Preeclampsia, Pregnancy Complications
Conditions
Keywords
Pregnancy, Folic Acid supplementation, Preeclampsia
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.
Interventions
DRUGFolic Acid 4 mg
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
DRUGPlacebo
Placebo x 4 tablets will be taken daily by oral administration.
Sponsors
Canadian Institutes of Health Research (CIHR)
Ottawa Hospital Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
| 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 | Participants will be followed from birth until 28 days of life | Neonatal death defined as death of a baby that occurred during first 28 days of life. |
| 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. |
| 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 |
| 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. |
| Need for Oxygen at 28 Days | Infants to the participants will be followed for 28 days after birth. | — |
| 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 |
| 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. |
| 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. |
Countries
Argentina, Australia, Canada, Jamaica, United Kingdom
Participant flow
Recruitment details
High risk pregnant women were recruited in Canada and internationally.
Participants by arm
| Arm | Count |
|---|---|
| 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
Folic Acid 4 mg: 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 | 1,227 |
| Placebo Women will be randomised in a 1:1 ratio to folic acid 4.0 mg or placebo
Placebo: Placebo x 4 tablets will be taken daily by oral administration. | 1,236 |
| Total | 2,463 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Early intrauterine fetal death | 6 | 6 |
| Overall Study | No primary outcome data | 17 | 11 |
| Overall Study | Spontaneous abortion (<20 weeks) | 22 | 15 |
| Overall Study | Withdrew consent | 39 | 47 |
Baseline characteristics
| Characteristic | Folic Acid 4 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 31 years STANDARD_DEVIATION 5.4 | 31 years STANDARD_DEVIATION 5.4 | 31 years STANDARD_DEVIATION 5.4 |
| Age, Customized Maternal age (years) <20 | 10 Participants | 10 Participants | 20 Participants |
| Age, Customized Maternal age (years) 20-29 | 439 Participants | 447 Participants | 886 Participants |
| Age, Customized Maternal age (years) 30-34 | 411 Participants | 441 Participants | 852 Participants |
| Age, Customized Maternal age (years) >=35 | 367 Participants | 338 Participants | 705 Participants |
| Alcohol during pregnancy No | 977 Participants | 955 Participants | 1932 Participants |
| Alcohol during pregnancy Quit during pregnancy | 227 Participants | 254 Participants | 481 Participants |
| Alcohol during pregnancy Yes | 23 Participants | 27 Participants | 50 Participants |
| Aspirin supplementation at randomisation | 358 Participants | 340 Participants | 698 Participants |
| Body mass index >=35 | 606 Participants | 656 Participants | 1262 Participants |
| Calcium supplementation at randomisation | 97 Participants | 109 Participants | 206 Participants |
| Chronic Hypertension | 203 Participants | 241 Participants | 444 Participants |
| Dietary Folate (µg) (Mean, SD) VIsit 1 (8-16 completed weeks' gestation) | 494 µg STANDARD_DEVIATION 209 | 504 µg STANDARD_DEVIATION 222 | 499 µg STANDARD_DEVIATION 216 |
| Dietary Folate (µg) (Mean, SD) Visit 2 (24-26 weeks' completed gestation) | 494 µg STANDARD_DEVIATION 209 | 500 µg STANDARD_DEVIATION 213 | 497 µg STANDARD_DEVIATION 211 |
| Education level College/University completed | 675 Participants | 689 Participants | 1364 Participants |
| Education level College/University not complete | 198 Participants | 197 Participants | 395 Participants |
| Education level High school and below | 353 Participants | 348 Participants | 701 Participants |
| Gestational age at recruitment | 14 weeks STANDARD_DEVIATION 1.9 | 14 weeks STANDARD_DEVIATION 1.9 | 14 weeks STANDARD_DEVIATION 1.9 |
| Gestational age (weeks) at recruitment 13-16 | 841 Participants | 803 Participants | 1644 Participants |
| Gestational age (weeks) at recruitment 8-12 | 386 Participants | 433 Participants | 819 Participants |
| History of Pre-eclampsia | 308 Participants | 303 Participants | 611 Participants |
| Parity 0 | 413 Participants | 420 Participants | 833 Participants |
| Parity 1 | 498 Participants | 499 Participants | 997 Participants |
| Parity >=2 | 316 Participants | 317 Participants | 633 Participants |
| Pre-pregnancy BMI (kg/m2) <18.5 | 15 Participants | 11 Participants | 26 Participants |
| Pre-pregnancy BMI (kg/m2) 18.5 to <25 | 230 Participants | 225 Participants | 455 Participants |
| Pre-pregnancy BMI (kg/m2) 25 to <30 | 211 Participants | 199 Participants | 410 Participants |
| Pre-pregnancy BMI (kg/m2) 30 to <35 | 164 Participants | 146 Participants | 310 Participants |
| Pre-pregnancy BMI (kg/m2) >=35 | 607 Participants | 655 Participants | 1262 Participants |
| Prepregnancy Body Mass Index | 34 kg/m^2 STANDARD_DEVIATION 8.6 | 34 kg/m^2 STANDARD_DEVIATION 13 | 34 kg/m^2 STANDARD_DEVIATION 11 |
| Race/Ethnicity, Customized Maternal Background Asian | 45 Participants | 50 Participants | 95 Participants |
