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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01355159
First Posted: May 17, 2011
Last Update Posted: August 30, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Ottawa Hospital Research Institute
May 11, 2011
May 17, 2011
August 30, 2017
April 2011
July 2016   (Final data collection date for primary outcome measure)
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.

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.

Or HELLP (Haemolysis, Elevated, Liver Enzymes, Low Platelets) syndrome Or Superimposed pre-eclampsia, defined as history of pre-existing hypertension (diagnosed pre-pregnancy or before 20+0 weeks' gestation) with new proteinuria.

Complete list of historical versions of study NCT01355159 on ClinicalTrials.gov Archive Site
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)
  • 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
  • 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.
  • 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.
  • Need for oxygen at 28 days [ Time Frame: Infants to the participants will be followed for 28 days after birth. ]
  • 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. ]
  • Maternal death [ Time Frame: Participants will be followed from randomization 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.
  • Severe preeclampsia [ Time Frame: Participants will be followed from 20+0 weeks of gestation until 42 days postpartum (after delivery) ]
    Severe preeclampsia is defined as preeclampsia with onset before 34+0 weeks gestation, with heavy proteinuria (3-5 g/d) or with one or more adverse conditions which consist of maternal symptoms, maternal signs of end-organ dysfunction, abnormal maternal laboratory testing , or fetal morbidity.
  • Placenta abruptio [ 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • Stillbirth [ Time Frame: Participants will be followed from 20+0 weeks of gestation until 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.
  • 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.
  • Retinopathy of prematurity [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 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.
  • Intraventricular hemorrhage (IVH) [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 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)
  • Early onset sepsis [ Time Frame: Participants will be followed first 48 hours of life ]
    Within first 48hr of life, confirmed by positive blood or cerebrospinal fluid cultures
  • Necrotising enterocolitis [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 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.
  • Ventilation [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 6 weeks ]
    Ventilatory support after initial resuscitation, with/without intubation.
  • Need for oxygen at 28 days [ Time Frame: Participants will be followed for 28 days after birth ]
  • Length of stay in 'high level' neonatal care unit [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 6 weeks ]
Not Provided
Not Provided
 
High Dose Folic Acid Supplementation Throughout Pregnancy for Preeclampsia Prevention
Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia-Folic Acid Clinical Trial (FACT)
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.

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.

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
  • Pregnancy Complications
  • Preeclampsia
  • 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
  • Drug: Placebo
    Placebo x 4 tablets will be taken daily by oral administration.
  • 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
    Intervention: Drug: Folic Acid 4 mg
  • Placebo Comparator: Placebo
    Women will be randomised in a 1:1 ratio to folic acid 4.0 mg or placebo
    Intervention: Drug: Placebo
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
2464
September 2016
July 2016   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: Female
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Argentina,   Australia,   Canada,   Jamaica,   United Kingdom
 
 
NCT01355159
2009-107
ISRCTN23781770 ( Other Identifier: controlled-trials.com )
Yes
Not Provided
Not Provided
Ottawa Hospital Research Institute
Ottawa Hospital Research Institute
Canadian Institutes of Health Research (CIHR)
Principal Investigator: Shi Wu Wen, PhD Ottawa Hospital Research Institute
Principal Investigator: Mark C Walker, MD Ottawa Hospital Research Institute
Ottawa Hospital Research Institute
August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP