Clinical trial NCT01355159: High Dose Folic Acid Supplementation Throughout Pregnancy for Preeclampsia Prevention
Official title: Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia-Folic Acid Clinical Trial (FACT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pregnancy Complications
Preeclampsia
Keywords: Pregnancy
Folic Acid supplementation
Preeclampsia
Lead sponsor: Ottawa Hospital Research Institute
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2011-05-17
Enrollment: 2464
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility 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

Primary outcomes:
measure: Preeclampsia
timeFrame: Participants will be followed from 20+0 weeks of gestational age until 42 days postpartum (after delivery)
Secondary outcomes:
measure: Maternal Death
timeFrame: Time Frame: Participants will be followed from 20+0 weeks of gestation until 42 days postpartum (after delivery)
measure: Spontaneous Abortion
timeFrame: Participants will be followed from randomization until 20+0 weeks of gestation
measure: Placenta Abruption
timeFrame: Participants will be followed from 20+0 weeks of gestation until delivery
measure: Premature Rupture of Membranes
timeFrame: Participants will be followed from randomization (8-16 weeks' completed gestation) until the onset of labor
measure: Preterm Birth
timeFrame: Participants will be followed from 20+0 weeks to 36+6 weeks of gestation
measure: HELLP (Hemolysis, Elevated Liver Enzyme Levels & Low Platelet Count)
timeFrame: Participants will be followed from 20+0 weeks of gestation until delivery
measure: Severe Preeclampsia
timeFrame: Participants will be followed from 20+0 weeks of gestation until delivery.
measure: Antenatal Inpatient Length of Stay
timeFrame: Participants will be followed from date of randomization (8-16 weeks' completed gestation) until admission for delivery
measure: Stillbirth
timeFrame: Participants will be followed from 20+0 weeks of gestation up to delivery.
measure: Intrauterine Growth Restriction (<3rd Percentile)
timeFrame: Participants will be followed from 20+0 weeks of gestation until delivery
measure: Intrauterine Growth Restriction (<10th Percentile)
timeFrame: Participants will be followed from 20+0 weeks of gestation until delivery
measure: Neonatal Death
timeFrame: Participants will be followed from birth until 28 days of life
measure: Perinatal Mortality
timeFrame: Participants will be followed from 20+0 weeks of gestation until 28 days of life.
measure: Retinopathy of Prematurity
timeFrame: Infants born to the participant will be followed for the duration of hospital stay, or up to 6 weeks
measure: Early Onset Sepsis
timeFrame: Infants born to the participants will be followed first 48 hours of life.
measure: Necrotising Enterocolitis
timeFrame: Infants borm to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
measure: Intraventricular Hemorrhage (IVH)
timeFrame: Time Frame: Infants born to the participants will be followed for the duration of hospital stay, or up to 6 weeks
measure: Ventilation
timeFrame: Infants born to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
measure: Need for Oxygen at 28 Days
timeFrame: Infants to the participants will be followed for 28 days after birth.
measure: Composite Severe Adverse Fetal/Neonatal Outcome
timeFrame: Outcomes included in the composite outcome were measured for each of their respective time frames, up to 6-weeks after birth
measure: Length of Stay in 'High Level' Neonatal Care Unit
timeFrame: Infants to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
measure: Neonatal Death
timeFrame: Infants to the participants will be followed for 28 days after birth.
measure: Periventricular Leukomalacia
timeFrame: Infants to the participants were followed for 28 days after birth.
measure: Neonatal Intensive Care Unit (NICU) Admission
timeFrame: Infants to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
Other outcomes:
Locations:
city: Rosario
country: Argentina
facility: Hospital Escuela Eva Perón
state: Santa Fe
city: Rosario
country: Argentina
facility: Hospital Provincial
state: Santa Fe
city: Rosario
country: Argentina
facility: Hospital Roque Saenz Penia
state: Santa Fe
city: Rosario
country: Argentina
facility: Maternidad Martin
state: Santa Fe
city: Rosario
country: Argentina
facility: Sanatorio de la Mujer
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: Cemic
city: Santa Fe
country: Argentina
facility: Hospital Cullen
city: Santa Fe
country: Argentina
facility: Hosptial Iturraspe
city: Penrith
country: Australia
facility: Nepean
state: New South Wales
city: Douglas
country: Australia
facility: Townsville
state: Queensland
city: Ipswich
country: Australia
facility: Ipswich
state: Queensland
city: North Adelaide
country: Australia
facility: Adelaide
state: South Australia
city: Parkville
country: Australia
facility: Royal Women's Hospital
state: Victoria
city: St Albans
country: Australia
facility: Sunshine
state: Victoria
city: Calgary
country: Canada
facility: Calgary Foothills Medical Center
state: Alberta
city: Edmonton
country: Canada
facility: Edmonton Lois Hole Hospital for Women
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver BC Women's Hospital and Health Center
state: British Columbia
