- Email: [email protected]
Learn from our errors
CORRESPONDENCE
4
Soriano V, Dona C, Rodriguez-Rosado R, Barreiro P, Gonzalez-Lahoz J. Discontinuation of secondary prophylaxis for opportunistic infections in HIV-infected patients receiving highly active antiretroviral therapy. AIDS 2000, 14: 383–86.
Prevention of pre-eclampsia Sir—Gus Dekker and Baha Sibai (Jan 20, p 209)1 draw attention to the need for effective preventive therapy for preeclampsia based on prevention of pathology. We agree with this sound principle. They discuss our randomised control trial in 283 women at high risk for the disease,2 in which we show that ascorbic acid (1000 mg) and vitamin E (400 IU) supplementation from the second trimester was associated with an 0·24 odds ratio for the occurrence of preeclampsia. Dekker and Sibai acknowledge the clinical benefit of the antioxidants, but state that the 11 women who developed pre-eclampsia in the vitamin-treated group had a worse perinatal outcome than the 24 with preeclampsia in the placebo group. This representation of the data is incorrect. The study was not sufficiently powered to detect differences in perinatal outcome measures, and no outcome mentioned (birthweight and gestational age at delivery) differed significantly between groups. There is little value in comparing perinatal characteristics between these two subgroups since they were selected post hoc, on the basis of outcome. The most important comparison should be based on the total study population, as randomised.3 In the vitamin-treated group, fewer neonates were small for gestational age than in the placebo group. There were ten adverse perinatal events in the placebo group compared with eight in the treated group. The more serious of these adverse events (placental abruption and intrauterine death) were also more common in the placebo group, but the differences were not significant. Dekker and Sibai use our study of ascorbic acid and vitamin E supplementation as a good example of prevention on the basis of the clinical definition of pre-eclampsia rather than on pathology, which they advocate. Our study is actually a good example of the latter. The primary outcome measure was not the definition of the disease but the pathological markers of vascular endothelial and placental function, which improved significantly in the vitamin-treated group. The clinical disease was a secondary endpoint that achieved significance due to the large treatment benefit associated with the
1534
antioxidants. We have since reported improvement in the vitamin-treated group of maternal plasma concentrations of 8-epi-prostaglandin-F2a,4 a marker of lipid peroxidation, thought to be pivotal to vascular dysfunction in preeclampsia.5 We have provided a sound biochemical basis for the benefit of antioxidants on the pathology of preeclampsia, which was also associated with a reduction in the current clinical definition of the disease. Poor as it may be, until other indices of pathology are well established, this clinical definition must remain the primary goal of prevention for clinicians. *Andrew H Shennan, Lucilla Poston, Lucy C Chappell, Paul T Seed Maternal and Fetal Research Group, Guy’s, King’s and St Thomas’ School of Medicine, King’s College, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK (e-mail: [email protected]) 1
2
3 4
5
Dekker G, Sibai B. Primary, secondary, and tertiary prevention of pre-eclampsia. Lancet 2001; 357: 209–15. Chappell LC, Seed P, 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. Pocock SJ. Clinical trials: a practical approach. Chichester, UK: John Wiley, 1983. Chappell, LC, O’Brien-Coker I, Mallet A, Briley A, Seed P, Poston L. Reduction in occurrence of pre-eclampsia with antioxidants is associated with decreased concentrations of plasma 8-epi-prostaglandin-F2a. J Soc Gynecol Invest 2000; 7: 182A. Hubel CA. Oxidative stress in the pathogenesis of preeclampsia. Proc Soc Exp Biol Med 1999; 222: 222–35.
Authors’ reply Sir—The intention of our review was not to throw doubt on the importance of Andrew Shennan and colleagues’ study. We believe the use of ascorbic acid and vitamin E in women at a high-risk of developing pre-eclampsia represents an exciting potential new approach, and their findings are extremely relevant. Our comment on prevention of the definition of pre-eclampsia is based on the recognition that current classifications and definitions are only indirect risk markers and do not reflect real morbidity. There is an urgent need to completely redefine the syndrome on the basis of hard outcome criteria—in other words, actual maternal and fetal or neonatal morbidity, mortality, or both. In making our post-hoc comments, we attempted to illustrate that readers of all journals are required to carefully separate real pathology, such as being born prematurely or growth restriction, from indirect markers, such as fulfilling textbook criteria for the diagnosis preeclampsia. In this case, use of early-onset pre-eclampsia (<34 weeks’ gestation),
birthweight less than 1500 g, or both as hard morbidity endpoints would have resulted in a completely different perspective. We do understand that their study was not designed that way. However, after going through our aspirin experience,1 we were keen to prevent potentially false hope that a miracle cure had been identified. Further studies will allow timely introduction of a cheap strategy or prevent premature use of vitamin supplementation for preeclampsia. *Gus Dekker, Baha Sibai *University of Adelaide, Lyell McEwin Hospital, North Western Adelaide Health Service, Elizabeth Vale, 5112 SA, Australia; and Department of Obstetrics and Gynecology, University of Cincinnati, OH, USA 1
Wallenburg HC, Dekker GA, Makovitz JW, Rotmans P. Low-dose aspirin prevents pregnancy-induced hypertension and preeclampsia in angiotensin-sensitive primigravidae. Lancet 1986; 1: 1–3.
