Impact of Pre-pregnancy Micronutrient Supplementation on Maternal and Child Outcomes

Impact of Pre-Pregnancy Micronutrient Supplementation on Maternal and Child Outcomes

The study evaluates the efficacy of providing weekly iron-folate (IFA) supplements or Multiple Micronutrient (MM) supplements before pregnancy in increasing birth weight and duration of gestation as well as maternal and infant iron status.

Study Overview

• Status: Completed
• Conditions: Anemia; Iron Deficiency; Preterm Delivery; Intrauterine Growth Retardation
• Intervention / Treatment: Dietary supplement: Multiple Micronutrient; Dietary supplement: Iron and Folic Acid; Dietary supplement: Folic Acid

Detailed Description

Low birth weight and anemia remain intractable problems in many developing countries despite considerable efforts to address them. Intervening with just prenatal iron-folate (IFA) supplements may not be the best approach given the substantial demands for iron by maternal and fetal tissues. Therefore, there is an urgent need to evaluate the additional contribution of prepregnancy interventions.

The study evaluates the efficacy of providing weekly iron-folate (IFA) supplements or Multiple Micronutrient (MM) supplements before pregnancy in increasing birth weight and duration of gestation as well as maternal and infant iron status.

• Study Type: Interventional
• Enrollment (Actual): 5011
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Vietnam
  • Thái Nguyên
    • Hành Phố Thái Nguyên, Thái Nguyên, Vietnam, 24000
      • Thainguyen University of Medicine and Pharmacy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• 18-35 years old
• Currently married
• Currently living in one of the 10 communes and intends to live in the areas for 24 months following recruitment
• Plans to have children in the next year
• Agrees to participate with informed consent

Exclusion Criteria:

• Currently pregnant
• Delivered in the previous six months
• Regularly consumed IFA or MM supplements in the past 2 months
• Severe anemia (Hb < 7 g/L)
• History of high risk pregnancy including abruptio placenta, placenta previa, gestational diabetes, pregnancy induced hypertension, coagulation disorders, thrombocytopenia or chronic vascular, renal or systemic disease and drug use
• Chronic hematological diseases, hereditary defects of red cells or hemoglobin