city: Vancouver
country: Canada
facility: St-Paul's Hospital
state: British Columbia
city: Fredericton
country: Canada
facility: Fredericton Dr. Everett Chalmers Regional Hospital
state: New Brunswick
city: Moncton
country: Canada
facility: Moncton Hospital
state: New Brunswick
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: Winnipeg
country: Canada
facility: Winnipeg St. Boniface General Hospital
state: New Brunswick
city: Winnipeg
country: Canada
facility: Winnipeg University of Manitoba
state: New Brunswick
city: St John's
country: Canada
facility: St-John's Women's Health Centre
state: Newfoundland and Labrador
city: Hamilton
country: Canada
facility: Hamilton McMaster University
state: Ontario
city: Kingston
country: Canada
facility: Kingston
state: Ontario
city: London
country: Canada
facility: London
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Civic Hospital
state: Ontario
city: Sault Ste. Marie
country: Canada
facility: Sault Ste- Marie Sault Area Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences
state: Ontario
city: Montreal
country: Canada
facility: Quebec City (CHUL) Centre Hospitalier Universitaire
state: Quebec
city: Montreal
country: Canada
facility: Saint-Luc CHUM - Montreal
state: Quebec
city: Montreal
country: Canada
facility: McGill University Royal Victoria Hospital
state: Quebec
city: Montreal
country: Canada
facility: Sainte-Justine
state: Quebec
city: Montreal
country: Canada
facility: St-Mary's Hospital
state: Quebec
city: Regina
country: Canada
facility: Regina Qu'Appelle Health Region
state: Saskatchewan
city: Kingston 7
country: Jamaica
facility: University of West Indies
city: Kingston
country: Jamaica
facility: Jubilee
city: Kingston
country: Jamaica
facility: Spanishtown
city: Huntingdon
country: United Kingdom
facility: Hinchingbrooke
state: Cambridgeshire
city: Warrington
country: United Kingdom
facility: Warrington and Halton Hospitals NHS Foundation Trust
state: Cheshire
city: Darlington
country: United Kingdom
facility: Darlington Memorial Hospital
state: County Durham
city: Durham
country: United Kingdom
facility: University Hospital of North Durham
state: County Durham
city: Carlisle
country: United Kingdom
facility: Cumberland Infirmary
state: Cumbria
city: Whitehaven
country: United Kingdom
facility: West Cumberland Hospital
state: Cumbria
city: Bury
country: United Kingdom
facility: Fairfield
state: Lancashire
city: Rochdale
country: United Kingdom
facility: Rochdale
state: Lancashire
city: Lincoln
country: United Kingdom
facility: Lincolnshire
state: Lincolnshire
city: Southport
country: United Kingdom
facility: Ormskirk
state: Merseyside
city: Harrow
country: United Kingdom
facility: Northwick Park Hospital
state: Middlesex
city: Isleworth
country: United Kingdom
facility: West Middlesex University Hospital
state: Middlesex
city: Whitley Bay
country: United Kingdom
facility: 49 Marine Avenue & CCGs
state: Newcastle Upon Tyne
city: Ashington
country: United Kingdom
facility: Wansbeck General Hospital
state: Northumberland
city: London
country: United Kingdom
facility: St George's Hospital
state: Tooting
city: Gateshead
country: United Kingdom
facility: Gateshead Queen Elizabeth Hospital
state: Tyne And Wear
city: South Shields
country: United Kingdom
facility: South Tyneside District Hospital
state: Tyne And Wear
city: Wolverhampton
country: United Kingdom
facility: The Royal Wolverhampton NHS Trust, New Cross Hospital
state: West Midlands
city: Blackburn
country: United Kingdom
facility: Blackburn
city: Burnley
country: United Kingdom
facility: Burnley
city: Crumpsall
country: United Kingdom
facility: North Manchester
city: London
country: United Kingdom
facility: Guy's & St Thomas' Hospital
city: Middlesbrough
country: United Kingdom
facility: South Tees Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: Newcastle upon Tyne Hospitals
city: North Shields
country: United Kingdom
facility: North Tyneside General Hospital
city: Norwich
country: United Kingdom
facility: Norfolk & Norwich
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham Queens Medical Centre
city: Oldham
country: United Kingdom
facility: Oldham
city: Stockton
country: United Kingdom
facility: North Tees Hospital
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
city: Uxbridge
country: United Kingdom
facility: Hillingdon Hospital
Study officials:
affiliation: Ottawa Hospital Research Institute
name: Shi Wu Wen, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ottawa Hospital Research Institute
name: Mark C Walker, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rose EG, Murphy MSQ, Erwin E, Muldoon KA, Harvey ALJ, Rennicks White R, MacFarlane AJ, Wen SW, Walker MC. Gestational Folate and Folic Acid Intake among Women in Canada at Higher Risk of Pre-Eclampsia. J Nutr. 2021 Jul 1;151(7):1976-1982. doi: 10.1093/jn/nxab063.
citation: Corsi DJ, Gaudet LM, El-Chaar D, White RR, Rybak N, Harvey A, Muldoon K, Wen SW, Walker M. Effect of high-dose folic acid supplementation on the prevention of preeclampsia in twin pregnancy. J Matern Fetal Neonatal Med. 2022 Feb;35(3):503-508. doi: 10.1080/14767058.2020.1725882. Epub 2020 Feb 18.
citation: 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.
citation: 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.