Infant Mortality, Low Birth Weight, Neonatal Mortality, Perinatal Mortality, Preterm Birth
Conditions
Keywords
micronutrients, deficiency, pregnancy, birth outcomes, infant mortality, neonatal mortality, malnutrition, antenatal
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.
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.
Interventions
DIETARY_SUPPLEMENTIron (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.
DIETARY_SUPPLEMENTMultiple 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.
Sponsors
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.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
12 Years to 45 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Infant Mortality Through 6 mo of Age | 6-months post-birth | Infant Mortality to Age 6 months (180 days from birth) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-neonatal Mortality | 1-6 months post-birth | Risk of Post-neonatal Mortality (29th -180th day of life) |
| Still Birth Rates | 24 weeks gestation to delivery | Stillbirth (born \>=24 weeks without breathing, crying, or moving limbs). |
| Preterm Birth | Up to 37 weeks of gestation | Being born before 37 weeks of gestation |
| Extremely Pre-term | Up to 28 weeks of gestation | Birth before 28 weeks gestation |
| Neonatal Mortality | 1 month post-birth | Neonatal Mortality (28 days of life) |
| Moderate to Late Preterm | Between 31 and 38 weeks of gestation | Birth between 32 and 37 weeks gestation |
| Low Birth Weight | Measured at delivery/birth | Birth weight below 2500g |
| Small for Gestation Age | At delivery/birth | 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). |
| Very Pre-term | Between 27 and 33 weeks of gestation | Birth between 28 and 32 weeks of gestation |
Countries
Bangladesh, United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Iron and Folate 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. | 22 |
| Multiple Micronutrient 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. | 22 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 6 | 10 |
| Overall Study | Lost to Follow-up | 34 | 39 |
| Overall Study | Moved away | 8 | 10 |
Baseline characteristics
| Characteristic | Iron and Folate | Multiple Micronutrient | Total |
|---|---|---|---|
| Age, Continuous | 24.3 years STANDARD_DEVIATION 6.43 | 24.4 years STANDARD_DEVIATION 6.44 | 24.3 years STANDARD_DEVIATION 6.43 |
| Gestational Age in weeks | 10.34 weeks STANDARD_DEVIATION 4.7 | 10.28 weeks STANDARD_DEVIATION 4.7 | 10.30 weeks STANDARD_DEVIATION 4.7 |
| Literacy Illiterate | 9,346 participants | 9,420 participants | 18766 participants |
| Literacy Literate | 12,816 participants | 12,985 participants | 25801 participants |
| Parity 0 | 6,671 participants with reported data | 6,647 participants with reported data | 13318 participants with reported data |
| Parity 1-3 | 13,255 participants with reported data | 13,520 participants with reported data | 26775 participants with reported data |
| Parity >=4 | 2,186 participants with reported data | 2,194 participants with reported data | 4380 participants with reported data |
| Previous Pregnancy Loss | 4,974 participants | 5,106 participants | 10080 participants |
| Race/Ethnicity, Customized Asian, Bangladeshi | 22,162 participants | 22,405 participants | 44567 participants |
| Region of Enrollment Bangladesh | 22,162 participants | 22,405 participants | 44567 participants |
| Sex: Female, Male Female | 22,162 Participants | 22,405 Participants | 44567 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 22,114 | 0 / 22,346 |
| serious Total, serious adverse events | 0 / 22,114 | 0 / 22,346 |
Outcome results
Primary
Infant Mortality Through 6 mo of Age
Infant Mortality to Age 6 months (180 days from birth)
Time frame: 6-months post-birth
Population: Not all women recruited into the trial had pregnancies yielding live births. This represents all live births by arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iron and Folate | Infant Mortality Through 6 mo of Age | 764 participants |
| Multiple Micronutrient | Infant Mortality Through 6 mo of Age | 741 participants |
p-value: 0.3695% CI: [0.86, 1.06]Regression, Logistic
Secondary
Extremely Pre-term
Birth before 28 weeks gestation
Time frame: Up to 28 weeks of gestation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iron and Folate | Extremely Pre-term | 136 participants |
| Multiple Micronutrient | Extremely Pre-term | 106 participants |
p-value: 0.0395% CI: [0.57, 0.97]Regression, Logistic
Secondary
Low Birth Weight
Birth weight below 2500g
Time frame: Measured at delivery/birth
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iron and Folate | Low Birth Weight | 4809 participants |
| Multiple Micronutrient | Low Birth Weight | 4275 participants |
p-value: <0.00195% CI: [0.85, 0.91]Regression, Logistic
Secondary
Moderate to Late Preterm
Birth between 32 and 37 weeks gestation
Time frame: Between 31 and 38 weeks of gestation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iron and Folate | Moderate to Late Preterm | 2391 participants |
| Multiple Micronutrient | Moderate to Late Preterm | 2113 participants |
p-value: 0.8795% CI: [0.81, 0.93]Regression, Logistic
Secondary
Neonatal Mortality
Neonatal Mortality (28 days of life)
Time frame: 1 month post-birth
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iron and Folate | Neonatal Mortality | 625 participants |
| Multiple Micronutrient | Neonatal Mortality | 626 participants |
p-value: 0.7895% CI: [0.88, 1.2]Regression, Logistic
Secondary
Post-neonatal Mortality
Risk of Post-neonatal Mortality (29th -180th day of life)
Time frame: 1-6 months post-birth
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iron and Folate | Post-neonatal Mortality | 139 participants |
| Multiple Micronutrient | Post-neonatal Mortality | 115 participants |
p-value: 0.1195% CI: [0.63, 1.04]Regression, Logistic
Secondary
Preterm Birth
Being born before 37 weeks of gestation
Time frame: Up to 37 weeks of gestation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iron and Folate | Preterm Birth | 2912 participants |
| Multiple Micronutrient | Preterm Birth | 2510 participants |
p-value: <0.00195% CI: [0.8, 0.91]Regression, Logistic
Secondary
Small for Gestation Age
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: At delivery/birth
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iron and Folate | Small for Gestation Age | 6479 participants |
| Multiple Micronutrient | Small for Gestation Age | 6405 participants |
p-value: 0.1395% CI: [0.96, 1.01]Regression, Logistic
Secondary
Still Birth Rates
Stillbirth (born \>=24 weeks without breathing, crying, or moving limbs).
Time frame: 24 weeks gestation to delivery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iron and Folate | Still Birth Rates | 716 participants |
| Multiple Micronutrient | Still Birth Rates | 648 participants |
p-value: 0.0295% CI: [0.81, 0.99]Regression, Logistic
Secondary
Very Pre-term
Birth between 28 and 32 weeks of gestation
Time frame: Between 27 and 33 weeks of gestation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iron and Folate | Very Pre-term | 385 participants |
| Multiple Micronutrient | Very Pre-term | 291 participants |
p-value: <0.00195% CI: [0.62, 0.86]Regression, Logistic