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Volume 362:1282-1291

April 8th, 2012

Number 14

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Vitamins C and E to Prevent Complications of PregnancyPreeclampsia
James M. Roberts, M.D., Leslie Myatt, Ph.D., Catherine Y. Spong, M.D., Elizabeth A.
Thom, Ph.D., John C. Hauth, M.D., Kenneth J. Leveno, M.D., Gail D. Pearson, M.D.,
Sc.D., Ronald J. Wapner, M.D., Michael W. Varner, M.D., John M. Thorp, Jr., M.D.,
Brian M. Mercer, M.D., Alan M. Peaceman, M.D., Susan M. Ramin, M.D., Marshall
W. Carpenter, M.D., Philip Samuels, M.D., Anthony Sciscione, D.O., Margaret
Harper, M.D., Wendy J. Smith, M.D., George Saade, M.D., Yoram Sorokin, M.D.,
Garland B. Anderson, M.D., for the Eunice Kennedy Shriver National Institute of
Child Health and Human Development Maternal–Fetal Medicine Units Network

and neonatal outcomes related to pregnancy-associated hypertension.07. nulliparous women did not reduce the rate of adverse maternal . respectively. There was no significant difference between the vitamin and placebo groups in the rates of the primary outcome (6. 0. eclamptic seizure. initiated early in pregnancy. thrombocytopenia. 95% confidence interval [CI].154 women underwent randomization. fetal. medically indicated preterm birth.ABSTRACT Abstract PDF Background Oxidative stress has been proposed as a mechanism linking the poor placental perfusion characteristic of PDA Full Text PowerPoint Slide Set Disclosures preeclampsia with the clinical manifestations of the disorder. or perinatal death. fetal-growth restriction.25) or in the rates of preeclampsia (7. 0. Outcome data were available for 9969 women. 95% CI. relative risk. respectively. The two groups were similar with respect to baseline characteristics and adherence to the study drug.2% and 6. We assessed the effects of antioxidant supplementation with vitamins C and E.93 to 1. The primary outcome was severe pregnancyassociated hypertension alone or severe or mild hypertension with elevated liver-enzyme levels. Add to Personal Archive Add to Citation Manager Methods We conducted a multicenter.07.7%. relative risk in the vitamin group. double-blind Notify a Friend trial involving nulliparous women who were at low risk for E-mail When Cited preeclampsia. elevated serum creatinine levels. Results A total of 10.91 to 1. 1. Conclusions Vitamin C and E supplementation initiated in the 9th to 16th week of pregnancy in an unselected cohort of low-risk. randomized.1% and 5. on the risk of serious adverse maternal. 1.7%. Women were randomly assigned to begin daily E-mail When Letters Appear supplementation with 1000 mg of vitamin C and 400 IU of vitamin E or matching placebo between the 9th and 16th weeks of pregnancy.24). Rates of adverse perinatal outcomes did not differ significantly between the groups.

3. such as ascorbate.2. supplementation with vitamins C and E. to perform larger.1 Oxidative stress is one of several mechanisms that have been proposed to cause manifestations of the disease. which in turn lead to the characteristic maternal syndrome. our trial was designed to detect a modest effect size in serious outcomes associated with gestational hypertension and preeclampsia among low-risk women. Preeclampsia has been considered to be a two-stage disorder. NCT00135707 [ClinicalTrials. are reduced starting early in pregnancy in women in whom preeclampsia develops later in the pregnancy. This study stimulated several groups.8 Although not all data support this hypothesis. randomized trials involving women at high risk and women at low risk for the disorder. with treatment beginning early in the pregnancy.2 Support for this concept is provided by data showing that there are oxidative modifications of proteins.14 None of these studies replicated the original positive findings. it has been suggested that the generation of free radicals in response to reduced placental perfusion may lead to clinical manifestations. In contrast with the other studies. Abnormal placentation or perfusion results in an increased inflammatory response and endothelial dysfunction.9 there was enough evidence by the late 1990s to support the performance of a randomized. as compared with placebo.6 and DNA7 in the blood and tissue of women with preeclampsia and their infants. to prevent the clinical signs of preeclampsia.10 In a study involving 283 women at high risk for preeclampsia. there was a 60% reduction in the diagnosis of preeclampsia.4 lipids. including the Eunice Kennedy Shriver National Institutes of Child Health and Human Development Maternal–Fetal Medicine Units (MFMU) Network.or perinatal outcomes related to pregnancy-associated hypertension (ClinicalTrials. as well as the observation that the concentrations of buffering antioxidants.13. initiated early in pregnancy.5.gov] ).12. was effective in reducing evidence of endothelial activation. Methods Study Population .gov number. moreover.11. controlled trial of antioxidant therapy.

Those who returned. uterine malformation. who had taken at least 50% of the placebo that they were supposed to have taken. the preparation of the manuscript. boxes containing each participant's supply of capsules were packaged according to this sequence. . Neither the participants nor the investigators were aware of the treatment assignments. Other exclusion criteria were diabetes that was present before the pregnancy. serious medical condition. treatment with antiplatelet drugs or nonsteroidal antiinflammatory agents. known fetal anomaly or aneuploidy. and who still met the eligibility criteria were randomly assigned to receive capsules containing a combination of 1000 mg of vitamin C (ascorbic acid) and 400 IU of vitamin E (RRR-alphatocopherol acetate) or matching placebo (mineral oil). or a urine-dipstick result of 1+ or higher for protein). Women were eligible for inclusion if they had not had a previous pregnancy that lasted beyond 19 weeks 6 days. or were taking more than 150 mg of vitamin C or more than 75 IU of vitamin E daily. or the decision to submit the manuscript for publication. with stratification according to clinical center. or abuse of illicit drugs or alcohol. The simple urn method.We conducted the trial from July 2005 through February 2010at the 16 clinical centers and the independent data coordinating center of the MFMU Network. uterine bleeding within the week before recruitment. as measured in a 24-hour urine sample. which had no role in the design of the study. were taking or had taken antihypertensive medication. the analysis or interpretation of the data. Gestational age at randomization was between 9 weeks 0 days and 16 weeks 6 days. Women were not eligible if they had elevated systolic blood pressure (135 mm Hg or higher). Pregnant women who had a singleton fetus with a gestational age of less than 16 weeks 0 days at the time of screening were eligible for inclusion in the study. Both the vitamin and placebo capsules were manufactured by Strides. elevated diastolic blood pressure (85 mm Hg or higher). was used by the data coordinating center to create a randomization sequence16. or proteinuria (300 mg of protein or more. Gestational age was determined before randomization with the use of a previously described algorithm15 that took into account the date of the last menstrual period (if reliable information was available) and results of the earliest ultrasound examination. Study Design Eligible 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. in vitro fertilization resulting in the current pregnancy.

5 mg per deciliter [132. or a single blood-pressure measurement that was severely elevated and that led to treatment with an antihypertensive medication. report on side effects. excluding intraoperative blood pressures and intrapartum systolic pressures. All participants provided written informed consent before enrollment. The diagnosis of hypertension was based on bloodpressure measurements obtained during or after the 20th week of pregnancy. which was responsible for data analysis. receive a new supply of the study drug for the coming month. an indicated preterm birth before 32 weeks of gestation owing to hypertension-related disorders. All data were collected or abstracted by certified research personnel at the clinical centers and uploaded to a database that was managed by an independent data coordinating center. The study participants returned on a monthly basis to return any unused study drug from the previous month.000 per cubic millimeter). Primary Outcome The primary outcome was a composite of pregnancy-associated hypertension and serious adverse outcomes in the mother or her fetus or neonate — severe pregnancy-associated hypertension alone or severe or mild pregnancy-associated hypertension with one or more of the following: elevated liver enzyme levels (an aspartate aminotransferase level 100 U per liter).Women were instructed to take the study drug each day until they delivered their babies. and have their blood pressure and urine protein level (as assessed on dipstick testing) measured. Clinical research staff also obtained data on neonatal and maternal outcomes at delivery. or neonatal death. thrombocytopenia (a platelet count of <100.6 µmol per liter]). Mild pregnancy-associated hypertension was defined as a systolic pressure between 140 and 159 mm Hg or a diastolic pressure between 90 mm and 109 mm Hg on two occasions 2 . deidentified medical charts of all women with pregnancy-associated hypertension were reviewed centrally by at least three reviewers who were unaware of the treatment assignments. Severe pregnancy-associated hypertension was defined as a systolic pressure of 160 mm Hg or more or a diastolic pressure of 110 mm Hg or more on two occasions 2 to 240 hours apart. elevated serum creatinine level ( 1.17 fetal death after 20 weeks of gestation. a fetus that was small for gestational age (below the 3rd percentile) adjusted for sex and race or ethnic group. To determine the primary outcome and the diagnosis of preeclampsia. eclamptic seizure. The study was approved by the institutional review board at each clinical site and the data coordinating center.

elevated liver enzyme levels. only catheterized urine samples were considered in the diagnostic criteria. with a two-sided type I error rate of 5%. or a peripheral-blood smear showing nucleated red cells.18 We estimated that with a sample size of 10. an abnormal laboratory value had to be present within 10 days before or anytime after the onset of the pregnancy-associated hypertension.000 per cubic millimeter. Severe preeclampsia was defined as preeclampsia with either severe pregnancy-associated hypertension or protein excretion of 5 g or more in a 24-hour urine sample or as mild pregnancy-associated hypertension with oliguria (<500 ml in a 24-hour urine sample). an aspartate aminotransferase level of 100 U per liter or more. the study would have 90% power to show a 30% reduction in the rate of the primary outcome. from 4% in the placebo group to 2. or an elevated reticulocyte count). schistocytes.to 240 hours apart. and evidence of hemolysis (either a lactate dehydrogenase level 600 U per liter or a total bilirubin level 1.000 women. . Secondary Outcomes Secondary outcomes included preeclampsia and other maternal and neonatal outcomes. and a low platelet count) was considered to be present if pregnancy-associated hypertension occurred with all of the following: a platelet count of less than 100. Statistical Analysis The expected rate of the primary outcome in the placebo group was estimated from a previous MFMU Network study of low-dose aspirin to prevent preeclampsia in nulliparous women.35 or more if a 24-hour urine sample was not available. or a protein-to-creatinine ratio of 0. The HELLP syndrome (hemolysis. or thrombocytopenia (platelet count of <100. Proteinuria was defined as total protein excretion of 300 mg or more in a 24-hour urine sample or 2+ or higher on dipstick testing.8% in the vitamin group.000 per cubic millimeter). pulmonary edema (confirmed by radiography). Mild preeclampsia was defined as mild pregnancy-associated hypertension with documentation of proteinuria within 72 hours before or after an elevated blood-pressure measurement.2 mg per deciliter. After the rupture of membranes. To be considered part of the primary outcome.

since the adjustment is minimal. the chosen spending function was the Lan–DeMets generalization of the O'Brien–Fleming boundary. In the final analysis of the primary outcome. A total of 94 women in the vitamin group and 89 women in the placebo group (1. we report 95% confidence intervals. For all secondary outcomes. all analyses that are presented were prespecified.19 Three interim analyses were performed. nominal P values of less than 0. and 5066 to receive placebo.An independent data and safety monitoring committee monitored the trial and reviewed interim results.152 women. 5088 were assigned to receive vitamins. and categorical variables with the use of the chi-square test. resulting in a total of 10. Randomization. Results Study Population Figure 1 shows the enrollment and follow-up of the women who participated in the trial. and Follow-up of Study Participants. one at the patient's request and one at the request of the institutional review board at her site (after a lapse in approval by the institutional review board at that site). Unless indicated.05 were considered to indicate statistical significance. regardless of whether they took the study capsules. A total of 10. A group sequential method was used to characterize the rate at which the type I error was spent. Figure 1.045 were considered to indicate statistical significance. Enrollment.8% overall) were lost to follow-up. Continuous variables were compared with the use of the Wilcoxon rank-sum test. However. Data from all women were analyzed according to the group to which they were randomly assigned.154 women were randomly assigned to a study group. Data for two women were removed. P values have not been adjusted for multiple comparisons. two-tailed P values of less than 0. View larger version (25K): . IRB denotes institutional review board.

Side effects were reported by 11. was 88% in both study groups. The most common side effects were nausea (7. the median ratio of the number of study capsules taken to the number that should have been taken.3% in the vitamin group and 6. P=0. Among the 9969 women for whom pregnancy outcome data were available.4% in the vitamin group and 4. between the time of randomization and delivery.8% in the placebo group. There were no significant between-group differences in the rates of any of the reported side effects.2% of the women.23).31) and vomiting (4. Study Outcomes .0% in the placebo group.[in this window] [in a new window] Baseline characteristics were similar between the two groups (Table 1). P=0. A total of 77% of the enrolled subjects were taking a prenatal vitamin or multivitamin at the time of randomization.

.07. respectively). severe preeclampsia.27). the HELLP syndrome. There was no significant difference in the rate of preeclampsia between the women in the vitamin group and those in the placebo group (7.25). and 14. Rates of maternal secondary outcomes are shown in Table 3. 1. 95% CI. 1.2% and 6. No benefit of therapy was seen in women with severe pregnancyassociated hypertension or mild preeclampsia with one of the primary outcome components (relative risk.7%.07. There was no significant between-group difference in any component of the primary outcome (Table 2). Rates of adverse neonatal outcomes also did not differ significantly between the groups (Table 4).1%).8%) had severe hypertension only and 321 (54.89 to 1. 10. 164 (27. 95% confidence interval [CI]. 0. 0.91 to 1.4%) had preeclampsia (of whom 40 had mild preeclampsia. Among the women who met the criteria for the primary outcome.The criteria for the primary outcome were met by 305 women in the vitamin group (6. as compared with 285 in the placebo group (5. eclampsia). 257.7%) (relative risk. Two women (one in each study group) died from peripartum cardiomyopathy.

the primary outcome occurred in 6.6% of those in the placebo group (relative risk.9% of those in the placebo group (relative risk. Secondary Neonatal Outcomes.42).7% of those in the vitamin group and 5.89 to 1. 0. 13 weeks). supplementation with vitamins C and E did not reduce the frequency of the primary outcome or any of its components. 0. 1. Results did not differ significantly according to subgroup (P=0. Among the 4343 women who entered the study before the 13th week of pregnancy. 95% CI. We chose the primary outcome of new-onset pregnancy- .26).6% of those in the vitamin group. Discussion In our study. 95% CI. among the 5626 women who were enrolled in or after the 13th week of pregnancy.02. as compared with 5.82 to 1. 1.54 for the interaction).12. the primary outcome occurred in 5.View this table: Table 4. [in this window] [in a new window] We performed one post hoc subgroup analysis on the basis of the week of pregnancy at randomization (<13 weeks vs.

13 In no other study was therapy initiated as early as it was in our trial. so that we could assess whether therapy would prevent serious complications rather than merely modify diagnostic findings. The rates of mild preeclampsia. the HELLP syndrome. but a significant increase in the use of . There was also no evidence of a benefit with vitamin therapy with respect to any of the other prespecified secondary outcomes.com] ) of antioxidant supplementation to prevent preeclampsia in high-risk women showed that there was an increased rate of complications among women and infants when women received antioxidant vitamins during pregnancy.14 In that study. and eclampsia were not significantly affected by vitamin treatment. Each of the previous trials had a smaller sample than that in our study.21. post hoc analyses showed that the stillbirth rate was higher (and the neonatal death rate lower) in the vitamin group than in the control group.13. Although the rates of perinatal death were similar in the two groups. we used preeclampsia as a major secondary outcome. rather than the diagnosis of preeclampsia. gestational hypertension and the use of antihypertensive therapy were also more common in the vitamin group. We did not require the presence of proteinuria as part of the primary outcome. only one of the previous trials included low-risk subjects.associated hypertension with evidence of maternal.20 Furthermore. as compared with the placebo group.22. We did find an increase in the frequency of gestational hypertension in the vitamin group.23. there were significantly more babies with low birth weight (a prespecified outcome) in the group that received vitamin supplementation than in the control group. Current Controlled Trials number.24 Since our primary outcome was not based on a conventional diagnosis of preeclampsia. a diagnosis of proteinuria that is based on the qualitative assessment of random urine samples or even on protein-tocreatinine ratios cannot be compared with a diagnosis that is based on 24-hour urine collections.14 The doses of vitamins that were used in those trials were the same as those used in our trial. We did not collect data on the use of antihypertensive medications. or neonatal complications. fetal.12. severe preeclampsia. The Vitamins in Pre-eclampsia study (VIP. In contrast. since severe hypertension without proteinuria can be associated with adverse maternal and fetal outcomes. ISRCTN62368611 [controlled-trials. we did not find significant between-group differences in the rates of low birth weight and stillbirth. Several other trials have examined the effectiveness of vitamins C and E in preventing preeclampsia.11.

25 In our study. possible that although oxidative stress is present in preeclampsia. It has been suggested. 1.0. The antioxidants need to be present at the time of a relevant prooxidant challenge. We also cannot be certain that other antioxidants would not have been effective.26 The possibility that therapy might be effective specifically in women who are deficient in these vitamins was not supported by the World Health Organization study (ISRCTN86677348 [controlled-trials. oxidative stress may be relevant to pathogenesis in only a subgroup of women. In a post hoc subgroup analysis limited to women treated before the 13th week of pregnancy. of course. in relation to other trials. Alternatively.3).antihypertensive therapy was found with vitamin supplementation in the previous trial involving low-risk women. 95% CI. there was no apparent benefit of vitamin supplementation. did not reduce the risk of preeclampsia in a high-risk and nutritionally deficient population (relative risk with vitamins. as compared with placebo.com] ) of vitamin C and E supplementation. Burton and Jauniaux found that the initiation of intervillous blood flow at 8 to 10 weeks of gestation was associated with a burst of oxidative stress. . would be expected to increase plasma concentrations substantially above those achieved with prenatal vitamins.26 The doses of alpha-tocopherol used in this study. in which these doses not only appeared to reduce the frequency of preeclampsia but also decreased objective evidence of oxidative stress. with 44% of women beginning treatment before the 13th week of pregnancy.11 The doses of vitamins C and E used in our trial were determined on the basis of the preliminary study. almost 80% of the women were taking prenatal vitamins that contained an average of 100 mg of vitamin C and 22 IU of alphatocopherol when they entered the study.9 to 1. which showed that supplementation with these vitamins. Doses of ascorbate of 150 mg per day result in nearly maximal plasma and tissue concentrations.27 Antioxidant therapy in our study was initiated in the 9th to 16th week of pregnancy. it is not important in the pathophysiology of the condition.10 The timing of the administration of antioxidants is also important. 0. Administration of 1000 mg per day increases the plasma concentration by only 25% above that achieved with 150 mg per day.13 Why was therapy with these antioxidant vitamins not successful in altering the outcome of hypertension in pregnancy in our study or in previous studies? It is. however. with no appreciable benefit of antioxidants for the overall population. that the women may already have had adequate concentrations of vitamins C and E before therapy.

