Obstetrics & Gynecology:
Antioxidant Therapy to Prevent Preeclampsia: A Randomized Controlled Trial
Spinnato, Joseph A. II MD1; Freire, Salvio MD2; Pinto e Silva, Joao Luiz MD3; Cunha Rudge, Marilza Vieira MD4; Martins-Costa, Sérgio MD5; Koch, Matthew A. MD6; Goco, Norman6; Santos, Cleide de Barros MD2; Cecatti, Jose Guilherme MD3; Costa, Roberto MD4; Ramos, José Geraldo MD5; Moss, Nancy PhD7; Sibai, Baha M. MD1
From the 1University of Cincinnati College of Medicine, Cincinnati, Ohio; 2Universidade Federal de Pernambuco, Hospital das Clínicas, Recife, Brazil; 3Universidade Estadual de Campinas, Campinas, Brazil; 4Universidade Estadual Paulista, Botucatu, Brazil; 5Universidade Federal Do Rio Grande Do Sul, Hospital de Clínicas, Porto Alegre, Brazil; 6RTI International, Research Triangle Park, North Carolina; and 7National Institute of Child Health and Human Development, Bethesda, Maryland.
Supported by Grant Number 1 U01 HD40565 cosponsored by the National Institute of Child Health and Human Development and the Bill and Melinda Gates Foundation.
The authors thank Jutta Thornberry, Janet Bartz, Steve Litavecz, and Ty Hartwell, RTI International; Susie Meikle, our initial National Institute of Child Health and Human Development Project officer; and members of our site research teams: Cincinnati: Les Myatt; Recife: Elias Ferreira de Melo, Antonio Carlos Barbosa Lima, Angelo Manoel Barreto, José Remígio Neto, Eduardo Costa Ramos; Botucatu: José Carlos Peraçoli, Joelcio Francisco Abbade, Anice Vieira de Camargo Martins, Grasiela Bossolan, Kleber Campos, Tania Prevedel; Porto Alegre: Melissa Prade Hemesath, Cristiano Dhil Zaffari; Campinas: Fernanda G Surita, Eliana Amaral, Mary A. Parpinelli, Fabiana Krupa. Additionally, we thank Soubhi Kahhale and his research team at the University of Sao Paulo, Brasil, for their important initial contributions to this research.
Corresponding author: Joseph A. Spinnato II, MD, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, PO Box 2670526, Cincinnati, OH 40267-0526; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors have no potential conflicts of interest to disclose.
OBJECTIVE: To study whether antioxidant supplementation will reduce the incidence of preeclampsia among patients at increased risk.
METHODS: A randomized, placebo-controlled, double-blind clinical trial was conducted at four Brazilian sites. Women between 12 0/7 weeks and 19 6/7 weeks of gestation and diagnosed to have chronic hypertension or a prior history of preeclampsia were randomly assigned to daily treatment with both vitamin C (1,000 mg) and vitamin E (400 International Units) or placebo. Analyses were adjusted for clinical site and risk group (prior preeclampsia, chronic hypertension, or both). A sample size of 734 would provide 80% power to detect a 40% reduction in the risk of preeclampsia, assuming a placebo group rate of 21% and α=.05. The α level for the final analysis, adjusted for interim looks, was 0.0458.
RESULTS: Outcome data for 707 of 739 randomly assigned patients revealed no significant reduction in the rate of preeclampsia (study drug, 13.8% [49 of 355] compared with placebo, 15.6% [55 of 352], adjusted risk ratio 0.87 [95.42% confidence interval 0.61–1.25]). There were no differences in mean gestational age at delivery or rates of perinatal mortality, abruptio placentae, preterm delivery, and small for gestational age or low birth weight infants. Among patients without chronic hypertension, there was a slightly higher rate of severe preeclampsia in the study group (study drug, 6.5% [11 of 170] compared with placebo, 2.4% [4 of 168], exact P=.11, odds ratio 2.78, 95% confidence interval 0.79–12.62).
CONCLUSION: This trial failed to demonstrate a benefit of antioxidant supplementation in reducing the rate of preeclampsia among patients with chronic hypertension and/or prior preeclampsia.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.ClinicalTrials.gov, NCT00097110
LEVEL OF EVIDENCE: I
In response to evidence for the role of oxidative stress in the pathophysiology of the endothelial damage seen in preeclampsia,1 several clinical studies have been reported that attempt to improve the antioxidant capability of women at risk for preeclampsia. In 1999 Chappell et al2 reported the results of their randomized study of 283 women who were identified as being at an increased risk by abnormal two-stage uterine artery Doppler analysis or a previous history of preeclampsia. Preeclampsia occurred in 24 (17%) of 142 women in the placebo group and 11 (8%) of 141 in the group receiving daily vitamin C (1,000 mg) and vitamin E (400 International Units) (adjusted odds ratio (OR) 0.39, 95% confidence interval [CI] 0.17–0.90, P=.02).
Subsequent to this report, several consecutive studies have reported negative outcomes.3–7 In response to the Chappell study,2 we initiated a trial of antioxidant supplementation focusing upon patients with chronic hypertension and/or a history of preeclampsia.
MATERIALS AND METHODS
This clinical trial was conducted as a protocol within the National Institute of Child Health and Human Development Global Network for Women’s and Children’s Health Research. The primary clinical center (Recife) and three additional clinical sites (Campinas, Botucatu, and Porto Alegre) are staffed by the Senior Foreign Investigator (Recife) or Senior Collaborating Investigators (Campinas, Botucatu, and Porto Alegre), a program coordinator, research physicians, and a data manager or staff nurse. Each site’s major teaching hospital serves a primarily urban low-income population.
We enrolled women seeking prenatal care who were 12 0/7 to 19 6/7 weeks pregnant and diagnosed with nonproteinuric chronic hypertension or a prior history of preeclampsia in their most recent pregnancy that progressed beyond 20 weeks of gestation. Patients were enrolled with the criterion of chronic hypertension if they were receiving antihypertensive medication or if the systolic blood pressure was 140 mm Hg or more or diastolic blood pressure was 90 mm Hg or more on at least two occasions at least 4 hours apart or when the medical record was available and supported the diagnosis or if the medical record was not available, the patient answered affirmatively to one of the two following questions: 1) When not pregnant, were you ever prescribed medication by a health care provider to control your blood pressure? 2) When not pregnant, were you ever told by a health care provider that you had a problem with high blood pressure? Patients were enrolled with the criterion of history of preeclampsia/eclampsia if the medical record was available and supported the diagnosis of preeclampsia or, if the medical record was not available, in the opinion of the enrolling physician, the patient’s history of the events of that pregnancy were highly consistent with the diagnosis of prior preeclampsia. Exclusion criteria were planned delivery elsewhere, multifetal gestation, allergy to vitamin C or vitamin E, requirement for aspirin or anticoagulant medication, 24-hour urinary protein 300 mg or more, prepregnancy diabetes mellitus, known fetal anomaly incompatible with life, or prior participation in the study.
The protocol was approved by the National Institute of Child Health and Human Development and the institutional review boards at the University of Cincinnati, each participating site, and the data coordinating center. Each woman gave written informed consent. Planned interim analyses were monitored by the Global Network’s independent data monitoring committee.
Women were assigned randomly to receive daily vitamin C 1,000 mg and vitamin E 400 International Units or placebo. The medications were manufactured as softgel capsules by J R Carlson Laboratories (Arlington Heights, IL). Each active treatment gel capsule contained 500 mg of ascorbic acid, 100 International Units of d-alpha tocopherol, 100 International Units of d-alpha tocopherol acetate, and excipients (gelatin, soybean oil, glycerin, water lecithin, and caramel color). The placebo gel capsules contained excipients only and were externally identical to the active drug. Participants were instructed to ingest two gel capsules daily from enrollment until delivery or until the diagnosis of preeclampsia. Correct supplier randomization assignment was verified by the data coordinating center.
The randomization sequence was constructed by the data coordinating center as permuted blocks of random size, stratified by clinical center, and implemented by a program residing on the clinical center’s study computer. We calculated the sample size for 80% power, by intent-to-treat analysis, to detect a relative risk of 0.60 for study drug compared with placebo, assuming a placebo group preeclampsia rate of 21%, with (two-tailed) α=.05.
Study participants were discouraged from the use of antioxidant vitamins, calcium supplements, and chronic use of aspirin. The women were followed at routine prenatal visits, typically every 4 weeks until 26 to 28 weeks of gestation, every 2 to 3 weeks until 36 weeks of gestation, and then weekly until delivery or the onset of preeclampsia. At each visit, the women’s blood pressure, weight, and urinary protein excretion were measured. Urinary protein was measured with a dipstick in a fresh, clean, midstream urine sample.
Compliance with treatment was assessed by counting residual pills at monthly return visits. A computerized bottle cap, the MEMS V TrackCap Child Resistant (APREX, a division of AARDEX, Ltd., Union City, CA), which internally records the date and time of each opening of the pill bottle, was placed on the first pill bottle and then transferred to sequential bottles. Information from the TrackCap was shared with the patients at monthly intervals to motivate optimal compliance through encouragement and constructive problem solving.
