Objective
We sought to investigate whether prenatal vitamin C and E supplementation reduces the incidence of gestational hypertension (GH) and its adverse conditions among high- and low-risk women.
Study Design
In a multicenter randomized controlled trial, women were stratified by the risk status and assigned to daily treatment (1 g vitamin C and 400 IU vitamin E) or placebo. The primary outcome was GH and its adverse conditions.
Results
Of the 2647 women randomized, 2363 were included in the analysis. There was no difference in the risk of GH and its adverse conditions between groups (relative risk, 0.99; 95% confidence interval, 0.78–1.26). However, vitamins C and E increased the risk of fetal loss or perinatal death (nonprespecified) as well as preterm prelabor rupture of membranes.
Conclusion
Vitamin C and E supplementation did not reduce the rate of preeclampsia or GH, but increased the risk of fetal loss or perinatal death and preterm prelabor rupture of membranes.
Preeclampsia (PE), defined as gestational hypertension (GH) and proteinuria, is a syndrome unique to, and that complicates, 2-8% of human pregnancies. It accounts for about 10-15% of direct maternal deaths in low-, middle-, and high-income countries and is associated with low birthweight (<2500 g) infants and thereby perinatal deaths through both preterm birth and intrauterine growth restriction (IUGR).
See related editorial, page 207
Several lines of evidence support the hypothesis that oxidative stress, an imbalance between prooxidant and antioxidant forces, plays an essential role in the development of hypertensive disorders of pregnancy. Markers of oxidative stress, such as isoprostanes and malondialdehyde, are increased in plasma, small arteries, and decidua basalis of women with PE. In response to these findings, several clinical studies have been conducted that attempt to improve the antioxidant capability of pregnant women and thereby reduce the risk of PE. A pilot randomized trial by Chappell et al reported a 54% reduction in PE in the group that was supplemented with vitamins C and E (relative risk [RR], 0.39; 95% confidence interval [CI], 0.17–0.90) compared with the placebo group. Most women included in the trial were at an increased risk for PE as defined by abnormal uterine artery Doppler waveform finding or by history of the disease.
In response to the trial by Chappell et al, we designed the International Trial of Antioxidants in the Prevention of PE (INTAPP) to assess whether or not vitamin C and E supplementation during pregnancy reduces the risk of developing GH and its adverse conditions in: (1) nulliparous women without additional identified major risk factors; and (2) nulliparous and multiparous women having those risk factors.
Materials and Methods
From January 2004 through March 2006, we conducted a double-blinded, multicenter trial in Canada (17 centers) and Mexico (10 centers). Women were eligible for the trial if they were between 12 and 18 completed weeks of pregnancy on the basis of last menstrual period and confirmed by early ultrasound examination. The exclusion criteria were: (1) women who regularly consumed supplements >200 mg/day for vitamin C and/or 50 IU/day for vitamin E; (2) women who took warfarin; (3) women who had known fetal abnormalities (eg, hydatidiform mole), or known fetal chromosomal or major malformations in the current pregnancy; (4) women who had a history of medical complications including endocrine disease (eg, thyroid disease), renal disease with altered renal function, epilepsy, any collagen vascular disease (eg, systemic lupus erythematosus and scleroderma), active and chronic liver disease (eg, hepatitis), heart disease, serious pulmonary disease, cancer, or hematologic disorder (eg, anemia or thrombophilia); (5) women with repeated spontaneous abortion (women with a previous bleeding in the first trimester were included if the site documented a viable fetus at the time of recruitment); and (6) women who used an illicit drug during the current pregnancy.
