Vitamins C and E a Bust at Preventing Preeclampsia in Diabetic Women

Neil Osterweil

July 02, 2010

July 2, 2010 (Orlando, Florida) — Vitamins C and E get an F+ when it comes to preventing preeclampsia in women with type 1 diabetes, British investigators reported here at the American Diabetes Association (ADA) 70th Scientific Sessions. Their study was published online June 25 in the Lancet to coincide with its presentation.

Neither vitamin C nor vitamin E supplements were better than placebo at preventing preeclampsia in diabetic women. Vitamin supplementation also failed to reduce the frequency of gestational hypertension, low birth weight, and the ratio of plasminogen activator inhibitor (PAI)-1 to PAI-2, a measure of endothelial function

"Importantly however, we did not observe any adverse maternal or neonatal outcomes, and in 2 of 11 prespecified subgroup analyses, the risk for preeclampsia was significantly reduced in women with low antioxidant status at baseline randomized to vitamin treatment, compared with women of similar antioxidant status assigned to placebo," said David R. McCance, MD, professor of medicine at the Royal Victoria Hospital in Belfast, Northern Ireland.

Given the poor performance of vitamins as preventive measures in other conditions — with the notable exception of B vitamins for the prevention of neural tube defects — the results are not particularly surprising but are still disappointing, said M. Sue Kirkman, MD, vice-president of clinical affairs at the ADA, who was not involved in the study but who comoderated the session at which it was presented.

"Preeclampsia is such a problem, especially in women with type 1 diabetes, and we really haven't found an answer. It does seem to be related to glucose control, and we tell women who are pregnant to improve their glucose control because it will have X, Y, and Z benefits, but unfortunately, preeclampsia prevention is not one of them. So my question is, where do we go now to try to prevent this major complication of pregnancy," Dr. Kirkman said in an interview with Medscape Medical News.

Dr. McCance and colleagues enrolled 762 women from 25 pregnancy metabolic clinics in the United Kingdom in a randomized placebo-controlled trial. The women, all of whom had been diagnosed with type 1 diabetes before becoming pregnant, were between 8 and 22 weeks of gestation. The women were randomly assigned to receive vitamin C 1000 mg plus vitamin E 400 IU in the form of α-tocopherol, or a matched placebo daily until delivery.

The primary study end point was preclampsia, defined as gestational hypertension with proteinuria. Gestational hypertension was determined with 2 diastolic blood pressure (DBP) readings of 90 mm Hg or higher at least 4 hours apart, or 1 DBP reading of 110 mg Hg or higher in previously normotensive women. Women with chronic hypertension before pregnancy were considered to have gestational hypertension if there was a rise of 10 mm Hg on the first antenatal blood pressure reading after 20 weeks of gestation or for up to 48 hours after birth.

Investigators collected blood and urine samples at randomization and at 26 and 34 weeks of gestation, and analyzed them for the PAI-1 to PAI-2 ratio as a marker of endothelial activation, plasma ascorbate, serum α-tocopherol, glycosylated hemoglobin (HbA1c), and the urine albumin to creatinine ratio.

Preeclampsia occurred in 15% of women in the vitamin group and in 19% in the placebo group (risk ratio [RR], 0.81; 95% confidence interval [CI], 0.59 - 1.12; P = .20). Gestational hypertension rates were identical, occurring in 11% in each group (RR, 1.02; CI, 0.68 - 1.53; = .92). The proportion of women having children with birth weights below the 10th percentile trended slightly lower among women in the vitamin group than in the placebo group (6% vs 10%), but Dr. McCance noted that this difference was not statistically significant (RR, 0.64; CI, 0.39 - 1.05; = .08).

There were also no significant differences in miscarriage rates, elective terminations, maternal deaths, delivery following a hypertensive-related admission, eclampsia, pulmonary edema, or any other factor studied.

When the authors performed an analysis of the women stratified by HbA1c levels, baseline vitamin C and E status, and smoking at baseline (a total of 11 subcategories), they found that there was a significant advantage for vitamins in only 2 categories: women with baseline vitamin C levels in the lowest third — 10 µmol or lower (7% vs 46%; RR, 0.14; CI, 0.02 - 0.76; = .03), and women with baseline vitamin E levels in the middle third — from 3 to 5 µmol/mmol of cholesterol (8% vs 24%; RR, 0.35; CI, 0.12 - 0.97; = .04). The total numbers of women involved, however, were small, with just 7 women in the low vitamin C group developing preeclampsia, and 59 in the vitamin E group.

In an accompanying editorial, Baha M. Sibai, MD, professor and chair of obstetrics and gynecology at the University of Cincinnati in Ohio, notes that preeclampsia is a complex problem with no easy solutions.

"The etiology of preeclampsia might be multifactorial. Some cases might be caused by immunological factors, others by dietary factors, and others because of preexisting medical conditions, or by a combination of these factors. Therefore, any single intervention is unlikely to be effective in prevention," he writes.

The study was funded by the Wellcome Trust. Dr. McCance and Dr. Kirkman have disclosed no relevant financial relationships. Dr. Sibai reports serving as a consultant for Beckman-Coulter and Inverness Medical in the use of angiogenic markers in preeclampsia.

Lancet. Published online June 25, 2010. Abstract, Abstract

American Diabetes Association (ADA) 70th Scientific Sessions. Presented June 26, 2010.

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