The primary outcome was the development of preeclampsia, according to the following definitions: hypertension (defined as a systolic blood pressure of 140 mm Hg or a diastolic blood pressure of 90 mm Hg) was designated as severe if two or more systolic values obtained four or more hours apart were 160 mm Hg or if two or more diastolic values were 110 mm Hg. Among patients without chronic hypertension, gestational hypertension was defined as nonproteinuric hypertension after week 20 of gestation or during the postpartum period. Preeclampsia was defined as hypertension plus proteinuria (either 300 mg per 24 hours or 2+ or more by dipstick on two or more occasions 4 hours apart). Severe preeclampsia was defined as severe hypertension and proteinuria; urinary protein excretion 5 g per day with any degree of hypertension; hypertension complicated by pulmonary edema or a low platelet count (less than 100,000/mL); or hemolysis, an elevated serum aspartate aminotransferase concentration (more than 70 units/L), and a low platelet count (the hemolysis, elevated liver enzymes, low platelets syndrome). Among chronically hypertensive patients, superimposed preeclampsia was defined by hypertension plus proteinuria (either 300 mg/24 h or 2+ or more by dipstick). Women were considered to have eclampsia if they met the criteria for pregnancy-induced hypertension and had convulsions. Women were followed through the 14th day postpartum for the occurrence of preeclampsia. All reports of suspected gestational hypertension or preeclampsia underwent blinded review by the Senior Foreign Investigator (S.F.) and the Principal Investigator (J.A.S.).
Secondary outcomes included the severity of preeclampsia, gestational hypertension, abruptio placentae, premature rupture of membranes, preterm birth, small for gestational age and low birth weight infants. Premature rupture of membranes was defined as rupture of membranes before the onset of labor. Small for gestational age was defined as a birth weight below the 10th percentile according to the growth tables of Alexander et al.8 Abruptio placentae was diagnosed according to clinical findings or placental examination.
Data were analyzed using the intent-to-treat principle: all randomly assigned subjects were included in the treatment group to which they were originally assigned. Participants with missing outcomes due to withdrawal of consent or loss to follow-up were excluded from the analysis of outcomes. Secondary analyses of subjects who had received at least 80% of the intended doses, a threshold consistent with previous studies4,6 as assessed by returned pill counts, were performed, along with analyses by risk group (prior preeclampsia only, chronic hypertension only, or both) and adjusted for covariates. Two interim analyses that corresponded to 34% and 68% of the total planned results were performed according to the Lan-DeMets approach using an α-spending function analogous to the O’Brien-Fleming procedure9 at an overall level of α=.05 (two-tailed); the significance level for the final analysis was α=.0458. Comparisons between study drug and placebo groups were stratified by site and risk group using Cochran-Mantel-Haenszel statistics10 for binary outcomes and analysis of variance for continuous outcomes, with natural log transformation and supplemental Cochran-Mantel-Haenszel row mean tests with modified ridit scores (the nonparametric van Elteren test)10 where distributions were skewed. Covariate adjustments analyses used logistic regression models.11 Data were analyzed using SAS/STAT 9.3 (SAS Institute, Inc., Cary, NC). Exact Cochran-Mantel-Haenszel procedures in StatXact 7 (Cytel, Inc., Cambridge, MA) were used when binary outcomes were sparse, yielding odds ratios instead of risk ratios. Lan-DeMets calculations were performed using East 4 (Cytel, Inc., Cambridge, MA).
Screening for enrollment began on July 2, 2003, at Recife; May 19, 2004, at Botucatu; July 5, 2004, at Porto Alegre, and February 2, 2005, at Campinas; and concluded on May 15, 2006. Follow-up was completed on November 23, 2006. From the general population of obstetric clinic patients and of 835 women satisfying inclusion criteria, 739 of 753 (98%) eligible women were enrolled in the study (Recife, 265; Campinas, 202; Botucatu, 152; Porto Alegre, 120). Figure 1 describes the enrollment flow. In each treatment group, 4.3% of subjects were lost to follow-up or withdrew consent. Thus, outcome data were available for 707 women, of whom 355 were assigned to the study drug and 352 to the placebo. Of these, 19 (5.4%) and 7 (2.0%) had early treatment termination but remained in follow-up. The demographic and clinical characteristics of the enrolled subjects, including the criteria for inclusion in the study, were similar between the two groups (Table 1). Of patients enrolled with chronic hypertension, 52.8% were receiving antihypertensive therapy at onset of pregnancy. Gestational age at enrollment was determined by best obstetric estimate; ultrasound dating was performed on 61.3% of the women and rejected the last menstrual period dating in about half of those. Violations of inclusion or exclusion criteria occurred in 25 subjects. Twenty-three women were enrolled outside the 12 week to 19 week window for gestational age (7–11 weeks, n=13; 20–23 weeks, n=10). The majority were discovered by ultrasound examinations performed after enrollment. There were two twin gestations, one lost to spontaneous abortion, and one that delivered liveborns, resulting in one more infant analyzed than mothers in the group receiving study drug. All 25 women remained on their assigned study treatment and continued in follow-up. The percentage of patients judged by returned pill counts as having received at least 80% of the intended doses was substantial (606 of 707 patients [85.7%]) and was similar between treatment groups (84.5%, 86.9%).
