Randomized Trial of Vitamin B12 in Pregnant Indian Women (B12)

This study is a randomized, double-blind trial among 300 pregnant Indian women in order to determine the effectiveness of vitamin B12 supplementation in improving maternal B12 status. Secondary aims for this trial include maternal hemoglobin, maternal weight gain during pregnancy and infant birthweight. All women will receive standard of prenatal obstetric care, including routine supplementation with iron and folate.

Study Overview

• Status: Completed
• Conditions: Pregnancy
• Intervention / Treatment: Dietary supplement: Vitamin B12; Other: Placebo

Detailed Description

The incidence of poor fetal growth and adverse maternal and infant birth outcomes is quite high in India, and several lines of evidence suggest that maternal nutritional status may be an important factor. We have previously performed extensive evaluations of poor fetal and infant outcomes in other settings, and found that maternal micronutrient supplementation (B vitamins including vitamin B12, plus vitamins C and E) in HIV positive Tanzanian mothers decreased the risk of low birthweight (<2500 g) by 44% (RR (95% CI) 0.56 (0.38-0.82)), severe preterm birth (<34 weeks of gestation) by 39% (RR 0.61 (0.38-0.96)), and small size for gestational age at birth by 43% (RR 0.57 (0.39-0.82)). In a prospective cohort study of 410 pregnant Indian women, we recently found a strong relationship between maternal serum vitamin B12 concentration and risk of infant intrauterine growth retardation (IUGR). Compared to women in the highest tertile of serum B12 concentration, women in the lowest tertile were significantly more likely to have IUGR infants, after controlling for maternal age, weight, education, and parity (OR (95% CI) 5.98 (1.72-20.74)). We now propose a randomized, double-blind trial among 300 pregnant Indian women in order to determine the effectiveness of vitamin B12 supplementation (50 µg daily) in improving maternal B12 status. Secondary aims for this exploratory trial include maternal hemoglobin, maternal weight gain during pregnancy and infant birthweight. All women will receive standard of prenatal obstetric care, including routine supplementation with iron and folate. The study will be a collaborative effort between the Division of Nutrition, St John's Research Institute, Bangalore, India, and the Department of Nutrition, Harvard School of Public Health, Boston, US.

• Study Type: Interventional
• Enrollment (Actual): 366
• Phase: Not Applicable

Contacts and Locations

Study Locations

• India
  • Karnataka
    • Bangalore, Karnataka, India, 560-034
      • St. John's Medical Research Institute, St. John's National Academy of Health Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Pregnant women at or before 14 weeks gestational age.

Exclusion Criteria:

• Women who anticipate moving outside of the study area before study completion
• Those with twin or multiple pregnancies
• Those who test positive for hepatitis B (HepBSAg), HIV or Syphilis (VDRL)
• Those taking vitamin supplements in addition to folate and iron
• Those with a serious pre-existing medical condition, defined as conditions that require chronic or daily medical therapy such as connective tissue diseases, hypertension not related to pregnancy, inflammatory bowel disease, active tuberculosis, symptomatic heart disease, and insulin dependent diabetes.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Placebo taken daily from enrollment (at or before 14 weeks gestational age) until delivery
Active Comparator: Vitamin B12	Dietary supplement: Vitamin B12; Daily oral administration of 50 µg of Vitamin B12 taken from enrollment (at or before 14 weeks gestational age) until delivery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Changes in Maternal Serum B12 Concentration From 1st to 3rd Trimester	from 1st to 3rd trimester

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive Scale, Bayley Scales of Infant Development, 3rd Edition	The cognitive scale is a single scale that measures sensorimotor integration, concept formation, attention, habituation, and memory. Higher values represent better performance. The interquartile range provides an adequate assessment of the variability of the data. The minimum possible score of the cognitive scale is 0 and the maximum possible score is 91.	9 months
Receptive Language Scale, Bayley Scales of Infant Development, 3rd Edition	The Receptive Language Scale is a single scale that measures the ability of the child to recognize sounds and understand spoken words and directions. Higher values represent better performance. The interquartile range provides adequate assessment of the variability of the data. The minimum possible score is 0 and the maximum possible score is 49.	9 months
Expressive Language Scale, Bayley Scales of Infant Development, 3rd Edition	The Expressive Language Scale is a single scale that measures the ability of the child to communicate using sounds, gestures, or words. Higher scores represent better performance. The interquartile range provides adequate assessment of the variability of the data. The minimum possible value is 0 and the maximum possible value is 48.	9 months
Fine Motor Scale, Bayley Scales of Infant Development, 3rd Edition	The Fine Motor Scale is a single scale that measures prehension, perceptual-motor integration, motor planning and speed, visual tracking, reaching, object grasping, object manipulation, functional hand skills, and responses to tactile information. Higher values represent better performance. The interquartile range provides adequate assessment of the variability of the data. The minimum possible value is 0 and the maximum possible value is 66.	9 months
Gross Motor Scale, Bayley Scales of Infant Development, 3rd Edition	The Gross Motor Scale is a single scale that measures movement of the limbs and torso, static positioning (e.g., sitting, standing), dynamic movement including locomotion and coordination, balance, and motor planning. Higher values represent better performance. The interquartile range provides adequate assessment of the variability of the data. The minimum possible value is 0 and the maxiumum possible value is 72.	9 months
Kaufman's Assessment Battery for Children (KABC)	This test is used for assessing child intelligence	60-72 months
The Wechsler Preschool and Primary Scale of Intelligence (WPPSI)	WPPSI is an intelligence test designed for children ages 2 years 6 months to 7 years 7 months. It is a paper-pencil test that will be administered during the 78 month follow up to assess child's intellectual functioning.	78 months
Vineland Social Maturity Scale (VSMS)	This scale has 8 main domains which include, Self Help General, Self Help Dressing, Self Direction, Occupation, Communication, Locomotion and Socialization. It is possible to calculate Social age and Social quotient from VSMS which will provide a good idea about the social maturity of the infant. VSMS will be used in conjunction with KABC at age 60-72 months of age.	60-72 months
The Brief P Test	The Brief P test is a measure of infant executive function based on parental rating. It will be administered at 66 months postpartum.	66 months postpartum
Parental Version of Strengths and Difficulties Questionnaire (SDQ)	Administered at 78 months to assess childhood behavioral problems. The SDQ has 25 items and generates 5 scales: emotional problem, conduct problem, hyperactivity/inattention, peer relationship problems and pro-social behavior.	78 months
Bradley Infant-Toddler Home Tools	Home tools used to analyze aspects of home environment. This scale captures information on parenting behavior under 6 domains: responsivity, acceptance, organization, learning materials, parental involvement, and variety of stimulation at home). Trained study personnel will administer this questionnaire to participating families at 60 months.	60 months

