple micronutrient Multiple micronutrient: Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.	Total of all reporting groups
Overall Participants	22162	22405	44567
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	24.3 (6.43)	24.4 (6.44)	24.3 (6.43)
Gender (participants) [Number]
Female	22,162 NaN	22,405 NaN	44567 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
Asian, Bangladeshi	22,162 NaN	22,405 NaN	44567 100%
Region of Enrollment (participants) [Number]
Bangladesh	22,162 NaN	22,405 NaN	44567 100%
Gestational Age in weeks (weeks) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [weeks]	10.34 (4.7)	10.28 (4.7)	10.30 (4.7)
Literacy (participants) [Number]
Literate	12,816 NaN	12,985 NaN	25801 57.9%
Illiterate	9,346 NaN	9,420 NaN	18766 42.1%
Parity (participants) [Number]
0	6,671 NaN	6,647 NaN	13318 29.9%
1-3	13,255 NaN	13,520 NaN	26775 60.1%
>=4	2,186 NaN	2,194 NaN	4380 9.8%
Previous Pregnancy Loss (participants) [Number]
Number [participants]	4,974 NaN	5,106 NaN	10080 22.6%

Outcome Measures

1. Primary Outcome

Title	Infant Mortality Through 6 mo of Age
Description	Risk of Infant Mortality to Age 6 months (180 days)
Time Frame	Dec 2014

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iron and Folate	Multiple Micronutrient
Arm/Group Description	Iron (27 mg) and folic acid (600 ug) Iron (27 mg) - folic acid (600 ug): Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.	Multiple micronutrient: Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.
Measure Participants	14142	14374
Number [participants]	764 3.4%	741 3.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Iron and Folate, Multiple Micronutrient
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	Regression, Logistic
	Comments	Bonferroni-adjusted alpha=0.01 (for 5 comparisons)
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	GEE with log link function and exchangeable correlation was used to adjust confidence intervals for cluster randomised design; the iron-folic acid supplemented group was the referent.

2. Secondary Outcome

Title	Neonatal Mortality
Description	Risk of neonatal Mortality (28 days of life)
Time Frame	Dec 2014

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iron and Folate	Multiple Micronutrient
Arm/Group Description	Iron (27 mg) and folic acid (600 ug) Iron (27 mg) - folic acid (600 ug): Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.	Multiple micronutrient: Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.
Measure Participants	14142	14374
Number [participants]	625 2.8%	626 2.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Iron and Folate, Multiple Micronutrient
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.88 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	GEE with log link function and exchangeable correlation was used to adjust confidence intervals for cluster randomised design; the iron-folic acid supplemented group was the referent.

3. Secondary Outcome

Title	Post-neonatal Mortality
Description	Risk of Post-neonatal Mortality (29th -180th day of life)
Time Frame	Dec 2014

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iron and Folate	Multiple Micronutrient
Arm/Group Description	Iron (27 mg) and folic acid (600 ug) Iron (27 mg) - folic acid (600 ug): Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.	Multiple micronutrient: Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.
Measure Participants	13517	13748
Number [participants]	139 0.6%	115 0.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Iron and Folate, Multiple Micronutrient
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.63 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	GEE with log link function and exchangeable correlation was used to adjust confidence intervals for cluster randomised design; the iron-folic acid supplemented group was the referent.

4. Secondary Outcome

Title	Still Birth Rates
Description	Risk of Still birth
Time Frame	December 2014

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iron and Folate	Multiple Micronutrient
Arm/Group Description	Iron (27 mg) and folic acid (600 ug) Iron (27 mg) - folic acid (600 ug): Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.	Multiple micronutrient: Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.
Measure Participants	14858	15022
Number [participants]	716 3.2%	648 2.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Iron and Folate, Multiple Micronutrient
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Regression, Logistic
	Comments	Bonferroni-adjusted alpha=0.01 (for 5 comparisons)
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.81 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	GEE with log link function and exchangeable correlation was used to adjust confidence intervals for cluster randomised design; the iron-folic acid supplemented group was the referent.

5. Secondary Outcome

Title	Preterm Birth
Description	Risk of being born before 37 weeks of gestation
Time Frame	December 2014

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iron and Folate	Multiple Micronutrient
Arm/Group Description	Iron (27 mg) and folic acid (600 ug) Iron (27 mg) - folic acid (600 ug): Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.	Multiple micronutrient: Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.
Measure Participants	13333	13475
Number [participants]	2912 13.1%	2510 11.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Iron and Folate, Multiple Micronutrient
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments	Bonferroni-adjusted alpha=0.01 (for 5 comparisons)
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.80 to 0.91
	Parameter Dispersion	Type: Value:
	Estimation Comments	GEE with log link function and exchangeable correlation was used to adjust confidence intervals for cluster randomised design; the iron-folic acid supplemented group was the referent.

