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Vitamin C and vitamin E in pregnant women at risk of pre-eclampsia
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Vitamin C and vitamin E in pregnant women at risk of pre-eclampsia I, like many researchers, was disappointed in the results of Lucilla Poston and colleagues’ VIP trial (April 8, p 1145)1 in which supplementation with vitamins C and E did not reduce the risk of pre-eclampsia in a high-risk population. I was particularly interested in Poston and colleagues’ explanation for their null findings in light of their previously published work. In their previous small randomised trial,2 a similarly high-risk group was treated with an identical regimen to that used in the VIP trial. Although the primary endpoint was the effect of treatment on a biochemical endpoint (ratio of plasminogen activator inhibitor [PAI] 1 to PAI 2), Poston and colleagues reported a statistically and clinically significant reduction in the frequency of preeclampsia (11/141 [8%] vs 24/142 [17%], p=0·02). The explanation they provide for the discrepancy with the just-published VIP trial is that the earlier trial was probably subject to a type I error. However, this suggestion ignores the more likely, albeit less agreeable, conclusion that this large, multicentre randomised trial was less biased than the previous smaller one. Unlike the VIP trial, the initial publication is unclear in terms of how the determination of the outcome of pre-eclampsia was made. Certainly Poston and colleagues used standard and acceptable definitions, but it is not clear whether or not the person (or people) who abstracted data from the patients’ charts was unaware of the treatment allocation. Furthermore, in the VIP study, women for whom it was difficult for research staff to make a confident diagnosis were reviewed by a committee that was unaware of treatment allocation.
This would reduce any potential bias further. This is not the first, and probably not the last, time that promising findings from small, single-centre trials are not reproduced in large multicentre trials.3 What investigators should learn from all of this is the importance of using the same rigorous design and procedures in their pilot studies as they would in large multicentre trials. I declare that I have no conflict of interest.
Stephen Wood [email protected] Departments of Obstetrics and Gynecology and Community Health Sciences, University of Calgary, Calgary, Alberta T2N 2T9, Canada 1
2
3
Poston L, Briley A, Seed P, Kelly F, Shennan AH. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006; 367: 1145–54. Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet 1999; 354: 810–16. LeLorier J, Gregoire G, Benhaddad A, Lapierre J, Derderian F, Abramovich DR. Discrepancies between meta-analysis and subsequent large randomized controlled trials. N Engl J Med 1997; 337: 536–42.
From their placebo-controlled VIP trial, Lucilla Poston and colleagues1 conclude that supplementation with vitamins C and E from 14 to 22 weeks’ gestation does not prevent pre-eclampsia in women “at increased risk”—a finding at variance with their previous findings.2 Unlike Poston and colleagues, I believe that this discrepancy might be due to the difference in the study population chosen. The previous trial2 mostly included women with abnormal two-stage uterine-artery doppler screening at 16–22 weeks’ gestation. The soundness of this recruitment was supported by lower plasma markers of placental dysfunction and endothelial activation and lower rates of pre-eclampsia in the treatment group, further justifying the supplementation with vitamins
C and E in most of these patients. Moreover, Parra and colleagues3 confirmed that an abnormal uterineartery pulsatility index correlated better with later pre-eclampsia than markers of placental dysfunction and endothelial activation. In the VIP trial, only 3% of patients entered with an abnormal uterine-artery doppler waveform. Yet the positive and negative predictive values of uterine-artery doppler are high in patients with previous pre-eclampsia4 or chronic hypertension,5 which accounted for 59% of the patients included in this trial. Uterine-artery doppler screening would have identified much more accurately the patients with inadequate uteroplacental blood flow and probable defective placentation among these women with historical risk factors. This would also have avoided unnecessary treatment in patients without an oxidative stress process and would have prevented excess vitamin C concentration in their fetal tissue. I declare that I have no conflict of interest.
Lionel Carbillon [email protected] Department of Obstetrics and Gynecology, Assistance Publique - Hôpitaux de Paris, Paris 13 University, Hôpital Jean Verdier, Avenue du 14 Juillet, 93143 Bondy Cedex, France 1
2
3
4
5
Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006; 367: 1145–54. Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the occurrence of preeclampsia in women at increased risk: a randomised trial. Lancet 1999; 354: 810–16. Parra M, Rodrigo R, Barja P, et al. Screening test for preeclampsia through assessment of uteroplacental blood flow and biochemical markers of oxidative stress and endothelial dysfunction. Am J Obstet Gynecol 2005; 193: 1486–91. Harrington K, Fayyad A, Thakur V, Aquilina J. The value of uterine artery Doppler in the prediction of uteroplacental complications in multiparous women. Ultrasound Obstet Gynecol 2004; 23: 50–55. Fleischer A, Schulman H, Farmakides G, et al. Uterine artery Doppler velocimetry in pregnant women with hypertension. Am J Obstet Gynecol 1986; 154: 806–13.
www.thelancet.com Vol 368 July 15, 2006
Correspondence
We do not have the rights to reproduce this image on the web.
