Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Dec 1.
Published in final edited form as: BJOG. 2014 Dec 17;122(13):1740–1747. doi: 10.1111/1471-0528.13201

Prenatal Vitamin C and E Supplementation in Smokers is Associated with Reduced Placental Abruption and Preterm Birth: A Secondary Analysis

Adi Abramovici 1, Robin E Gandley 2, Rebecca G Clifton 3, Kenneth J Leveno 4, Leslie Myatt 5, Ronald J Wapner 6, John M Thorp Jr 7, Brian M Mercer 8, Alan M Peaceman 9, Philip Samuels 10, Anthony Sciscione 11, Margaret Harper 12, George Saade 13, Yoram Sorokin 14, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network
PMCID: PMC4470874  NIHMSID: NIHMS638066  PMID: 25516497

Abstract

OBJECTIVE

Smoking and Preeclampsia (PE) are associated with increases in preterm birth, placental abruption and low birth weight. We evaluated the relationship between prenatal vitamin C/E supplementation and perinatal outcomes by maternal self-reported smoking status focusing on outcomes known to be impacted by maternal smoking.

DESIGN/POPULATION

A secondary analysis of a multi-center trial of vitamin C/E supplementation starting at 9–16 weeks in low-risk nulliparous women with singleton gestations.

METHODS

We examined the effect of C/E by smoking status at randomization using the Breslow-Day test for interaction.

MAIN OUTCOME MEASURES

The trial’s primary outcomes were PE and a composite outcome of pregnancy-associated hypertension (PAH) with serious adverse outcomes. Perinatal outcomes included preterm birth and abruption.

RESULTS

There were no differences in baseline characteristics within subgroups (smokers vs. non-smokers) by vitamin supplementation status. The effect of prenatal vitamin C/E on the risk of PE (p=0.66) or PAH composite outcome (p=0.86) did not differ by smoking status. Vitamin C/E was protective for placental abruption in smokers [RR of 0.09 (95% CI 0.00, 0.87)], but not in non-smokers [RR 0.92 (0.52, 1.62)] (p= 0.01), and for preterm birth in smokers [RR 0.76 (0.58, 0.99)] but not in non-smokers [RR 1.03 (0.90, 1.17)] (p= 0.046).

CONCLUSION

In this cohort of women, smoking was not associated with a reduction in PE or the composite outcome of PAH.. Vitamin C/E supplementation appears to be associated with a reduction in placental abruption and preterm birth among smokers.

Tweetable abstract

Vitamin C/E associated with a reduction in placental abruption and preterm birth among smokers.

Keywords: Smoking, Placental abruption, Preterm birth

Introduction

Multiple studies have identified maternal tobacco use as one of the strongest modifiable risk factors for intrauterine growth restriction (IUGR). Smoking is also implicated in other adverse pregnancy outcomes such as preterm birth, placental abruption, and stillbirth.1–3 Further, there is a dose response to cigarette smoke and pregnancy complications. 4 The mechanisms leading to growth restriction and adverse outcomes following in-utero tobacco exposure are also poorly understood. One proposed mechanism is that nicotine may have direct effects on the uterine and umbilical vessels, causing vasoconstriction and subsequent compromise of utero-placental circulation and chronic fetal hypoxia.5

Preeclampsia (PE) is associated with adverse pregnancy outcomes similar to those found among pregnancies complicated by maternal tobacco use. Numerous studies have shown that smoking decreases the risk of PE by up to 32%.6 Combustion products of cigarette smoke have also been implicated in smoking related adverse pregnancy outcomes and the reduced risk of PE among smokers. 7 Some investigators have hypothesized that both smoking and PE are associated with alterations in hypoxia responsive pathways and circulating angiogenic factors.8, 9 Among women with PE who smoke, there is an increase in the risk of adverse pregnancy outcomes compared to preeclamptic women who do not smoke.10 These studies showed that smoking decreases the risk of PE, but smokers with PE have a 2–6 fold increased risk of adverse pregnancy outcomes when compared to non-smoking women with PE. 8 This paradoxical association is not completely understood.

Smoking is associated with reduced dietary intake as well as decreased consumption of vitamin C. 11 In humans and animals low birth weight has been associated with diets low in vitamin C even after controlling for smoking status. 12, 13 Like smokers, women with PE have lower circulating levels of vitamin C, heightened inflammation, and evidence of oxidative damage; these observations have prompted numerous multicenter trials of combined vitamin C and E prophylaxis during pregnancy. 13

Therefore, although the risk of PE overall is not influenced by Vitamin C/E supplementation,14, 15 we hypothesized that the effects of antioxidant supplementation with vitamin C and E may differ by smoking status, leading to sub-group specific reductions in the adverse maternal, fetal, or neonatal outcomes related to pregnancy-associated hypertension (PAH) and tobacco use.