6. Secondary Outcome

Title	Extremely Pre-term
Description	Risk of birth before 28 weeks gestation
Time Frame	December 2014

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iron and Folate	Multiple Micronutrient
Arm/Group Description	Iron (27 mg) and folic acid (600 ug) Iron (27 mg) - folic acid (600 ug): Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.	Multiple micronutrient: Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.
Measure Participants	13333	13475
Number [participants]	136 0.6%	106 0.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Iron and Folate, Multiple Micronutrient
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.57 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	GEE with log link function and exchangeable correlation was used to adjust confidence intervals for cluster randomised design; the iron-folic acid supplemented group was the referent.

7. Secondary Outcome

Title	Very Pre-term
Description	Risk of birth between 28 and 32 weeks of gestation
Time Frame	December 2014

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iron and Folate	Multiple Micronutrient
Arm/Group Description	Iron (27 mg) and folic acid (600 ug) Iron (27 mg) - folic acid (600 ug): Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.	Multiple micronutrient: Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.
Measure Participants	13333	13475
Number [participants]	385 1.7%	291 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Iron and Folate, Multiple Micronutrient
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	GEE with log link function and exchangeable correlation was used to adjust confidence intervals for cluster randomised design; the iron-folic acid supplemented group was the referent.

8. Secondary Outcome

Title	Moderate to Late Preterm
Description	Risk of birth between 32 and 37 weeks gestation
Time Frame	December 2014

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iron and Folate	Multiple Micronutrient
Arm/Group Description	Iron (27 mg) and folic acid (600 ug) Iron (27 mg) - folic acid (600 ug): Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.	Multiple micronutrient: Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.
Measure Participants	1333	13475
Number [participants]	2391 10.8%	2113 9.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Iron and Folate, Multiple Micronutrient
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.87
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.81 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	GEE with log link function and exchangeable correlation was used to adjust confidence intervals for cluster randomised design; the iron-folic acid supplemented group was the referent.

9. Secondary Outcome

Title	Low Birth Weight
Description	Birth weight below 2500g
Time Frame	December 2014

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iron and Folate	Multiple Micronutrient
Arm/Group Description	Iron (27 mg) and folic acid (600 ug) Iron (27 mg) - folic acid (600 ug): Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.	Multiple micronutrient: Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.
Measure Participants	10530	10642
Number [participants]	4809 21.7%	4275 19.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Iron and Folate, Multiple Micronutrient
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments	Bonferroni-adjusted alpha=0.01 (for 5 comparisons)
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.85 to 0.91
	Parameter Dispersion	Type: Value:
	Estimation Comments	GEE with log link function and exchangeable correlation was used to adjust confidence intervals for cluster randomised design; the iron-folic acid supplemented group was the referent.

10. Secondary Outcome

Title	Small for Gestation Age
Description	Small for Gestational Age defined as birth weight <10th percentile of a standard reference (Alexander GR, Himes JH, Kaufman RB, et al. Obstet Gynecol. 1996;87(2):163-68).
Time Frame	December 2014

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Iron and Folate	Multiple Micronutrient
Arm/Group Description	Iron (27 mg) and folic acid (600 ug) Iron (27 mg) - folic acid (600 ug): Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.	Multiple micronutrient: Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.
Measure Participants	10099	10161
Number [participants]	6479 29.2%	6405 28.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Iron and Folate
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Regression, Logistic
	Comments	Bonferroni-adjusted alpha=0.01 (for 5 comparisons)
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.96 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	GEE with log link function and exchangeable correlation was used to adjust confidence intervals for cluster randomised design; the iron-folic acid supplemented group was the referent.

Adverse Events

Arm/Group Title	Iron (27 mg) and Folic Acid (600 ug)		Multiple Micronutrient
Arm/Group Description	Iron (27 mg) and folic acid (600 ug) Iron (27 mg) - folic acid (600 ug): Supplement serves as the "Control" (providing the current standard of care during pregnancy). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.		Multiple micronutrient Multiple micronutrient: Containing 15 micronutrients all at an RDA including: vitamin A (770 ug retinol equivalents, vitamin D (5 ug), vitamin E (15 mg), folic acid (600 ug), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (18 mg), vitamin B-12 (2.6 mg), vitamin B-6 (1.9 mg), vitamin C (85 mg), iron (27 mg), zinc (12 mg), iodine (220 ug), copper (1000 ug), selenium (60 ug). Mothers instructed to take 1 tablet per day, from the 1st trimester through 12 weeks post-partum.
All Cause Mortality
	Iron (27 mg) and Folic Acid (600 ug)		Multiple Micronutrient
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Iron (27 mg) and Folic Acid (600 ug)		Multiple Micronutrient
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22114 (0%)		0/22346 (0%)
Other (Not Including Serious) Adverse Events
	Iron (27 mg) and Folic Acid (600 ug)		Multiple Micronutrient
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22114 (0%)		0/22346 (0%)

Limitations/Caveats

The study was run in an area where iron deficiency rates were low.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.