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Multiple micronutrient - 1; The study population has been divided into 6 arms receiving 3 different pre-pregnancy interventions. The study uses a double blind design therefore the supplements are differentiated by a letter and a color: P/Purple, Q/Black, S/Brown, M/Green, T/Orange, H/Red. Multiple micronutrient groups 1 and 2 receive: Vitamin A (μg) 800 Vitamin D (IU) 600 Vitamin E (mg) 10 Vitamin C (mg) 70 Thiamine (mg) 1.4 Riboflavin (mg) 1.4 Niacin (mg) 18 Vitamin B6 (mg) 1.9 Vitamin B12 (μg) 2.6 Folic acid (μg)* 2800 Iron (mg)* 60 Zinc (mg) 15 Copper (mg) 2 Selenium (μg) 65 Iodine (μg) 150	Dietary supplement: Multiple Micronutrient; There is no current recommendation for weekly MM supplements for WRA. Therefore, we propose a supplement that contains: The same amounts of iron and folic acid as the weekly, pre-natal IFA supplement; An amount of vitamin D based on the Food and Nutrition Board's Recommended Daily Allowances (RDA); UNICEF/WHO/UNU recommended amounts of remaining nutrients (UNIMMAP recommendations). The supplement is taken weekly during pre-pregnancy. Vitamin A (μg) 800 Vitamin D (IU) 600 Vitamin E (mg) 10 Vitamin C (mg) 70 Thiamine (mg) 1.4 Riboflavin (mg) 1.4 Niacin (mg) 18 Vitamin B6 (mg) 1.9 Vitamin B12 (μg) 2.6 Folic acid (μg)* 2800 Iron (mg)* 60 Zinc (mg) 15 Copper (mg) 2 Selenium (μg) 65 Iodine (μg) 150
Active Comparator: Iron and folic acid - 1; The study population has been divided into 6 arms receiving 3 different pre-pregnancy interventions. The study uses a double blind design therefore the supplements are differentiated by a letter and a color: P/Purple, Q/Black, S/Brown, M/Green, T/Orange, H/Red. Iron and folic acid groups 1 and 2 receive: iron (60mg) and folic acid (2800μg), based on current WHO recommendations for WRA.	Dietary supplement: Iron and Folic Acid; The doses of weekly and daily iron (60mg) and folic acid (2800μg) are based on current WHO recommendations for WRA.
Placebo Comparator: Folic Acid - 1; The study population has been divided into 6 arms receiving 3 different pre-pregnancy interventions. The study uses a double blind design therefore the supplements are differentiated by a letter and a color: P/Purple, Q/Black, S/Brown, M/Green, T/Orange, H/Red. Folic acid groups 1 and 2 receive: 2800 μg FA once a week during the pre-pregnancy period.	Dietary supplement: Folic Acid; It is unethical to have a placebo group as FA is universally recommended for WRA to prevent neural tube defects. Therefore, the control group will receive 2800 μg FA once a week during the pre-pregnancy period. This dosage is safe and meets the minimum recommended intake of 400 μg/d for Women of Reproductive Age (WRA). Recent studies have shown that a weekly dose of 2800 μg FA is as effective as a daily dose of 400 μg in improving folic acid and reducing homocysteine levels among WRA.
Experimental: Multiple Micronutrient - 2; The study population has been divided into 6 arms receiving 3 different pre-pregnancy interventions. The study uses a double blind design therefore the supplements are differentiated by a letter and a color: P/Purple, Q/Black, S/Brown, M/Green, T/Orange, H/Red. Multiple micronutrient groups 1 and 2 receive: Vitamin A (μg) 800 Vitamin D (IU) 600 Vitamin E (mg) 10 Vitamin C (mg) 70 Thiamine (mg) 1.4 Riboflavin (mg) 1.4 Niacin (mg) 18 Vitamin B6 (mg) 1.9 Vitamin B12 (μg) 2.6 Folic acid (μg)* 2800 Iron (mg)* 60 Zinc (mg) 15 Copper (mg) 2 Selenium (μg) 65 Iodine (μg) 150	Dietary supplement: Multiple Micronutrient; There is no current recommendation for weekly MM supplements for WRA. Therefore, we propose a supplement that contains: The same amounts of iron and folic acid as the weekly, pre-natal IFA supplement; An amount of vitamin D based on the Food and Nutrition Board's Recommended Daily Allowances (RDA); UNICEF/WHO/UNU recommended amounts of remaining nutrients (UNIMMAP recommendations). The supplement is taken weekly during pre-pregnancy. Vitamin A (μg) 800 Vitamin D (IU) 600 Vitamin E (mg) 10 Vitamin C (mg) 70 Thiamine (mg) 1.4 Riboflavin (mg) 1.4 Niacin (mg) 18 Vitamin B6 (mg) 1.9 Vitamin B12 (μg) 2.6 Folic acid (μg)* 2800 Iron (mg)* 60 Zinc (mg) 15 Copper (mg) 2 Selenium (μg) 65 Iodine (μg) 150