Randomization was performed through an electronic data management platform, which enabled randomization and data entry over the Internet through a secured and restricted-access World Wide Web site and stored the data in a centralized database. Randomization was stratified by center and by risk status according to prespecified clinical risk criteria. Women were at high risk if they were nulliparous or multiparous with prepregnancy chronic hypertension (or diastolic blood pressure >90 mm Hg at <20 gestational weeks or use of antihypertensive medication), prepregnancy diabetes (insulin-dependent or hypoglycemic agents), multiple pregnancy, or a history of PE in the previous pregnancy. Women were stratified into the low-risk stratum if they were nulliparous without any identified clinical risk factors. They were randomly allocated at a ratio of 1:1 to antioxidant supplementation (vitamins C and E) group or to placebo group through an electronic data management platform. None of the trial staff or any other person involved in the trial knew the treatment allocation for any women until after completion of the trial analysis. The Hôpital Ste-Justine Ethics Research Committee in Montreal, Quebec, Canada (No. 1863, Jan. 12, 2003) and the Instituto Mexicano del Seguro Sosial (IMSS) Ethics Board in Mexico City, Mexico, provided ethics approval, and we acquired ethics approval from each participating center. All participants gave written consent.
Women were provided either with the vitamins C and E or placebo (Carlson Laboratories Inc, Arlington Heights, IL). Women assigned to the vitamin group were advised to take 2 soft gel capsules, each containing 500 mg of vitamin C (as ascorbic acid) and 200 IU of vitamin E (100 IU d-α-tocopherol, 100 IU d-α-tocopheryl acetate). The total daily dose of vitamin C was 1000 mg, and that of vitamin E was 400 IU. Women in the placebo group were advised to take capsules that were identical in appearance to the active treatment capsules. Women were asked to swallow the capsules whole without crushing or chewing them and were advised not to take other antioxidant supplements.
Women and their infants received care according to standard practice in each center, with surveillance for hypertension using standardized measurements of blood pressure. Systolic and diastolic blood pressure were measured by the clinical staff at each visit using a sphygmomanometer and were assessed in a sitting position, with the cuffed arm resting on a desk at the level of the heart. Korotkoff phase V was used to measure diastolic blood pressure and Korotkoff phase IV was utilized when a phase V was absent.
The composite primary outcome was defined as GH and its adverse conditions. Our choice of the primary outcome for the trial relied on definitions proposed in the Canadian Consensus Statement of 1997. The goal was to assess the impact of antioxidants on clinically significant hypertensive disorders of pregnancy, whether or not proteinuria was present. GH was defined as ≥2 readings of diastolic blood pressure ≥90 mm Hg taken 4 hours apart but within 72 hours occurring at >20 weeks of gestation. Severe GH was defined as ≥2 readings of diastolic blood pressure systolic ≥110 mm Hg or systolic blood pressure ≥160 mm Hg at least 4 hours apart. Proteinuria was defined as the urinary excretion of ≥0.3 g/24 hours, or ≥2+ on diagnostic strips. PE was defined as GH or severe GH with proteinuria. For women with preexisting hypertension, PE is classified as new or worsening proteinuria as defined above. For women with preexisting proteinuria (eg, diabetes with renal involvement), the diagnosis of PE was made on clinical or biochemical grounds by identifying at least 1 additional adverse condition (eg, abnormal liver enzymes, low platelets, and eclampsia). All cases of GH and PE were further adjudicated by 2 independent investigators working in the trial coordinating center with failure to achieve consensus resolved by a third independent investigator.
Adverse conditions were defined as ≥1 of the following selected medical conditions: (1) diastolic pressure ≥110 mm Hg or systolic pressure ≥160 mm Hg; (2) proteinuria ≥300 mg/24-hour urine collection or ≥2+ on diagnostic strips; (3) convulsion (eclampsia); (4) thrombocytopenia (platelet count <100,000 × 10 9 /L); (5) elevated liver enzyme levels (aspartate aminotransferase or alanine aminotransferase >70 U/L); (6) hematocrit <24% or blood transfusion; (7) IUGR (ie, birthweight <3rd centile for gestational age using Canadian population-based birthweight for gestational age as reference ); and (8) perinatal death (fetal death >20 weeks or neonatal death within 7 days). Other maternal outcomes included death, severe GH, severe PE, prelabor rupture of membranes (PROM), preterm PROM (PPROM), and hospitalization prior to giving birth. Severe PE was defined as PE and the presence of at least 1 of the following adverse conditions: (1) diastolic pressure ≥110 mm Hg or systolic pressure ≥160 mm Hg; (2) proteinuria ≥5 g/24-hour urine collection or dipstick ≥3+; (3) convulsion; (4) thrombocytopenia; (5) elevated liver enzyme levels; (6) hematocrit <24% or blood transfusion; (7) IUGR; (8) perinatal death; or (9) preterm delivery (<34 weeks of gestational age). PROM was defined as spontaneous at ≥37 weeks of gestation and before onset of labor. PPROM was defined as spontaneous at <37 weeks of gestation and before onset of labor.
