Antioxidants in the treatment of severe pre‐eclampsis an explanatory randomised controlled trial Optimal Glycemic Control, Pre-eclampsia, and Gestational Hypertension in Women With Type 1 Diabetes in the Diabetes and Pre-eclampsia Intervention Trial Comparison of the effects of supplemental red palm oil and sunflower oil on maternal vitamin A status. Vitamins C and E for prevention of pre-eclampsia in women with type 1 diabetes (DAPIT): a randomised placebo-controlled trial Respiratory outcomes in early childhood following antenatal vitamin C and E supplementation The impact of prior preeclampsia on the risk of superimposed preeclampsia and other adverse pregnancy outcomes in patients with chronic hypertension. The Diabetes and Pre-eclampsia Intervention Trial. Vitamin C and E Supplementation to Prevent Spontaneous Preterm Birth: A Randomized Controlled Trial Vitamins C and E to prevent complications of pregnancy-associated hypertension. Haptoglobin Phenotype, Preeclampsia Risk and the Efficacy of Vitamin C and E Supplementation to Prevent Preeclampsia in a Racially Diverse Population Placental protein tyrosine nitration and MAPK in type 1 diabetic pre-eclampsia: Impact of antioxidant vitamin supplementation. A novel dietary intervention to optimize vitamin E intake of pregnant women to 15 mg/day. Antioxidant supplementation in pregnant women with low antioxidant status. Vitamins C and E in the latency period in women with preterm premature rupture of membranes. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial Vitamin C and E supplementation in women at risk of preeclampsia is associated with changes in indices of oxidative stress and placental function. An international trial of antioxidants in the prevention of preeclampsia (INTAPP). Relationship of prolonged pharmacologic serum levels of vitamin E to incidence of sepsis and necrotizing enterocolitis in infants with birth weight 1,500 grams or less. Vitamin C and E supplementation in women at high risk for preeclampsia: a double-blind, placebo-controlled trial. Effects of maternal antioxidant supplementation on maternal and fetal antioxidant levels: a randomized, double-blind study. Does vitamin C and vitamin E supplementation prolong the latency period before delivery following the preterm premature rupture of membranes? A randomized controlled study. Vitamin C and E Supplementation Does Not Reduce the Risk of Superimposed PE in Pregnancy Outcome of pregnancies complicated by type 1 insulin-dependent diabetes in Sweden: acute pregnancy complications, neonatal mortality and morbidity. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial Antioxidant supplementation and premature rupture of the membranes: a planned secondary analysis. Antenatal supplementation of antioxidant vitamins to reduce the oxidative stress at delivery--a pilot study. PP170. Prenatal vitamin C and E supplementation is associated with a reduction in placental abruption and preterm birth in smokers.
Objective To determine whether antioxidant therapy alters the disease process in severe early onset pre‐eclampsia , in support of the hypothesis that increased lipid peroxides and reactive oxygen species production play an important role in the pathogenesis of the disease OBJECTIVE To assess the relationship between glycemic control , pre-eclampsia , and gestational hypertension in women with type 1 diabetes . RESEARCH DESIGN AND METHODS Pregnancy outcome ( pre-eclampsia or gestational hypertension ) was assessed prospect ively in 749 women from the r and omized controlled Diabetes and Pre-eclampsia Intervention Trial ( DAPIT ) . HbA1c  ( A1C )  values were available up to 6 months before pregnancy ( n = 542 ) , at the first antenatal visit ( median 9 weeks ) ( n = 721 ) , at 26 weeks ’ gestation ( n = 592 ) , and at 34 weeks ’ gestation ( n = 519 ) and were categorized as optimal ( < 6.1 % : referent ) , good ( 6.1–6.9 % ) , moderate ( 7.0–7.9 % ) , and poor ( ≥8.0 % ) glycemic control , respectively . RESULTS Pre-eclampsia and gestational hypertension developed in 17 and 11 % of pregnancies , respectively . Women who developed pre-eclampsia had significantly higher A1C values before and during pregnancy compared with women who did not develop pre-eclampsia ( P < 0.05 , respectively ) . In early pregnancy , A1C ≥8.0 % was associated with a significantly increased risk of pre-eclampsia ( odds ratio 3.68 [ 95 % CI 1.17–11.6 ] ) compared with optimal control . At 26 weeks ’ gestation , A1C values ≥6.1 % ( good : 2.09 [ 1.03–4.21 ] ; moderate : 3.20 [ 1.47–7.00 ] ; and poor : 3.81 [ 1.30–11.1 ] ) and at 34 weeks ’ gestation A1C values ≥7.0 % ( moderate : 3.27 [ 1.31–8.20 ] and poor : 8.01 [ 2.04–31.5 ] ) significantly increased the risk of pre-eclampsia compared with optimal control . The adjusted odds ratios for pre-eclampsia for each 1 % decrement in A1C before pregnancy , at the first antenatal visit , at 26 weeks ’ gestation , and at 34 weeks ’ gestation were 0.88 ( 0.75–1.03 ) , 0.75 ( 0.64–0.88 ) , 0.57 ( 0.42–0.78 ) , and 0.47 ( 0.31–0.70 ) , respectively . Glycemic control was not significantly associated with gestational hypertension . CONCLUSIONS Women who developed pre-eclampsia had significantly higher A1C values before and during pregnancy . These data suggest that optimal glycemic control both early and throughout pregnancy may reduce the risk of pre-eclampsia in women with type 1 diabetes BACKGROUND Conflicting results have been reported on the ability of dietary carotenoids to improve vitamin A status in lactating women .  Red palm oil is one of the richest dietary sources of beta-carotene . OBJECTIVE We aim ed to determine the efficacy of red palm oil in increasing retinol and provitamin A status in pregnant and lactating women . DESIGN Ninety rural , pregnant Tanzanian women from 3 r and omly selected villages were recruited during their third trimester to participate in 3 dietary intervention groups : a control group , who were encouraged to maintain the traditional practice of eating staples with dark-green leafy vegetables , and 2 study groups , who were given either sunflower or red palm oil for use in household food preparations . The intervention lasted 6 mo . Plasma sample s were collected at the third trimester and 1 and 3 mo postpartum , and breast-milk sample s were collected 1 and 3 mo postpartum . RESULTS Supplementation with red palm oil , which is rich in provitamin A , increased alpha- and beta-carotene concentrations significantly ( P < 0.001 ) in both plasma and breast milk . Plasma retinol concentrations were similar in all dietary groups . Breast-milk retinol concentrations tended to decrease from 1 to 3 mo postpartum in the control group , but were maintained in both oil groups . The difference in change in breast-milk retinol concentration between the red palm oil group and the control group was significant ( P = 0.041 ) . CONCLUSIONS Consumption of red palm oil increases concentrations of alpha- and beta-carotene in both breast milk and serum and maintains breast-milk retinol concentrations . Sunflower oil consumption seems to conserve breast-milk retinol similarly to consumption of red palm oil . Breast-milk retinol might be maintained through increased dietary intake of these vegetable oils and use of mild cooking preparation methods ( such as the addition of oil at the end of cooking and avoidance of frying ) Summary Background Results of several trials of antioxidant use during pregnancy have not shown a reduction in pre-eclampsia , but the effect in women with diabetes is unknown . We aim ed to assess whether supplementation with vitamins C and E reduced incidence of pre-eclampsia in women with type 1 diabetes . Methods We enrolled women from 25 UK antenatal metabolic clinics in a multicentre r and omised placebo-controlled trial . Eligibility criteria were type 1 diabetes preceding pregnancy , presentation between 8 weeks ' and 22 weeks ' gestation , singleton pregnancy , and age 16 years or older . Women were r and omly allocated in a 1:1 ratio to receive 1000 mg vitamin C and 400 IU vitamin E ( α-tocopherol ) or matched placebo daily until delivery . The r and omisation sequence was stratified by centre with balanced blocks of eight patients . All trial personnel and participants were masked to treatment allocation . The primary endpoint was pre-eclampsia , which we defined as gestational hypertension with proteinuria . Analysis was by modified intention to treat . This study is registered , IS RCT N27214045 . Findings Between April , 2003 , and June , 2008 , 762 women were r and omly allocated to treatment groups ( 379 vitamin supplementation , 383 placebo ) . The primary endpoint was assessed for 375 women allocated to receive vitamins , and 374 allocated to placebo . Rates of pre-eclampsia did not differ between vitamin ( 15 % , n=57 ) and placebo ( 19 % , 70 ) groups ( risk ratio 0·81 , 95 % CI 0·59–1·12 ) . No adverse maternal or neonatal outcomes were reported . Interpretation Supplementation with vitamins C and E did not reduce risk of pre-eclampsia in women with type 1 diabetes . However , the possibility that vitamin supplementation might be beneficial in women with a low antioxidant status at baseline needs further testing . Funding The Wellcome Trust Background Prenatal antioxidant supplementation might influence fetal lung growth and development and reduce infant respiratory morbidity . The aim of this study was to test the hypothesis that infants of mothers at risk of pre-eclampsia who were r and omised to receive high-dose vitamins C and E ( 1000 mg vitamin C and 400 IU RRR α-tocopherol daily ) during pregnancy would have better respiratory outcomes than infants whose mothers were r and omised to receive placebo . Methods Respiratory outcomes to 2 years of age were documented using question naires and , in a subset , by recording their healthcare utilisation and calculating the cost of care data . Results 330 women who had taken vitamin supplementation and 313 who had taken placebo completed the respiratory question naire ( 386 and 366 infants , respectively ) . There were no significant differences between the two groups in the proportions diagnosed with asthma . 54 women who had taken vitamin supplementation and 45 who had taken placebo  took part in the healthcare utilisation study ( 65 and 53 infants , respectively ) . On average , infants of mothers receiving vitamin supplementation had 2.6 ( 99 % CI 0.8 to 5.1 ) times more A&E/outpatient visits and 3.2 ( 99 % CI 0.2 to 6.9 ) times more GP visits than infants of mothers receiving placebo , and their costs of care were £ 226 ( 99 % CI £ 27 to £ 488 ) more for outpatient admissions , £ 57 ( 99 % CI £ 3 to £ 123 ) more for GP visits and £ 22 ( 99 % CI £ 3 to £ 50 ) more for medications . Conclusions High-dose antenatal vitamin C and E supplementation  does not improve infant respiratory outcome and is associated with increased healthcare utilisation and cost of care OBJECTIVE We sought to compare the rates of superimposed preeclampsia and adverse outcomes in women with chronic hypertension with or without prior preeclampsia . STUDY DESIGN We conducted secondary analysis of 369 women with chronic hypertension ( 104 with prior preeclampsia ) enrolled at 12 - 19 weeks as part of a multisite trial of antioxidants  to prevent preeclampsia ( no reduction was found ) . Outcome measures were rates of superimposed preeclampsia and other adverse perinatal outcomes . RESULTS Prepregnancy body mass index , blood pressure , and smoking status at enrollment were similar between groups . The rates of superimposed preeclampsia ( 17.3 % vs 17.7 % ) , abruptio placentae ( 1.0 % vs 3.1 % ) , perinatal death ( 6.7 % vs 8.7 % ) , and small for gestational age ( 18.4 % vs 14.3 % ) were similar between groups , but preterm delivery < 37 weeks was higher in the prior preeclampsia group ( 36.9 % vs 27.1 % ; adjusted risk ratio , 1.46 ; 95 % confidence interval , 1.05 - 2.03 ; P = .032 ) . CONCLUSION In women with chronic hypertension , a history of preeclampsia does not increase the rate of superimposed preeclampsia , but is associated with an increased rate of delivery at < 37 weeks OBJECTIVE Rates of  pre-eclampsia  in women with type 1 diabetes are two to four times higher than in normal pregnancies . Diabetes is associated with antioxidant depletion and increased free radical production , and an increasing body of evidence suggests that oxidative stress and endothelial cell activation may be relevant to disease pathogenesis in pre-eclampsia . The Diabetes and Pre-eclampsia Intervention Trial ( DAPIT ) aims to establish if pregnant women with type 1 diabetes supplemented with vitamins C and E have lower rates of pre-eclampsia and endothelial activation compared with placebo treatment . METHODS DAPIT is a r and omised multicentre double-blind placebo-controlled trial that will recruit 756 pregnant women with type 1 diabetes from 20 metabolic-antenatal clinics in the UK over 4 years . Women are r and omised to daily vitamin C ( 1000 mg ) and vitamin E ( 400 IU ) or placebo at 8 - 22 weeks of gestation until delivery . Maternal venous blood is obtained at r and omisation , 26 and 34 weeks , for markers of endothelial activation and oxidative stress and to assess glycaemic control . The primary outcome of DAPIT is pre-eclampsia . Secondary outcomes include endothelial activation ( PAI-1/PAI-2 ) and birthweight centile OBJECTIVE : To estimate whether maternally administered vitamins C and E lower the risk of spontaneous preterm birth . METHODS : This is a secondary analysis of a r and omized , double-masked , placebo-controlled trial in nulliparous women at low-risk administered 1,000 mg vitamin C and 400 international units vitamin E or placebo daily from 9 to 16 weeks of gestation until delivery . Outcomes include preterm birth attributable to premature rupture of membranes ( PROM ) and total spontaneous preterm births ( spontaneous preterm birth attributable to PROM or spontaneous labor ) . RESULTS : Of the 10,154 women r and omized , outcome data were available for 9,968 ( 4,992 vitamin group and 4,976 placebo group ) . A total of 1,038 women ( 10.4 % ) delivered preterm , of whom 698 ( 7.0 % ) had  spontaneous preterm birth . A spontaneous preterm birth occurred in 356 women ( 7.1 % ) assigned to daily vitamin C and E supplementation and in 342 ( 6.9 % ) assigned to placebo . There were 253 women ( 2.5 % ) who delivered after preterm PROM and 445 ( 4.5 % ) after a spontaneous preterm labor . In women supplemented with vitamins C and E , births attributed to preterm PROM were similar at less than 37 and 35 weeks of gestation , but births were less frequent before 32 weeks of gestation ( 0.3 % compared with 0.6 % , adjusted odds ratio 0.3–0.9 ) . However , total spontaneous preterm births across gestation in women supplemented with vitamins C and E or a placebo were similar . CONCLUSION : Maternal supplementation with vitamins C and E beginning at 9 to 16 weeks of gestation in nulliparous women at low risk did not reduce spontaneous preterm births . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00135707 . LEVEL OF EVIDENCE : BACKGROUND Oxidative stress has been proposed as a mechanism linking the poor placental perfusion characteristic of preeclampsia with the clinical manifestations of the disorder . We assessed the effects of antioxidant supplementation with vitamins C and E , initiated early in pregnancy , on the risk of serious adverse maternal , fetal , and neonatal outcomes related to pregnancy-associated hypertension . METHODS We conducted a multicenter , r and omized , double-blind trial involving nulliparous women who were at low risk for preeclampsia . Women were r and omly assigned to begin daily supplementation with 1000 mg of vitamin C and 400 IU of vitamin E or matching placebo between the 9th and 16th weeks of pregnancy . The primary outcome was severe pregnancy-associated hypertension alone or severe or mild hypertension with elevated liver-enzyme levels , thrombocytopenia , elevated serum creatinine levels , eclamptic seizure , medically indicated preterm birth , fetal-growth restriction , or perinatal death . RESULTS A total of 10,154 women underwent r and omization . The two groups were similar with respect to baseline characteristics and adherence to the study drug . Outcome data were available for 9969 women . There was no significant difference between the vitamin and placebo groups in the rates of the primary outcome ( 6.1 % and 5.7 % , respectively ; relative risk in the vitamin group , 1.07 ; 95 % confidence interval [ CI ] , 0.91 to 1.25 ) or in the rates of preeclampsia ( 7.2 % and 6.7 % , respectively ; relative risk , 1.07 ; 95 % CI , 0.93 to 1.24 ) . Rates of adverse perinatal outcomes did not differ significantly between the groups . CONCLUSIONS Vitamin C and E supplementation initiated in the 9th to 16th week of pregnancy in an unselected cohort of low-risk , nulliparous women did not reduce the rate of adverse maternal or perinatal outcomes related to pregnancy-associated hypertension ( Clinical Trials.gov number , NCT00135707 ) Haptoglobin ’s ( Hp ) antioxidant and pro-angiogenic properties differ between the 1 - 1 , 2 - 1 , and 2 - 2 phenotypes . Hp phenotype affects cardiovascular disease risk and treatment response to antioxidant vitamins in some non-pregnant population s. We previously demonstrated that  preeclampsia  risk was doubled in white Hp 2 - 1 women , compared to Hp 1 - 1 women . Our objectives were to determine whether we could reproduce this finding in a larger cohort , and to determine whether Hp phenotype influences lack of efficacy of antioxidant vitamins in preventing preeclampsia and serious complications of pregnancy-associated hypertension ( PAH ) . This is a secondary analysis of a r and omized controlled trial in which 10,154 low-risk women received daily vitamin C and E , or placebo , from 9 - 16 weeks gestation until delivery . Hp phenotype was determined in the study prediction cohort ( n = 2,393 ) and a case-control cohort ( 703 cases , 1,406 controls ) . The primary outcome was severe PAH , or mild or severe PAH with elevated liver enzymes , elevated serum creatinine , thrombocytopenia , eclampsia , fetal growth restriction , medically indicated preterm birth or perinatal death . Preeclampsia was a secondary outcome . Odds ratios were estimated by logistic regression . Sampling weights were used to reduce bias from an overrepresentation of women with preeclampsia or the primary outcome . There was no relationship between Hp phenotype and the primary outcome or  preeclampsia in Hispanic , white/other or black women .  Vitamin supplementation did not reduce the risk of the primary outcome or preeclampsia in women of any phenotype . Supplementation increased preeclampsia risk ( odds ratio 3.30 ; 95 % confidence interval 1.61–6.82 , p<0.01 ) in Hispanic Hp 2 - 2 women . Hp phenotype does not influence preeclampsia risk , or identify a subset of women who may benefit from vitamin C and E supplementation to prevent preeclampsia AIM To examine the role of placental protein tyrosine nitration and p38-Mitogen-Activated Protein Kinase α ( p38-MAPKα ) , Extra Cellular-Signal Regulated Kinase ( ERK ) and c-Jun NH2-Terminal Kinase ( JNK ) activity , in the pathogenesis of type 1 diabetic pre-eclampsia , and the putative modulation of these indices by maternal vitamin C and E supplementation . METHODS Placental sample s were obtained from a sub-cohort of the DAPIT trial : a r and omised placebo-controlled trial of antioxidant supplementation to reduce pre-eclampsia in type 1 diabetic pregnancy . Placenta from placebo-treated : normotensive ( NT ) [ n=17 ] , gestational hypertension ( GH ) [ n=7 ] and pre-eclampsia ( PE ) [ n=6 ] and vitamin-treated : NT ( n=20 ) , GH ( n=4 ) and PE ( n=3 ) was analysed . Protein tyrosine nitration was assessed by immunohistochemistry in paraffin-embedded tissue . Catalytic activities of placental p38-MAPKα , ERK and JNK were measured by enzyme-linked immunosorbent assay ( ELISA ) . RESULTS Nitrotyrosine immunostaining was present in placebo-treated NT , GH and PE placentae , with no significant difference observed between the groups . There was a non-significant trend towards decreased p38-MAPKα activity in PE vs NT control placentae . ERK and JNK were similar among the three outcome placebo groups and vitamin supplementation did not significantly alter their activity . CONCLUSION Nitrotyrosine immunopositivity in normotensive diabetic placentae indicates some degree of tyrosine nitration in uncomplicated diabetic pregnancy , possibly due to inherent oxidative stress and peroxynitrite production . Our results suggest that p38-MAPKα , ERK and JNK are not directly involved in the pathogenesis of type 1 diabetic pre-eclampsia and are not modulated by vitamin-supplementation Associations have been reported between suboptimal maternal vitamin E intake during pregnancy and childhood asthma . This pilot study conducted in 2008/2009 investigated the feasibility and acceptability of a food-based r and omized controlled trial in pregnant women to optimize dietary vitamin E intake to 15 mg/day . A food-based intervention using " food exchanges " to individually optimize dietary vitamin E intake to 15 mg/day was developed and included in an advice booklet . Forty-three pregnant women with a personal/partner history of asthma were recruited at 12 weeks gestation and r and omized to food-based intervention or a control group until 20 weeks gestation . A registered dietitian assessed the  vitamin E intake of 22 women and provided tailored advice on food-based exchanges to optimize their intake to 15 mg/day . The 21 control women were not given dietary advice . The food-based intervention was completed by 19 women and increased mean vitamin E intake : food diary data , 7.13 mg/day ( 95 % confidence interval : 5.63 to 18.6 ) to 17.4 mg/day ( 95 % confidence interval : 14.4 to 20.5 ) ( P<0.001 ) . This pilot study demonstrates the feasibility and acceptability of a food-exchange-based intervention to  optimize dietary vitamin E intake during pregnancy . Additional work is required to determine whether this intervention , if sustained for the rest of pregnancy , reduces the likelihood of childhood asthma . The methodology used in the design of this novel food-based intervention could be transferred to other nutrients AIM The aim of this study was to investigate the benefit of antioxidant supplementation in a cohort of women with low antioxidant status and determine the changes in cell-free mRNA . MATERIAL AND METHODS This study was a r and omized , placebo-controlled trial of 8 - 12 weeks ' pregnant women who had low antioxidant status treated with either antioxidants or control diets daily until 2 weeks ' postpartum . The primary end-point was the risk of pre-eclampsia and the secondary end-point was the changes of angiogenic and anti-oxidant mRNA markers related to the outcome ( Clinical Trial.gov , number NCT01232205 ) . RESULTS There were 110 women enrolled in the study , r and omly assigned to the supplementation ( n = 52 ) and control group ( n = 58 ) . The overall rate of pre-eclampsia was 8.7 % ( nine subjects ) . There were significant differences ( P = 0.034 ) between the supplementation and control group in the incidence of pre-eclampsia ( 2.0 % [ one case ] and 14.5 % [ eight cases ] , respectively ) and mRNA level of superoxide-dismutase , heme oxygenase-1 , vascular endothelial growth factor receptor-1 , endoglin and placental growth factor after supplementation . CONCLUSION Supplementation of women with low antioxidant status  with micronutrients containing antioxidants during early gestation might reduce the risk of pre-eclampsia OBJECTIVE To determine whether supplementation with vitamins C and E  after preterm premature rupture of membranes ( PPROM ) is associated with an increased latency period . METHODS In this double-blind , r and omized , controlled trial , 60 women with singleton pregnancies of 26 to 34 weeks ' duration and PPROM were r and omly assigned to vitamin C ( 500 mg/day ) and vitamin E ( 400 IU/day ) or placebo until delivery . All women received 2 doses of betamethasone in the first 24 h after admission as well as broad-spectrum antibiotic prophylaxis . RESULTS Important demographic , as well as clinical characteristics such as number of cases of chorioamnionitis , early neonatal sepsis , and respiratory distress syndrome , were similar in the 2 groups . A statically significant difference in the mean+/-S.D. number of days of latency was found between the groups ( 10.5+/-5.2 days vs. 3.5+/-4.0 days ( P = 0.03 ) . CONCLUSION Vitamins C and E supplementation of after PPROM is associated with a longer latency before delivery BACKGROUND Oxidative stress could play a part in pre-eclampsia , and there is some evidence to suggest that vitamin C and vitamin E supplements could reduce the risk of the disorder . Our aim was to investigate the potential benefit of these antioxidants in a cohort of women with a range of clinical risk factors . METHODS We did a r and omised , placebo-controlled trial to which we enrolled 2410 women identified as at increased risk of pre-eclampsia from 25 hospitals . We assigned the women 1000 mg vitamin C and 400 IU vitamin E ( RRR alpha tocopherol ; n=1199 ) or matched placebo ( n=1205 ) daily from the second trimester of pregnancy until delivery . Our primary endpoint was pre-eclampsia , and our main secondary endpoints were low birthweight ( < 2.5 kg ) and small size for gestational age ( < 5th customised birthweight centile ) . Analyses were by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N 62368611 . FINDINGS Of 2404 patients treated , we analysed 2395 ( 99.6 % ) . The incidence of pre-eclampsia was similar in treatment placebo groups ( 15 % [ n=181 ] vs 16 % [ n=187 ] , RR 0.97 [ 95 % CI 0.80 - 1.17 ] ) . More low birthweight babies were born to women who took antioxidants than to controls ( 28 % [ n=387 ] vs 24 % [ n=335 ] , 1.15 [ 1.02 - 1.30 ] ) , but small size for gestational age did not differ between groups ( 21 % [ n=294 ] vs 19 % [ n=259 ] , 1.12 [ 0.96 - 1.31 ] ) . INTERPRETATION Concomitant supplementation with vitamin C and vitamin E does not prevent pre-eclampsia in women at risk , but does increase the rate of babies born with a low birthweight . As such , use of these high-dose antioxidants is not justified in pregnancy OBJECTIVE We have previously reported a reduced incidence of preeclampsia in women who were at risk and were taking vitamin C ( 1000 mg/d ) and vitamin E ( 400 IU/d ) supplements . In this study , we determined whether supplementation in the same cohort was associated with an improvement in indices of placental dysfunction and oxidative stress toward values determined in women who were at low risk of preeclampsia . STUDY DESIGN Seventy-nine women who were at high risk and who were taking vitamin supplements and 81 who were taking placebos were compared with 32 women who were at low risk and who were not taking supplements who were studied simultaneously . RESULTS Indices of oxidative stress and placental function were abnormal in the placebo group . When the placebo group was compared with the women who were at low risk , ascorbic acid , plasminogen activator inhibitor-2 , and placenta growth factor concentrations were decreased ; and 8-epi-prostagl and in F(2alpha),leptin , and the plasminogen activator inhibitor-1/-2 ratio were increased . In the group that received vitamin supplements , ascorbic acid , 8-epi-prostagl and in F(2alpha ) , leptin , and plasminogen activator inhibitor-1/-2 values were similar to women who were at low risk . CONCLUSION Antioxidant supplementation in women who were at risk of preeclampsia was associated with improvement in biochemical indices of the disease OBJECTIVE We sought to investigate whether prenatal vitamin C and E supplementation reduces the incidence of gestational hypertension ( GH ) and its adverse conditions among high- and low-risk women . STUDY DESIGN In a multicenter r and omized controlled trial , women were stratified by the risk status and assigned to daily treatment ( 1 g vitamin C and 400 IU vitamin E ) or placebo . The primary outcome was GH and its adverse conditions . RESULTS Of the 2647 women r and omized , 2363 were included in the analysis . There was no difference in the risk of GH and its adverse conditions between groups ( relative risk , 0.99 ; 95 % confidence interval , 0.78 - 1.26 ) . However , vitamins C and E increased the risk of fetal loss or perinatal death ( nonprespecified ) as well as preterm prelabor rupture of membranes . CONCLUSION Vitamin C and E supplementation did not reduce the rate of preeclampsia or GH , but increased the risk of fetal loss or perinatal death and preterm prelabor rupture of membranes The incidence of culture-proven neonatal sepsis and necrotizing enterocolitis ( NEC ) in preterm infants maintained at pharmacologic ( mean 5.1 mg/dL + /- 1.45 SD ) serum vitamin E levels for long periods was prospect ively studied as part of a double-masked clinical trial of the effect of prophylactic vitamin E v placebo treatment on the development and course of retinopathy of prematurity ( ROP ) . Within a few days of birth , 914 preterm infants were enrolled in the study ; 545 ( 275 placebo-treated infants , 270 vitamin E-treated infants had birth weight of 1,500 g or less . A significant difference in incidence of neonatal sepsis ( 17 placebo-treated infants , 37 vitamin E-treated infants ) and NEC ( 18 placebo-treated infants , 32 vitamin E-treated infants ) was observed among infants who had been treated for eight or more days and who had developed neither sepsis nor NEC before that time . The association of vitamin E treatment with increased incidence of disease was much higher with sepsis than with NEC . The most likely reason for these observations is a pharmacologic serum vitamin E-related decrease in oxygen-dependent intracellular killing ability which results in a decreased resistance to infection in preterm infants . The data suggest that , if this occurs , it is clinical ly significant only in the more immature infants . In view of the known variability of absorption of oral vitamin E and the association between high serum vitamin E levels and increased incidence of sepsis and late-onset NEC reported here , it can be concluded that serum vitamin E levels must be monitored when supplemental vitamin E is administered to premature infants , especially those with birth weight 1,500 g or less . The risk-benefit ratio of long-term treatment using vitamin E at high serum levels should be clearly assessed OBJECTIVE We sought to determine the effect of supplemental antioxidant vitamins C and E on the rate of preeclampsia in high-risk pregnant women . STUDY DESIGN Women at risk for preeclampsia ( previous preeclampsia , chronic hypertension , pregestational diabetes , or multifetal gestation ) were recruited at 14 to 20 weeks ' gestation and r and omly assigned to receive either 1000 mg of vitamin C and 400 IU of vitamin E or placebo daily in addition to their regular prenatal vitamins . The primary outcome was the occurrence of preeclampsia . An estimated sample size of 220 women in each arm was determined to be necessary to demonstrate a 50 % reduction in the rate of preeclampsia . RESULTS Funding was terminated after 109 women had been recruited ; 9 were lost to follow-up or withdrew . We analyzed data from the remaining 100 women to look for differences in outcome and to estimate the required sample size for future studies . The rate of preeclampsia was not different : 17.3 % in women who received supplemental vitamins C and E , versus 18.8 % in the placebo group . Assuming a baseline rate of preeclampsia in the placebo group between 15 % and 20 % , we can estimate that 500 to 950 women in each arm will be required to show a clinical ly important reduction in the rate of preeclampsia . CONCLUSION The potential benefit of vitamin C and E supplementation to prevent  preeclampsia in women with clinical risk factors is smaller than we estimated . Future studies of antioxidant vitamin supplementation in this population will require more than 500 women in each arm OBJECTIVE We sought to determine whether vitamins C and E could be delivered to the fetal-placental unit through maternal oral supplementation . STUDY DESIGN In a r and omized , double-blind study , 20 women received a daily prenatal vitamin with or without 400 IU of vitamin E and 500 mg of vitamin C , starting at 35 weeks ' gestation . At r and omization , a nutritional question naire , plasma vitamin C and E and  red blood cell ( RBC ) vitamin E levels were determined . At delivery , concentrations of maternal and fetal plasma vitamin C and E , maternal and fetal RBC vitamin E , amniotic fluid vitamin C , and chorioamnion vitamin E and tensile strength were determined . RESULTS Maternal plasma vitamin E levels increased in the supplemented women but not in the control subjects . No changes in maternal vitamin C levels were noted . Maternal plasma vitamin C concentrations at delivery correlated closely with amniotic fluid vitamin C levels . Similarly , maternal plasma vitamin E levels at delivery correlated with the chorioamnion concentration of vitamin E. CONCLUSIONS Maternal plasma vitamin E levels are increased by oral supplementation . Maternal plasma vitamin C and E concentrations correlate with the concentration of vitamin C in the amniotic fluid and vitamin E in the chorioamnion , respectively OBJECTIVE To determine whether maternal vitamin C and vitamin E supplementation after the premature rupture of membranes is associated with an increase in the latency period before delivery . METHODS In the present prospect i ve open r and omized trial , 229 pregnant women with preterm premature rupture of membranes ( PPROM ) at ≥ 24.0 and < 34.0 weeks ' gestation were r and omly assigned to receive either 1,000 mg of vitamin C and 400 IU of vitamin E ( n = 126 ) or a placebo ( n = 123 ) . The primary outcome was the latency period until delivery . Analysis was performed on an intention-to-treat basis . RESULTS No significant differences in demographic or clinical characteristics were observed between the groups . Latency period until delivery was significantly higher in the group that received vitamins compared with the control group ( 11.2 ± 6.3 days versus 6.2 ± 4.0 days ; p < 0.001 ) . Gestational age at delivery was also significantly higher in the vitamin group compared with the control group ( 31.9 ± 2.6 weeks versus 31.0 ± 2.6 weeks ; p = 0.01 ) . No significant differences in adverse maternal outcome ( i.e. , chorioamnionitis or endometritis ) or neonatal outcome ( i.e. , neonatal sepsis , neonatal death , necrotizing enterocolitis , or grade 3 to 4 intraventricular hemorrhage ) were noted between groups . CONCLUSIONS The findings of the present study suggest that the use of vitamins C and E in women with PPROM is associated with a longer latency period before delivery . Moreover , adverse neonatal and maternal outcomes , which are often associated with prolonged latency periods , were similar between the groups Background . Oxidative stress could play a role in the development of preeclampsia . There is some evidence to suggest that vitamin C and E supplements can reduce the risk of the disorder . We hypothesized its beneficial role in a group of pregnant women with essential hypertension . Methods . In this r and omized controlled trial , we enrolled 50 pregnant women with essential hypertension . We assigned the women 1000 mg vitamin C and 400 IU natural vitamin E ( RRR α tocopherol ; n = 25 ) , daily from the second trimester of pregnancy until delivery or no supplementation ( n = 25 ) . Our primary endpoint was development of superimposed preeclampsia , and main secondary endpoints were aggravation of hypertension , need for admission , need to increase antihypertensive drugs , and small size for gestational age ( < fifth customized birthweight centile ) . Results . We analyzed 50 women who completed the study .  The incidence of superimposed preeclampsia was similar in vitamin and control groups ( 8 % [ n = 2 ] vs 12 % [ n = 3 ] , p = 1.000 ) . Vitamin C and E supplementation also did not prevent aggravation of hypertension in group of women who took it ( 12 % [ n = 3 ] vs 32 % [ n = 8 ] , p = 0.172 ) . Small size for gestational age babies did not differ between groups ( 4 % [ n = 2 ] vs 6 % [ n = 3 ] , p = 1.000 ) . Conclusion . Vitamin C and E supplementation does not prevent development of superimposed preeclampsia in women with essential hypertension . Our results did not show any significant benefit of vitamin supplementation . There was some trend in lessening of hypertensive complications of pregnancy . Our results failed to find any correlation between development of superimposed preeclampsia and oxidative stress This prospect i ve nationwide study conducted during 1982 - 1985 examined the rates of  hypertensive disorders , perinatal mortality and morbidity in 491 insulin-dependent diabetic pregnancies ( White 's classes : B , 164 ; C , 129 ; D , 172 ; F , 26 ) and in the total population of 279,000 . The rates of pregnancy-induced hypertension ( PIH ) or pre-eclampsia ( 20.6 % ) , premature delivery ( 24.6 % ) , and cesarean section ( 45.2 % ) in the diabetic group were more than four times higher than normal . PIH or preeclampsia occurred significantly ( p < 0.01 ) more frequently in patients with diabetic microangiopathy .  Mean birthweight was similar in the two population s but gestational age was significantly ( p < 0.001 ) shorter ( 38 weeks ) in the diabetic group . The rate of large for gestational age infants ( 20 % ) in the diabetic group was considerably above normal ( 3.5 % ) . Although perinatal mortality rate in the diabetic group was only 3.1 % , it was 4.4 times higher than normal ; five of ten fetal deaths were associated with poor glycemic control and thus may not really be unexplained . Neonatal morbidity was significantly more frequent in the diabetic group ; still , the incidence of idiopathic respiratory distress syndrome was only 1.6 % compared with 0.6 % in the general population . Discriminant analysis revealed that gestational age at birth and elevated maternal HbA1c values in early pregnancy independently of each other had a significant impact on the occurrence of neonatal morbidity BACKGROUND Oxidative stress has been implicated in the pathophysiology of pre-eclampsia . This r and omised controlled trial investigated the effect of supplementation with vitamins C and E in women at increased risk of the disorder on plasma markers of vascular endothelial activation and placental insufficiency and the occurrence of pre-eclampsia . METHODS 283 women were identified as being at increased risk of pre-eclampsia by abnormal two-stage uterine-artery doppler analysis or a previous history of the disorder and were r and omly assigned vitamin C ( 1000 mg/day ) and vitamin E ( 400 IU/day ) or placebo at 16 - 22 weeks ' gestation . Plasma markers of endothelial activation ( plasminogen-activator inhibitor 1 [ PAI-1 ] ) and placental dysfunction ( PAI-2 ) were measured every month until delivery . Pre-eclampsia was assessed by the development of proteinuric hypertension . Analyses were done by intention to treat , and in the cohort who completed the study . FINDINGS Supplementation with vitamins C and E was associated with a 21 % decrease in the PAI-1/PAI-2 ratio during gestation ( 95 % CI 4 - 35 , p=0.015 ) . In the intention-to-treat cohort , pre-eclampsia occurred in 24 ( 17 % ) of 142 women in the placebo group and 11 ( 8 % ) of 141 in the vitamin group ( adjusted odds ratio 0.39 [ 0.17 - 0.90 ] , p=0.02 ) . In the cohort who completed the study ( 81 placebo group , 79 vitamin group ) , the odds ratio for pre-eclampsia was 0.24 ( 0.08 - 0.70 , p=0.002 ) . INTERPRETATION Supplementation with vitamins C and E may be beneficial in the prevention of pre-eclampsia in women at increased risk of the disease . Multicentre trials are needed to show whether vitamin supplementation affects the occurrence of pre-eclampsia in low-risk women and to confirm our results in larger groups of high-risk women from different population OBJECTIVE The purpose of this study was to determine if antioxidant supplementation during pregnancy reduces the incidence of  premature rupture of the membranes ( PROM ) .  STUDY DESIGN A placebo-controlled , double-blind trial was conducted . PROM and preterm PROM ( PPROM ) were planned secondary outcomes of the trial . Women between 12(0/7 ) and 19(6/7 ) weeks of gestation and diagnosed to have chronic hypertension or a prior history of preeclampsia were r and omized to daily treatment with both vitamin C ( 1000 mg ) and E ( 400 IU ) or placebo . RESULTS Outcome data for PROM were available for 697 of 739 patients . The rates of PROM ( 37/349 [ 10.6 % ] vs 19/348 [ 5.5 % ] ; adjusted risk ratio [ RR ] 1.89 [ 95.42 % CI , 1.11 - 3.23 ] ; P = .015 ) , and PPROM ( 16/349 [ 4.6 % ] vs 6/348 [ 1.7 % ] ; RR 2.68 [ 1.07 - 6.71 ] ; P = .025 ) were increased in the antioxidant group . CONCLUSION Contrary to expectations , vitamins C and E supplementation in this dose combination may be associated with an increased risk of PROM and PPROM BACKGROUND Preterm infants are at increased risk of oxidative stress and free-radical mediated diseases partly related to deficient antioxidant state . The purpose of this study was to investigate if maternal supplementation of antioxidant vitamins prior to delivery would reduce the oxidative stress in the mothers and their infants . STUDY DESIGN A pilot case-control study . PATIENTS AND METHODS Five mothers at risk of preterm delivery between 30 and 36 weeks were given a daily oral dose of betacarotene 20 mg , vitamin E 167.8 mg and vitamin C 1000 mg until delivery . Plasma levels of MDA and vitamins A , E and beta-carotene  were measured prior to treatment in mothers and at delivery in both mothers and neonates . Seven mother-infant pairs comparable in gestation and birthweight acted as controls . RESULTS In the supplemented group , median maternal plasma MDA at delivery was significantly lower compared to the pretreatment level ( 1.9 vs. 3.2 micromol/l , p=0.04 ) and it was also lower than the control group ( 1.9 vs. 3.65 micromol/l , p<0.001 ) . In the supplemented group , median maternal plasma vitamin E at delivery was significantly higher than the levels prior to treatment ( 46 vs. 31 micromol/l , p=0.007 ) in the same group and those at delivery in the control group ( 46 vs. 30 micromol/l , p=0.03 ) . There was a trend of lower plasma MDA and higher vitamin E at birth in infants born to supplemented mothers , but it did not reach statistical significance . CONCLUSION A short supplementation of multiple antioxidant vitamins to a small sample of preterm pregnant women reduced the oxidative stress at delivery in mothers and probably in their neonates . Larger studies probably using larger doses are needed to evaluate the efficacy of this strategy INTRODUCTION Maternal tobacco use increases the incidence of numerous adverse pregnancy outcomes including miscarriage , small for gestational age infants , spontaneous preterm birth and placental abruption . OBJECTIVES We evaluated the relationship between prenatal vitamin C/E supplementation and perinatal outcomes by maternal smoking status . METHODS Secondary analysis of a multicenter trial of vitamin C/E starting at 9 - 16 weeks in low-risk nulliparous women with singletons . We examined the effect of vitamin supplementation by reported smoker or non-smoker at time of r and omization . The primary outcomes were preeclampsia ( new onset hypertension and proteinuria ) and a composite outcome of severe pregnancy associated hypertension ( severe hypertension OR mild or severe hypertension with elevated liver enzymes , elevated serum creatinine , thrombocytopenia , eclamptic seizure , fetal growth restriction , medically indicated preterm birth or perinatal death ) . Perinatal outcomes included preterm birth and abruption . The Breslow-Day test was used to ascertain whether there was an interaction between smoking status and vitamin supplementation . RESULTS Of 9969 women , 4993 received vitamins C/E and 4976 received placebo .  The  prevalence of smoking ( 15.6 % overall ; 788 vitamin , 763 placebo ) was similar in treatment groups . The analysis of vitamin C/E by smoking status for perinatal outcomes is given ( Table 1 ) . The effect of prenatal vitamin C/E on the risk preeclampsia or pregnancy associated hypertension composite outcome did not differ by smoking status . Vitamin C/E was protective for placental abruption and preterm birth among smokers . CONCLUSION The effect of vitamin C/E supplementation on preeclampsia/pregnancy associated hypertension did not differ by smoking status . However , vitamin C/E supplementation was associated with a > 40 % reduction in placental abruption and > 30 % reduction in preterm birth among smokers warranting further study . ACKNOWLEDGEMENT This project supported in part by National Institutes of Health Grant PO1-HD30367
BACKGROUND Vitamin E supplementation may help reduce the risk of pregnancy complications involving oxidative stress , such as pre-eclampsia .
There is a need to evaluate the efficacy and safety of vitamin E supplementation in pregnancy .
OBJECTIVES To assess the effects of vitamin E supplementation , alone or in combination with other separate supplements , on pregnancy outcomes , adverse events , side effects and use of health services .