Preeclampsia
Conditions
Keywords
Antioxidants, Preeclampsia, Pregnancy, Hypertension
Brief summary
Preeclampsia is one of the most common complications of pregnancy and is characterized by high blood pressure and protein in the urine. This can cause problems in the second half of pregnancy for both the mother and fetus. This study of preeclampsia consists of two parts: 1) a randomized, placebo controlled, multicenter clinical trial of 10,000 low-risk nulliparous women between 9 and 16 weeks gestation and 2) an observational, cohort study of 4,000 patients between 9 and 12 weeks gestation who are also enrolled in the trial. Subjects in both parts will receive either 1000 mg of vitamin C and 400 IU of vitamin E or matching placebo daily. The purpose of the randomized, clinical trial is to find out if high doses of vitamin C and E will reduce the risk of preeclampsia and other problems associated with the disease. The study will also evaluate the safety of antioxidant therapy for mother and infant. Patients will be seen monthly to receive their supply of study drug, to have weight and blood pressure recorded, to have urine protein measured, and to assess any side effects. At two visits, blood and urine will be collected. The observational, cohort study will prospectively measure potential biochemical and biophysical markers that might predict preeclampsia. These patients will have additional procedures including uterine artery Doppler and blood drawn for a complete blood count (CBC).
Detailed description
A Randomized, Clinical Trial of Antioxidants to Prevent Preeclampsia: Preeclampsia is the leading cause of maternal morbidity, as well as perinatal morbidity and mortality. Once the diagnosis has been established, therapy other than delivery has not been successful except to prolong pregnancy minimally (at some risk to mother and infant). Prevention efforts to reduce or eliminate preeclampsia are directed at the pathophysiology of the disorder prior to clinically evident preeclampsia and before irreversible changes have occurred. This double-masked, placebo-controlled trial of 10,000 subjects is designed to evaluate the effects of antioxidant therapy in preventing serious complications associated with pregnancy-related hypertension in low risk, nulliparous women who begin treatment at 9-16 weeks gestation. The hypothesis being tested is that antioxidant therapy initiated prior to 16 weeks gestation will reduce the frequency of serious maternal and infant complications associated with pregnancy-related hypertension. After randomization, subjects will receive either 1000 mg of vitamin C and 400 IU of vitamin E or matching placebo daily. They will be seen for monthly pill counts and to assess side effects, weight, blood pressure, and urine for protein. Blood and urine are collected at 24 and 32 weeks' gestation. An Observational Cohort Study to Predict Preeclampsia: A prospective, cohort study has been designed to complement the randomized, controlled, trial (RCT) and will test various biochemical and biophysical markers for ability to predict preeclampsia in 4,000 of the women who are enrolled in the RCT and are between 9 and 12 weeks gestation. These subjects will have additional procedures including a CBC and uterine artery Doppler.
Interventions
Vitamin C (1000 mg) and Vitamin E (400 IU) per capsule, two capsules daily between randomization (at 9 - 16 weeks gestation) up to delivery.
DRUGPlacebo for Vitamin C and Vitamin E
Placebo two capsules daily between randomization (at 9 - 16 weeks gestation) up to delivery.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
The George Washington University Biostatistics Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
Yes
Inclusion criteria
RCT Inclusion Criteria: * Gestational age 9 -16 weeks * Singleton pregnancy * Nulliparous Observational Inclusion Criteria: * Women randomized to the RCT * Gestational age 9 - 12 wks
Exclusion criteria
RCT and Observational: * BP \>= 135/85 * Proteinuria * History or current use of anti-hypertensive medication or diuretics * Use of vitamins C \> 150 mg and/or E \> 75 IU per day * Pregestational diabetes * Current pregnancy is a result of in vitro fertilization * Regular use of platelet active drugs or non-steroidal anti-inflammatory drugs (NSAIDS) * Known fetal abnormalities * Documented uterine bleeding within a week of screening * Uterine malformations * History of medical complications * Illicit drug or alcohol abuse during current pregnancy * Intent to deliver elsewhere * Participating in another interventional study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Pregnancy-associated Hypertension and Serious Adverse Outcomes in the Mother or Fetus or Neonate | 20 weeks through discharge following delivery | Severe hypertension (blood pressure \[BP\]\>= 160/110) or mild hypertension (BP\>= 140/90) \>= 20 weeks gestation in conjunction with one of the following: elevated liver enzymes, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, an indicated preterm birth before 32 weeks of gestation owing to hypertension-related disorders, a fetus that was small for gestational age (below 3rd percentile) adjusted for sex and race or ethnic group, fetal death after 20 weeks of gestation, or neonatal death |
