High Dose Folic Acid Supplementation Throughout Pregnancy for Preeclampsia Prevention

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia-Folic Acid Clinical Trial (FACT)

Conditions
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Pregnancy Complications, Preeclampsia

Intervention / Treatment
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* Drug: Folic Acid 4 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capability of subject to comprehend and comply with study requirements ≥ 18 years of age at time of consent Subject is taking ≤1.1 mg of folic acid daily at the time of randomization Live fetus (documented positive fetal heart prior to randomization) 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) Subject plans to give birth in a participating hospital site 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: 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 Known major fetal anomaly or fetal demise History of medical complications, including: renal disease with altered renal function, epilepsy, cancer, or use of folic acid antagonists such as valproic acid 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) Known presence of: Alcohol abuse (≥ 2 drinks per day) or alcohol dependence Illicit drug/substance use and/or dependence Known hypersensitivity to folic acid Multiple Pregnancy (triplets or more) Participation in this study in a previous pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Folic Acid 4 mg<br>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<br>* 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<br>* Other names: Folate;|
| Placebo Comparator: Placebo<br>Women will be randomised in a 1:1 ratio to folic acid 4.0 mg or placebo | Drug: Placebo<br>* Placebo x 4 tablets will be taken daily by oral administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preeclampsia | 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. | Participants will be followed from 20+0 weeks of gestational age until 42 days postpartum (after delivery) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal Death | 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. | Time Frame: Participants will be followed from 20+0 weeks of gestation until 42 days postpartum (after delivery) | 
| Spontaneous Abortion | Spontaneous abortion or miscarriage defined as death of a fetus <500g or <20 weeks of gestation | Participants will be followed from randomization until 20+0 weeks of gestation | 
| Placenta Abruption | Placental abruption (abruptio placentae) is the premature detachment of a normally positioned placenta from the wall of the uterus. | Participants will be followed from 20+0 weeks of gestation until delivery | 
| Premature Rupture of Membranes | Rupture of the membranes (rupture of the amniotic sac) before the onset of labor. | Participants will be followed from randomization (8-16 weeks' completed gestation) until the onset of labor | 
| Preterm Birth | Birth that occur earlier than 37+0 weeks of gestational age. | Participants will be followed from 20+0 weeks to 36+6 weeks of gestation | 
| HELLP (Hemolysis, Elevated Liver Enzyme Levels & Low Platelet Count) | Haemolysis (characteristic peripheral blood smear), Serum LDH >=600U/L, Serum AST >=70U/L, Platelet count <100 x109/L | Participants will be followed from 20+0 weeks of gestation until delivery | 
| Severe Preeclampsia | Severe PE: Defined as PE with convulsion or HELLP or delivery <34 weeks. | Participants will be followed from 20+0 weeks of gestation until delivery. | 
| Antenatal Inpatient Length of Stay | Length of inpatient stay before admission for delivery in days | Participants will be followed from date of randomization (8-16 weeks' completed gestation) until admission for delivery | 
| Stillbirth | 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. | Participants will be followed from 20+0 weeks of gestation up to delivery. | 
| Intrauterine Growth Restriction (<3rd Percentile) | Intrauterine growth restriction is defined as a birth weight less than the 3rd percentile of the population, adjusted for sex and gestational age, based on the current population-based Canadian reference standard. | Participants will be followed from 20+0 weeks of gestation until delivery | 
| Intrauterine Growth Restriction (<10th Percentile) | 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. | Participants will be followed from 20+0 weeks of gestation until delivery | 
| Neonatal Death | Neonatal death defined as death of a baby that occurred during first 28 days of life. | Participants will be followed from birth until 28 days of life | 
| Perinatal Mortality | 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. | Participants will be followed from 20+0 weeks of gestation until 28 days of life. | 
| Retinopathy of Prematurity | 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. | Infants born to the participant will be followed for the duration of hospital stay, or up to 6 weeks | 
| Early Onset Sepsis | Within first 48hr of life, confirmed by positive blood or cerebrospinal fluid cultures | Infants born to the participants will be followed first 48 hours of life. | 
| Necrotising Enterocolitis | 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. | Infants borm to the participants will be followed for the duration of hospital stay, or up to 6 weeks. | 
| Intraventricular Hemorrhage (IVH) | 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) | Time Frame: Infants born to the participants will be followed for the duration of hospital stay, or up to 6 weeks | 
| Ventilation | Ventilatory support after initial resuscitation, with/without intubation. | Infants born to the participants will be followed for the duration of hospital stay, or up to 6 weeks. | 
| Need for Oxygen at 28 Days |  | Infants to the participants will be followed for 28 days after birth. | 
| Composite Severe Adverse Fetal/Neonatal Outcome | Composite outcome included any of retinopathy of prematurity, periventricular leukomacia, early onset sepsis, necrotizing enterocolitis, intraventricular haemorrhage, ventilation. Need for O2at 28 days, NICU admission | Outcomes included in the composite outcome were measured for each of their respective time frames, up to 6-weeks after birth | 
| Length of Stay in 'High Level' Neonatal Care Unit |  | Infants to the participants will be followed for the duration of hospital stay, or up to 6 weeks. | 
| Neonatal Death | Neonatal death defined as death of the infant occurred before 28 days of life | Infants to the participants will be followed for 28 days after birth. | 
| Periventricular Leukomalacia | One of the two outcomes used to measure neonatal morbidity. | Infants to the participants were followed for 28 days after birth. | 
| Neonatal Intensive Care Unit (NICU) Admission | This outcome measured whether or not the infant was admitted into the NICU. | Infants to the participants will be followed for the duration of hospital stay, or up to 6 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pregnancy, Folic Acid supplementation, Preeclampsia