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Tocolytic magnesium sulphate and paediatric mortality
CORRESPONDENCE
Authors’ reply “An event has happened, upon which it is difficult to speak, and impossible to be silent”. Edmund Burke, 1789.
SIR—In the MAGnet Trial, there were ten twin pairs in 75 mothers randomised to MgSO4 and six in 75 mothers randomised to other tocolytics or control. The difference was not statistically significant (two-sided Fisher’s exact test, p=0·431). Moreover, with Zeger and Liang’s method2 to allow for the potential correlation between twins, (although twin status was marginally associated with increased risk [OR 3·3, 95% CI 0·86–12·7, p=0·082]) the MgSO4exposure effect remained significant after adjustment for twins (9·6, 1·2–78·8, p=0·035). Thus, twinning was not a confounder. In Leveno’s trial,3 the frequency of death among singletons (6·2% [nine of 145]) was greater than it was for twins (4·5% [one of 22]). It is not unusual for twin siblings with the same drug exposure in utero to have different outcomes. All four of the identical twins enrolled in the Chicago diethylstilbestrol registry had vaginal clear-cell adenocarcinoma whereas the identical sibling did not.4 In the tocolytic trial overall, 67% (58/77) of fetuses were actually exposed to MgSO4; among extremely low birthweight (ELBW <1000 g) neonates, 64% (14/22) of fetuses were actually exposed to MgSO4. In fetuses exposed to MgSO4 the median weight was 834 g, and among controls it was 873 g (Wilcoxon rank sum test, p=0·21). MAGnet was an extended feasibility trial which was suspended because of excess deaths. All the exposureassociated deaths took place in the year of feasibility determination. Ascertainment of death information was uniform in all arms and was done independent of exposure status. Thus, there was no selection bias. Leveno’s comments about exclusion from exposure analyses (comparison of mortality among those randomised and exposed to drug or control) refer to data we shared with him before the publication of our Research Letter. Although not germane to our discussion here, 23—not 32—control fetuses were excluded for reasons typical of any randomised controlled trial. Summing the exposure data of MAGnet and the Leveno trial,3 there were 15 deaths after 136 fetal exposures to tocolytic MgSO4, and two after 118 fetal exposures to normal saline or other tocolytics. In the Leveno trial,3 MgSO4 proved no more effective as a tocolytic than physiological saline. We believe the significance of the
THE LANCET • Vol 351 • January 24, 1998
intent-to-treat analysis to be fairly robust. Even if 30% (three of ten) deaths related to MgSO4 are excluded, the association remains marginally significant (p=0·064). However, it is a violation of methodological rigor to exclude outcomes retrospectively since the patients met the original inclusion criteria. Crossing over is common in randomised trials of tocolytics. All the exposure deaths in MAGnet were in those who were originally randomised to MgSO4. Mortality in MAGnet controls was low (1·4%). However, Leveno’s data3 showed a similar low mortality in the controls—2·2% (two of 89). All our unexplained deaths happened in the first 6 months of infant life (corrected for gestational age at birth). Analysis of US linked birth-death files with preeclampsia as a surrogate measure of MgSO4 exposure would not be helpful since the pathophysiology of preeclampsia and preterm labour are different. Our meta-analysis was based on the only two published trials of MgSO4 tocolytic that included information on total paediatric mortality, the most appropriate endpoint. ACTOMgSO4 and the Beneficial Effects of Antenatal Magnesium Trial (BEAM) alluded to by Grether and colleagues are preventive—not tocolytic—trials, in which the dose of prophylactic MgSO4 is 28 g and 30 g, respectively. The median dose of tocolytic MgSO4 given in MAGnet was 49·8 g, and the minimum dose received in Leveno’s trial3 was 50 g. If there is a dose-response relation between exposure to MgSO4 and mortality,5 lower preventive doses, such as those in ACTOMgSO4 and BEAM, might prove to reduce the frequency of cerebral palsy, while not being associated with excess total paediatric deaths.
5
utero. Teratol 1995; 51: 435–45. Reynolds JD, Chestnut DH, Dexter F, McGrath J, Penning DH. Magnesium sulfate adversely affects fetal lamb survival and blocks fetal cerebral blood flow response during maternal hemorrhage. Anesth Analg 1996; 83: 493–99.