| Severe Hypertension | 20 weeks through discharge following delivery | Included here are women who had severe hypertension only and those who had severe hypertension with elevated liver enzyme levels, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, medically indicated preterm birth, fetal-growth restriction, or fetal death after 20 weeks of gestation, or neonatal death. |
| Severe or Mild Pregnancy-associated Hypertension With Elevated Liver Enzyme Levels | 20 weeks through discharge following delivery | Elevated liver enzyme levels are specified as an aspartate aminotransferase level of \>= 100 U per liter. Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome. |
| Severe or Mild Pregnancy-associated Hypertension With Thrombocytopenia | 20 weeks through discharge following delivery | Thrombocytopenia defined as a platelet count of \<100,000 per cubic millimeter. Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome. |
| Severe or Mild Pregnancy-associated Hypertension With an Elevated Serum Creatinine Level | 20 weeks through discharge following delivery | Elevated serum creatinine defined as ≥1.5 mg per deciliter or 132.6 μmol per liter. Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome. |
| Severe or Mild Pregnancy-associated Hypertension With an Eclamptic Seizure | 20 weeks through discharge following delivery | Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome. |
| Severe or Mild Pregnancy-associated Hypertension With an Indicated Preterm Birth Before 32 Weeks of Gestation Owing to Hypertension-related Disorders | 20 weeks through discharge following delivery | Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome. |
| Severe or Mild Pregnancy-associated Hypertension With a Fetus That Was Small for Gestational Age (Below the 3rd Percentile) Adjusted for Sex and Race or Ethnic Group | 20 weeks through discharge following delivery | Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome. |
| Severe or Mild Pregnancy-associated Hypertension With a Fetal Death After 20 Weeks of Gestation or Neonatal Death | 20 weeks through discharge or prior to discharge following delivery admission | Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Preeclampsia (Mild, Severe, HELLP Syndrome, Eclampsia) | 20 weeks through discharge following delivery | HELLP denotes hemolytic anemia, elevated liver enzymes, and low platelet count. |
| Pregnancy Associated Hypertension | 20 weeks through discharge following delivery | — |
| Apgar Score <=3 at 5 Minutes | At birth | — |
| Neonatal Hospital Stay | Birth through discharge from hospital | — |
| Medically Indicated Delivery Because of Hypertension | 20 weeks through discharge following delivery | — |
| Aspartate Aminotransferase ≥100 U/Liter | 20 weeks through discharge | — |
| Creatinine ≥1.5 mg/dl (133 μmol/Liter) | 20 weeks through discharge | — |
| Antepartum Bleeding | During pregnancy | — |
| Premature Rupture of Membranes | During pregnancy | — |
| Placental Abruption | During pregnancy | — |
| Cesarean Delivery | Delivery | — |
| Maternal Death | Delivery through hospital discharge | — |
| Postpartum Pulmonary Edema | After delivery through discharge | — |
| Hematocrit ≤24% With Transfusion | Delivery admission to discharge | — |
| Maternal Hospital Stay | Delivery through discharge | — |
| Gestational Age at Delivery | Delivery | — |
| Preterm Birth | Delivery | — |
| Fetal or Neonatal Death | During pregnancy or thorugh discharge | — |
| Birth Weight | At birth | — |
| Small for Gestational Age | At birth | A baby whose birth weight is less than the 3rd percentile is considered to be small for gestational age (adjusted for sex and race or ethnic group) |
| Birth Weight <2500 Grams | At birth | — |
| Admission to NICU | Delivery through discharge | NICU denotes neonatal intensive care unit. |
| Respiratory Distress Syndrome | Delivery through discharge | — |
| Intraventricular Hemorrhage, Grade III or IV | Delivery through discharge | — |
| Sepsis | Delivery through discharge | — |
| Necrotizing Enterocolitis | Delivery through discharge | — |
| Retinopathy of Prematurity | Within 1 month of birth | — |
Countries
United States
Participant flow
Recruitment details
The trial was conducted from July 2003 through February 2008 at the 16 clinical centers and the independent data coordinating center of the MFMU Network. Gestational age at randomization was between 9 weeks 0 days and 16 weeks 6 days. Women were eligible for inclusion if they had not had a previous pregnancy that lasted beyond 19 weeks 6 days.
