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

• Sponsor: Ottawa Hospital Research Institute
• Collaborator: Canadian Institutes of Health Research (CIHR)
• Information provided by (Responsible Party): Ottawa Hospital Research Institute

Study Description

Brief Summary:

The hypothesis of the study is: high dose (4.0 mg per day) supplementation for pregnant women at high risk of developing preeclampsia starting in early pregnancy and continued throughout the entire pregnancy will lower the incidence of preeclampsia.

Condition or disease	Intervention/treatment	Phase
Pregnancy Complications; Preeclampsia	Drug: Folic Acid 4 mg; Drug: Placebo	Phase 3

Detailed 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.

Even though the results of these studies showed that folic acid may play role in the prevention of preeclampsia, an additional study is needed to determine conclusively that high dose supplementation of folic acid throughout pregnancy has a preventative effect in pregnant women who are at higher risk than the average pregnant women of developing preeclampsia.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	2464 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia-Folic Acid Clinical Trial (FACT)
Study Start Date :	April 2011
Actual Primary Completion Date :	July 2016
Actual Study Completion Date :	September 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Folic Acid 4 mg; 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	Drug: Folic Acid 4 mg; Folic Acid 1.0 mg or placebo 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; Other Name: folate
Placebo Comparator: Placebo; Women will be randomised in a 1:1 ratio to folic acid 4.0 mg or placebo	Drug: Placebo; Placebo x 4 tablets will be taken daily by oral administration.

Outcome Measures

Primary Outcome Measures :

1. Preeclampsia [ Time Frame: Participants will be followed from 20+0 weeks of gestational age until 42 days postpartum (after delivery) ]

   PE is defined as diastolic blood pressure ≥90 mmHg on two occasions ≥4 hours apart and proteinuria developed in women greater than 20+0 weeks of gestation. Proteinuria is defined as: urinary protein ≥300mg in 24 hour urine collection OR in the absence of 24 hour collection, ≥2+ dipstick proteinuria, OR random protein-creatinine ratio ≥30mg protein/mmol.

   OR HELLP (Haemolysis, Elevated, Liver Enzymes, Low Platelets) syndrome defined as: Haemolysis (characteristic peripheral blood smear), Serum LDH ≥ 600U/L, Serum AST ≥ 70U/L, and Platelet count <100 x109/L

   OR Superimposed pre-eclampsia, defined as history of pre-existing hypertension (diagnosed pre-pregnancy or before 20+0 weeks' gestation) with new proteinuria.

Secondary Outcome Measures :

