High Dose Folic Acid Supplementation Throughout Pregnancy for Preeclampsia Prevention

NCT01355159 | Completed Phase 3 Results DMC

• 2 other identifiers: 2009-107ISRCTN23781770
• Study Type: interventional
• Target: 2,464
• Locations: 5 countries
• Sites: 72

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.

Conditions

Pregnancy Complications; Preeclampsia

Keywords

Pregnancy; Folic Acid supplementation; Preeclampsia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (24)

• Maternal Death

  Time Frame: Participants will be followed from 20+0 weeks of gestation until 42 days postpartum (after delivery)

• Spontaneous Abortion

  Participants will be followed from randomization until 20+0 weeks of gestation

• Placenta Abruption

  Participants will be followed from 20+0 weeks of gestation until delivery

• Premature Rupture of Membranes

  Participants will be followed from randomization (8-16 weeks' completed gestation) until the onset of labor

• Preterm Birth

  Participants will be followed from 20+0 weeks to 36+6 weeks of gestation

Study Arms (2)

Folic Acid 4 mg

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Folic Acid 4 mg DRUG

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

Also known as: Folate

Folic Acid 4 mg

Placebo DRUG

Placebo x 4 tablets will be taken daily by oral administration.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Ottawa Hospital Research Institute: lead
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (72)

