High Dose Folic Acid Supplementation Throughout Pregnancy for Preeclampsia Prevention (FACT)

Ottawa Hospital Research Institute

Status and phase: Completed; Phase 3

Conditions: Pregnancy Complications; Preeclampsia

Treatments: Drug: Placebo; Drug: Folic Acid 4 mg

Study type: Interventional

Funder types: Other

Identifiers

NCT01355159

2009-107

ISRCTN23781770 (Other Identifier)

Details and patient eligibility

About

To determine the efficacy of high dose folic acid supplementation for prevention of preeclampsia in women with at least one risk factor: pre-existing hypertension, pre-pregnancy diabetes (type 1 or 2), twin pregnancy, preeclampsia in a previous pregnancy, or body mass index ≥35. It was hypothesized that high dose (4.0 mg per day) supplementation starting in early pregnancy and continued throughout the entire pregnancy will lower the incidence of preeclampsia in pregnant women at high risk of developing preeclampsia.

Full description

Preeclampsia is a complication of pregnancy which affects at least 5% of all pregnancies worldwide and has serious health consequences to these women and their babies. Preeclampsia is hypertension (high blood pressure) in pregnancy with proteinuria. Proteinuria is when protein is found in the urine, and it is a sign that the kidneys are not functioning properly. The only effective treatment for preeclampsia is delivery of the baby. Because delivery may be required before the anticipated date of delivery; preeclampsia is also one of the leading causes of preterm delivery and accounts for 25% of very low birth weight infants. Recent research has also shown that women who have had preeclampsia during pregnancy are more likely to be at risk for future cardiovascular events later in life.

Recently some studies have shown that supplementation with multivitamins containing folic acid is associated with a reduced risk of developing preeclampsia. These findings also suggested that for the prevention of preeclampsia, a high dose of folic acid (much higher than the amount of folate received from food intake or what is usually taken during pregnancy) may be needed.

A randomized controlled trial was conducted in 70 obstetrical centres in 5 countries (Argentina, Australia, Canada, Jamaica, and the UK) to evaluate the effect of high dose folic acid started in early pregnancy on the risk of developing preeclampsia in high-risk women. A sample size of 2464 allowed for 80% power and a 10% loss to follow-up/study withdrawal. Participants received either placebo or four 1.0 mg oral tablets of folic acid.

Enrollment: 2,464 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Capability of subject to comprehend and comply with study requirements

2. ≥ 18 years of age at time of consent

3. Subject is taking ≤1.1 mg of folic acid daily at the time of randomization

4. Live fetus (documented positive fetal heart prior to randomization)

5. Gestational age between 8+0 and 16+6 weeks of pregnancy (Gestational age (GA) of subjects will be calculated based on the first day of the last menstrual period (LMP) or ultrasound performed before 12+6. If early ultrasound and LMP dates differ by ≤ 7 days, base GA estimate on LMP date; if > 7 days, use early < 12+6 ultrasound)

6. Subject plans to give birth in a participating hospital site

7. Pregnant subjects must fulfill at least one of the following identified risk factors for pre-eclampsia (PE):

   • Pre-existing hypertension (documented evidence of diastolic blood pressure ≥ 90 mmHg on two separate occasions or at least 4 hours apart prior to randomization, or use of antihypertensive medication during this pregnancy specifically for the treatment of hypertension prior to randomization)
   • Pre-pregnancy diabetes (documented evidence of Type I or type II DM)
   • Twin pregnancy
   • Documented evidence of history of PE in a previous pregnancy
   • BMI > 35 kg/m2 within 3 months prior to this pregnancy and up to randomization of this pregnancy (documented evidence of height and weight to calculate BMI is required)

Exclusion criteria

1. Known history or presence of any clinically significant disease or condition which would be a contraindication to folic acid supplementation of up to 5 mg daily for the duration of pregnancy

2. Known major fetal anomaly or fetal demise

3. History of medical complications, including:

   • renal disease with altered renal function,
   • epilepsy,
   • cancer, or
   • use of folic acid antagonists such as valproic acid

4. Individual who is currently enrolled or has participated in another clinical trial or who received an investigational drug within 3 months of the date of randomization (unless approved by the Trial Coordinating Centre)

5. Known presence of:

   • Alcohol abuse (≥ 2 drinks per day) or alcohol dependence
   • Illicit drug/substance use and/or dependence

6. Known hypersensitivity to folic acid

7. Multiple Pregnancy (triplets or more)

8. Participation in this study in a previous pregnancy

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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2,464 participants in 2 patient groups, including a placebo group

Folic Acid 4 mg

Experimental group

Description:

Folic Acid 1.0 mg x 4 tablets will be taken daily by oral administration. The majority of women in the study will routinely take 1.0 mg folic acid in a prenatal vitamin supplement, as recommended by their primary obstetrical provider; the study requirements do not require that participants change their practice. Therefore the actual total daily dose may be up to 5.1 mg of folic acid

Treatment:

Drug: Folic Acid 4 mg

Placebo

Placebo Comparator group

Description:

Women will be randomised in a 1:1 ratio to folic acid 4.0 mg or placebo

Treatment:

Drug: Placebo