1. Maternal death [ Time Frame: Time Frame: Participants will be followed from 20+0 weeks of gestation until 42 days postpartum (after delivery) ]
   According to the World Health Organization, "A maternal death is defined as the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes.
2. Severe preeclampsia [ Time Frame: Participants will be followed from 20+0 weeks of gestation until delivery. ]
   Severe PE: Defined as PE with convulsion or HELLP or delivery <34 weeks.
3. Placenta abruption [ Time Frame: Participants will be followed from 20+0 weeks of gestation until delivery ]
   Placental abruption (abruptio placentae) is the premature detachment of a normally positioned placenta from the wall of the uterus.
4. Preterm birth [ Time Frame: Participants will be followed from 20+0 weeks to 36+6 weeks of gestation ]
   Birth that occur earlier than 37+0 weeks of gestational age.
5. Premature rupture of membranes [ Time Frame: Participants will be followed from randomization until the onset of labor ]
   Rupture of the membranes (rupture of the amniotic sac) before the onset of labor.
6. Antenatal inpatient length of stay [ Time Frame: Participants will be followed from date of randomization until admission for delivery ]
   Length of inpatient stay before admission for delivery in days
7. Intrauterine growth restriction [ Time Frame: Participants will be followed from 20+0 weeks of gestation until delivery ]
   Intrauterine growth restriction is defined as a birth weight less than the 10th percentile of the population, adjusted for sex and gestational age, based on the current population-based Canadian reference standard.
8. Spontaneous abortion [ Time Frame: Participants will be followed from randomization until 20+0 weeks of gestation ]
   Spontaneous abortion or miscarriage defined as death of a fetus <500g or <20 weeks of gestation
9. Perinatal mortality [ Time Frame: Participants will be followed from 20+0 weeks of gestation until 28 days of life. ]
   The perinatal mortality is defined as the number of deaths (fetal deaths and neonatal deaths) of babies ≥ 500 grams birth weight or, if birth weight is unavailable, a gestational age ≥ 20+0 weeks, up to 28 completed days after birth.
10. Stillbirth [ Time Frame: Participants will be followed from 20+0 weeks of gestation up to delivery. ]
    Fetal death defined as death of fetus of at least 500 grams birth weight or, if birth weight is unavailable, a gestational age of at least 20+0 weeks of gestation.
11. Neonatal death [ Time Frame: Participants will be followed from birth until 28 days of life ]
    Neonatal death defined as death of a baby that occurred during first 28 days of life.
12. Retinopathy of prematurity [ Time Frame: Infants born to the participant will be followed for the duration of hospital stay, or up to 6 weeks ]
    Retinopathy of prematurity a retinopathy typically occurring in premature infants treated with high concentrations of oxygen, characterized by vascular dilatation, proliferation, tortuosity, edema, retinal detachment, and fibrous tissue behind the lens confirmed by retinal examination according to an International Committee for the Classification of Retinopathy of Prematurity.
13. Intraventricular hemorrhage (IVH) [ Time Frame: Time Frame: Infants born to the participants will be followed for the duration of hospital stay, or up to 6 weeks ]
    • IVH Grade 1(Blood in germinal matrix)
    • IVH Grade 2 (Blood in germinal matrix and extending into the ventricles)
    • IVH Grade 3 (Ventricular enlargement)
    • IVH Grade 4 (Intraparenchymal lesion)
14. Early onset sepsis [ Time Frame: Infants born to the participants will be followed first 48 hours of life. ]
    Within first 48hr of life, confirmed by positive blood or cerebrospinal fluid cultures
15. Necrotising enterocolitis [ Time Frame: Infants borm to the participants will be followed for the duration of hospital stay, or up to 6 weeks. ]
    Necrotizing enterocolitis (NEC) according to modified Bell's criteria stage 2 or higher (grossly bloody stool, plus absent bowel sounds with or without abdominal tenderness and radiographic findings such as intestinal dilation, ileus, pneumatosis intestinalis), excluding isolated spontaneous intestinal perforations.
16. Ventilation [ Time Frame: Infants born to the participants will be followed for the duration of hospital stay, or up to 6 weeks. ]
    Ventilatory support after initial resuscitation, with/without intubation.
17. Need for oxygen at 28 days [ Time Frame: Infants to the participants will be followed for 28 days after birth. ]
18. Length of stay in 'high level' neonatal care unit [ Time Frame: Infants to the participants will be followed for the duration of hospital stay, or up to 6 weeks. ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Sponsors and Collaborators

Ottawa Hospital Research Institute

Canadian Institutes of Health Research (CIHR)

Investigators

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Principal Investigator:	Shi Wu Wen, PhD	Ottawa Hospital Research Institute
Principal Investigator:	Mark C Walker, MD	Ottawa Hospital Research Institute

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wen SW, White RR, Rybak N, Gaudet LM, Robson S, Hague W, Simms-Stewart D, Carroli G, Smith G, Fraser WD, Wells G, Davidge ST, Kingdom J, Coyle D, Fergusson D, Corsi DJ, Champagne J, Sabri E, Ramsay T, Mol BWJ, Oudijk MA, Walker MC; FACT Collaborating Group. Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial. BMJ. 2018 Sep 12;362:k3478. doi: 10.1136/bmj.k3478.

Wen SW, Champagne J, Rennicks White R, Coyle D, Fraser W, Smith G, Fergusson D, Walker MC. Effect of folic acid supplementation in pregnancy on preeclampsia: the folic acid clinical trial study. J Pregnancy. 2013;2013:294312. doi: 10.1155/2013/294312. Epub 2013 Nov 18.

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Responsible Party:	Ottawa Hospital Research Institute
ClinicalTrials.gov Identifier:	NCT01355159 History of Changes
Other Study ID Numbers:	2009-107; ISRCTN23781770 ( Other Identifier: controlled-trials.com )
First Posted:	May 17, 2011
Last Update Posted:	August 30, 2017
Last Verified:	August 2017

Keywords provided by Ottawa Hospital Research Institute:

Pregnancy; Folic Acid supplementation; Preeclampsia

Additional relevant MeSH terms:

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Pre-Eclampsia; Pregnancy Complications; Hypertension, Pregnancy-Induced; Folic Acid; Vitamin B Complex; Hematinics	Vitamins; Micronutrients; Nutrients; Growth Substances; Physiological Effects of Drugs