Hospital Escuela Eva Perón

Rosario, Santa Fe Province, S2000DKR, Argentina

Location

Hospital Provincial

Rosario, Santa Fe Province, Argentina

Location

Hospital Roque Saenz Penia

Rosario, Santa Fe Province, Argentina

Location

Maternidad Martin

Rosario, Santa Fe Province, Argentina

Location

Sanatorio de la Mujer

Rosario, Santa Fe Province, Argentina

Location

Cemic

Buenos Aires, Argentina

Location

Hospital Cullen

Santa Fe, Argentina

Location

Hosptial Iturraspe

Santa Fe, Argentina

Location

Nepean

Penrith, New South Wales, 2750, Australia

Location

Townsville

Douglas, Queensland, 4814, Australia

Location

Ipswich

Ipswich, Queensland, 4305, Australia

Location

Adelaide

North Adelaide, South Australia, 5006, Australia

Location

Royal Women's Hospital

Parkville, Victoria, 3052, Australia

Location

Sunshine

St Albans, Victoria, 3021, Australia

Location

Calgary Foothills Medical Center

Calgary, Alberta, T2N2T9, Canada

Location

Edmonton Lois Hole Hospital for Women

Edmonton, Alberta, T5H 3V9, Canada

Location

Vancouver BC Women's Hospital and Health Center

Vancouver, British Columbia, V5Z 4H4, Canada

Location

St-Paul's Hospital

Vancouver, British Columbia, V6Z 2K5, Canada

Location

Fredericton Dr. Everett Chalmers Regional Hospital

Fredericton, New Brunswick, E3B 5N5, Canada

Location

Moncton Hospital

Moncton, New Brunswick, E1C 6Z8, Canada

Location

Saint John Regional Hospital

Saint John, New Brunswick, E2L 4L2, Canada

Location

Winnipeg St. Boniface General Hospital

Winnipeg, New Brunswick, R2H 2A6, Canada

Location

Winnipeg University of Manitoba

Winnipeg, New Brunswick, R3E 3P4, Canada

Location

St-John's Women's Health Centre

St. John's, Newfoundland and Labrador, A1B 3V6, Canada

Location

Hamilton McMaster University

Hamilton, Ontario, L8S 4K1, Canada

Location

Kingston

Kingston, Ontario, K7L 2V7, Canada

Location

London

London, Ontario, N6A 5W9, Canada

Location

Ottawa Hospital

Ottawa, Ontario, K1H 8L6, Canada

Location

Civic Hospital

Ottawa, Ontario, K1Y 4E9, Canada

Location

Sault Ste- Marie Sault Area Hospital

Sault Ste. Marie, Ontario, P6B 0A8, Canada

Location

Sunnybrook Health Sciences

Toronto, Ontario, M4N 3M5, Canada

Location

Quebec City (CHUL) Centre Hospitalier Universitaire

Montreal, Quebec, G1V 4G2, Canada

Location

Saint-Luc CHUM - Montreal

Montreal, Quebec, H2X 3J4, Canada

Location

McGill University Royal Victoria Hospital

Montreal, Quebec, H3A 1A1, Canada

Location

Sainte-Justine

Montreal, Quebec, H3T 1C5, Canada

Location

St-Mary's Hospital

Montreal, Quebec, H3T 1M5, Canada

Location

Regina Qu'Appelle Health Region

Regina, Saskatchewan, S4P 0W5, Canada

Location

Jubilee

Kingston, Jamaica

Location

Spanishtown

Kingston, Jamaica

Location

University of West Indies

Kingston, Jamaica

Location

Hinchingbrooke

Huntingdon, Cambridgeshire, PE29 6NT, United Kingdom

Location

Warrington and Halton Hospitals NHS Foundation Trust

Warrington, Cheshire, WA51QC, United Kingdom

Location

Darlington Memorial Hospital

Darlington, County Durham, DL3 6HX, United Kingdom

Location

University Hospital of North Durham

Durham, County Durham, DH1 5TW, United Kingdom

Location

Cumberland Infirmary

Carlisle, Cumbria, CA27HY, United Kingdom

Location

West Cumberland Hospital

Whitehaven, Cumbria, CA288JG, United Kingdom

Location

Fairfield

Bury, Lancashire, BL9 7TD, United Kingdom

Location

Rochdale

Rochdale, Lancashire, OL12 0NB, United Kingdom

Location

Lincolnshire

Lincoln, Lincolnshire, LN2 4AX, United Kingdom

Location

Ormskirk

Southport, Merseyside, PR8 6PN, United Kingdom

Location

Northwick Park Hospital

Harrow, Middlesex, HA1 3UJ, United Kingdom

Location

West Middlesex University Hospital

Isleworth, Middlesex, TW7 6AF, United Kingdom

Location

49 Marine Avenue & CCGs

Whitley Bay, Newcastle Upon Tyne, NE13 9BA, United Kingdom

Location

Wansbeck General Hospital

Ashington, Northumberland, NE63 9JJ, United Kingdom

Location

St George's Hospital

London, Tooting, SW17 0QT, United Kingdom

Location

Gateshead Queen Elizabeth Hospital

Gateshead, Tyne and Wear, NE9 6SX, United Kingdom

Location

South Tyneside District Hospital

South Shields, Tyne and Wear, NE34 0PL, United Kingdom

Location

The Royal Wolverhampton NHS Trust, New Cross Hospital

Wolverhampton, West Midlands, WV100QP, United Kingdom

Location

Blackburn

Blackburn, BB2 3HH, United Kingdom

Location

Burnley

Burnley, BB10 2PQ, United Kingdom

Location

North Manchester

Crumpsall, M8 5RB, United Kingdom

Location

Guy's & St Thomas' Hospital

London, SE1 9RT, United Kingdom

Location

South Tees Hospital

Middlesbrough, TS4 3BW, United Kingdom

Location

Newcastle upon Tyne Hospitals

Newcastle upon Tyne, NE1 4LP, United Kingdom

Location

North Tyneside General Hospital

North Shields, NE29 8NH, United Kingdom

Location

Norfolk & Norwich

Norwich, NR4 7UY, United Kingdom

Location

Nottingham City Hospital

Nottingham, NG5 1PB, United Kingdom

Location

Nottingham Queens Medical Centre

Nottingham, NG7 2UH, United Kingdom

Location

Oldham

Oldham, OL1 2JH, United Kingdom

Location

North Tees Hospital

Stockton, TS19 9AH, United Kingdom

Location

Sunderland Royal Hospital

Sunderland, SR4 7TP, United Kingdom

Location

Hillingdon Hospital

Uxbridge, UB8 3NN, United Kingdom

Location

Related Publications (5)

• Muldoon KA, McLean C, El-Chaar D, Corsi DJ, Rybak N, Dagvadorj A, Guo Y, Rennicks White R, Dingwall-Harvey ALJ, Gaudet LM, Walker MC, Wen SW; FACT Collaborating Group. Persisting risk factors for preeclampsia among high-risk pregnancies already using prophylactic aspirin: a multi-country retrospective investigation. J Matern Fetal Neonatal Med. 2023 Dec;36(1):2200879. doi: 10.1080/14767058.2023.2200879.

  PMID: 37073421 DERIVED

• 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.

  PMID: 33851221 DERIVED

• 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.

  PMID: 32067533 DERIVED

• 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.

  PMID: 30209050 DERIVED

• 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.

  PMID: 24349782 DERIVED

MeSH Terms

Conditions

Pregnancy Complications; Pre-Eclampsia

Interventions

Folic Acid

Condition Hierarchy (Ancestors)

Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Hypertension, Pregnancy-Induced

Intervention Hierarchy (Ancestors)

Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

The diagnosis of PE is complex due to its heterogenous aetiology. The criteria for PE have remained consistent with NICE guidelines, but there have been revisions in other settings. Therefore additional women in the study might have had PE.

Results Point of Contact

• Title: Dr. Mark Walker
• Organization: Ottawa Hospital Research Institute

mwalker@ohri.ca

6137378899

Study Officials

• Shi Wu Wen, PhD

  Ottawa Hospital Research Institute

  PRINCIPAL INVESTIGATOR

• Mark C Walker, MD

  Ottawa Hospital Research Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 11, 2011
• First Posted: May 17, 2011
• Study Start: April 1, 2011
• Primary Completion: July 1, 2016
• Study Completion: September 1, 2016
• Last Updated: July 7, 2020
• Results First Posted: July 7, 2020

Record last verified: 2020-06

Locations

AU (6); CA (23); AR (8); JA (3); GB (32)