Collaborators and Investigators

• Sponsor: Harvard School of Public Health (HSPH)
• Collaborators: St. John's Research Institute
• Investigators: Principal Investigator: Christopher P Duggan, MD, MPH, Harvard School of Public Health (HSPH); Principal Investigator: Anura Kurpad, MBBS, PhD, St. John's Research Institute; Principal Investigator: Krishnamachari Srinivasan, MD, St. John's Research Institute

Publications and helpful links

General Publications

• Muthayya S, Dwarkanath P, Mhaskar M, Mhaskar R, Thomas A, Duggan C, Fawzi WW, Bhat S, Vaz M, Kurpad A. The relationship of neonatal serum vitamin B12 status with birth weight. Asia Pac J Clin Nutr. 2006;15(4):538-43.
• Muthayya S, Kurpad AV, Duggan CP, Bosch RJ, Dwarkanath P, Mhaskar A, Mhaskar R, Thomas A, Vaz M, Bhat S, Fawzi WW. Low maternal vitamin B12 status is associated with intrauterine growth retardation in urban South Indians. Eur J Clin Nutr. 2006 Jun;60(6):791-801. doi: 10.1038/sj.ejcn.1602383. Epub 2006 Jan 11.
• Srinivasan K, Thomas S, Anand S, Jayachandra M, Thomas T, Strand TA, Kurpad AV, Duggan CP. Vitamin B-12 Supplementation during Pregnancy and Early Lactation Does Not Affect Neurophysiologic Outcomes in Children Aged 6 Years. J Nutr. 2020 Jul 1;150(7):1951-1957. doi: 10.1093/jn/nxaa123.
• Anand S, Thomas S, Jayachandra M, Thomas T, Strand TA, Kurpad AV, Duggan CP, Srinivasan K. Effects of maternal B12 supplementation on neurophysiological outcomes in children: a study protocol for an extended follow-up from a placebo randomised control trial in Bangalore, India. BMJ Open. 2019 Feb 19;9(2):e024426. doi: 10.1136/bmjopen-2018-024426.
• Winje BA, Kvestad I, Krishnamachari S, Manji K, Taneja S, Bellinger DC, Bhandari N, Bisht S, Darling AM, Duggan CP, Fawzi W, Hysing M, Kumar T, Kurpad AV, Sudfeld CR, Svensen E, Thomas S, Strand TA. Does early vitamin B12 supplementation improve neurodevelopment and cognitive function in childhood and into school age: a study protocol for extended follow-ups from randomised controlled trials in India and Tanzania. BMJ Open. 2018 Feb 22;8(2):e018962. doi: 10.1136/bmjopen-2017-018962.
• Duggan C, Srinivasan K, Thomas T, Samuel T, Rajendran R, Muthayya S, Finkelstein JL, Lukose A, Fawzi W, Allen LH, Bosch RJ, Kurpad AV. Vitamin B-12 supplementation during pregnancy and early lactation increases maternal, breast milk, and infant measures of vitamin B-12 status. J Nutr. 2014 May;144(5):758-64. doi: 10.3945/jn.113.187278. Epub 2014 Mar 5.
• Lukose A, Ramthal A, Thomas T, Bosch R, Kurpad AV, Duggan C, Srinivasan K. Nutritional factors associated with antenatal depressive symptoms in the early stage of pregnancy among urban South Indian women. Matern Child Health J. 2014 Jan;18(1):161-170. doi: 10.1007/s10995-013-1249-2.

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: March 17, 2008
• First Submitted That Met QC Criteria: March 21, 2008
• First Posted (Estimate): March 24, 2008

Study Record Updates

• Last Update Posted (Actual): July 28, 2020
• Last Update Submitted That Met QC Criteria: July 13, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Pregnancy; Vitamin B12; Maternal Nutritional Status
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Hematinics; Vitamin B 12; Hydroxocobalamin
• Other Study ID Numbers: HD052143