HD34136.S..S. for central review of outcomes. HD21410. and Trisha Boekhoudt. Allison Northen. HD40485. NHLBI. and UL1 RR024989). the National Heart. nulliparous women.N. Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD34208. Lung.N. Joan Moss. HD53097. and Blood Institute (NHLBI).S.. B.P. HD53118.S. M. HD27917.. Previous studies have shown a similar lack of efficacy among high-risk women and among women who were likely to have had a deficiency of vitamins C and E.D. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of the NICHD. or the National Institutes of Health. Sabine Bousleiman. M. B. M.. Financial and other disclosures provided by the authors are available with the full text of this article at NEJM. R. for coordination between clinical research centers and central review of outcomes. Jo-Ann Tillinghast. and the National Center for Research Resources (NCRR) (M01 RR00080...H. We thank Rebecca G.N. HD40544.. HD27915. B.. for protocol and data management and statistical analysis.N. and Matthew Hoffman. supplementation with vitamin C (at a dose of 1000 mg daily) and vitamin E (at a dose of 400 IU daily) did not reduce the rates of either serious adverse outcomes of pregnancyassociated hypertension or preeclampsia among low-risk. UL1 RR024153. HD27860. NCRR. HD27869. M.S.org. Stephanie Fyffe.In summary. R.. M. Gail Mallett.N.S. Ph. and Margaret Cotroneo. Karen Dorman. M. * Other members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network are listed in the Appendix.D..N. HD34116.S. HD40560.. HD40545.N. Source Information . The findings of these several studies provide no support for the use of vitamin C and E supplementation in pregnancy to reduce the risk of preeclampsia or its complications.N. HD40500. Clifton.. HD40512. and HD36801).

W. Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.). Fasting serum triglycerides.M. References 1 Redman CW.M.J. free fatty acids.H.C. [CrossRef][Web of Science][Medline] .) and the National Heart. and Blood Institute (G.T.).A.J. Galveston.).B. Columbia University.).308:1592-1594. Hypertension 2005 33:83-89. University of Texas Southwestern Medical Center.M. are positively correlated.M.Y.H.). University of Cincinnati College of Medicine. Protein carbonyls in decidua and placenta of pre-eclamptic women as markers for oxidative stress. Placenta 2009.M.R.W.S.S. Evidence for peroxynitrite formation in the vasculature of women with preeclampsia.).S. Brown University.From the Departments of Obstetrics and Gynecology.A.). Sims CJ. Salt Lake City (M. Chicago (A. Houston (S. [Free Full Text] 1 Roggensack AM.). Lung.22:213-219.).) — both in Bethesda. MD. Providence. and decrease within 48 hours post partum. Detroit (Y.S.D. Hauth BA.). Case Western Reserve University.L. University of Pittsburgh. Davidge ST. Roelofs HM.).).P. Proc Soc Exp Biol Med 2005. DC (E.). and malondialdehyde are increased in preeclampsia.). Columbus (P.P. University of Texas Medical Branch (G. Sargent IL.). Zhang Y. Latest advances in understanding preeclampsia.C.) and Medical Center (G. University of Utah. McLaughlin MK. [CrossRef][Web of Science][Medline] 1 Hubel CA.M.222:222-235. Pittsburgh (J.174:975-982.) — both in North Carolina. Winston-Salem (M. Rutten H. Peters WH.). Oxidative stress in the pathogenesis of preeclampsia.R.S. RI (M.M. Roberts JM. [Free Full Text] 1 Hubel CA. Oregon Health and Science University. [Free Full Text] 1 Zusterzeel PL. George Washington University Biostatistics Center.J. and Wayne State University. University of North Carolina at Chapel Hill. Cleveland (B.). Science 2008. Ohio State University. Drexel University.T. New York (R. Steegers EA. Chapel Hill (J. Birmingham (J. University of Texas Health Science Center at Houston. Cincinnati (L. University of Alabama at Birmingham. Portland (W. and Wake Forest University Health Sciences. Washington.S.V. Northwestern University. Evans RW. Am J Obstet Gynecol 2009. Dallas (K. Philadelphia (A.W.

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