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Reply to: Tocolytic magnesium sulfate: Are the epidemiologic data reassuring?
280 Letters
July 1998
AmJ Obstet Gynecol
Tocolytic magnesium sulfate: Are the epidemiologic data reassuring? To the Editors: We disagree with the conclusions from the case-control data analyzed by Grether et al (Grether JK, Hoogstrate J, Selvin S, Nelson KB. Magnesium sulfate tocolysis and risk of neonatal death. Am J Obstet Gynecol 1998; 178: 1-6). Although multivariate regression controls for confounding, it does not control at all for the many forms of bias found in case-control studies. Indeed, there are numerous examples of such data leading to incorrect conclusions that were later corrected by prospectively acquired, less biased data from cohort studies or randomized controlled trials-the acknowledged standard for decision making in clinical medicine. In 1979, with use of case-control data, Rothman et al from the School of Public Health at Harvard University reported statistically significant associations (odds ratio 1. 72, 95% confidence interval 1.04 to 2.85 [Cornfield method]) between doxylamine succinate with pyridoxine hydrochloride (Bendectin) and congenital heart disease. Subsequently, a meta-analysis of cohort studies 1 showed no such association (summary odds ratio 0.95, 95% confidence interval 0.62 to 1.45). Although Rothman et al acknowledged that information bias could be present in their data, in fact, they were unable to correct for, or quantity, the bias. In the case-control data analyzed by Grether et ai, the various forms of bias may also be substantial and even the sole explanation for the reported association. In spite of legitimate attempts to control for confounding, it would be erroneous to believe it is possible to sufficiently control for the inherent and silent biases of these data. The less-biased data of the only 2 randomized controlled trials of tocolytic magnesium sulfate in which information was collected on total (fetal, neonatal, and postneonatal) pediatric mortality have shown an excess of death after the use of magnesium. 2 In the combined data from these 2 trials, 15 of 122 randomized exposures to tocolytic magnesium sulfate were associated with total pediatric mortality, whereas only 2 of 127 randomized exposures to saline solution or other tocolytics were associated with death. A random-effects meta-analysis of these data shows a 10% excess mortality (risk difference 10.7%, 95% confidence interval 3.9% to 17.6%, 2-sided P value .002) associated with the use of tocolytic magnesium sulfatenot a protective effect. Such an enormous discrepancy between randomized data and the case-control data with all their limitations that were analyzed by Grether et al requires explanation before we would feel reassured about the safety of tocolytic magnesium. Thus we say caveat emptor. Robert Mittendorf, MD, and Peter Pryde, MD Department of Obstetrics and Gynecology, Chicago Lying-In Hospital, MC2050, 5841 S Maryland Ave, Chicago, IL 60637
REFERENCES 1. Einarson TR, Leeder jS, Koren C. A method for meta-analysis of epidemiological studies. Drug lntell Clin Pharm 1988;22:813-
24. 2. Mittendorf R, Covert R, Boman j, Khoshnood B, Lee K-S, Siegler M. Is tocolytic magnesium sulphate associated with increased total paediatric mortality? Lancet 1997;350:1517-8.
6/8/91597
Reply To the Editors: It is true that the acknowledged standard for decision making in clinical medicine is the well-designed, well-conducted, randomized controlled trial. It is also true that a poorly conducted clinical trial-one that is too small, does not take into account major determinants of the outcome, and does not ascertain outcome fully in both arms of the trial-can be profoundly misleading. Some of these limitations may be present in the small clinical trial to which Mittendorf and Pryde allude, as suggested by the letters that followed its publication. 1-3 Several large randomized controlled trials are now in progress to evaluate the relationship of antenatal treatment with magnesium to perinatal and infant mortality and neurologic outcome. These trials are likely to be informative and possibly conclusive_ In the meantime, obstetric management must rely on available evidence and, in doing so, must judge the quality of that evidence. Casecontrol studies have played an important role in the history of medical science and disease reduction. Unless Mittendorf and Pryde can identity some specific source of bias in our study or particular flaws in its analyses, it should not be summarily dismissed because of its casecontrol design. Judith K. Grether, PhD, Steven Selvin, PhD, Jennifer Hoogstrate, MFA, and Karin Nelson, MD California Birth Defects Monitoring Program, Suite 1050, 1900 Powell St, Emeryville, CA 94608-1811
REFERENCES 1. Benichou j, Zupan V, Fernandez H, Marpeau L, Manet S. Tocolytic magnesium sulphate and paediatric mortality [letter]. Lancet 1998;351 :5-6. 2. Crowther C, Hiller j, Doyle L, Lumley j, Carlin]. Tocolytic magnesium sulphate and paediatric mortality [letter]. Lancet 1998;351 :6-7. 3. Leveno K]. Tocolytic magnesium sulphate and paediatric mortality [letter]. Lancet 1998;351:7-8.
