Impact of Maternal Vitamin A or Beta-Carotene Supplementation on Maternal and Infant Mortality in Bangladesh

• All-cause pregnancy-related maternal mortality
• Perinatal and neonatal mortality
• Three-month infant mortality

• All-cause 3-month Infant Mortality [ Time Frame: Deaths through the 1st 12 weeks of life ] [ Designated as safety issue: No ]
• Maternal Morbidity, Including Obstetric Complications [ Time Frame: through the 1st 24 weeks following termination of pregnancy ] [ Designated as safety issue: No ]
• Gestational Age at Birth [ Time Frame: within 24 weeks after birth ] [ Designated as safety issue: No ]
• Fetal Growth and Postnatal Infant Growth Through Three Months of Age [ Time Frame: through the 1st 12 weeks after birth ] [ Designated as safety issue: No ]
• Infant Morbidity Through 3 Months of Age [ Time Frame: within 24 weeks after birth ] [ Designated as safety issue: No ]
• Plasma Beta-carotene in the Third Trimester of Pregnancy(Nutritonal Status of the Mother) [ Time Frame: Third trimester of pregnancy (about the 32nd week of gesatation) ] [ Designated as safety issue: No ]
• Plasma Retinol at the Third Trimester of Pregnancy (Nutritional Status of the Mother) [ Time Frame: Third trimester of pregnancy (about the 32nd week of gestation) ] [ Designated as safety issue: No ]

• Maternal morbidity, including obstetric complications
• Gestational age at birth
• Fetal and postnatal growth through three months of age
• Infant morbidity through three months of age
• Maternal and infant nutritional status

The purpose of this trial is to determine whether providing women with a weekly oral supplement of vitamin A, either preformed or as beta-carotene, at a dosage equivalent to a recommended intake from early pregnancy through three months postpartum, can reduce the risk of maternal mortality, fetal loss, or infant mortality.

Maternal mortality and vitamin A deficiency coexist in rural South Asia. In Nepal, weekly supplementation with vitamin A or beta-carotene during the child-bearing years reduced all-cause maternal mortality and, in night blind women, also infant mortality. The present trial is testing the efficacy of the same supplements from ~9 weeks' gestation to 12 weeks postpartum. The planned sample size is 68,000 pregnancies. It is being conducted in 19 rural unions, covering an area of ~750 sq km with a population of ~580,000 in Gaibandha and Southern Rangpur Districts in Northern Bangladesh. The study area was mapped as 596 "sectors" (unit of randomization), each comprising 200-275 households; ~135,000 houses were numerically addressed and, at the outset, 103,000 women were listed. Women are visited at home every 5 weeks by 596 trained female staff to detect pregnancy by a combination of menstrual history and urine testing. Newly married women are prospectively enlisted for pregnancy surveillance. Following informed consent urine-positive (pregnant) women detected during surveillance are enrolled to receive weekly a capsule containing 7000 retinol equivalents of preformed vitamin A, 42 mg of beta-carotene or placebo. Vital events are recorded weekly through 3 months postpartum. Trained interviewers conduct maternal nutritional and health and household socioeconomic assessments in the 1st trimester. At 3 months postpartum, interviewers assess both mother and infant for health and nutritional status, including apparent birth defects that are later physician-confirmed. An additional home health assessment occurs at 6 months post partum, and vital status is recorded for mother and infant at one year postpartum. A ~3% subsample of enrolled pregnant women participate in a substudy involving enhanced clinical, anthropometric, biochemical, body compositional, morbidity and interview-based assessment protocols in the 1st, 2nd and 3rd trimesters, and at 3 months post-partum. Reported maternal and infant deaths are verified and causes ascertained during "verbal autopsy" interviews with family members of the deceased.

• Vitamin A Deficiency
• Maternal Mortality
• Infant Mortality

• Experimental: 1
  Weekly oral supplement with 7000 µg retinol equivalents from early pregnancy through 12 weeks following termination of pregnancy
  Intervention: Dietary Supplement: Vitamin A or Beta-Carotene Supplements
• Experimental: 2
  Weekly oral supplement with 42 mg of beta-carotene from early pregnancy through 12 weeks following termination of pregnancy
  Intervention: Dietary Supplement: Vitamin A or Beta-Carotene Supplements
• Placebo Comparator: 3
  Weekly oral supplement with placebo from early pregnancy through 12 weeks following termination of pregnancy
  Intervention: Dietary Supplement: Vitamin A or Beta-Carotene Supplements

