To determine whether supplementation with vitamins C and E during pregnancy reduces the risk of preeclampsia and other adverse maternal and perinatal outcomes.
Systematic review and metaanalysis of randomized controlled trials.
Nine trials involving a total of 19,810 women were included. Overall, there were no significant differences between the vitamin and placebo groups in the risk of preeclampsia (9.6% vs 9.6%; relative risk, 1.00, 95% confidence interval, 0.92–1.09). Similar results were obtained when subgroup analyses were restricted to women at high risk or low/moderate risk for preeclampsia. Women supplemented with vitamins C and E were at increased risk of developing gestational hypertension and premature rupture of membranes, and decreased risk of abruptio placentae. There were no significant differences between the vitamin and placebo groups in the risk of other adverse maternal or fetal/perinatal outcomes.
Supplementation with vitamins C and E during pregnancy does not prevent preeclampsia.
Preeclampsia complicates 1.3% to 6.7% of all pregnancies and remains a major cause of maternal and perinatal morbidity and mortality worldwide. Preeclampsia has been considered a 2-stage disorder in which a poorly perfused placenta (stage 1), due to inadequate remodeling of the spiral arteries supplying the intervillous space, produces factor(s) leading to the clinical manifestations of preeclampsia (stage 2). Stage 1 is not sufficient to cause the maternal syndrome but interacts with maternal factors (genetic, behavioral, or environmental) to result in stage 2. Oxidative stress of the placenta is considered to be a key intermediary step in the pathogenesis of preeclampsia. This hypothesis is supported by strong evidence of increased concentrations of biomarkers for oxidative stress and decreased concentrations of antioxidants, such as vitamins C and E, in the serum and tissues of women with established preeclampsia, compared to those without this disorder.
Antioxidants are important in maintaining cellular function in normal pregnancy and act through inhibition of peroxidation, thus protecting enzymes and proteins, as well as cell integrity. Vitamins C and E are antioxidants: vitamin C scavenges free radicals in the aqueous phase, whereas vitamin E acts in vivo to prevent lipid peroxidation, protecting against oxidative stress-related damage of cellular and intracellular structures. In addition to acting as a scavenger of free radicals, vitamin C can interact with the tocopheroxyl radical and regenerate reduced tocopherol. Furthermore, vitamins C and E are able to interact with glutathione-related enzymes to control the production of lipid peroxidation products. These observations led to the hypothesis that early supplementation with antioxidants could be effective in decreasing oxidative stress and improving vascular endothelial function, thereby preventing or ameliorating the course of preeclampsia.
In 1999, Chappell et al published the results of a randomized controlled trial in which 283 women (identified as being at increased risk for preeclampsia because of an abnormal 2-stage uterine artery Doppler analysis or a previous history of preeclampsia) were randomly assigned to receive vitamins C and E or placebo at 16-22 weeks of gestation. Vitamin supplementation was associated with a significant reduction in the maternal concentrations of biomarkers for preeclampsia (plasminogen-activator inhibitor [PAI]-1-to-PAI-2 ratio) and a 54% reduction in the risk of preeclampsia. These encouraging results led to the performance of several recently published larger trials involving women at both high risk and low/moderate risk for the disorder. Questions concerning the efficacy and safety of administering vitamins C and E during pregnancy for preventing preeclampsia have been raised.
We conducted a systematic review and metaanalysis of all available randomized controlled trials to determine the efficacy and safety of supplementation with vitamins C and E during pregnancy for the prevention of preeclampsia and other adverse maternal and perinatal outcomes.
Materials and Methods
The study was conducted according to a prospectively prepared protocol and reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for metaanalysis of randomized controlled trials.
Data sources and searches
We searched MEDLINE, EMBASE, CINAHL, and LILACS (all from inception to Nov. 30, 2010), the Cochrane Central Register of Controlled Trials ( www.mrw.interscience.wiley.com.easyaccess1.lib.cuhk.edu.hk/cochrane/cochrane_clcentral_articles_fs.html ) (1960 to Nov. 30, 2010), ISI Web of Science ( www.isiknowledge.com.easyaccess1.lib.cuhk.edu.hk ) (1960 to Nov. 30, 2010), Research Registers of ongoing trials ( www.clinicaltrials.gov , www.controlled-trials.com , www.centerwatch.com , www.anzctr.org.au , www.nihr.ac.uk , and www.umin.ac.jp/ctr ), and Google scholar using a combination of keywords and text words related to vitamins C and E or antioxidants , and preeclampsia . Proceedings of the Society for Maternal-Fetal Medicine and international meetings on preeclampsia, reference lists of identified studies, textbooks, previously published systematic reviews, and review articles were also searched. No language restrictions were used.
We included randomized controlled trials that compared supplementation with vitamins C and E during pregnancy with placebo or no supplementation and whose primary aim was to prevent preeclampsia, or whose primary aim was otherwise but data on preeclampsia were reported. Trials were excluded if: (1) they were quasirandomized; (2) they evaluated vitamins C or E alone; (3) they evaluated vitamins C and E combined with other vitamins or nutritional supplements; (4) they did not report clinical outcomes; or (5) they evaluated vitamins C and E in women with established preeclampsia or premature rupture of membranes (PROM). Trials were classified according to women’s risk status for preeclampsia. Pregnant women were considered to be at high risk for preeclampsia if they had 1 or more of the following: previous preeclampsia, eclampsia or hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, chronic hypertension, renal disease, pregestational diabetes, a body mass index (BMI) ≥ 30 kg/m 2 in the first pregnancy, abnormal uterine artery Doppler velocimetry, antiphospholipid syndrome, or multiple pregnancy. Pregnant women were considered at low/moderate risk for preeclampsia if they were nulliparous and did not meet any of the above mentioned criteria for high risk. We subdivided the trials as a function of the risk for preeclampsia to determine whether the efficacy of vitamins C and E might vary according to the presence or absence of clinical risk factors of the women participating in the trials.
All published studies deemed suitable were retrieved and reviewed independently by 2 authors (A.C-A. and J.P.K.) to determine inclusion. Disagreements were resolved through consensus.
The primary outcome of interest was preeclampsia. Secondary maternal outcomes included severe preeclampsia, eclampsia, HELLP syndrome, gestational hypertension, severe gestational hypertension, use of any antihypertensive therapy, antenatal hospitalization for hypertension, use of magnesium sulfate, abruptio placentae, pulmonary edema, admission to intensive care unit, maternal death, PROM, and preterm PROM (PPROM). Secondary fetal and perinatal outcomes included low birthweight, small for gestational age, preterm birth <37 weeks, fetal death <24 weeks, stillbirth, neonatal death, perinatal mortality, congenital malformation, admission to the neonatal intensive care unit (NICU), respiratory distress syndrome, necrotizing enterocolitis, neonatal sepsis, retinopathy of prematurity, intraventricular hemorrhage (all grades), grade III/IV intraventricular hemorrhage, periventricular leukomalacia, neonatal seizures, use of surfactant, mechanical ventilation, and chronic lung disease.
Assessment of risk of bias in included studies
The risk of bias in each trial included in this review was assessed individually by 2 reviewers (A.C-A. and J.P.K.) not associated with any of the trials. When differences in assessment of risk of bias existed, the differences were resolved by consensus. We assessed the risk of bias using the criteria recently outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Six domains related to risk of bias were assessed in each included trial, because there is evidence that these issues are associated with biased estimates of treatment effect: (1) sequence generation; (2) allocation concealment; (3) blinding of participants, clinical staff, and outcome assessors; (4) incomplete outcome data; (5) selective outcome reporting; and (6) other sources of bias. We assessed the risk of bias by answering a prespecified questionnaire about the adequacy of the study in relation to the entry, such that a judgment of “Yes” indicates low risk of bias, “No” indicates high risk of bias, and “Unclear” indicates unclear or unknown risk of bias.
Two authors (A.C-A. and J.P.K.) extracted data from each study on participants (inclusion and exclusion criteria, number of women and fetuses/infants in randomized groups, baseline characteristics, and country and date of recruitment), study characteristics (randomization procedure, concealment allocation method, blinding of clinicians, women and outcome assessors, completeness of outcome data for each outcome, including attrition and exclusions from the analysis, and intention-to-treat analysis), details of intervention (aim, daily dose of vitamins, gestational age at trial entry, and duration of treatment), and outcomes (number of outcome events/total number). In an attempt to obtain additional data, we contacted 4 authors by e-mail, of whom 3 responded. Disagreements in extracted data were resolved by discussion among reviewers.
Statistical analysis was performed according to the guidelines of the Cochrane Collaboration. We analyzed outcomes on an intent-to-treat basis. If this was not clear from the original article, we carried out reanalysis when possible. If data for similar outcomes from 2 or more separate studies were available, we combined the data in a metaanalysis and calculated a summary relative risk (RR) with associated 95% confidence interval (CI). Heterogeneity of the results among studies was tested with the quantity I 2 , which describes the percentage of total variation across studies that is due to heterogeneity rather than chance. A value of 0% indicates no observed heterogeneity, whereas I 2 values of 50% or more indicate a substantial level of heterogeneity. We planned to pool data across studies using the fixed-effects models if substantial statistical heterogeneity was not present. Random-effects models were used to pool data across studies if I 2 values were ≥50% and possible causes of heterogeneity were explored by performing subgroup analyses for the main outcomes according to study characteristics. A predefined sensitivity analysis was performed, by excluding trials with any risk of bias, to explore the impact of study quality on the effect size for the primary outcome.
Further subgroup analyses were planned to assess the primary outcome in women who were at low/moderate and high risk for preeclampsia. In addition, in women who were at high risk for developing preeclampsia, we assessed the primary outcome according to the presence of the following risk factors: previous preeclampsia, chronic hypertension, pregestational diabetes, multiple pregnancy, BMI ≥30 kg/m 2 in the first pregnancy, abnormal uterine artery Doppler velocimetry, chronic renal disease, and antiphospholipid syndrome.
The number needed to treat (NNT) for benefit or harm with their 95% CIs was calculated for outcomes for which there was a statistically significant reduction or increase in risk difference. NNT was computed from the results of metaanalysis of relative risks as follows:
NNT = | 1 Control group event rate × ( 1-relative risk ) |