Methods

We performed a secondary analysis of the NICHD Maternal-Fetal Medicine Units Network multicenter randomized, double–masked trial of low risk nulliparas assigned to daily vitamin C and E supplementation or matching placebo to prevent PAH.14 The trial was conducted from July 2003 through February 2008 and included 16 participating centers. Eligibility criteria included singleton gestation between 9 weeks 0 days and 16 weeks and 6 days at time of randomization.16 Gestational age was determined before randomization by a previously described algorithm using the date of the last menstrual period (if reliable) and the results of the earliest ultrasound examination. Women were excluded for preexisting hypertension or proteinuria, intake of more than 150 mg of vitamin C or more than 75 IU of vitamin E daily, pregestational diabetes, treatment with antiplatelet drugs, serious medical complication, known fetal anomaly or aneuploidy, or illicit drug or alcohol abuse. Eligible women were randomly assigned to receive either a combination of 1000 mg of vitamin C (ascorbic acid) and 400 IU of vitamin E (RRR-alpha-tocopherol acetate) or matching placebo (mineral oil) with stratification by clinical center17. All data were collected by certified research personnel at the clinical centers and uploaded to a database that was managed by an independent data coordination center. The diagnosis of the key study outcomes were confirmed by central review by at least three reviewers of de-identified medical charts of all women with PAH, PE, and the composite outcome. The institutional review board at each clinical site and the data coordination center approved the study. All participants provided written informed consent before enrollment.

For this secondary analysis of women randomized to vitamin or placebo supplementation, we examined outcomes by smoking status. Smoking status was self-reported as never smoked, quit smoking before the start of pregnancy, quit smoking after start of pregnancy, or currently smoking. Those women who reported any smoking during pregnancy (quit smoking after the start of pregnancy or currently smoking) were classified in the smoking group. The average number of cigarettes/day was recorded for the patients in the currently smoking group.

The main outcomes of interest were maternal or fetal outcomes potentially influenced by maternal smoking status. The maternal outcomes included PE (overall, severe and early onset), the trial composite of adverse outcomes associated with PAH, gestational hypertension, placental abruption, and preterm premature rupture of membranes (PPROM). The composite outcome was defined as severe hypertension OR mild hypertension with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, small for gestational age (<3rd centile), medically indicated preterm birth or perinatal death. Mild PE was defined as mild PAH (≥140/90 mmHg on two occasions 2–240 hours apart) with documentation of proteinuria within 72 hours before or after an elevated blood-pressure measurement. 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, or a protein –to-creatinine ratio of 0.35 or more if a 24-hour urine sample was not available. Severe PE was defined as PE with either severe PAH (≥160/110 on two occasions 2240 hours apart, or a single occurrence treated with antihypertensive medications) 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), pulmonary edema (confirmed by radiography), or thrombocytopenia (platelet count of <100,000 per cubic millimeter). PE included mild and severe preeclampsia, HELLP and eclampsia. Early PE was defined as onset of diagnosis prior to 34 weeks gestation. PPROM was defined as spontaneous rupture of membranes and one of the following: membrane rupture 60 minutes or more before the onset of labor, labor induced for pre-labor ruptured membranes, or no labor and onset of rupture 60 minutes or more before delivery.

Neonatal outcomes included: preterm birth (categorized as delivery either prior to 37 weeks’ gestation or prior to 32 weeks’ gestation), small for gestational age (SGA; birthweight <3rd centile or <10th centile), and a composite perinatal morbidity (including RDS, sepsis, retinopathy of prematurity, intraventricular hemorrhage, or necrotizing enterocolitis).

Categorical variables were compared using the chi-square test and continuous variables using the Wilcoxon rank-sum test. The incidence, relative risk, and 95% confidence interval relating the outcomes of interest to Vitamin C and E supplementation status within each subgroup (smokers and nonsmokers) were computed. Exact confidence intervals were computed as appropriate. For each outcome, the Breslow-Day test for homogeneity was used to estimate if there was a difference in treatment effect (Vitamin C/E supplementation vs. placebo) between smokers and non-smokers. For all outcomes, a nominal p value less than 0.05 was considered to indicate statistical significance. Analysis was performed using SAS software (Cary, NC).

Results

Of the 10,154 women randomized to the trial, 9,969 had outcome data available for analysis (4,993 were assigned to receive vitamins, and 4,976 were assigned to receive placebo). Of the 9,969 women, 1,551 (16%) self-reported current tobacco use during the pregnancy (n=571) or having quit after the start of pregnancy (n=980), and 8,418 (84%) reported never having smoked or quitting before the start of pregnancy. Of the currently smoking population, 49% (n=280) reported smoking 0–4 cigs/day and 51% (n=291) reported ≥ 5 cigs/day. Of the selfreported tobacco users, 51% (n=788) received vitamin C and E supplementation and 49% (n=763) received placebo. Of the women without tobacco use, 50% (n=4,205) received vitamin supplementation, and 50% (n=4,213) received placebo.

Table 1 shows patient characteristics for the subgroups of smokers and non-smokers, by vitamin C/E vs. placebo. Overall, there were no differences in baseline characteristics including maternal age, race/ethnicity, BMI and previous pregnancy between treatment groups within smoking categories. Mean gestational age at entry was approximately 13 weeks.

Table 1.

Patient Characteristics by Smoking Status and Vitamin C/E Supplementation*

Subject Characteristics Smoker Placebo (n = 763 ) Smoker Vitamins (n = 788 ) p-Value Non- Smokers Placebo (n = 4213 ) Non- Smoker Vitamins (n = 4205 ) p- Value
Age – years 22.2±4.6 22.4±4.6 0.31 23.8±5.3 23.7±5.3 0.43
Gestational age at randomization – week 13.1±2.2 13.1±2.2 0.54 13.5±2.1 13.4±2.1 0.69
Race or ethnic group – n (% within treatment group) Caucasian 382 (50.1%) 428 (54.3%) 0.29 1698 (40.3%) 1678 (39.9%) 0.59
African American 292 (38.3%) 265 (33.6%) 981 (23.3%) 980 (23.3%)
Hispanic 82 (10.7%) 88 (11.2%) 1442 (34.2%) 1471 (35.0%)
Other 7 (0.9%) 7 (0.9%) 92 (2.2%) 76 (1.8%)
Pre-pregnancy body mass index – kg/m2 26.6±7.1 26.2±6.7 0.57 25.2±5.7 25.2±5.9 0.55
Total years of schooling 12.3±2.0 12.3±2.0 0.88 12.9±2.8 12.9±2.8 0.80
Use of prenatal vitamins or multivitamins prior to randomization – n (%) 656 (86.0%) 687 (87.2%) 0.49 3182 (75.5%) 3166 (75.3%) 0.80
Previous pregnancy – n (%) 260 (34.1%) 234 (29.7%) 0.06 889 (21.1%) 904 (21.5%) 0.66
Family history of preeclampsia – n (%) 113 (14.8%) 89 (11.3%) 0.04 546 (13.0%) 549 (13.1%) 0.90
Blood pressure at entry (9–16 weeks) – mmHg Systolic 110±10 111±10 0.11 109±10 109±10 0.82
Diastolic 65±8 65±8 0.22 65±8 66±8 0.19
Drinking alcohol during pregnancy 170 (22.3%) 165 (20.9%) 0.52 397 (9.4%) 383 (9.1%) 0.62
Open in a new tab
*

Plus-minus values are mean ± standard deviation

The effect of vitamin C/E supplementation on selected maternal outcomes stratified by smoking status are presented in Table 2. The effect of vitamin supplementation on PE (p=0.66) and the composite outcome of PAH (p=0.86) did not differ by smoking status; vitamin supplementation did not reduce these outcomes in either group. Similar findings were observed for pregnancy associated hypertension, PPROM, severe PE and early onset PE (Table 2). However, vitamin C/E supplementation was associated with a significantly lower risk of placental abruption in smokers RR of 0.09 (95% CI 0.00, 0.87) but not in non-smokers (RR 0.92; 95% CI (0.52, 1.62), with the p-value for interaction <0.01.

Table 2.

Effect of Vitamin C/E Supplementation on Maternal Outcomes by Smoking Status

Outcome Smoker Placebo (n = 763) Smoker Vitamins (n = 788) Non-Smokers Placebo (n = 4213) Non-Smoker Vitamins (n = 4205) Smokers Non-Smokers B-D Test*
Relative Risk (95% CI) Relative Risk (95% CI) p- Value
Preeclampsia 52/763 (6.8%) 62/788 (7.9%) 280/4213 (6.6%) 296/4205 (7.0%) 1.15 (0.81,1.65) 1.06 (0.90,1.24) 0.66
Primary Composite Outcome† 58/763 (7.6%) 62/788 (7.9%) 227/4213 (5.4%) 243/4205 (5.8%) 1.04 (0.73,1.46) 1.07 (0.90,1.28) 0.86
Pregnancy Associated Hypertension 236/763 (30.9%) 278/786 (35.4%) 1086/4209 (25.8%) 1179/4203 (28.1%) 1.14 (0.99,1.32) 1.09 (1.01,1.17) 0.47
Placental Abruption 11/748 (1.5%) 1/782 (0.1%) 25/4190 (0.6%) 23/4175 (0.6%) 0.09 (0.00,0.87) ** 0.92 (0.52,1.62) 0.010
PPROM 24/744 (3.2%) 20/774 (2.6%) 105/4179 (2.5%) 104/4160 (2.5%) 0.80 (0.45,1.44) 1.00 (0.76,1.30) 0.51
Severe Preeclampsia 28/763 (3.7%) 27/788 (3.4%) 113/4213 (2.7%) 119/4205 (2.8%) 0.93 (0.56,1.57) 1.06 (0.82,1.36) 0.68
Pre-eclampsia Early Onset± 12/763 (1.6%) 8/788 (1.0%) 31/4213 (0.7%) 30/4205 (0.7%) 0.65 (0.27,1.57) 0.97 (0.59,1.60) 0.43
Open in a new tab
*

Breslow-Day Test for Homogeneity comparing smokers to non-smokers

†

Severe hypertension OR mild hypertension with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, SGA (<3rd%), medically indicated preterm birth or perinatal death.

±

Onset <34 weeks

**

Exact estimate of 95% confidence interval

Results for selected neonatal outcomes are presented in Table 3. There was no significant difference in vitamin effect by smoking status for SGA<3rd% (p=0.28), NICU admissions (p=0.13), neonatal morbidity (p=0.44) and neonatal composite outcome (p=0.54). However, the risk for preterm birth <37 weeks was significantly reduced among smokers receiving vitamin supplementation (RR 0.76; 95% CI 0.58, 0.99) but not in non-smokers (RR 1.03; 95% CI 0.90, 1.17), with p-value for interaction < 0.05. The incidence of preterm birth (<37 weeks) among smokers in the placebo group was 13.9%. The incidence was reduced to 10.5% in smokers receiving vitamin C/E, which was comparable to non- smokers (10.0% in placebo group and 10.2% in vitamins group).

Table 3.

Effect of Vitamin C/E Supplementation on Fetal Outcomes by Smoking Status

Outcome Smoker Placebo (n =763 ) Smoker Vitamins (n =788 ) Non- Smokers Placebo (n =4213 ) Non- Smoker Vitamins (n = 4205) Smokers Non-Smokers B-D Test*
Relative Risk (95% CI) Relative Risk (95% CI) p-Value
Preterm Birth (<32 wks) 49/763 (6.4%) 32/788 (4.1%) 124/4213 (2.9%) 117/4205 (2.8%) 0.63 (0.41,0.98) 0.95 (0.74,1.21) 0.11
Preterm Birth (<37 wks) 106/763 (13.9%) 83/788 (10.5%) 420/4213 (10.0%) 430/4205 (10.2%) 0.76 (0.58,0.99) 1.03 (0.90,1.17) 0.046
Small for Gest. Age (<3rd%) 22/734 (3.0%) 30/766 (3.9%) 110/4138 (2.7%) 103/4129 (2.5%) 1.31 (0.76,2.24) 0.94 (0.72,1.22) 0.28
Small for Gest. Age (<10th%) 88/734 (12.0%) 116/766 (15.1%) 438/4138 (10.6%) 446/4129 (10.8%) 1.26 (0.98,1.63) 1.02 (0.90,1.16) 0.14
NICU Admissions 94/761 (12.4%) 82/785 (10.4%) 463/4200 (11.0%) 495/4196 (11.8%) 0.85 (0.64,1.12) 1.07 (0.95,1.21) 0.13
Neonatal Morbidity 31/732 (4.2%) 29/764 (3.8%) 127/4129 (3.1%) 141/4120 (3.4%) 0.90 (0.55,1.47) 1.11 (0.88,1.41) 0.44
Neonatal Composite Outcomes 227/761 (29.8%) 230/782 (29.4%) 1043/4194 (24.9%) 1086/4190 (25.9%) 0.99 (0.85,1.15) 1.04 (0.97,1.12) 0.54
Open in a new tab
*

Breslow-Day Test for Homogeneity comparing smokers to non-smokers

In additional analyses, we performed subgroup analyses using the number of cigarettes smoked per day (0, 1–4, 5–9 and ≥ 10) and none of the tests for interaction were significant. This may be due to the very small number (n=138) of women that smoked ten or more cigarettes per day. Lastly, we examined the effect of self-reported smoking on pregnancy outcomes regardless of vitamin supplementation. Smoking was associated with increases in most adverse outcomes (Table 4). Rates of PE and placental abruption did not differ significantly by smoking status.

Table 4.

Select Pregnancy Outcomes by Smoking Status

Subject Outcomes Smokers (n = 1551) Non-Smokers (n = 8418) p- Value
Preeclampsia 114/1551 (7.4%) 576/8418 (6.8%) 0.47
Primary Composite Outcome* 120/1551 (7.7%) 470/8418 (5.6%) 0.001
Pregnancy Associated Hypertension 514/1549 (33.2%) 2265/8412 (26.9%) <0.001
Preterm <37 weeks gestation 189/1551 (12.2%) 850/8418 (10.1%) 0.013
Preterm <32 weeks gestation 81/1551 (5.2%) 241/8414 (2.9%) <0.001
Placental Abruption 12/1530 (0.78%) 48/8365 (0.57%) 0.33
SGA <3rd% 52/1500 (3.5%) 213/8267 (2.6%) 0.05
SGA<10th% 204/1500 (13.6%) 884/8267 (10.7%) 0.001
Neonatal Composite of Adverse Smoking Perinatal Outcomes† 457/1543 (29.6%) 2129/8348 (25.4%) <0.001
Open in a new tab
*

Severe hypertension OR mild hypertension with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, SGA (<3rd%), medically indicated preterm birth or perinatal death

†

RDS, sepsis, retinopathy of prematurity, intraventricular hemorrhage, or necrotizing enterocolitis

Discussion

Main findings

Vitamin C/E supplementation in this low-risk nulliparous cohort of women had no effect on the primary outcomes of PE, severe PE, or the PAH composite outcome by smoking status. However, we did observe a reduction in placental abruption and preterm birth <37 weeks among smokers assigned to daily vitamin C/E compared with placebo in this secondary analysis. The incidence of preterm birth among smokers was reduced to levels seen among the non-smokers in the cohort (13.9% to 10.5%) with vitamin supplementation however, this was not associated with reduction in neonatal composite outcome or neonatal morbidity. Previous studies have linked vitamin C deficiency to the occurrence of spontaneous preterm birth.18–20 This may be compounded by maternal tobacco use. There is also evidence indicating that vitamin C/E supplementation in pregnancy may ameliorate deleterious placental effects.21, 22 Gallo and colleagues proposed that the adverse effects of prenatal smoking on the placenta may be counteracted by antioxidant therapy such as vitamin C and E, two essential nutrients that can scavenge free radicals. In an in vitro model, they were able to demonstrate that vitamin C and E in combination had protective placental properties and can prevent the decrease of glutathione(antioxidant molecule) and increase the secretion of malondialdehyde (oxidative stress molecule); both induced by nicotine.23

Similar to our study, a recent systematic review and meta-analysis of nine trials, which included the MFMU Network trial of Vitamin C/E supplementation for the prevention of PE, confirmed no benefit of C/E supplementation on the outcome PE, regardless of maternal risk, while some studies have highlighted adverse maternal effects. In the five trials that included the outcome of placental abruption, all found a decreased risk of 37% among women who received supplementation. 15 Smoking was not considered in this review, and most studies focused on high risk women. With regard to preterm birth, Hauth et al. have already reported reduced preterm births among women receiving daily vitamin supplementation prior to 32 weeks of gestation in this cohort which was attributed to a reduction in preterm PROM.20 While smoking was controlled for in this study, the potential interaction with smoking was not addressed. However, smoking is associated with an increased rate of preterm birth prior to 32 weeks of gestation.24

We found that self-reported smoking was associated with increased incidences of the maternal composite outcome, neonatal composite outcome, preterm birth, low birth weight and small for gestational age which is consistent with previous studies1–3. Surprisingly, in this cohort, smoking was not associated with a decreased rate of preeclampsia. Although these findings, specifically the lack of risk reduction for preeclampsia among smokers is contradictory to previous reported literature.7, 8, 24 It is possible that the large proportion (~50%) of women identified as smokers in this study who smoked less than 5 cigarettes per day contributed to this result by reducing the dose of cigarette smoke in our smoking group.4 Secondly, our study consisted of a large proportion of African American and Hispanic women, who were not equally distributed between smokers and non-smokers, which could potentially influence the interpretation of our outcomes data.25 More recent literature suggests that tobacco use during pregnancy and its risk of PE is dependent on timing of exposure, specifically that smoking habits in the middle or late rather than in the beginning of pregnancy that seem to affect the risk of PE.7 Our study is limited by the knowledge of smoking habits only at recruitment, or early in the pregnancy, among this cohort. As in our study, other investigators have shown that although smoking decreases the risk of PE, women who smoke during their pregnancy and develop PE have an increased risk of adverse pregnancy outcomes, i.e. preterm birth (OR 5.77), abruption (OR 6.16), and stillbirth (OR 3.39) when compared with nonsmoking preeclamptics.8

Strengths/Limitations

This study is not without limitations. Although the findings for abruption and preterm birth were statistically different by smoking status, the possibility that they were the result of Type I (alpha) error is a plausible explanation. We conducted multiple comparisons for our analysis and the likelihood of two positive chance findings especially given the test for interaction was significant for only two outcomes must be taken into consideration as a limitation of our study Alternatively, in patients who smoke, only in the outcomes that were significantly influenced by smoking in the cohort would vitamin C/E supplementation have potential effectiveness. Another limitation is the small number of cases of abruption, as a slight change in the numbers may materially change our results, and a definitive association between vitamin intake and reduction in adverse outcomes therefore cannot be made.

Interpretation

However, we did note a higher rate of placental abruption in the smokers who received placebo (1.5%) when compared to the smokers receiving vitamin C/E (0.1%) and the non-smoking group (0.6%) which is consistent with previously reported adverse outcomes among smokers. Another potential limitation is the reliance on self-reported tobacco use in our cohort. However, self admission to tobacco use has been well validated based on prior publications demonstrating high concordance with serum and urine cotinine levels.26–29 We would anticipate that error in self reported smoking would trend toward under-reporting which would introduce error into the large non-smoking control group for our study. We acknowledge that analysis of blood samples would enhance our findings and future projects.

Conclusion

In summary, our findings suggest the possibility that maternal supplementation with vitamin C and E among smokers may reduce the risk of placental abruption and preterm birth <37 weeks. We do not believe a trial of supplementation restricted only to pregnant women who smoke is indicated at this time because there have been several trials of vitamin C/E supplementation for PE prevention.14, 30–36 Additional systematic reviews and even individual patient data meta-analysis combining the data and patients from these randomized trials with consideration of smoking status may further assess the robustness of and validate our findings. Such studies should specifically examine abruption and preterm birth. Although smoking cessation remains the most important intervention to prevent these outcomes in smokers, 2–3,8 unfortunately this is not achieved in a considerable proportion of pregnant patients. Therefore, the potential role of vitamin C/E supplementation as an adjunctive intervention in this at-risk group to prevent adverse outcomes deserves further investigation.

Acknowledgments

Funding: The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD34208, HD27869, HD40485, HD40560, HD40544, HD34116, HD40512, HD21410, HD40545, HD40500, HD27915, HD34136, HD27860, HD53118, HD53097, HD27917, and HD36801]; the National Heart, Lung, and Blood Institute; and the National Center for Research Resources [M01 RR00080, UL1 RR024153, UL1 RR024989] and its contents do not necessarily represent the official view of NICHD, NHLBI, NCRR or NIH.

The authors thank the following subcommittee members who participated in protocol development and coordination between clinical research centers (Sabine Bousleiman, R.N.C., M.S.N. and Margaret Cotroneo, R.N.), protocol/data management and statistical analysis (Elizabeth Thom, Ph.D.), and protocol development and oversight (John C. Hauth, M.D., James M. Roberts, M.D., Catherine Y. Spong, M.D., and Gail D. Pearson, M.D., Sc.D.).

In addition to the authors, other members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network are as follows:

University of Alabama at Birmingham, Birmingham, AL – J. Hauth, D.J. Rouse, A. Northen, P. Files, J. Grant, M. Wallace, K. Bailey

University of Pittsburgh, Pittsburgh, PA – J. Roberts, S. Caritis, T. Kamon (deceased), M. Cotroneo, D. Fischer

University of Utah, Salt Lake City, UT – M. Varner, P. Reed, S. Quinn (LDS Hospital), V. Morby (McKay-Dee Hospital), F. Porter (LDS Hospital), R. Silver, J. Miller (Utah Valley Regional Medical Center), K. Hill

Columbia University, New York, NY – S. Bousleiman, R. Alcon, K. Saravia, F. Loffredo, A. Bayless (Christiana), C. Perez (St. Peter’s University Hospital), M. Lake (St. Peter’s University Hospital), M. Talucci

University of North Carolina at Chapel Hill, Chapel Hill, NC – K. Boggess, K. Dorman, J. Mitchell, K. Clark, S. Timlin

Case Western Reserve University-MetroHealth Medical Center, Cleveland, OH – J. Bailit, C. Milluzzi, W. Dalton, C. Brezine, D. Bazzo

University of Texas Southwestern Medical Center, Dallas, TX – J. Sheffield, L. Moseley, M. Santillan, K. Buentipo, J. Price, L. S. Hermann, C. Melton, Y. Gloria-McCutchen, B. Espino

Northwestern University, Chicago, IL – M. Dinsmoor (NorthShore University HealthSystem), T. Matson-Manning, G. Mallett

University of Texas Health Science Center at Houston-Children’s Memorial Hermann Hospital, Houston, TX – S. Ramin, S. Blackwell, K. Cannon, S. Lege-Humbert, Z. Spears

Brown University, Providence, RI – M. Carpenter, J. Tillinghast, M. Seebeck

The Ohio State University, Columbus, OH – J. Iams, F. Johnson, S. Fyffe, C. Latimer, S. Frantz, S. Wylie

Drexel University, Philadelphia, PA – M. Talucci, M. Hoffman (Christiana), J. Benson (Christiana), Z. Reid, C. Tocci

Wake Forest University Health Sciences, Winston-Salem, NC – P. Meis, M. Swain

Oregon Health & Science University, Portland, OR – J. Tolosa, W. Smith, L. Davis, E. Lairson, S. Butcher, S. Maxwell, D. Fisher

University of Texas Medical Branch, Galveston, TX – J. Moss, B. Stratton, G. Hankins, J. Brandon, C. Nelson-Becker, G. Olson, L. Pacheco

Wayne State University, Detroit, MI – G. Norman, S. Blackwell, P. Lockhart, D. Driscoll, M. Dombrowski

The George Washington University Biostatistics Center, Washington, DC – E. Thom, T. Boekhoudt, L. Leuchtenburg

National Heart, Lung, and Blood Institute, Bethesda, MD – G. Pearson, V. Pemberton, J. Cutler, W. Barouch

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD – C. Spong, S. Tolivaisa

MFMU Steering Committee Chair (University of Texas Medical Center, Galveston, TX) – G.D. Anderson, M.D.

Footnotes

Disclosure of interests: The authors have no relevant conflict of interests to disclose

Contribution to authorship:

Adi Abramovici, MD: Study concept/design and primary author of manuscript.

Robin E. Gandley, PhD: Study concept/design and assistance with edits/review of manuscript.

Rebecca G. Clifton, Ph.D.: Primary statistical analysis and manuscript review edits.

The following authors equally contributed with edits/review of manuscript: Kenneth J. Leveno, M.D., Leslie Myatt, Ph.D. Ronald J. Wapner, M.D. John M. Thorp, Jr., M.D. Brian M. Mercer, M.D. Alan M. Peaceman, M.D. Philip Samuels, M.D. Anthony Sciscione, D.O. Margaret Harper, M.D. M.Sc. George Saade, M.D. and Yoram Sorokin, M.D.

Ethics Approval: N/A

References

  • 1.Butler NR, Goldstein H, Ross EM. Cigarette smoking in pregnancy: its influence on birth weight and perinatal mortality. British medical journal. 1972;2:127–30. doi: 10.1136/bmj.2.5806.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Cnattingius S. The epidemiology of smoking during pregnancy: smoking prevalence, maternal characteristics, and pregnancy outcomes. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 2004;6 (Suppl 2):S125–40. doi: 10.1080/14622200410001669187. [DOI] [PubMed] [Google Scholar]
  • 3.Cnattingius S, Granath F, Petersson G, Harlow BL. The influence of gestational age and smoking habits on the risk of subsequent preterm deliveries. The New England journal of medicine. 1999;341:943–8. doi: 10.1056/NEJM199909233411303. [DOI] [PubMed] [Google Scholar]
  • 4.Hammoud AO, Bujold E, Sorokin Y, Schild C, Krapp M, Baumann P. Smoking in pregnancy revisited: findings from a large population-based study. American journal of obstetrics and gynecology. 2005;192:1856–62. doi: 10.1016/j.ajog.2004.12.057. discussion 62–3. [DOI] [PubMed] [Google Scholar]
  • 5.Clark KE, Irion GL. Fetal hemodynamic response to maternal intravenous nicotine administration. American journal of obstetrics and gynecology. 1992;167:1624–31. doi: 10.1016/0002-9378(92)91752-v. [DOI] [PubMed] [Google Scholar]
  • 6.Conde-Agudelo A, Althabe F, Belizan JM, Kafury-Goeta AC. Cigarette smoking during pregnancy and risk of preeclampsia: a systematic review. American journal of obstetrics and gynecology. 1999;181:1026–35. doi: 10.1016/s0002-9378(99)70341-8. [DOI] [PubMed] [Google Scholar]
  • 7.Wikstrom AK, Stephansson O, Cnattingius S. Tobacco use during pregnancy and preeclampsia risk: effects of cigarette smoking and snuff. Hypertension. 2010;55:1254–9. doi: 10.1161/HYPERTENSIONAHA.109.147082. [DOI] [PubMed] [Google Scholar]
  • 8.Bainbridge SA, Sidle EH, Smith GN. Direct placental effects of cigarette smoke protect women from pre-eclampsia: the specific roles of carbon monoxide and antioxidant systems in the placenta. Medical hypotheses. 2005;64:17–27. doi: 10.1016/j.mehy.2004.06.019. [DOI] [PubMed] [Google Scholar]
  • 9.Raijmakers MT, Dechend R, Poston L. Oxidative stress and preeclampsia: rationale for antioxidant clinical trials. Hypertension. 2004;44:374–80. doi: 10.1161/01.HYP.0000141085.98320.01. [DOI] [PubMed] [Google Scholar]
  • 10.Cnattingius S, Mills JL, Yuen J, Eriksson O, Salonen H. The paradoxical effect of smoking in preeclamptic pregnancies: smoking reduces the incidence but increases the rates of perinatal mortality, abruptio placentae, and intrauterine growth restriction. American journal of obstetrics and gynecology. 1997;177:156–61. doi: 10.1016/s0002-9378(97)70455-1. [DOI] [PubMed] [Google Scholar]
  • 11.Uusitalo L, Uusitalo U, Ovaskainen ML, et al. Sociodemographic and lifestyle characteristics are associated with antioxidant intake and the consumption of their dietary sources during pregnancy. Public health nutrition. 2008;11:1379–88. doi: 10.1017/S1368980008003522. [DOI] [PubMed] [Google Scholar]
  • 12.Ramirez RJ, Hubel CA, Novak J, DiCianno JR, Kagan VE, Gandley RE. Moderate ascorbate deficiency increases myogenic tone of arteries from pregnant but not virgin ascorbate-dependent rats. Hypertension. 2006;47:454–60. doi: 10.1161/01.HYP.0000201444.80784.59. [DOI] [PubMed] [Google Scholar]
  • 13.Haggarty P, Campbell DM, Duthie S, et al. Diet and deprivation in pregnancy. The British journal of nutrition. 2009;102:1487–97. doi: 10.1017/S0007114509990444. [DOI] [PubMed] [Google Scholar]
  • 14.Roberts JM, Myatt L, Spong CY. Vitamins C and E to prevent complications of pregnancy-associated hypertension. The New England journal of medicine. 2010;362:1282–91. doi: 10.1056/NEJMoa0908056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Conde-Agudelo A, Romero R, Kusanovic JP, Hassan SS. Supplementation with vitamins C and E during pregnancy for the prevention of preeclampsia and other adverse maternal and perinatal outcomes: a systematic review and metaanalysis. American journal of obstetrics and gynecology. 2011;204:503, e1–12. doi: 10.1016/j.ajog.2011.02.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Carey JC, Klebanoff MA, Hauth JC. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. The New England journal of medicine. 2000;342:534–40. doi: 10.1056/NEJM200002243420802. [DOI] [PubMed] [Google Scholar]
  • 17.Lachin JM, Matts JP, Wei LJ. Randomization in clinical trials: conclusions and recommendations. Controlled clinical trials. 1988;9:365–74. doi: 10.1016/0197-2456(88)90049-9. [DOI] [PubMed] [Google Scholar]
  • 18.Woods JR, Jr, Plessinger MA, Miller RK. Vitamins C and E: missing links in preventing preterm premature rupture of membranes? American journal of obstetrics and gynecology. 2001;185:5–10. doi: 10.1067/mob.2001.115868. [DOI] [PubMed] [Google Scholar]
  • 19.Siega-Riz AM, Promislow JH, Savitz DA, Thorp JM, Jr, McDonald T. Vitamin C intake and the risk of preterm delivery. American journal of obstetrics and gynecology. 2003;189:519–25. doi: 10.1067/s0002-9378(03)00363-6. [DOI] [PubMed] [Google Scholar]
  • 20.Hauth JC, Clifton RG, Roberts JM. Vitamin C and E supplementation to prevent spontaneous preterm birth: a randomized controlled trial. Obstetrics and gynecology. 2010;116:653–8. doi: 10.1097/AOG.0b013e3181ed721d. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Voigt M, Briese V, Jorch G, Henrich W, Schneider KT, Straube S. The influence of smoking during pregnancy on fetal growth. Considering daily cigarette consumption and the SGA rate according to length of gestation. Zeitschrift fur Geburtshilfe und Neonatologie. 2009;213:194–200. doi: 10.1055/s-0029-1214405. [DOI] [PubMed] [Google Scholar]
  • 22.Slotkin TA, Seidler FJ, Spindel ER. Prenatal nicotine exposure in rhesus monkeys compromises development of brainstem and cardiac monoamine pathways involved in perinatal adaptation and sudden infant death syndrome: amelioration by vitamin C. Neurotoxicology and teratology. 2011;33:431–4. doi: 10.1016/j.ntt.2011.02.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Gallo C, Renzi P, Loizzo S. Potential therapeutic effects of vitamin e and C on placental oxidative stress induced by nicotine: an in vitro evidence. The open biochemistry journal. 2010;4:77–82. doi: 10.2174/1874091X01004010077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Miller EC, Cao H, Wen SW, Yang Q, Lafleche J, Walker M. The risk of adverse pregnancy outcomes is increased in preeclamptic women who smoke compared with nonpreeclamptic women who do not smoke. American journal of obstetrics and gynecology. 2010;203:334, e1–8. doi: 10.1016/j.ajog.2010.05.020. [DOI] [PubMed] [Google Scholar]
  • 25.Windham GC, Hopkins B, Fenster L, Swan SH. Prenatal active or passive tobacco smoke exposure and the risk of preterm delivery or low birth weight. Epidemiology. 2000;11:427–33. doi: 10.1097/00001648-200007000-00011. [DOI] [PubMed] [Google Scholar]
  • 26.Klebanoff MA, Levine RJ, Morris CD. Accuracy of self-reported cigarette smoking among pregnant women in the 1990s. Paediatric and perinatal epidemiology. 2001;15:140–3. doi: 10.1046/j.1365-3016.2001.00321.x. [DOI] [PubMed] [Google Scholar]
  • 27.England LJ, Grauman A, Qian C. Misclassification of maternal smoking status and its effects on an epidemiologic study of pregnancy outcomes. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 2007;9:1005–13. doi: 10.1080/14622200701491255. [DOI] [PubMed] [Google Scholar]
  • 28.Silbergeld EK, Patrick TE. Environmental exposures, toxicologic mechanisms, and adverse pregnancy outcomes. American journal of obstetrics and gynecology. 2005;192:S11–21. doi: 10.1016/j.ajog.2004.06.117. [DOI] [PubMed] [Google Scholar]
  • 29.McDonald SD, Perkins SL, Walker MC. Correlation between self-reported smoking status and serum cotinine during pregnancy. Addictive behaviors. 2005;30:853–7. doi: 10.1016/j.addbeh.2004.08.016. [DOI] [PubMed] [Google Scholar]
  • 30.Chappell LC, Seed PT, Briley AL. Effect of antioxidants on the occurrence of preeclampsia in women at increased risk: a randomised trial. Lancet. 1999;354:810–6. doi: 10.1016/S0140-6736(99)80010-5. [DOI] [PubMed] [Google Scholar]
  • 31.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, placebocontrolled trial. American journal of obstetrics and gynecology. 2005;192:520–1. doi: 10.1016/j.ajog.2004.09.005. [DOI] [PubMed] [Google Scholar]
  • 32.Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamins in Pre-eclampsia Trial C. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet. 2006;367:1145–54. doi: 10.1016/S0140-6736(06)68433-X. [DOI] [PubMed] [Google Scholar]
  • 33.Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson JS, Group AS. Vitamins C and E and the risks of preeclampsia and perinatal complications. The New England journal of medicine. 2006;354:1796–806. doi: 10.1056/NEJMoa054186. [DOI] [PubMed] [Google Scholar]
  • 34.Spinnato JA, 2nd, Freire S, Pinto ESJL. Antioxidant therapy to prevent preeclampsia: a randomized controlled trial. Obstetrics and gynecology. 2007;110:1311–8. doi: 10.1097/01.AOG.0000289576.43441.1f. [DOI] [PubMed] [Google Scholar]
  • 35.Villar J, Purwar M, Merialdi M. World Health Organisation multicentre randomised trial of supplementation with vitamins C and E among pregnant women at high risk for pre-eclampsia in populations of low nutritional status from developing countries. BJOG : an international journal of obstetrics and gynaecology. 2009;116:780–8. doi: 10.1111/j.1471-0528.2009.02158.x. [DOI] [PubMed] [Google Scholar]
  • 36.Xu H, Perez-Cuevas R, Xiong X. An international trial of antioxidants in the prevention of preeclampsia (INTAPP) American journal of obstetrics and gynecology. 2010;202:239 e1–39 e10. doi: 10.1016/j.ajog.2010.01.050. [DOI] [PubMed] [Google Scholar]

RESOURCES