Pre-assignment details
Women who were no more than 15 weeks pregnant and who consented to participate in the study were given a supply of placebo and asked to return within 2 weeks. Those who returned, who had taken at least 50% of the placebo they were supposed to have taken, and who still met the eligibility criteria were randomly assigned to receive study drug.
Participants by arm
| Arm | Count |
|---|---|
| Daily Vitamin Supplements 1000mg of Vitamin C and 400IU of Vitamin E per capsule, twice daily between randomization (at 9 to 16 weeks) up to delivery. | 5,087 |
| Placebo for Vitamins C and E Placebo capsules consisting of Mineral Oil, Hydrogenated Vegetable Oil, Lecithin, Yellow wax, Soft Gelatin Shell, twice daily between randomization (at 9 to 16 weks) up to delivery. | 5,065 |
| Total | 10,152 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Institutional review board request | 1 | 0 |
| Overall Study | Lost to Follow-up | 94 | 89 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Daily Vitamin Supplements | Total | Placebo for Vitamins C and E |
|---|---|---|---|
| <13th week of pregnancy at randomization | 2227 Participants | 4430 Participants | 2203 Participants |
| Age, Continuous | 23.5 years STANDARD_DEVIATION 5.2 | 23.5 years STANDARD_DEVIATION 5.2 | 23.5 years STANDARD_DEVIATION 5.2 |
| Blood pressure Diastolic | 66 mm Hg STANDARD_DEVIATION 8 | 65 mm Hg STANDARD_DEVIATION 6.6 | 65 mm Hg STANDARD_DEVIATION 8 |
| Blood pressure Systolic | 109 mm Hg STANDARD_DEVIATION 10 | 109 mm Hg STANDARD_DEVIATION 9.1 | 109 mm Hg STANDARD_DEVIATION 10 |
| Daily dose of vitamin C | 120 mg | 100 mg | 100 mg |
| Daily dose of vitamin E | 22 IU | 22 IU | 22 IU |
| Educational level | 12.8 year STANDARD_DEVIATION 2.7 | 12.8 year STANDARD_DEVIATION 2.7 | 12.8 year STANDARD_DEVIATION 2.7 |
| Family history of preeclampsia | 650 Participants | 1324 Participants | 674 Participants |
| Prepregnancy body-mass index | 25.4 kg/m2 STANDARD_DEVIATION 6 | 25.4 kg/m2 STANDARD_DEVIATION 6 | 25.4 kg/m2 STANDARD_DEVIATION 5.9 |
| Previous pregnancy | 1161 Participants | 2331 Participants | 1170 Participants |
| Race/Ethnicity, Customized Black | 1268 Participants | 2563 Participants | 1295 Participants |
| Race/Ethnicity, Customized Hispanic | 1602 Participants | 3168 Participants | 1566 Participants |
| Race/Ethnicity, Customized Other | 2217 Participants | 4421 Participants | 2204 Participants |
| Sex: Female, Male Female | 5087 Participants | 10152 Participants | 5065 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Smoker | 812 Participants | 1593 Participants | 781 Participants |
| Use of prenatal vitamins or multivitamins | 3903 Participants | 7792 Participants | 3889 Participants |
| Week of pregnancy at randomization | 13.4 weeks STANDARD_DEVIATION 2.1 | 13.4 weeks STANDARD_DEVIATION 2.1 | 13.4 weeks STANDARD_DEVIATION 2.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 5,087 | 1 / 5,065 |
| other Total, other adverse events | 0 / 5,087 | 0 / 5,065 |
| serious Total, serious adverse events | 108 / 5,087 | 173 / 5,065 |
Outcome results
Primary
Composite of Pregnancy-associated Hypertension and Serious Adverse Outcomes in the Mother or Fetus or Neonate
Severe hypertension (blood pressure \[BP\]\>= 160/110) or mild hypertension (BP\>= 140/90) \>= 20 weeks gestation in conjunction with one of the following: elevated liver enzymes, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, an indicated preterm birth before 32 weeks of gestation owing to hypertension-related disorders, a fetus that was small for gestational age (below 3rd percentile) adjusted for sex and race or ethnic group, fetal death after 20 weeks of gestation, or neonatal death
Time frame: 20 weeks through discharge following delivery
Population: The analysis was intent to treat.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Composite of Pregnancy-associated Hypertension and Serious Adverse Outcomes in the Mother or Fetus or Neonate | 305 Participants |
| Placebo | Composite of Pregnancy-associated Hypertension and Serious Adverse Outcomes in the Mother or Fetus or Neonate | 285 Participants |
Comparison: The primary hypothesis states that antioxidant therapy initiated prior to 16 weeks gestation in women will reduce the frequency of serious maternal and infant complications associated with pregnancy related hypertension. We estimated that with a sample size of 10,000 women, the study would have 90% power to show a 30% reduction in the rate of the primary outcome, from 4% in the placebo to 2.8% in the vitamin group, with a two-sided type I error rate of 5%.p-value: 0.4295% CI: [0.91, 1.25]Chi-squared
Primary
Severe Hypertension
Included here are women who had severe hypertension only and those who had severe hypertension with elevated liver enzyme levels, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, medically indicated preterm birth, fetal-growth restriction, or fetal death after 20 weeks of gestation, or neonatal death.