A composite outcome “fetal loss or perinatal death” was defined as any fetal loss at <20 weeks, stillbirth, or neonatal death. Other fetal or neonatal outcomes included: (1) preterm birth <37 weeks of gestational age (gestational age corrected by early ultrasound scan); (2) preterm birth <34 weeks of gestational age; (3) small for gestational age (defined as <5th or 10th centile); (4) perinatal mortality; (5) spontaneous abortion; and (6) neonatal morbidity indicators such as Apgar score <4 at 5 minutes, retinopathy of prematurity, periventricular leukomalacia, thrombocytopenia, neutropenia, sepsis, necrotizing enterocolitis, hypotonia, intraventricular hemorrhage, convulsion, sepsis, respiratory distress requiring oxygen therapy and/or assisted ventilation for >24 hours, and the need for intensive care for >4 days.
Based on published data from the trial of calcium to prevent PE in low-risk women and 1-year delivery records from 2 collaborating tertiary obstetric centers (the Royal Alexandra Hospital, Edmonton, Alberta, Canada [1996] and St-Francois d’Assise Hospital, Quebec, Quebec, Canada [1999]), we estimated 4% and 15% incidences of the primary outcome in the low- and high-risk strata, respectively. We planned to recruit 5000 patients per group in stratum I (low risk) for a total of 10,000 patients and 1250 women per group in stratum II (high risk) for a total of 2500 patients to detect 30% reduction of PE, with a power of 90% and alpha error of 5%. After reviewing the evidence from the trials conducted by a United Kingdom research group (vitamin C and vitamin E in pregnant women at risk for PE-VIP trial) and the Australian Collaborative Trial of Supplements Study group as well as our internal data on serious adverse events, and in accordance with the recommendations of the data safety and monitoring committee, the trial steering committee decided to terminate the trial. A total of 2640 consenting eligible women were recruited. The last woman was recruited on March 30, 2006, and the last infant was born on Sept. 1, 2006.
The analysis was carried out on an intention-to-treat basis. We used Student t tests to compare continuous variables and the χ 2 test or Fisher’s exact test for categorical variables, as appropriate. The effects of the intervention were expressed as RR (95% CI). Participants with missing outcomes due to withdrawal or loss to follow-up were excluded from the analysis of outcomes. We assessed twin and triplet infants as if cluster randomized (the cluster being the mother). Neonatal outcomes were analyzed by adjusting for the multiplicity of the pregnancy as the main neonatal outcomes were strongly affected by multiple births except for the outcome of preterm birth. Stratified analysis and multivariable logistic regression were performed to assess whether the effect estimates differed according to country, ethnic group and socioeconomic status, smoking, maternal age (<20 and >35 years), commercial and dietary vitamin C and E consumption (estimated by the Food Frequency Questionnaire) at the time of randomization and at 26 weeks of gestation, or patient compliance that was: (1) calculated as the proportion of tablets not returned in the bottles over the total number of tablets given to each woman; and (2) defined as compliant to treatment if >80% of tablets were used.
The study was registered as an International Standard Randomized Controlled Trial (RCT), No. ISRCTN 85024310.