6/8/91596
July 1998
AmJ Obstet Gynecol
Tocolytic magnesium sulfate: Are the epidemiologic data reassuring? To the Editors: We disagree with the conclusions from the case-control data analyzed by Grether et al (Grether JK, Hoogstrate J, Selvin S, Nelson KB. Magnesium sulfate tocolysis and risk of neonatal death. Am J Obstet Gynecol 1998; 178: 1-6). Although multivariate regression controls for confounding, it does not control at all for the many forms of bias found in case-control studies. Indeed, there are numerous examples of such data leading to incorrect conclusions that were later corrected by prospectively acquired, less biased data from cohort studies or randomized controlled trials-the acknowledged standard for decision making in clinical medicine. In 1979, with use of case-control data, Rothman et al from the School of Public Health at Harvard University reported statistically significant associations (odds ratio 1. 72, 95% confidence interval 1.04 to 2.85 [Cornfield method]) between doxylamine succinate with pyridoxine hydrochloride (Bendectin) and congenital heart disease. Subsequently, a meta-analysis of cohort studies 1 showed no such association (summary odds ratio 0.95, 95% confidence interval 0.62 to 1.45). Although Rothman et al acknowledged that information bias could be present in their data, in fact, they were unable to correct for, or quantity, the bias. In the case-control data analyzed by Grether et ai, the various forms of bias may also be substantial and even the sole explanation for the reported association. In spite of legitimate attempts to control for confounding, it would be erroneous to believe it is possible to sufficiently control for the inherent and silent biases of these data. The less-biased data of the only 2 randomized controlled trials of tocolytic magnesium sulfate in which information was collected on total (fetal, neonatal, and postneonatal) pediatric mortality have shown an excess of death after the use of magnesium. 2 In the combined data from these 2 trials, 15 of 122 randomized exposures to tocolytic magnesium sulfate were associated with total pediatric mortality, whereas only 2 of 127 randomized exposures to saline solution or other tocolytics were associated with death. A random-effects meta-analysis of these data shows a 10% excess mortality (risk difference 10.7%, 95% confidence interval 3.9% to 17.6%, 2-sided P value .002) associated with the use of tocolytic magnesium sulfatenot a protective effect. Such an enormous discrepancy between randomized data and the case-control data with all their limitations that were analyzed by Grether et al requires explanation before we would feel reassured about the safety of tocolytic magnesium. Thus we say caveat emptor. Robert Mittendorf, MD, and Peter Pryde, MD Department of Obstetrics and Gynecology, Chicago Lying-In Hospital, MC2050, 5841 S Maryland Ave, Chicago, IL 60637
REFERENCES 1. Einarson TR, Leeder jS, Koren C. A method for meta-analysis of epidemiological studies. Drug lntell Clin Pharm 1988;22:813-
24. 2. Mittendorf R, Covert R, Boman j, Khoshnood B, Lee K-S, Siegler M. Is tocolytic magnesium sulphate associated with increased total paediatric mortality? Lancet 1997;350:1517-8.
6/8/91597
Reply To the Editors: It is true that the acknowledged standard for decision making in clinical medicine is the well-designed, well-conducted, randomized controlled trial. It is also true that a poorly conducted clinical trial-one that is too small, does not take into account major determinants of the outcome, and does not ascertain outcome fully in both arms of the trial-can be profoundly misleading. Some of these limitations may be present in the small clinical trial to which Mittendorf and Pryde allude, as suggested by the letters that followed its publication. 1-3 Several large randomized controlled trials are now in progress to evaluate the relationship of antenatal treatment with magnesium to perinatal and infant mortality and neurologic outcome. These trials are likely to be informative and possibly conclusive_ In the meantime, obstetric management must rely on available evidence and, in doing so, must judge the quality of that evidence. Casecontrol studies have played an important role in the history of medical science and disease reduction. Unless Mittendorf and Pryde can identity some specific source of bias in our study or particular flaws in its analyses, it should not be summarily dismissed because of its casecontrol design. Judith K. Grether, PhD, Steven Selvin, PhD, Jennifer Hoogstrate, MFA, and Karin Nelson, MD California Birth Defects Monitoring Program, Suite 1050, 1900 Powell St, Emeryville, CA 94608-1811
REFERENCES 1. Benichou j, Zupan V, Fernandez H, Marpeau L, Manet S. Tocolytic magnesium sulphate and paediatric mortality [letter]. Lancet 1998;351 :5-6. 2. Crowther C, Hiller j, Doyle L, Lumley j, Carlin]. Tocolytic magnesium sulphate and paediatric mortality [letter]. Lancet 1998;351 :6-7. 3. Leveno K]. Tocolytic magnesium sulphate and paediatric mortality [letter]. Lancet 1998;351:7-8.
6/8/91596