Time frame: 20 weeks through discharge following delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Severe Hypertension | 210 Participants |
| Placebo | Severe Hypertension | 204 Participants |
p-value: 0.7995% CI: [0.85, 1.24]Chi-squared
Primary
Severe or Mild Pregnancy-associated Hypertension With a Fetal Death After 20 Weeks of Gestation or Neonatal Death
Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.
Time frame: 20 weeks through discharge or prior to discharge following delivery admission
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Severe or Mild Pregnancy-associated Hypertension With a Fetal Death After 20 Weeks of Gestation or Neonatal Death | 12 Participants |
| Placebo | Severe or Mild Pregnancy-associated Hypertension With a Fetal Death After 20 Weeks of Gestation or Neonatal Death | 11 Participants |
p-value: 0.8495% CI: [0.48, 2.46]Chi-squared
Primary
Severe or Mild Pregnancy-associated Hypertension With a Fetus That Was Small for Gestational Age (Below the 3rd Percentile) Adjusted for Sex and Race or Ethnic Group
Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.
Time frame: 20 weeks through discharge following delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Severe or Mild Pregnancy-associated Hypertension With a Fetus That Was Small for Gestational Age (Below the 3rd Percentile) Adjusted for Sex and Race or Ethnic Group | 60 Participants |
| Placebo | Severe or Mild Pregnancy-associated Hypertension With a Fetus That Was Small for Gestational Age (Below the 3rd Percentile) Adjusted for Sex and Race or Ethnic Group | 46 Participants |
p-value: 0.1895% CI: [0.89, 1.9]Chi-squared
Primary
Severe or Mild Pregnancy-associated Hypertension With an Eclamptic Seizure
Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.
Time frame: 20 weeks through discharge following delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Severe or Mild Pregnancy-associated Hypertension With an Eclamptic Seizure | 10 Participants |
| Placebo | Severe or Mild Pregnancy-associated Hypertension With an Eclamptic Seizure | 4 Participants |
p-value: 0.1195% CI: [0.78, 7.94]Chi-squared
Primary
Severe or Mild Pregnancy-associated Hypertension With an Elevated Serum Creatinine Level
Elevated serum creatinine defined as ≥1.5 mg per deciliter or 132.6 μmol per liter. Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.
Time frame: 20 weeks through discharge following delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Severe or Mild Pregnancy-associated Hypertension With an Elevated Serum Creatinine Level | 7 Participants |
| Placebo | Severe or Mild Pregnancy-associated Hypertension With an Elevated Serum Creatinine Level | 11 Participants |
p-value: 0.3495% CI: [0.25, 1.63]Chi-squared
Primary
Severe or Mild Pregnancy-associated Hypertension With an Indicated Preterm Birth Before 32 Weeks of Gestation Owing to Hypertension-related Disorders
Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.
Time frame: 20 weeks through discharge following delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Severe or Mild Pregnancy-associated Hypertension With an Indicated Preterm Birth Before 32 Weeks of Gestation Owing to Hypertension-related Disorders | 13 Participants |
| Placebo | Severe or Mild Pregnancy-associated Hypertension With an Indicated Preterm Birth Before 32 Weeks of Gestation Owing to Hypertension-related Disorders | 16 Participants |
p-value: 0.5795% CI: [0.39, 1.68]Chi-squared
Primary
Severe or Mild Pregnancy-associated Hypertension With Elevated Liver Enzyme Levels
Elevated liver enzyme levels are specified as an aspartate aminotransferase level of \>= 100 U per liter. Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.