Results
The Figure displays the trial profile. Of the 2647 eligible women who were randomized, a total of 2640 women were validly randomized (randomization error in 3 women, recruitment halted at randomization visit in 2 women, 2 women noneligible after randomization). Of these, 1315 (49.81%) women were assigned to vitamins C and E group and 1325 women (50.19%) were allocated to the placebo group. Patients who were lost to follow-up were excluded from the analyses and a total of 2363 women and their 2536 infants (vitamin group: 1167 women and 1243 infants; placebo group: 1196 women and 1293 infants) were included in the final analyses.
At study entry, maternal baseline characteristics were similar in 2 groups, except that there was a slightly higher proportion of multiple pregnancies in the placebo group ( Table 1 ). There was no significant difference in patient compliance between the vitamin and the placebo groups (85.5% vs 86.5%; P = .3640).
| Characteristic | Vitamins C and E n = 1167 | Placebo n = 1196 |
|---|---|---|
| Maternal age, y | 28.66 (5.57) | 28.68 (5.44) |
| Maternal education, y | 14.48 (3.47) | 14.53 (3.62) |
| Maternal prepregnancy BMI a | 25.45 (5.69) | 25.47 (2.09) |
| Maternal visit-1 BMI a | 26.69 (5.81) | 26.75 (6.21) |
| Ethnic origin | ||
| Asian | 26 (2.23) | 12 (1.01) |
| South Asian | 6 (0.51) | 4 (0.34) |
| Caucasian | 364 (31.22) | 406 (34.00) |
| French Canadian | 285 (24.44) | 279 (23.37) |
| African | 10 (0.86) | 16 (1.34) |
| Hispanic | 403 (34.56) | 416 (34.84) |
| First Nation | 7 (0.60) | 5 (0.42) |
| Other | 65 (5.57) | 56 (4.69) |
| Gestational age, wk | 15.19 (2.10) | 15.28 (2.09) |
| Gravidity | 1.65 (1.02) | 1.67 (1.10) |
| Nulliparous | 934 (80.03) | 957 (80.02) |
| Employed | 890 (76.33) | 911 (76.36) |
| Smoking before pregnancy | 340 (29.16) | 330 (27.64) |
| Current smoker | 76 (6.56) | 88 (7.43) |
| Current drinker | 14 (1.20) | 23 (1.93) |
| Blood pressure | ||
| Systolic | 108.92 (13.13) | 109.27 (13.57) |
| Diastolic | 67.50 (9.03) | 67.33 (9.07) |
| Dipstick proteinuria | ||
| Normal or trace | 1109 (96.43) | 1137 (96.85) |
| 1+ | 40 (3.48) | 33 (2.81) |
| 2+ | 1 (0.09) | 4 (0.34) |
| High-risk group (stratum) | 338 (28.96) | 346 (28.93) |
| Chronic hypertension | 78 (6.68) | 70 (5.85) |
| Diabetes | 82 (7.03) | 76 (6.35) |
| Multiple pregnancy b | 67 (5.74) | 93 (7.78) b |
| History of PE | 147 (12.60) | 148 (12.37) |
| Multiple risk factors | 33 (2.83) | 38 (3.18) |
| Use of supplements | ||
| Multivitamins | 711 (61.29) | 756 (63.26) |
| Vitamin C | 20 (1.72) | 10 (0.84) |
| Vitamin E | 2 (0.17) | 1 (0.08) |
| Folate | 527 (45.35) | 519 (43.54) |
| Calcium | 164 (14.11) | 163 (13.67) |
| Iron | 272 (23.41) | 271 (22.75) |
| Family history of PE, eclampsia, or GH | 156 (13.37) | 143 (11.96) |
| Family history of PE | 95 (8.14) | 84 (7.02) |
| Family history of eclampsia | 16 (1.37) | 10 (0.84) |
| Family history of GH | 89 (7.63) | 82 (6.86) |
| Obstetric history | ||
| History of abortion | 316 (27.10) | 315 (26.36) |
| History of stillbirth | 17 (1.46) | 11 (0.92) |
| History of preterm birth | 97 (8.32) | 84 (7.03) |
| History of low birthweight | 60 (5.15) | 48 (4.02) |
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