Table 2 reports the rate of preeclampsia by treatment and risk group. No significant differences were noted for either the intent-to-treat cohort or the compliant subgroup. In the intent-to-treat cohort, 49 of 355 patients (13.8%) in the vitamin group and 55 of 352 patients (15.6%) in the placebo group developed preeclampsia (P=.43, adjusted risk ratio (RR) 0.87 [95.42% CI 0.61–1.25]). No significant treatment differences in the frequency of preeclampsia were noted within risk group. The results remained nonsignificant after additional adjustment by logistic regression for three baseline covariates specified a priori: prepregnancy body mass, maternal cigarette smoking at enrollment, and mean arterial pressure at enrollment. Of these, only the mean arterial pressure at enrollment was significantly associated with the subsequent development of preeclampsia (P=.0018, OR [for 10 mm Hg difference] 1.31, 95% CI 1.10–1.56]).
Among patients without chronic hypertension, severe preeclampsia occurred more frequently in the study group (6.5% [11 of 170]) compared with placebo (2.4% [4 of 168]; P=.11, OR 2.78, 95% CI 0.79–12.62), but not significantly so. There were no maternal deaths. There was one occurrence of eclampsia in a patient with prior preeclampsia who was assigned to the placebo group. Four patients (two in each group) developed hemolysis, elevated liver enzymes, low platelets syndrome.
There were no (study drug compared with placebo) differences in the frequency of gestational diabetes (3.4% compared with 3.7%), abruptio placentae (1.1% compared with 2.3%), induction of labor (14.6% compared with 18.3%) or cesarean delivery (66.0% compared with 67.6%). Premature rupture of the membranes was more frequently observed in the study drug group (10.6% compared with 5.5%, P=.015, RR 1.89, 95% CI 1.11–3.23).
Tables 3 and 4 detail perinatal outcomes. No significant differences were noted in the rate of fetal and neonatal deaths, preterm delivery, low birth weight, small for gestational age, low 1- or 5-minute Apgar score, and neonatal morbidities.
The study treatment was well tolerated by the patients. Nine patients discontinued treatment permanently because of difficulty taking the pills. Thirteen (seven study drug, six placebo) were discontinued permanently because of perceived side effects, including itching (three), eczema (one), vomiting (two), abdominal pain (two), abdominal pain and diarrhea (one), headache (one), constipation (one), and malaise and diminished vision (one). The remaining treatment discontinuations were related to other medical conditions or were for unknown reasons, including women who were lost to follow-up. Reported adverse events were almost exclusively related to expected pregnancy-related events. One mother attempted suicide by ingesting 26 pills (placebo). Three fetuses had developmental abnormalities, one with multiple malformations (study drug), one with neural tube defect (placebo), and one with trisomy 13 (placebo).
This study failed to demonstrate a significant effect of vitamins C and E on the rate of preeclampsia. These findings were noted despite narrow inclusion criteria, a population at risk, excellent patient compliance, and a limited number of clinical sites. Reassuringly, we failed to identify a deleterious influence of supplementation on the frequency of low birthweight, small for gestational age, stillbirth, or measures of birth asphyxia. The more frequent occurrence of premature rupture of membranes among supplemented patients was not expected, and it will be further analyzed and presented as a separate communication.
As determined by pill counts, 86% of the patients in this study were compliant with their study medication, taking at least 80% of the expected number of pills. The recently reported trials noted similarly defined compliance rates of 65–67%.4,6 Whether the improved compliance noted in the current study represents population differences or was achieved in response to feedback and encouragement using information gained from the electronic pill caps or other factors is uncertain.