| Race/Ethnicity, Customized Maternal Background Black | 93 Participants | 107 Participants | 200 Participants |
| Race/Ethnicity, Customized Maternal Background Caucasian | 970 Participants | 987 Participants | 1957 Participants |
| Race/Ethnicity, Customized Maternal Background Declined to answer | 8 Participants | 10 Participants | 18 Participants |
| Race/Ethnicity, Customized Maternal Background Indian/South Asian | 45 Participants | 36 Participants | 81 Participants |
| Race/Ethnicity, Customized Maternal Background Latino/Hispanic | 31 Participants | 22 Participants | 53 Participants |
| Race/Ethnicity, Customized Maternal Background Native/Aboriginal | 35 Participants | 24 Participants | 59 Participants |
| Region of Enrollment Argentina | 157 participants | 153 participants | 310 participants |
| Region of Enrollment Australia | 29 participants | 32 participants | 61 participants |
| Region of Enrollment Canada | 600 participants | 607 participants | 1207 participants |
| Region of Enrollment Jamaica | 380 participants | 383 participants | 763 participants |
| Region of Enrollment United Kingdom | 61 participants | 61 participants | 122 participants |
| Sex: Female, Male Female | 1227 Participants | 1236 Participants | 2463 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Smoking during pregnancy No | 1046 Participants | 1035 Participants | 2081 Participants |
| Smoking during pregnancy Quit during pregnancy | 83 Participants | 106 Participants | 189 Participants |
| Smoking during pregnancy Yes | 98 Participants | 95 Participants | 193 Participants |
| Supplementation of FA at randomisation (yes) | 989 Participants | 1016 Participants | 2005 Participants |
| Supplementation of high dose FA at randomisation (yes) | 346 Participants | 335 Participants | 681 Participants |
| Twin Pregnancy | 233 Participants | 229 Participants | 462 Participants |
| Type 1 Diabetes | 84 Participants | 72 Participants | 156 Participants |
| Type 2 Diabetes | 98 Participants | 84 Participants | 182 Participants |
| Visit 2 Compliance ≤50% | 108 Participants | 106 Participants | 214 Participants |
| Visit 2 Compliance 50-75% | 140 Participants | 122 Participants | 262 Participants |
| Visit 2 Compliance ≥75% | 716 Participants | 749 Participants | 1465 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 961 / 1,227 | 968 / 1,236 |
| serious Total, serious adverse events | 227 / 1,227 | 195 / 1,236 |
Outcome results
Primary
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)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Preeclampsia | 169 Participants |
| Placebo | Preeclampsia | 156 Participants |
p-value: 0.3795% CI: [0.9, 1.34]Chi-squared
Secondary
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
Population: Not all participants had secondary outcome data. Numbers above reflect those that had information available for this secondary outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Folic Acid 4 mg | Antenatal Inpatient Length of Stay | 5.6 days | Standard Deviation 7.7 |
| Placebo | Antenatal Inpatient Length of Stay | 5.2 days | Standard Deviation 6.2 |
p-value: 0.6195% CI: [-0.96, 1.63]t-test, 2 sided
Secondary
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
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Composite Severe Adverse Fetal/Neonatal Outcome | 63 Participants |
| Placebo | Composite Severe Adverse Fetal/Neonatal Outcome | 51 Participants |
p-value: 0.3895% CI: [0.8, 1.8]Chi-squared
Secondary
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.
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Early Onset Sepsis | 3 Participants |
| Placebo | Early Onset Sepsis | 9 Participants |
p-value: 0.195% CI: [0.09, 1.23]Chi-squared
Secondary
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
Population: Not all participants had secondary outcome data. Numbers above reflect those that had information available for this secondary outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | HELLP (Hemolysis, Elevated Liver Enzyme Levels & Low Platelet Count) | 6 Participants |
| Placebo | HELLP (Hemolysis, Elevated Liver Enzyme Levels & Low Platelet Count) | 5 Participants |
p-value: 0.7595% CI: [0.37, 3.96]Chi-squared
Secondary
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
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Intrauterine Growth Restriction (<10th Percentile) | 151 Participants |
| Placebo | Intrauterine Growth Restriction (<10th Percentile) | 144 Participants |
p-value: 0.8295% CI: [0.81, 1.3]Chi-squared
Secondary
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
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Intrauterine Growth Restriction (<3rd Percentile) | 20 Participants |
| Placebo | Intrauterine Growth Restriction (<3rd Percentile) | 25 Participants |
p-value: 0.3795% CI: [0.41, 1.39]Chi-squared
Secondary
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
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Intraventricular Hemorrhage (IVH) | 18 Participants |
| Placebo | Intraventricular Hemorrhage (IVH) | 19 Participants |
p-value: 0.9495% CI: [0.47, 2]Chi-squared
Secondary
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.