Active Comparator: Iron and Folic Acid - 2; The study population has been divided into 6 arms receiving 3 different pre-pregnancy interventions. The study uses a double blind design therefore the supplements are differentiated by a letter and a color: P/Purple, Q/Black, S/Brown, M/Green, T/Orange, H/Red. Iron and folic acid groups 1 and 2 receive: iron (60mg) and folic acid (2800μg), based on current WHO recommendations for WRA.	Dietary supplement: Iron and Folic Acid; The doses of weekly and daily iron (60mg) and folic acid (2800μg) are based on current WHO recommendations for WRA.
Placebo Comparator: Folic acid - 2; The study population has been divided into 6 arms receiving 3 different pre-pregnancy interventions. The study uses a double blind design therefore the supplements are differentiated by a letter and a color: P/Purple, Q/Black, S/Brown, M/Green, T/Orange, H/Red. Folic acid groups 1 and 2 receive: 2800 μg FA once a week during the pre-pregnancy period.	Dietary supplement: Folic Acid; It is unethical to have a placebo group as FA is universally recommended for WRA to prevent neural tube defects. Therefore, the control group will receive 2800 μg FA once a week during the pre-pregnancy period. This dosage is safe and meets the minimum recommended intake of 400 μg/d for Women of Reproductive Age (WRA). Recent studies have shown that a weekly dose of 2800 μg FA is as effective as a daily dose of 400 μg in improving folic acid and reducing homocysteine levels among WRA.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Birth Size	Infants' weight, length and head circumference will be measured as early as possible within 24 hours after birth using standard procedures. All measurements will be obtained in duplicate by the same data collector. Weight-for-age and length-for-age z scores will be calculated using the 2006 WHO reference data.	At birth
Gestational Age	Gestational age will be calculated based on the date of last menstrual period. This method has been shown to be reliable in previous work and we expect precise estimates since we will be visiting women weekly from baseline during the prepregnancy period and will exclude women who may be have delivered in the past 6 months.	At birth
Child growth	Length and weight will be measured at birth, 1, 3, 6, 9, 12, 15, 18, and 24 mo	From birth through 24 months
Child development	Child development will be measured using the Bayley Scales for Infant Development III at 12 and 24 mo and the Wechsler Intelligence Scale for Children at age 6-7 y	Up to 7 years post enrollment
Weight-for-age Z score (WAZ)	Weight-for-age Z score (WAZ) in offspring of women receiving only FA, offspring of women who receive weekly pre-pregnancy IFA, and offspring of women who receive weekly MM supplements	Up to 7 years post enrollment
Height-for-age Z score (HAZ)	Height-for-age Z score (HAZ) in offspring of women receiving only FA, offspring of women who receive weekly pre-pregnancy IFA, and offspring of women who receive weekly MM supplements	Up to 7 years post enrollment
Weight -for-Height Z (WHZ) or Body Mass Index Z score (BMIZ)	Weight -for-Height Z score (WHZ) or BMIZ in offspring of women receiving only FA, offspring of women who receive weekly pre-pregnancy IFA, and offspring of women who receive weekly MM supplements	Up to 7 years post enrollment
Body composition (Lean mass/fat free mass index)	Body composition (Lean mass/fat free mass index) in offspring of women receiving only FA, offspring of women who receive weekly pre-pregnancy IFA, and offspring of women who receive weekly MM supplements	Up to 7 years post enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mothers' iron status	Venous blood samples (5 ml) will be collected from women at: baseline, the first prenatal visit and at 1 and 3 months post partum. Anemia will be defined as Hb value <12 g/L for non-pregnant women,and <11g/L for pregnant women and infants, and iron deficiency as serum ferritin <12 μg/L (93).	At baseline and 1 and 3 months post partum
Infants' iron status	Infant iron status will be measured in cord blood samples (5 ml) obtained at delivery and at 3 months of age using a capillary blood sample (100 l) that will be obtained from a heel prick. The hemoglobin concentration will be measured from a drop of blood using the HEMOCUE B- Hb photometer. The blood samples will then be centrifuged and serum samples will be aliquotted into microcuvettes and handled in the same way as described for mothers. Serum ferritin and transferrin receptor concentrations will be assayed using the ELISA method.	1 and 3 months of age
Maternal depression	Center for Epidemiological Studies Depression Scale (CES-D) and Edinburgh Postnatal Depression Scale (EPDS)	At baseline, during pregnancy, 3 months postpartum

