Multi-micronutrient Supplementation During Peri-conception and Congenital Heart Disease

Primary Prevention of Multi-micronutrient Supplementation During Peri-conception Against Congenital Heart Disease: A Community-based Randomised Controlled Trial in China

The purpose of this study is to determine whether daily oral supplements of vitamin B complex along with folic acid or supplements of iron plus folic acid given to women during peri-conception can reduce the risk of congenital heart disease when compared with folic acid alone.

Study Overview

• Status: Completed
• Conditions: Congenital Heart Disease
• Intervention / Treatment: Dietary supplement: Vitamin B Complex and Folic Acid; Dietary supplement: Iron and Folic Acid; Dietary supplement: Folic Acid

Detailed Description

Congenital heart disease (CHD) is among the most prevalent congenital abnormalities with an incidence of about 8-12/1,000 live births, and is also the leading cause of infant morbidity and death from birth defects. A series of studies pointed out that the poor nutritional status of the mother during peri-conception might be the important cause of CHD. In maternal folic acid/ vitamin B deficiency homocysteine accumulates in the serum, and elevated circulating homocysteine concentrations have been associated with the risk of CHD. However, it is still questionable whether multiple vitamin B supplements during peri-conception can reduce CHD risk more effectively compared with the supplement of folic acid alone. Moreover, one randomized controlled trial performed in Shaanxi China confirmed that the supplement of iron and folic acid during pregnancy can significantly reduce early neonatal deaths. It is noteworthy that one-fourth of newborn deaths are attributable to birth defects. Thus, it is worthwhile to investigate whether iron supplement can reduce the risk of CHD.

This community-based randomized controlled trial will assess and compare the impact of daily oral supplements of vitamin B complex along with folic acid or supplements of iron plus folic acid vs. folic acid alone given to women during peri-conception on CHD. It will also assess the effects of the three different supplementations on other pregnancy outcomes and maternal health. The study will be conducted in three rural poor counties including Xunyi, Changwu, and Bin, which are located in Shaanxi Province of Northwest China. All participants will sign informed consent before the study. The investigators hypothesize that the newborn infants of women receiving supplements of vitamin B complex along with folic acid or supplements of iron plus folic acid will experience a reduction in the prevalence of infants with the pulse oxygen saturation less than 95% and other adverse pregnancy outcomes compared with those receiving folic acid alone. The results of this trial will provide evidence needed to formulate policy on maternal micronutrient supplementation during peri-conception and the rationale for the necessary investment of public funds to implement appropriate programs against birth defects.

• Study Type: Interventional
• Enrollment (Actual): 7315
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Shaanxi
    • Xi'an, Shaanxi, China, 710061
      • Xi'an Jiaotong University College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 49 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Women of reproductive age (15-49 years) who reside in the study areas;
2. Women who are prepared for pregnancy in 1-3 months or have already been pregnant for less than 20 months;
3. Women who have provided written informed consent.

Exclusion Criteria:

1. Women who have already taken supplements containing vitamin B complex, iron, or folic acid for more than two weeks at enrollment;
2. Women who have given birth to children with congenital heart disease or other birth defects before;
3. Women with diabetes;
4. women with severe heart, liver or kidney disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vitamin B Complex and Folic Acid; Daily supplements containing vitamin B1 (2 mg), vitamin B2 (2 mg), vitamin B6 (2 mg), vitamin B12 (2 μg), calcium pantothenate (2 mg), nicotinamide (15 mg) and folic acid (0.4 mg).	Dietary supplement: Vitamin B Complex and Folic Acid; Daily oral dose containing 2 mg vitamin B1, 2 mg vitamin B2, 2 mg vitamin B6, 2 μg vitamin B12, 2 mg calcium pantothenate, 15 mg nicotinamide and 0.4 mg folic acid.
Experimental: Iron and Folic Acid; Daily supplements of iron (60 mg) and folic acid (0.4 mg).	Dietary supplement: Iron and Folic Acid; Daily oral dose of 60 mg iron and 0.4 mg folic acid.
Active Comparator: Folic Acid; Daily supplement of 0.4 mg folic acid.	Dietary supplement: Folic Acid; Daily oral dose of 0.4 mg folic acid.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neonatal pulse oximetry oxygen saturation measured by pulse oximetry	Neonatal pulse oximetry oxygen saturation (SpO2) is tested by pulse oximetry in babies aged between 6 h and 72 h after birth. Pulse oximetry testing is repeated 4 h later if the first measurement is between 90% and 95%. The result of SpO2 will be reported as a dichotomous variable, in which the result is deemed positive if an SpO2 less than 95% is obtained both on the right hand and on either foot on two measures, separated by 4 h; a difference between the two extremities was more than 3% on two measures, separated by 4 h; or any measure is less than 90%. The result of SpO2 will also be reported as a continuous variable.	6-72 hours after delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of congenital heart disease and the subtypes	Congenital heart disease will be diagnosed by trained clinicians with the help of echocardiography, pulse oximetry, clinical examination, cardiac surgery, or autopsy. The incidence of congenital heart disease and the subtypes will be reported in each group.	Half a year after delivery
Incidence of birth defects and the subtypes	Birth defects will be diagnosed by trained clinicians. The incidence of birth defects and the subtypes will be reported in each group.	Half a year after delivery
Birth weight measured by baby scale	Birth weight will be measured within 1 hour of delivery using a baby scale with the precision to the nearest 50 gram.	Within 1 hours of delivery
Incidence of low birth weight	Birth weight will be measured within 1 hour of delivery using a baby scale. The incidence of low birth weight will be reported in each group based on the criteria of birth weight less than 2500 gram.	Within 1 hour of delivery
Gestational age at birth	Gestational age at birth will be measured as completed days based on the last menstrual period.	At delivery
Incidence of preterm birth	Gestational age at birth will be measured as completed days based on the last menstrual period. The incidence of preterm birth (infant born less than 37 weeks gestational age) will be reported in each group.	At delivery
Incidence of perinatal mortality	The incidence of perinatal mortality (Infants death between 28 weeks of gestational duration and 7 days after delivery) will be reported in each group.	Between 28 weeks of gestational duration and 7 days after delivery
Incidence of stillbirth	The incidence of stillbirth (infants death at delivery) will be reported in each group.	At delivery
Incidence of neonatal mortality	The incidence of neonatal mortality (infants death during the first 28 days after birth) will be reported in each group.	First 28 days after birth
Incidence of early neonatal mortality	The incidence of early neonatal mortality (infants death during the first 7 days after birth) will be reported in each group.	First 7 days after birth
Incidence of pregnancy complications: hypertension, preeclampsia, antepartum haemorrhage, and infections	Pregnancy complications (hypertension, preeclampsia, antepartum haemorrhage, and infections) will be diagnosed by trained clinicians during antenatal care checks. All information will be recorded in the pregnant women's medical records of antenatal care checks and delivery. The incidence of hypertension, preeclampsia, antepartum haemorrhage, and infections among participants will be reported in each group.	After enrollment until at delivery

Collaborators and Investigators

• Sponsor: Health Science Center of Xi'an Jiaotong University
• Investigators: Principal Investigator: Hong Yan, Professor, Health Science Center of Xi'an Jiaotong University

Publications and helpful links

General Publications

• Mi B, Wen X, Li S, Liu D, Lei F, Liu R, Shen Y, Chen Y, Zeng L, Liu X, Dang S, Yan H. Vegetable dietary pattern associated with low risk of preeclampsia possibly through reducing proteinuria. Pregnancy Hypertens. 2019 Apr;16:131-138. doi: 10.1016/j.preghy.2019.04.001. Epub 2019 Apr 8.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2015
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: August 27, 2015
• First Submitted That Met QC Criteria: August 27, 2015
• First Posted (Estimate): September 1, 2015

Study Record Updates

• Last Update Posted (Actual): July 8, 2020
• Last Update Submitted That Met QC Criteria: July 6, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Diseases; Heart Defects, Congenital; Physiological Effects of Drugs; Micronutrients; Vitamins; Hematinics; Folic Acid; Vitamin B Complex
• Other Study ID Numbers: NSFC81230016

Plan for Individual participant data (IPD)

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