High Dose Folic Acid Supplementation Throughout Pregnancy for Preeclampsia Prevention

Phase 3

Completed

Conditions: Pregnancy Complications
Preeclampsia

Interventions: Drug: Placebo
Drug: Folic Acid 4 mg

Registration Number: NCT01355159

Lead Sponsor: Ottawa Hospital Research Institute

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 2464

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Women will be randomised in a 1:1 ratio to folic acid 4.0 mg or placebo
Folic Acid 4 mg	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

Primary Outcome Measures

Name	Time	Method
Preeclampsia	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

Name	Time	Method
Preterm Birth	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.
Perinatal Mortality	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.
Retinopathy of Prematurity	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.
Early Onset Sepsis	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
Premature Rupture of Membranes	Participants will be followed from randomization (8-16 weeks' completed gestation) until the onset of labor	Rupture of the membranes (rupture of the amniotic sac) before the onset of labor.
Severe Preeclampsia	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.
Maternal Death	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.
HELLP (Hemolysis, Elevated Liver Enzyme Levels & Low Platelet Count)	Participants will be followed from 20+0 weeks of gestation until delivery	Haemolysis (characteristic peripheral blood smear), Serum LDH \>=600U/L, Serum AST \>=70U/L, Platelet count \<100 x109/L
Antenatal Inpatient Length of Stay	Participants will be followed from date of randomization (8-16 weeks' completed gestation) until admission for delivery	Length of inpatient stay before admission for delivery in days
Stillbirth	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.
Spontaneous Abortion	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
Placenta Abruption	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.
Intrauterine Growth Restriction (<3rd Percentile)	Participants will be followed from 20+0 weeks of gestation until delivery	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.
Intrauterine Growth Restriction (<10th Percentile)	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.
Neonatal Death	Infants to the participants will be followed for 28 days after birth.	Neonatal death defined as death of the infant occurred before 28 days of life
Necrotising Enterocolitis	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.
Intraventricular Hemorrhage (IVH)	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)
Ventilation	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.
Composite Severe Adverse Fetal/Neonatal Outcome	Outcomes included in the composite outcome were measured for each of their respective time frames, up to 6-weeks after birth	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
Need for Oxygen at 28 Days	Infants to the participants will be followed for 28 days 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.
Periventricular Leukomalacia	Infants to the participants were followed for 28 days after birth.	One of the two outcomes used to measure neonatal morbidity.
Neonatal Intensive Care Unit (NICU) Admission	Infants to the participants will be followed for the duration of hospital stay, or up to 6 weeks.	This outcome measured whether or not the infant was admitted into the NICU.

Trial Locations

Locations (72): Fredericton Dr. Everett Chalmers Regional Hospital
🇨🇦
Fredericton, New Brunswick, Canada
Fairfield
🇬🇧
Bury, Lancashire, United Kingdom
Ipswich
🇦🇺
Ipswich, Queensland, Australia
Hospital Roque Saenz Penia
🇦🇷
Rosario, Santa Fe, Argentina
Calgary Foothills Medical Center
🇨🇦
Calgary, Alberta, Canada
St-Paul's Hospital
🇨🇦
Vancouver, British Columbia, Canada
Blackburn
🇬🇧
Blackburn, United Kingdom
Hospital Cullen
🇦🇷
Santa Fe, Argentina
Townsville
🇦🇺
Douglas, Queensland, Australia
Maternidad Martin
🇦🇷
Rosario, Santa Fe, Argentina
Regina Qu'Appelle Health Region
🇨🇦
Regina, Saskatchewan, Canada
Adelaide
🇦🇺
North Adelaide, South Australia, Australia
Jubilee
🇯🇲
Kingston, Jamaica
Royal Women's Hospital
🇦🇺
Parkville, Victoria, Australia
Hospital Provincial
🇦🇷
Rosario, Santa Fe, Argentina
Hosptial Iturraspe
🇦🇷
Santa Fe, Argentina
Lincolnshire
🇬🇧
Lincoln, Lincolnshire, United Kingdom
Oldham
🇬🇧
Oldham, United Kingdom
Rochdale
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Rochdale, Lancashire, United Kingdom
49 Marine Avenue & CCGs
🇬🇧
Whitley Bay, Newcastle Upon Tyne, United Kingdom
University Hospital of North Durham
🇬🇧
Durham, County Durham, United Kingdom
Darlington Memorial Hospital
🇬🇧
Darlington, County Durham, United Kingdom
St-Mary's Hospital
🇨🇦
Montreal, Quebec, Canada
Sanatorio de la Mujer
🇦🇷
Rosario, Santa Fe, Argentina
Hospital Escuela Eva Perón
🇦🇷
Rosario, Santa Fe, Argentina
Cemic
🇦🇷
Buenos Aires, Argentina
Nepean
🇦🇺
Penrith, New South Wales, Australia
Sunshine
🇦🇺
St Albans, Victoria, Australia
Edmonton Lois Hole Hospital for Women
🇨🇦
Edmonton, Alberta, Canada
Vancouver BC Women's Hospital and Health Center
🇨🇦
Vancouver, British Columbia, Canada
Saint John Regional Hospital
🇨🇦
Saint John, New Brunswick, Canada
Winnipeg University of Manitoba
🇨🇦
Winnipeg, New Brunswick, Canada
Moncton Hospital
🇨🇦
Moncton, New Brunswick, Canada
St-John's Women's Health Centre
🇨🇦
St John's, Newfoundland and Labrador, Canada
Hamilton McMaster University
🇨🇦
Hamilton, Ontario, Canada
Winnipeg St. Boniface General Hospital
🇨🇦
Winnipeg, New Brunswick, Canada
Kingston
🇨🇦
Kingston, Ontario, Canada
Sunnybrook Health Sciences
🇨🇦
Toronto, Ontario, Canada
Sault Ste- Marie Sault Area Hospital
🇨🇦
Sault Ste. Marie, Ontario, Canada
Ottawa Hospital
🇨🇦
Ottawa, Ontario, Canada
Civic Hospital
🇨🇦
Ottawa, Ontario, Canada
Quebec City (CHUL) Centre Hospitalier Universitaire
🇨🇦
Montreal, Quebec, Canada
Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
Saint-Luc CHUM - Montreal
🇨🇦
Montreal, Quebec, Canada
McGill University Royal Victoria Hospital
🇨🇦
Montreal, Quebec, Canada
University of West Indies
🇯🇲
Kingston 7, Jamaica
Spanishtown
🇯🇲
Kingston, Jamaica
Cumberland Infirmary
🇬🇧
Carlisle, Cumbria, United Kingdom
Hinchingbrooke
🇬🇧
Huntingdon, Cambridgeshire, United Kingdom
Warrington and Halton Hospitals NHS Foundation Trust
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Warrington, Cheshire, United Kingdom
Ormskirk
🇬🇧
Southport, Merseyside, United Kingdom
West Cumberland Hospital
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Whitehaven, Cumbria, United Kingdom
Northwick Park Hospital
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Harrow, Middlesex, United Kingdom
West Middlesex University Hospital
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Isleworth, Middlesex, United Kingdom
St George's Hospital
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London, Tooting, United Kingdom
Wansbeck General Hospital
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Ashington, Northumberland, United Kingdom
Gateshead Queen Elizabeth Hospital
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Gateshead, Tyne And Wear, United Kingdom
South Tyneside District Hospital
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South Shields, Tyne And Wear, United Kingdom
The Royal Wolverhampton NHS Trust, New Cross Hospital
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Wolverhampton, West Midlands, United Kingdom
Burnley
🇬🇧
Burnley, United Kingdom
North Manchester
🇬🇧
Crumpsall, United Kingdom
Guy's & St Thomas' Hospital
🇬🇧
London, United Kingdom
North Tyneside General Hospital
🇬🇧
North Shields, United Kingdom
South Tees Hospital
🇬🇧
Middlesbrough, United Kingdom
Norfolk & Norwich
🇬🇧
Norwich, United Kingdom
Nottingham City Hospital
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Nottingham, United Kingdom
Newcastle upon Tyne Hospitals
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Newcastle upon Tyne, United Kingdom
Nottingham Queens Medical Centre
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Nottingham, United Kingdom
Sunderland Royal Hospital
🇬🇧
Sunderland, United Kingdom
Hillingdon Hospital
🇬🇧
Uxbridge, United Kingdom
North Tees Hospital
🇬🇧
Stockton, United Kingdom
London
🇨🇦
London, Ontario, Canada