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: Micronutrient Initiative; The Mathile Institute for the Advancement of Human Nutrition
• Investigators: Principal Investigator: Usha Ramakrishnan, PhD, Emory University

Publications and helpful links

General Publications

• Nguyen PH, Gonzalez-Casanova I, Young MF, Truong TV, Hoang H, Nguyen H, Nguyen S, DiGirolamo AM, Martorell R, Ramakrishnan U. Preconception Micronutrient Supplementation with Iron and Folic Acid Compared with Folic Acid Alone Affects Linear Growth and Fine Motor Development at 2 Years of Age: A Randomized Controlled Trial in Vietnam. J Nutr. 2017 Aug;147(8):1593-1601. doi: 10.3945/jn.117.250597. Epub 2017 Jun 14.
• Nguyen PH, Lowe AE, Martorell R, Nguyen H, Pham H, Nguyen S, Harding KB, Neufeld LM, Reinhart GA, Ramakrishnan U. Rationale, design, methodology and sample characteristics for the Vietnam pre-conceptual micronutrient supplementation trial (PRECONCEPT): a randomized controlled study. BMC Public Health. 2012 Oct 24;12:898. doi: 10.1186/1471-2458-12-898.
• Nguyen PH, DiGirolamo AM, Gonzalez-Casanova I, Pham H, Hao W, Nguyen H, Truong TV, Nguyen S, Harding KB, Reinhart GA, Martorell R, Ramakrishnan U. Impact of preconceptional micronutrient supplementation on maternal mental health during pregnancy and postpartum: results from a randomized controlled trial in Vietnam. BMC Womens Health. 2017 Jun 17;17(1):44. doi: 10.1186/s12905-017-0401-3.
• Nguyen PH, Young M, Gonzalez-Casanova I, Pham HQ, Nguyen H, Truong TV, Nguyen SV, Harding KB, Reinhart GA, Martorell R, Ramakrishnan U. Impact of Preconception Micronutrient Supplementation on Anemia and Iron Status during Pregnancy and Postpartum: A Randomized Controlled Trial in Rural Vietnam. PLoS One. 2016 Dec 5;11(12):e0167416. doi: 10.1371/journal.pone.0167416. eCollection 2016.
• Ramakrishnan U, Nguyen PH, Gonzalez-Casanova I, Pham H, Hao W, Nguyen H, Truong TV, Nguyen S, Harding KB, Reinhart GA, Neufeld LM, Martorell R. Neither Preconceptional Weekly Multiple Micronutrient nor Iron-Folic Acid Supplements Affect Birth Size and Gestational Age Compared with a Folic Acid Supplement Alone in Rural Vietnamese Women: A Randomized Controlled Trial. J Nutr. 2016 Jul;146(7):1445S-52S. doi: 10.3945/jn.115.223420. Epub 2016 Jun 8.
• Nguyen PH, Young MF, Khuong LQ, Tran LM, Duong TH, Nguyen HC, Martorell R, Ramakrishnan U. Maternal Preconception Body Size and Early Childhood Growth during Prenatal and Postnatal Periods Are Positively Associated with Child-Attained Body Size at Age 6-7 Years: Results from a Follow-up of the PRECONCEPT Trial. J Nutr. 2021 May 11;151(5):1302-1310. doi: 10.1093/jn/nxab004.
• Gonzalez-Casanova I, Nguyen PH, Young MF, Harding KB, Reinhart G, Nguyen H, Nechitillo M, Truong TV, Pham H, Nguyen S, Neufeld LM, Martorell R, Ramakrishnan U. Predictors of adherence to micronutrient supplementation before and during pregnancy in Vietnam. BMC Public Health. 2017 May 16;17(1):452. doi: 10.1186/s12889-017-4379-4.
• Young MF, Hong Nguyen P, Addo OY, Pham H, Nguyen S, Martorell R, Ramakrishnan U. Timing of Gestational Weight Gain on Fetal Growth and Infant Size at Birth in Vietnam. PLoS One. 2017 Jan 23;12(1):e0170192. doi: 10.1371/journal.pone.0170192. eCollection 2017.
• Deputy NP, Nguyen PH, Pham H, Nguyen S, Neufeld L, Martorell R, Ramakrishnan U. Validity of gestational age estimates by last menstrual period and neonatal examination compared to ultrasound in Vietnam. BMC Pregnancy Childbirth. 2017 Jan 11;17(1):25. doi: 10.1186/s12884-016-1192-5.
• Young MF, Nguyen PH, Addo OY, Hao W, Nguyen H, Pham H, Martorell R, Ramakrishnan U. The relative influence of maternal nutritional status before and during pregnancy on birth outcomes in Vietnam. Eur J Obstet Gynecol Reprod Biol. 2015 Nov;194:223-7. doi: 10.1016/j.ejogrb.2015.09.018. Epub 2015 Sep 28.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2011
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: August 13, 2012
• First Submitted That Met QC Criteria: August 14, 2012
• First Posted (Estimate): August 15, 2012

Study Record Updates

• Last Update Posted (Actual): July 8, 2021
• Last Update Submitted That Met QC Criteria: July 7, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: health; supplementation; child; maternal; micronutrient; prepregnancy
• Additional Relevant MeSH Terms: Pathologic Processes; Fetal Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Growth Disorders; Premature Birth; Fetal Growth Retardation; Physiological Effects of Drugs; Vitamins; Hematinics; Micronutrients; Trace Elements; Folic Acid; Vitamin B Complex
• Other Study ID Numbers: IRB00051384; 10-1196-UEMORY-01 (Other Identifier: Other)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO