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 prospective open randomized trial, 229 pregnant women with preterm premature rupture of membranes (PPROM) at ≥24.0 and < 34.0 weeks' gestation were randomly 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.
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 populations. 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 randomized 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.
OBJECTIVE: The phenotype of the antioxidant and pro-angiogenic protein haptoglobin (Hp) predicts cardiovascular disease risk and treatment response to antioxidant vitamins in individuals with diabetes. Our objective was to determine whether Hp phenotype influences pre-eclampsia risk, or the efficacy of vitamins C and E in preventing pre-eclampsia, in women with type-1 diabetes.
DESIGN: This is a secondary analysis of a randomised controlled trial in which women with diabetes received daily vitamins C and E, or placebo, from 8 to 22 weeks of gestation until delivery.
SETTING: Twenty-five antenatal metabolic clinics across the UK (in north-west England, Scotland, and Northern Ireland).
POPULATION: Pregnant women with type-1 diabetes.
METHODS: Hp phenotype was determined in white women who completed the study and had plasma samples available (n = 685).
MAIN OUTCOME MEASURE: Pre-eclampsia.
RESULTS: Compared with Hp 2-1, Hp 1-1 (OR 0.59, 95% CI 0.30-1.16) and Hp 2-2 (OR 0.93, 95% CI 0.60-1.45) were not associated with significantly decreased pre-eclampsia risk after adjusting for treatment group and HbA1c at randomisation. Our study was not powered to detect an interaction between Hp phenotype and treatment response; however, our preliminary analysis suggests that vitamins C and E did not prevent pre-eclampsia in women of any Hp phenotype (Hp 1-1, OR 0.77, 95% CI 0.22-2.71; Hp 2-1, OR 0.81, 95% CI 0.46-1.43; Hp 2-2, 0.67, 95% CI 0.34-1.33), after adjusting for HbA1c at randomisation.
CONCLUSIONS: The Hp phenotype did not significantly affect pre-eclampsia risk in women with type-1 diabetes.
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 randomization. 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 (Table presented) 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 are 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.
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 randomized 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.
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 prospectively in 749 women from the randomized controlled Diabetes and Pre-eclampsia Intervention Trial (DAPIT). HbA(1c) (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: 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 aimed 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 randomised 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 randomly allocated in a 1:1 ratio to receive 1000 mg vitamin C and 400 IU vitamin E (alpha-tocopherol) or matched placebo daily until delivery. The randomisation 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, ISRCTN27214045.
FINDINGS: Between April, 2003, and June, 2008, 762 women were randomly 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 preeclampsia who were randomised 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 randomised to receive placebo. Methods: Respiratory outcomes to 2 years of age were documented using questionnaires 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 questionnaire (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.
<b>BACKGROUND: </b>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.<b>METHODS: </b>We conducted a multicenter, randomized, double-blind trial involving nulliparous women who were at low risk for preeclampsia. Women were randomly 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.<b>RESULTS: </b>A total of 10,154 women underwent randomization. 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.<b>CONCLUSIONS: </b>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 (ClinicalTrials.gov number, NCT00135707).
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 prospective open randomized trial, 229 pregnant women with preterm premature rupture of membranes (PPROM) at ≥24.0 and < 34.0 weeks' gestation were randomly 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.