198
Vitamin C and vitamin E in pregnant women at risk of pre-eclampsia I, like many researchers, was disappointed in the results of Lucilla Poston and colleagues’ VIP trial (April 8, p 1145)1 in which supplementation with vitamins C and E did not reduce the risk of pre-eclampsia in a high-risk population. I was particularly interested in Poston and colleagues’ explanation for their null findings in light of their previously published work. In their previous small randomised trial,2 a similarly high-risk group was treated with an identical regimen to that used in the VIP trial. Although the primary endpoint was the effect of treatment on a biochemical endpoint (ratio of plasminogen activator inhibitor [PAI] 1 to PAI 2), Poston and colleagues reported a statistically and clinically significant reduction in the frequency of preeclampsia (11/141 [8%] vs 24/142 [17%], p=0·02). The explanation they provide for the discrepancy with the just-published VIP trial is that the earlier trial was probably subject to a type I error. However, this suggestion ignores the more likely, albeit less agreeable, conclusion that this large, multicentre randomised trial was less biased than the previous smaller one. Unlike the VIP trial, the initial publication is unclear in terms of how the determination of the outcome of pre-eclampsia was made. Certainly Poston and colleagues used standard and acceptable definitions, but it is not clear whether or not the person (or people) who abstracted data from the patients’ charts was unaware of the treatment allocation. Furthermore, in the VIP study, women for whom it was difficult for research staff to make a confident diagnosis were reviewed by a committee that was unaware of treatment allocation.
This would reduce any potential bias further. This is not the first, and probably not the last, time that promising findings from small, single-centre trials are not reproduced in large multicentre trials.3 What investigators should learn from all of this is the importance of using the same rigorous design and procedures in their pilot studies as they would in large multicentre trials. I declare that I have no conflict of interest.
Stephen Wood [email protected] Departments of Obstetrics and Gynecology and Community Health Sciences, University of Calgary, Calgary, Alberta T2N 2T9, Canada 1
2
3
Poston L, Briley A, Seed P, Kelly F, Shennan AH. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006; 367: 1145–54. Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet 1999; 354: 810–16. LeLorier J, Gregoire G, Benhaddad A, Lapierre J, Derderian F, Abramovich DR. Discrepancies between meta-analysis and subsequent large randomized controlled trials. N Engl J Med 1997; 337: 536–42.
From their placebo-controlled VIP trial, Lucilla Poston and colleagues1 conclude that supplementation with vitamins C and E from 14 to 22 weeks’ gestation does not prevent pre-eclampsia in women “at increased risk”—a finding at variance with their previous findings.2 Unlike Poston and colleagues, I believe that this discrepancy might be due to the difference in the study population chosen. The previous trial2 mostly included women with abnormal two-stage uterine-artery doppler screening at 16–22 weeks’ gestation. The soundness of this recruitment was supported by lower plasma markers of placental dysfunction and endothelial activation and lower rates of pre-eclampsia in the treatment group, further justifying the supplementation with vitamins
C and E in most of these patients. Moreover, Parra and colleagues3 confirmed that an abnormal uterineartery pulsatility index correlated better with later pre-eclampsia than markers of placental dysfunction and endothelial activation. In the VIP trial, only 3% of patients entered with an abnormal uterine-artery doppler waveform. Yet the positive and negative predictive values of uterine-artery doppler are high in patients with previous pre-eclampsia4 or chronic hypertension,5 which accounted for 59% of the patients included in this trial. Uterine-artery doppler screening would have identified much more accurately the patients with inadequate uteroplacental blood flow and probable defective placentation among these women with historical risk factors. This would also have avoided unnecessary treatment in patients without an oxidative stress process and would have prevented excess vitamin C concentration in their fetal tissue. I declare that I have no conflict of interest.
Lionel Carbillon [email protected] Department of Obstetrics and Gynecology, Assistance Publique - Hôpitaux de Paris, Paris 13 University, Hôpital Jean Verdier, Avenue du 14 Juillet, 93143 Bondy Cedex, France 1
2
3
4
5
Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006; 367: 1145–54. Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the occurrence of preeclampsia in women at increased risk: a randomised trial. Lancet 1999; 354: 810–16. Parra M, Rodrigo R, Barja P, et al. Screening test for preeclampsia through assessment of uteroplacental blood flow and biochemical markers of oxidative stress and endothelial dysfunction. Am J Obstet Gynecol 2005; 193: 1486–91. Harrington K, Fayyad A, Thakur V, Aquilina J. The value of uterine artery Doppler in the prediction of uteroplacental complications in multiparous women. Ultrasound Obstet Gynecol 2004; 23: 50–55. Fleischer A, Schulman H, Farmakides G, et al. Uterine artery Doppler velocimetry in pregnant women with hypertension. Am J Obstet Gynecol 1986; 154: 806–13.
www.thelancet.com Vol 368 July 15, 2006