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Folic Acid 4 mg | Length of Stay in 'High Level' Neonatal Care Unit | 16 days | Standard Deviation 27 |
| Placebo | Length of Stay in 'High Level' Neonatal Care Unit | 17 days | Standard Deviation 23 |
p-value: 4695% CI: [-5.84, 2.64]t-test, 2 sided
Secondary
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)
Population: Participants who completed study and were analyzed for primary outcome
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Maternal Death | 0 Participants |
| Placebo | Maternal Death | 0 Participants |
Secondary
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.
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Necrotising Enterocolitis | 8 Participants |
| Placebo | Necrotising Enterocolitis | 3 Participants |
p-value: 0.3395% CI: [0.49, 8.57]Chi-squared
Secondary
Need for Oxygen at 28 Days
Time frame: Infants to the participants will be followed for 28 days after birth.
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Need for Oxygen at 28 Days | 9 Participants |
| Placebo | Need for Oxygen at 28 Days | 3 Participants |
p-value: 0.2195% CI: [0.61, 9.14]Chi-squared
Secondary
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.
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Neonatal Death | 151 Participants |
| Placebo | Neonatal Death | 144 Participants |
p-value: 0.7995% CI: [0.31, 2.44]Chi-squared
Secondary
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
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Neonatal Death | 8 Participants |
| Placebo | Neonatal Death | 11 Participants |
p-value: 0.7995% CI: [0.31, 2.44]Chi-squared
Secondary
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.
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Neonatal Intensive Care Unit (NICU) Admission | 299 Participants |
| Placebo | Neonatal Intensive Care Unit (NICU) Admission | 267 Participants |
Secondary
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.
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Perinatal Mortality | 23 Participants |
| Placebo | Perinatal Mortality | 37 Participants |
p-value: 0.0795% CI: [0.37, 1.05]Chi-squared
Secondary
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.
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Periventricular Leukomalacia | 4 Participants |
| Placebo | Periventricular Leukomalacia | 2 Participants |
p-value: 0.4295% CI: [0.37, 10.92]Chi-squared
Secondary
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
Population: Not all participants had secondary outcome data. Numbers above reflect those that had information available for this secondary outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Placenta Abruption | 12 Participants |
| Placebo | Placenta Abruption | 19 Participants |
p-value: 0.2195% CI: [0.31, 1.31]Chi-squared
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Premature Rupture of Membranes | 215 Participants |
| Placebo | Premature Rupture of Membranes | 224 Participants |
p-value: 0.7195% CI: [0.82, 1.15]Chi-squared
Secondary
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
Population: Not all participants had secondary outcome data. Numbers above reflect those that had information available for this secondary outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Preterm Birth | 297 Participants |
| Placebo | Preterm Birth | 304 Participants |
p-value: 0.8795% CI: [0.86, 1.13]Chi-squared
Secondary
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
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Retinopathy of Prematurity | 21 Participants |
| Placebo | Retinopathy of Prematurity | 13 Participants |
p-value: 0.6595% CI: [0.54, 2.66]Chi-squared
Secondary
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.
Population: Not all participants had secondary outcome data. Numbers above reflect those that had information available for this secondary outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Severe Preeclampsia | 24 Participants |
| Placebo | Severe Preeclampsia | 16 Participants |
p-value: 0.1995% CI: [0.81, 2.84]Chi-squared
Secondary
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
Population: Not all participants had secondary outcome data. Numbers above reflect those that had information available for this secondary outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Spontaneous Abortion | 27 Participants |
| Placebo | Spontaneous Abortion | 21 Participants |
p-value: 0.3795% CI: [0.74, 2.28]Chi-squared
Secondary
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.
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Stillbirth | 15 Participants |
| Placebo | Stillbirth | 26 Participants |
p-value: 0.1495% CI: [0.3, 1.19]Chi-squared
Secondary
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.
Population: A total of 2738 infants were born to women recruited into the trial (1364 in folic acid group and 1374 in placebo group). This is an infant outcome. Some participants had missing data for this outcome and therefore were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid 4 mg | Ventilation | 49 Participants |
| Placebo | Ventilation | 30 Participants |
p-value: 0.0695% CI: [0.97, 2.66]Chi-squared