• West KP Jr, Christian P, Labrique AB, Rashid M, Shamim AA, Klemm RD, Massie AB, Mehra S, Schulze KJ, Ali H, Ullah B, Wu LS, Katz J, Banu H, Akhter HH, Sommer A. Effects of vitamin A or beta carotene supplementation on pregnancy-related mortality and infant mortality in rural Bangladesh: a cluster randomized trial. JAMA. 2011 May 18;305(19):1986-95.
• 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.
• Gunnsteinsson S, Labrique AB, West KP Jr, Christian P, Mehra S, Shamim AA, Rashid M, Katz J, Klemm RD. Constructing indices of rural living standards in Northwestern Bangladesh. J Health Popul Nutr. 2010 Oct;28(5):509-19.
• West KP Jr, Katz J, Khatry SK, LeClerq SC, Pradhan EK, Shrestha SR, Connor PB, Dali SM, Christian P, Pokhrel RP, Sommer A. Double blind, cluster randomised trial of low dose supplementation with vitamin A or beta carotene on mortality related to pregnancy in Nepal. The NNIPS-2 Study Group. BMJ. 1999 Feb 27;318(7183):570-5.
• Katz J, West KP Jr, Khatry SK, Pradhan EK, LeClerq SC, Christian P, Wu LS, Adhikari RK, Shrestha SR, Sommer A. Maternal low-dose vitamin A or beta-carotene supplementation has no effect on fetal loss and early infant mortality: a randomized cluster trial in Nepal. Am J Clin Nutr. 2000 Jun;71(6):1570-6.
• Christian P, West KP Jr, Khatry SK, LeClerq SC, Kimbrough-Pradhan E, Katz J, Shrestha SR. Maternal night blindness increases risk of mortality in the first 6 months of life among infants in Nepal. J Nutr. 2001 May;131(5):1510-2.
• Christian P, West KP Jr, Khatry SK, Katz J, LeClerq SC, Kimbrough-Pradhan E, Dali SM, Shrestha SR. Vitamin A or beta-carotene supplementation reduces symptoms of illness in pregnant and lactating Nepali women. J Nutr. 2000 Nov;130(11):2675-82.
• Christian P, West KP Jr, Khatry SK, Kimbrough-Pradhan E, LeClerq SC, Katz J, Shrestha SR, Dali SM, Sommer A. Night blindness during pregnancy and subsequent mortality among women in Nepal: effects of vitamin A and beta-carotene supplementation. Am J Epidemiol. 2000 Sep 15;152(6):542-7.
• West KP Jr. Extent of vitamin A deficiency among preschool children and women of reproductive age. J Nutr. 2002 Sep;132(9 Suppl):2857S-2866S. Erratum in: J Nutr 2002 Nov;132(11):3432.
• Christian P, Klemm R, Shamim AA, Ali H, Rashid M, Shaikh S, Wu L, Mehra S, Labrique A, Katz J, West KP Jr. Effects of vitamin A and β-carotene supplementation on birth size and length of gestation in rural Bangladesh: a cluster-randomized trial. Am J Clin Nutr. 2013 Jan;97(1):188-94. doi: 10.3945/ajcn.112.042275. Epub 2012 Nov 14.
• Christian P, Labrique AB, Ali H, Richman MJ, Wu L, Rashid M, West KP Jr. Maternal vitamin A and ?-carotene supplementation and risk of bacterial vaginosis: a randomized controlled trial in rural Bangladesh. Am J Clin Nutr. 2011 Dec;94(6):1643-9. Epub 2011 Nov 9.
• Shamim AA, Christian P, Schulze KJ, Ali H, Kabir A, Rashid M, Labrique A, Salamatullah Q, West KP Jr. Iodine status in pregnancy and household salt iodine content in rural Bangladesh. Matern Child Nutr. 2012 Apr;8(2):162-73. doi: 10.1111/j.1740-8709.2010.00282.x. Epub 2010 Oct 26.

Inclusion Criteria:

• Married women of reproductive age
• First pregnancy during time period of trial

Exclusion Criteria:

• Premenarchial girls
• Married women with a previous pregnancy enrolled into the trial
• Previously married women who have moved into the study area
• Single women (never married, widowers)
• Women who are sterilized (or whose husbands are sterilized)
• Menopausal women

• United States Agency for International Development (USAID)
• Bill and Melinda Gates Foundation
• Canadian International Development Agency
• The Sight and Life Research Institute
• Access Business Group