Time frame: 20 weeks through discharge following delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Severe or Mild Pregnancy-associated Hypertension With Elevated Liver Enzyme Levels | 26 Participants |
| Placebo | Severe or Mild Pregnancy-associated Hypertension With Elevated Liver Enzyme Levels | 33 Participants |
p-value: 0.3595% CI: [0.47, 1.31]Chi-squared
Primary
Severe or Mild Pregnancy-associated Hypertension With Thrombocytopenia
Thrombocytopenia defined as a platelet count of \<100,000 per cubic millimeter. Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.
Time frame: 20 weeks through discharge following delivery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vitamins | Severe or Mild Pregnancy-associated Hypertension With Thrombocytopenia | 21 participants |
| Placebo | Severe or Mild Pregnancy-associated Hypertension With Thrombocytopenia | 31 participants |
p-value: 0.1695% CI: [0.39, 1.17]Chi-squared
Secondary
Admission to NICU
NICU denotes neonatal intensive care unit.
Time frame: Delivery through discharge
Population: Live born infants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Admission to NICU | 577 Participants |
| Placebo | Admission to NICU | 557 Participants |
p-value: 0.5895% CI: [0.92, 1.15]Chi-squared
Secondary
Antepartum Bleeding
Time frame: During pregnancy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Antepartum Bleeding | 56 Participants |
| Placebo | Antepartum Bleeding | 46 Participants |
p-value: 0.3395% CI: [0.82, 1.79]Chi-squared
Secondary
Apgar Score <=3 at 5 Minutes
Time frame: At birth
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vitamins | Apgar Score <=3 at 5 Minutes | 23 participants |
| Placebo | Apgar Score <=3 at 5 Minutes | 27 participants |
p-value: 0.5695% CI: [0.49, 1.48]Chi-squared
Secondary
Aspartate Aminotransferase ≥100 U/Liter
Time frame: 20 weeks through discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Aspartate Aminotransferase ≥100 U/Liter | 35 Participants |
| Placebo | Aspartate Aminotransferase ≥100 U/Liter | 48 Participants |
p-value: 0.1595% CI: [0.47, 1.12]Chi-squared
Secondary
Birth Weight
Time frame: At birth
Population: Liveborn infants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamins | Birth Weight | 3247 grams | Standard Deviation 575 |
| Placebo | Birth Weight | 3244 grams | Standard Deviation 581 |
p-value: 0.55Wilcoxon (Mann-Whitney)
Secondary
Birth Weight <2500 Grams
Time frame: At birth
Population: Live born infants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Birth Weight <2500 Grams | 345 Participants |
| Placebo | Birth Weight <2500 Grams | 369 Participants |
p-value: 0.3295% CI: [0.81, 1.07]Chi-squared
Secondary
Cesarean Delivery
Time frame: Delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Cesarean Delivery | 1269 Participants |
| Placebo | Cesarean Delivery | 1224 Participants |
p-value: 0.3595% CI: [0.97, 1.11]Chi-squared
Secondary
Creatinine ≥1.5 mg/dl (133 μmol/Liter)
Time frame: 20 weeks through discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Creatinine ≥1.5 mg/dl (133 μmol/Liter) | 9 Participants |
| Placebo | Creatinine ≥1.5 mg/dl (133 μmol/Liter) | 12 Participants |
p-value: 0.5195% CI: [0.32, 1.77]Chi-squared
Secondary
Fetal or Neonatal Death
Time frame: During pregnancy or thorugh discharge
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vitamins | Fetal or Neonatal Death | All Fetal or Neonatal Deaths | 113 Participants |
| Vitamins | Fetal or Neonatal Death | Fetal loss at < 20 weeks | 55 Participants |
| Vitamins | Fetal or Neonatal Death | Fetal death at ≥20 weeks | 38 Participants |