Learn from our errors Sir—Juan Rodés and Miquel Bruguera (March 10, p 791)1 ask what attitude we should take towards our colleagues who have erred. A personal experience has caused me to reflect on this issue. About 10 years ago I trained in paediatrics in Dublin, Ireland, with a friend, who is now a consultant paediatrician. Our paths diverged when I moved into academic epidemiology, and I haven’t seen him in that time. Lately, however, I saw his name in the papers in connection with evidence that he gave at an inquest in the UK, into the death of a young man 5 years after he administered a dose of intrathecal vincristine. Like many other paediatric senior house officers, I too have given intrathecal drugs to children with cancers. And, like all too many other paediatric senior house officers, I have been protected from paralysing someone, not by good judgement but by good fortune, or perhaps the beneficence of God. The misery caused by this particular medical accident is well known, as is the remedy. There is no compelling reason for having intrathecal needles that accept standard syringe barrels. A consensus in injury-prevention work would hold that creating solutions to hazards through engineering is preferable. How many more children will be paralysed by unfortunate young doctors before such a change is made compulsory? Anthony Staines Department of Public Health Medicine and Epidemiology, University College, Dublin, Earlsfort Terrace, Dublin 2, Ireland (e-mail: [email protected]) 1
Rodés J, Bruguera M. The uses of error: Iatrogenic hepatitis. Lancet 2001; 357: 791.
THE LANCET • Vol 357 • May 12, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
4
Soriano V, Dona C, Rodriguez-Rosado R, Barreiro P, Gonzalez-Lahoz J. Discontinuation of secondary prophylaxis for opportunistic infections in HIV-infected patients receiving highly active antiretroviral therapy. AIDS 2000, 14: 383–86.
Prevention of pre-eclampsia Sir—Gus Dekker and Baha Sibai (Jan 20, p 209)1 draw attention to the need for effective preventive therapy for preeclampsia based on prevention of pathology. We agree with this sound principle. They discuss our randomised control trial in 283 women at high risk for the disease,2 in which we show that ascorbic acid (1000 mg) and vitamin E (400 IU) supplementation from the second trimester was associated with an 0·24 odds ratio for the occurrence of preeclampsia. Dekker and Sibai acknowledge the clinical benefit of the antioxidants, but state that the 11 women who developed pre-eclampsia in the vitamin-treated group had a worse perinatal outcome than the 24 with preeclampsia in the placebo group. This representation of the data is incorrect. The study was not sufficiently powered to detect differences in perinatal outcome measures, and no outcome mentioned (birthweight and gestational age at delivery) differed significantly between groups. There is little value in comparing perinatal characteristics between these two subgroups since they were selected post hoc, on the basis of outcome. The most important comparison should be based on the total study population, as randomised.3 In the vitamin-treated group, fewer neonates were small for gestational age than in the placebo group. There were ten adverse perinatal events in the placebo group compared with eight in the treated group. The more serious of these adverse events (placental abruption and intrauterine death) were also more common in the placebo group, but the differences were not significant. Dekker and Sibai use our study of ascorbic acid and vitamin E supplementation as a good example of prevention on the basis of the clinical definition of pre-eclampsia rather than on pathology, which they advocate. Our study is actually a good example of the latter. The primary outcome measure was not the definition of the disease but the pathological markers of vascular endothelial and placental function, which improved significantly in the vitamin-treated group. The clinical disease was a secondary endpoint that achieved significance due to the large treatment benefit associated with the
1534
antioxidants. We have since reported improvement in the vitamin-treated group of maternal plasma concentrations of 8-epi-prostaglandin-F2a,4 a marker of lipid peroxidation, thought to be pivotal to vascular dysfunction in preeclampsia.5 We have provided a sound biochemical basis for the benefit of antioxidants on the pathology of preeclampsia, which was also associated with a reduction in the current clinical definition of the disease. Poor as it may be, until other indices of pathology are well established, this clinical definition must remain the primary goal of prevention for clinicians. *Andrew H Shennan, Lucilla Poston, Lucy C Chappell, Paul T Seed Maternal and Fetal Research Group, Guy’s, King’s and St Thomas’ School of Medicine, King’s College, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK (e-mail: [email protected]) 1
2
3 4
5
Dekker G, Sibai B. Primary, secondary, and tertiary prevention of pre-eclampsia. Lancet 2001; 357: 209–15. Chappell LC, Seed P, 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. Pocock SJ. Clinical trials: a practical approach. Chichester, UK: John Wiley, 1983. Chappell, LC, O’Brien-Coker I, Mallet A, Briley A, Seed P, Poston L. Reduction in occurrence of pre-eclampsia with antioxidants is associated with decreased concentrations of plasma 8-epi-prostaglandin-F2a. J Soc Gynecol Invest 2000; 7: 182A. Hubel CA. Oxidative stress in the pathogenesis of preeclampsia. Proc Soc Exp Biol Med 1999; 222: 222–35.
