A Phase 3 interventional study of Folic Acid 4 mg and Placebo in Pregnancy Complications and Preeclampsia, sponsored by Ottawa Hospital Research Institute. Completed at 72 sites in 5 countries. Open to female participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-07-07.
Sponsored by Ottawa Hospital Research Institute · Phase 3, Interventional, and Prevention
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.
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.
Pregnant subjects must fulfill at least one of the following identified risk factors for pre-eclampsia (PE):
Exclusion Criteria:
History of medical complications, including:
Known presence of:
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
Women will be randomised in a 1:1 ratio to folic acid 4.0 mg or placebo
Drug: Placebo
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
Placebo x 4 tablets will be taken daily by oral administration.
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.
Time frame: Participants will be followed from 20+0 weeks of gestational age until 42 days postpartum (after delivery)
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: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Infants to the participants will be followed for 28 days after birth.
Periventricular Leukomalacia
One of the two outcomes used to measure neonatal morbidity.
Time frame: 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.
Time frame: Infants to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
High risk pregnant women were recruited in Canada and internationally.
| Milestone | Folic Acid 4 mg | Placebo |
|---|---|---|
| Started | 1228 | 1236 |
| Completed | 1144 | 1157 |
| Not completed | 84 | 79 |
| Withdrew: Withdrew consent | 39 | 47 |
| Withdrew: No primary outcome data | 17 | 11 |
| Withdrew: Spontaneous abortion (<20 weeks) | 22 | 15 |
| Withdrew: Early intrauterine fetal death | 6 | 6 |
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 | Folic Acid 4 mg | Placebo |
|---|---|---|
| Preeclampsia | 169 | 156 |
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.
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Maternal Death | 0 | 0 |
Spontaneous abortion or miscarriage defined as death of a fetus \<500g or \<20 weeks of gestation
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Spontaneous Abortion | 27 | 21 |
Placental abruption (abruptio placentae) is the premature detachment of a normally positioned placenta from the wall of the uterus.
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Placenta Abruption | 12 | 19 |
Rupture of the membranes (rupture of the amniotic sac) before the onset of labor.
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Premature Rupture of Membranes | 215 | 224 |
Birth that occur earlier than 37+0 weeks of gestational age.
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Preterm Birth | 297 | 304 |
Haemolysis (characteristic peripheral blood smear), Serum LDH \>=600U/L, Serum AST \>=70U/L, Platelet count \<100 x109/L
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| HELLP (Hemolysis, Elevated Liver Enzyme Levels & Low Platelet Count) | 6 | 5 |
Severe PE: Defined as PE with convulsion or HELLP or delivery \<34 weeks.
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Severe Preeclampsia | 24 | 16 |
Length of inpatient stay before admission for delivery in days
| days | Folic Acid 4 mg | Placebo |
|---|---|---|
| Antenatal Inpatient Length of Stay | 5.6 ± 7.7 | 5.2 ± 6.2 |
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 | Folic Acid 4 mg | Placebo |
|---|---|---|
| Stillbirth | 15 | 26 |
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 | Folic Acid 4 mg | Placebo |
|---|---|---|
| Intrauterine Growth Restriction (<3rd Percentile) | 20 | 25 |
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 | Folic Acid 4 mg | Placebo |
|---|---|---|
| Intrauterine Growth Restriction (<10th Percentile) | 151 | 144 |
Neonatal death defined as death of a baby that occurred during first 28 days of life.
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Neonatal Death | 8 | 11 |
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 | Folic Acid 4 mg | Placebo |
|---|---|---|
| Perinatal Mortality | 23 | 37 |
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.
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Retinopathy of Prematurity | 21 | 13 |
Within first 48hr of life, confirmed by positive blood or cerebrospinal fluid cultures
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Early Onset Sepsis | 3 | 9 |
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.
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Necrotising Enterocolitis | 8 | 3 |
* 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)
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Intraventricular Hemorrhage (IVH) | 18 | 19 |
Ventilatory support after initial resuscitation, with/without intubation.
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Ventilation | 49 | 30 |
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Need for Oxygen at 28 Days | 9 | 3 |
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
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Composite Severe Adverse Fetal/Neonatal Outcome | 63 | 51 |
| days | Folic Acid 4 mg | Placebo |
|---|---|---|
| Length of Stay in 'High Level' Neonatal Care Unit | 16 ± 27 | 17 ± 23 |
Neonatal death defined as death of the infant occurred before 28 days of life
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Neonatal Death | 151 | 144 |
One of the two outcomes used to measure neonatal morbidity.
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Periventricular Leukomalacia | 4 | 2 |
This outcome measured whether or not the infant was admitted into the NICU.
| Participants | Folic Acid 4 mg | Placebo |
|---|---|---|
| Neonatal Intensive Care Unit (NICU) Admission | 299 | 267 |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Folic Acid 4 mg | — | 227/1,227 (18.5%) | 961/1,227 (78.3%) |
| Placebo | — | 195/1,236 (15.8%) | 968/1,236 (78.3%) |
| Event | Folic Acid 4 mg | Placebo |
|---|---|---|
| Other SAEPregnancy, puerperium and perinatal conditions | 167/1227 | 150/1236 |
| HypertensionPregnancy, puerperium and perinatal conditions | 31/1227 | 25/1236 |
| PrematurityPregnancy, puerperium and perinatal conditions | 29/1227 | 20/1236 |
| Event | Folic Acid 4 mg | Placebo |
|---|---|---|
| Other AEPregnancy, puerperium and perinatal conditions | 961/1227 | 968/1236 |
One participant (in the Folic Acid group) withdrew consent on the same day of randomization and was excluded completely from the baseline and outcome analysis.
| Age, Continuous(years) | Folic Acid 4 mg | Placebo | Total |
|---|---|---|---|
| Mean | 31 ± 5.4 | 31 ± 5.4 | 31 ± 5.4 |
| Age, Customized(Participants) | Folic Acid 4 mg | Placebo | Total |
|---|---|---|---|
| Maternal age (years) — <20 | 10 | 10 | 20 |
| Maternal age (years) — 20-29 | 439 | 447 | 886 |
| Maternal age (years) — 30-34 | 411 | 441 | 852 |
| Maternal age (years) — >=35 | 367 | 338 | 705 |
| Sex: Female, Male(Participants) | Folic Acid 4 mg | Placebo | Total |
|---|---|---|---|
| Female | 1227 | 1236 | 2463 |
| Male | 0 | 0 | 0 |
| Race/Ethnicity, Customized(Participants) | Folic Acid 4 mg | Placebo | Total |
|---|---|---|---|
| Maternal Background — Native/Aboriginal | 35 | 24 | 59 |
| Maternal Background — Caucasian | 970 | 987 | 1957 |
| Maternal Background — Black | 93 | 107 | 200 |
| Maternal Background — Asian | 45 | 50 | 95 |
| Maternal Background — Latino/Hispanic | 31 | 22 | 53 |
| Maternal Background — Indian/South Asian | 45 | 36 | 81 |
| Maternal Background — Declined to answer | 8 | 10 | 18 |
| Region of Enrollment(participants) | Folic Acid 4 mg | Placebo | Total |
|---|---|---|---|
| Canada | 600 | 607 | 1207 |
| Argentina | 157 | 153 | 310 |
| United Kingdom | 61 | 61 | 122 |
| Australia | 29 | 32 | 61 |
| Jamaica | 380 | 383 | 763 |
| Parity(Participants) | Folic Acid 4 mg | Placebo | Total |
|---|---|---|---|
| 0 | 413 | 420 | 833 |
| 1 | 498 | 499 | 997 |
| >=2 | 316 | 317 | 633 |
| Pre-pregnancy BMI (kg/m2)(Participants) | Folic Acid 4 mg | Placebo | Total |
|---|---|---|---|
| <18.5 | 15 | 11 | 26 |
| 18.5 to <25 | 230 | 225 | 455 |
| 25 to <30 | 211 | 199 | 410 |
| 30 to <35 | 164 | 146 | 310 |
| >=35 | 607 | 655 | 1262 |
| Education level(Participants) | Folic Acid 4 mg | Placebo | Total |
|---|---|---|---|
| High school and below | 353 | 348 | 701 |
| College/University not complete | 198 | 197 | 395 |
| College/University completed | 675 | 689 | 1364 |
17 further baseline measures are reported on the registry.
This study is completed, as verified in Jun 2020. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Ottawa Hospital Research Institute