This study is the second completed trial among high-risk patients reported since the Chappell trial.2 The subsequently reported studies3,4,6 employed the same dose of study drug as the Chappell trial. Beazley et al3 randomly allocated 109 patients at increased risk for preeclampsia (previous preeclampsia, chronic hypertension, pregestational diabetes, or multifetal gestation) to receive either vitamin C/E or placebo. No difference in the rates of preeclampsia was observed between groups (17.3% compared with 18.8%). This incomplete study was stopped prematurely due to a loss of funding. Poston et al6 enrolled 2,410 patients between 14 and 21 weeks of gestation and identified to be at increased risk of preeclampsia at 25 clinical sites in the United Kingdom. The population included a heterogeneous mix of patients with prior preeclampsia before 37 weeks of gestation, chronic hypertension, type 1 or 2 diabetes mellitus, antiphospholipid syndrome, chronic renal disease, multiple pregnancy, abnormal uterine artery Doppler, and primiparous women with body mass index greater than 30 kg/m2. The incidence of preeclampsia was similar in treatment and placebo groups (15% compared with 16%). Of note, there were significantly more low birth weight babies born to mothers in the supplemented group, but small for gestational age frequency did not differ between groups. Among those with preeclampsia, the mean gestational age at diagnosis of preeclampsia and the mean gestational age at delivery were significantly earlier in the antioxidant group. Neither of these untoward findings was observed in the current study.
Rumbold et al4 enrolled 1,877 normotensive, nulliparous women at 14 to 22 weeks of gestation at nine centers in Australia. Of the women enrolled in the study, 935 were randomly assigned to the vitamin group and 942 to the placebo group. There were no significant differences between the vitamin and placebo groups in the risk of preeclampsia (6.0% and 5.0%, respectively), death or serious outcomes in the infant, or having an infant with a birth weight below the 10th percentile for gestational age. But, as noted in the editorial accompanying the article5; the therapeutic group was also noted to have increases in the risk of hospitalization for hypertension (5.2% compared with 3.4%) and for the use of antihypertensive therapy (4.6% compared with 2.8%). Similar to the current study, these findings raised the question whether supplementation was associated with more severe disease when hypertension occurred.
The current study has limitations. It was powered for a RR of preeclampsia of 0.60, in hopes of confirming the positive results of Chappell.2 Additionally, the pathways to preeclampsia may differ for patients with prior preeclampsia compared with chronic hypertension. Thus the confidence intervals for the primary outcome and for enrollment subsets may fail to exclude some differences that, if real, would be clinically important. However, taken in the context of other recently published studies, the results suggesting a lack of benefit are largely compelling.
It seems unlikely that further study of supplementation of vitamins C and E, initiated in the second trimester, in combination at the doses used in these studies is warranted. However, it would be overreaching to suggest that these studies directly or indirectly challenge the validity of the suspected role of lipid perioxidation in the pathogenesis of preeclampsia. Recently, Banerjee et al12 hypothesized that vitamin E pharmacotherapy could prevent an immunologic switch from T-helper cell 1 to T-helper cell 2 that is thought to be vital for early-to-late transition in normal pregnancies. Additionally, they suggest that vitamin E could be a potential interferon-gamma mimic that might facilitate persistent proinflammatory reactions at the maternal–fetal interface. When vitamins C and E are used in combination, either of these mechanisms could mask a potential beneficial effect of vitamin C on the incidence of preeclampsia.
1. Spinnato JA, Livingston JC. Prevention of preeclampsia with antioxidants: evidence from randomized trials. Clin Obstet Gynecol 2005;48:416–29.
2. Chappell LC, Seed PT, Briley AL, Kelly FJ, Lee R, Hunt BJ, et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet 1999;354:810–6.
3. Beazley D, Ahokas R, Livingston J, Griggs M, Sibai BM. Vitamin C and E supplementation in women at high risk for preeclampsia: a double-blind, placebo-controlled trial. Am J Obstet Gynecol 2005;192:520–1.
4. Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson JS, ACTS Study Group. Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med 2006; 354:1796–806.
5. Jeyabalan A, Caritis SN. Antioxidants and the prevention of preeclampsia—unresolved issues. N Engl J Med 2006;354:1841–3.
6. Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH, Vitamins in Pre-eclampsia (VIP) Trial Consortium. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006;367:1145–54.
7. Lindheimer MD, Sibai BM. Antioxidant supplementation in pre-eclampsia. Lancet 2006;367:1119–20.
8. Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol 1996;87:163–8.
9. DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med 1994;13:1341–56.
10. Kuritz SJ, Landis JR, Koch GG. A general overview of Mantel-Haenszel methods: applications and recent developments. Annu Rev Public Health 1988;9:123–60.
11. Hosmer DW, Lemeshow S. Applied logistic regression. 2nd ed. New York (NY): John Wiley & Sons; 2000.
12. Banerjee S, Chambers AE, Campbell S. Is vitamin E a safe prophylaxis for preeclampsia? Am J Obstet Gynecol 2006;194:1228–33.
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