Authors’ reply Sir—The intention of our review was not to throw doubt on the importance of Andrew Shennan and colleagues’ study. We believe the use of ascorbic acid and vitamin E in women at a high-risk of developing pre-eclampsia represents an exciting potential new approach, and their findings are extremely relevant. Our comment on prevention of the definition of pre-eclampsia is based on the recognition that current classifications and definitions are only indirect risk markers and do not reflect real morbidity. There is an urgent need to completely redefine the syndrome on the basis of hard outcome criteria—in other words, actual maternal and fetal or neonatal morbidity, mortality, or both. In making our post-hoc comments, we attempted to illustrate that readers of all journals are required to carefully separate real pathology, such as being born prematurely or growth restriction, from indirect markers, such as fulfilling textbook criteria for the diagnosis preeclampsia. In this case, use of early-onset pre-eclampsia (<34 weeks’ gestation),
birthweight less than 1500 g, or both as hard morbidity endpoints would have resulted in a completely different perspective. We do understand that their study was not designed that way. However, after going through our aspirin experience,1 we were keen to prevent potentially false hope that a miracle cure had been identified. Further studies will allow timely introduction of a cheap strategy or prevent premature use of vitamin supplementation for preeclampsia. *Gus Dekker, Baha Sibai *University of Adelaide, Lyell McEwin Hospital, North Western Adelaide Health Service, Elizabeth Vale, 5112 SA, Australia; and Department of Obstetrics and Gynecology, University of Cincinnati, OH, USA 1
Wallenburg HC, Dekker GA, Makovitz JW, Rotmans P. Low-dose aspirin prevents pregnancy-induced hypertension and preeclampsia in angiotensin-sensitive primigravidae. Lancet 1986; 1: 1–3.
Learn from our errors Sir—Juan Rodés and Miquel Bruguera (March 10, p 791)1 ask what attitude we should take towards our colleagues who have erred. A personal experience has caused me to reflect on this issue. About 10 years ago I trained in paediatrics in Dublin, Ireland, with a friend, who is now a consultant paediatrician. Our paths diverged when I moved into academic epidemiology, and I haven’t seen him in that time. Lately, however, I saw his name in the papers in connection with evidence that he gave at an inquest in the UK, into the death of a young man 5 years after he administered a dose of intrathecal vincristine. Like many other paediatric senior house officers, I too have given intrathecal drugs to children with cancers. And, like all too many other paediatric senior house officers, I have been protected from paralysing someone, not by good judgement but by good fortune, or perhaps the beneficence of God. The misery caused by this particular medical accident is well known, as is the remedy. There is no compelling reason for having intrathecal needles that accept standard syringe barrels. A consensus in injury-prevention work would hold that creating solutions to hazards through engineering is preferable. How many more children will be paralysed by unfortunate young doctors before such a change is made compulsory? Anthony Staines Department of Public Health Medicine and Epidemiology, University College, Dublin, Earlsfort Terrace, Dublin 2, Ireland (e-mail: [email protected]) 1
Rodés J, Bruguera M. The uses of error: Iatrogenic hepatitis. Lancet 2001; 357: 791.
THE LANCET • Vol 357 • May 12, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.