| Vitamins | Fetal or Neonatal Death | Neonatal death | 20 Participants |
| Placebo | Fetal or Neonatal Death | Neonatal death | 27 Participants |
| Placebo | Fetal or Neonatal Death | All Fetal or Neonatal Deaths | 122 Participants |
| Placebo | Fetal or Neonatal Death | Fetal death at ≥20 weeks | 36 Participants |
| Placebo | Fetal or Neonatal Death | Fetal loss at < 20 weeks | 59 Participants |
p-value: 0.5395% CI: [0.72, 1.19]Chi-squared
Secondary
Gestational Age at Delivery
Time frame: Delivery
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Vitamins | Gestational Age at Delivery | 38.9 weeks | Standard Deviation 3.5 |
| Placebo | Gestational Age at Delivery | 38.8 weeks | Standard Deviation 3.5 |
p-value: 0.21Wilcoxon (Mann-Whitney)
Secondary
Hematocrit ≤24% With Transfusion
Time frame: Delivery admission to discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Hematocrit ≤24% With Transfusion | 40 Participants |
| Placebo | Hematocrit ≤24% With Transfusion | 59 Participants |
p-value: 0.0595% CI: [0.45, 1.01]Chi-squared
Secondary
Intraventricular Hemorrhage, Grade III or IV
Time frame: Delivery through discharge
Population: Live born infants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Intraventricular Hemorrhage, Grade III or IV | 6 Participants |
| Placebo | Intraventricular Hemorrhage, Grade III or IV | 7 Participants |
p-value: 0.7895% CI: [0.29, 2.54]Chi-squared
Secondary
Maternal Death
Time frame: Delivery through hospital discharge
Population: One maternal death in each group due to peripartum cardiomyopathy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Maternal Death | 1 Participants |
| Placebo | Maternal Death | 1 Participants |
Secondary
Maternal Hospital Stay
Time frame: Delivery through discharge
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vitamins | Maternal Hospital Stay | 2.0 days |
| Placebo | Maternal Hospital Stay | 2.0 days |
p-value: 0.65Wilcoxon (Mann-Whitney)
Secondary
Medically Indicated Delivery Because of Hypertension
Time frame: 20 weeks through discharge following delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Medically Indicated Delivery Because of Hypertension | 509 Participants |
| Placebo | Medically Indicated Delivery Because of Hypertension | 473 Participants |
p-value: 0.2595% CI: [0.95, 1.21]Chi-squared
Secondary
Necrotizing Enterocolitis
Time frame: Delivery through discharge
Population: Live born infants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Necrotizing Enterocolitis | 10 Participants |
| Placebo | Necrotizing Enterocolitis | 14 Participants |
p-value: 0.4195% CI: [0.32, 1.6]Chi-squared
Secondary
Neonatal Hospital Stay
Time frame: Birth through discharge from hospital
Population: Live born infants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vitamins | Neonatal Hospital Stay | 2.0 days |
| Placebo | Neonatal Hospital Stay | 2.0 days |
p-value: 0.79Wilcoxon (Mann-Whitney)
Secondary
Placental Abruption
Time frame: During pregnancy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Placental Abruption | 24 Participants |
| Placebo | Placental Abruption | 36 Participants |
p-value: 0.1295% CI: [0.4, 1.11]Chi-squared
Secondary
Postpartum Pulmonary Edema
Time frame: After delivery through discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Postpartum Pulmonary Edema | 3 Participants |
| Placebo | Postpartum Pulmonary Edema | 10 Participants |
p-value: 0.0595% CI: [0.08, 1.08]Chi-squared
Secondary
Preeclampsia (Mild, Severe, HELLP Syndrome, Eclampsia)
HELLP denotes hemolytic anemia, elevated liver enzymes, and low platelet count.
Time frame: 20 weeks through discharge following delivery
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vitamins | Preeclampsia (Mild, Severe, HELLP Syndrome, Eclampsia) | Mild Preeclampsia | 212 Participants |
| Vitamins | Preeclampsia (Mild, Severe, HELLP Syndrome, Eclampsia) | HELLP Syndrome | 2 Participants |
| Vitamins | Preeclampsia (Mild, Severe, HELLP Syndrome, Eclampsia) | Severe Preeclampsia | 134 Participants |
| Vitamins | Preeclampsia (Mild, Severe, HELLP Syndrome, Eclampsia) | Eclampsia | 10 Participants |
| Vitamins | Preeclampsia (Mild, Severe, HELLP Syndrome, Eclampsia) | Total Preeclampsia | 358 Participants |
| Placebo | Preeclampsia (Mild, Severe, HELLP Syndrome, Eclampsia) | Eclampsia | 4 Participants |
| Placebo | Preeclampsia (Mild, Severe, HELLP Syndrome, Eclampsia) | Total Preeclampsia | 332 Participants |
| Placebo | Preeclampsia (Mild, Severe, HELLP Syndrome, Eclampsia) | Mild Preeclampsia | 191 Participants |
| Placebo | Preeclampsia (Mild, Severe, HELLP Syndrome, Eclampsia) | Severe Preeclampsia | 129 Participants |
| Placebo | Preeclampsia (Mild, Severe, HELLP Syndrome, Eclampsia) | HELLP Syndrome | 8 Participants |
p-value: 0.3395% CI: [0.93, 1.24]Chi-squared
Secondary
Pregnancy Associated Hypertension
Time frame: 20 weeks through discharge following delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Pregnancy Associated Hypertension | 1457 Participants |
| Placebo | Pregnancy Associated Hypertension | 1322 Participants |
p-value: 0.00495% CI: [1.03, 1.17]Chi-squared
Secondary
Premature Rupture of Membranes
Time frame: During pregnancy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Premature Rupture of Membranes | 124 Participants |
| Placebo | Premature Rupture of Membranes | 129 Participants |
p-value: 0.7495% CI: [0.75, 1.22]Chi-squared
Secondary
Preterm Birth
Time frame: Delivery
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vitamins | Preterm Birth | <37 weeks' gestation | 513 Participants |
| Vitamins | Preterm Birth | <32 weeks' gestation | 149 Participants |
| Placebo | Preterm Birth | <37 weeks' gestation | 526 Participants |
| Placebo | Preterm Birth | <32 weeks' gestation | 173 Participants |
Comparison: \<37 weeks' gestationp-value: 0.6395% CI: [0.87, 1.09]Chi-squared
Comparison: \<32 weeks' gestationp-value: 0.1695% CI: [0.69, 1.06]Chi-squared
Secondary
Respiratory Distress Syndrome
Time frame: Delivery through discharge
Population: Live born infants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Respiratory Distress Syndrome | 150 Participants |
| Placebo | Respiratory Distress Syndrome | 144 Participants |
p-value: 0.7595% CI: [0.83, 1.3]Chi-squared
Secondary
Retinopathy of Prematurity
Time frame: Within 1 month of birth
Population: Live born infants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Retinopathy of Prematurity | 19 Participants |
| Placebo | Retinopathy of Prematurity | 16 Participants |
p-value: 0.6295% CI: [0.61, 2.3]Chi-squared
Secondary
Sepsis
Time frame: Delivery through discharge
Population: Live born infants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Sepsis | 30 Participants |
| Placebo | Sepsis | 23 Participants |
p-value: 0.3495% CI: [0.76, 2.23]Chi-squared
Secondary
Small for Gestational Age
A baby whose birth weight is less than the 3rd percentile is considered to be small for gestational age (adjusted for sex and race or ethnic group)
Time frame: At birth
Population: Live born infants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Small for Gestational Age | 133 Participants |
| Placebo | Small for Gestational Age | 132 Participants |
p-value: 0.9895% CI: [0.79, 1.27]Chi-squared
Post Hoc
Analysis of Primary Composite Outcome in Participants Randomized Before the 13th Week of Pregnancy
Subgroup analysis of the primary composite outcome (severe pregnancy associated hypertension or severe or mild hypertension with elevated liver-enzyme levels, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, indicated preterm birth, fetal-growth restriction or prenatal death) in participants who were randomized before the 13th week of pregnancy.
Time frame: During pregnancy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Analysis of Primary Composite Outcome in Participants Randomized Before the 13th Week of Pregnancy | 144 Participants |
| Placebo | Analysis of Primary Composite Outcome in Participants Randomized Before the 13th Week of Pregnancy | 127 Participants |
p-value: 0.3295% CI: [0.89, 1.42]Chi-squared
Post Hoc
Analysis of Primary Composite Outcome in Participants Randomized on or After the 13th Week of Pregnancy
Subgroup analysis of the primary composite outcome (severe pregnancy associated hypertension or severe or mild hypertension with elevated liver-enzyme levels, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, indicated preterm birth, fetal-growth restriction or prenatal death) in participants who were randomized on or after the 13th week of pregnancy.
Time frame: During pregnancy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamins | Analysis of Primary Composite Outcome in Participants Randomized on or After the 13th Week of Pregnancy | 161 Participants |
| Placebo | Analysis of Primary Composite Outcome in Participants Randomized on or After the 13th Week of Pregnancy | 158 Participants |
p-value: 0.8695% CI: [0.82, 1.26]Chi-squared