SIR—Clinicians have a responsibility to ensure relevant research findings are put into practice within their own sphere of influence, but this is not always straightforward. For example, in 1995, The Lancet published strong evidence, from a large randomised controlled trial,1 that MgSO4 is better than either diazepam or phenytoin for women with eclampsia. Although fairly cheap, MgSO4 is still not available for women presenting with eclampsia, especially in African countries. This is even the situation in some centres that collaborated in the original research, where clinicians are forced to continue to use diazepam. WHO have recently added MgSO4 to their essential drugs list. It is thus imperative that policy makers now urgently address this issue of poor supplies of the drug. In this respect, governments and international agencies could also help to ensure that effective drugs are made available to those that need them, and that patients and clinicians are not held hostage by whether or not pharmaceutical companies make profit from supplying such life-saving drugs. *Kassam Mahomed, Paul Garner, Lelia Duley *Department of Obstetrics, University of Zimbabwe Medical School, PO Box A178, Avondale, Harare, Zimbabwe; Liverpool School of Tropical Medicine, Liverpool, UK; and Institute of Health Sciences, Oxford, UK 1
The Eclampsia Trial Collaborative Group. Which anticonvulsant for which women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 1995; 345: 1455–63.
We thank Theodore Karrison for assistance with additional statistical analyses.
*Robert Mittendorf, Nancy Roizen, Mark Siegler, Babak Khoshnood, Kwang-Sun Lee Departments or *Obstetrics and Gynaecology and Paediatrics, and MacLean Centre for Clinical Medical Ethics, Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA 1 2
3
4
Stata Corporation. 1997. Stata Statistical Software: Release 5.0. College Station, TX. Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986; 42: 121–30. Cox SM, Sherman ML, Leveno KJ. Randomized investigation of magnesium sulfate for prevention of preterm birth. Am J Obstet Gynecol 1990; 163; 767–72. Mittendorf R. Teratogen update: Carcinogenesis and teratogenesis associated with exposure to diethylstilbestrol (DES) in
Jet-lag SIR—I wish to add to the comments made by Jim Waterhouse and colleagues (Nov 29, p 1611)1 about the efficacy and mechanism of action of melatonin in alleviating jet-lag. There is substantial evidence in laboratory and field studies that melatonin acts by increasing sleepiness and by hastening adjustment of the body clock.2 In the largest controlled study reported to date,3 320 people received 5 mg fast-release melatonin after the flight at bedtime for 4 days. Melatonin improved sleep latency, sleep quality, daytime sleepiness, and fatigue, compared with placebo. A lower dose (0·5 mg) of fast-release preparation was
293
Authors’ reply “An event has happened, upon which it is difficult to speak, and impossible to be silent”. Edmund Burke, 1789.
SIR—In the MAGnet Trial, there were ten twin pairs in 75 mothers randomised to MgSO4 and six in 75 mothers randomised to other tocolytics or control. The difference was not statistically significant (two-sided Fisher’s exact test, p=0·431). Moreover, with Zeger and Liang’s method2 to allow for the potential correlation between twins, (although twin status was marginally associated with increased risk [OR 3·3, 95% CI 0·86–12·7, p=0·082]) the MgSO4exposure effect remained significant after adjustment for twins (9·6, 1·2–78·8, p=0·035). Thus, twinning was not a confounder. In Leveno’s trial,3 the frequency of death among singletons (6·2% [nine of 145]) was greater than it was for twins (4·5% [one of 22]). It is not unusual for twin siblings with the same drug exposure in utero to have different outcomes. All four of the identical twins enrolled in the Chicago diethylstilbestrol registry had vaginal clear-cell adenocarcinoma whereas the identical sibling did not.4 In the tocolytic trial overall, 67% (58/77) of fetuses were actually exposed to MgSO4; among extremely low birthweight (ELBW <1000 g) neonates, 64% (14/22) of fetuses were actually exposed to MgSO4. In fetuses exposed to MgSO4 the median weight was 834 g, and among controls it was 873 g (Wilcoxon rank sum test, p=0·21). MAGnet was an extended feasibility trial which was suspended because of excess deaths. All the exposureassociated deaths took place in the year of feasibility determination. Ascertainment of death information was uniform in all arms and was done independent of exposure status. Thus, there was no selection bias. Leveno’s comments about exclusion from exposure analyses (comparison of mortality among those randomised and exposed to drug or control) refer to data we shared with him before the publication of our Research Letter. Although not germane to our discussion here, 23—not 32—control fetuses were excluded for reasons typical of any randomised controlled trial. Summing the exposure data of MAGnet and the Leveno trial,3 there were 15 deaths after 136 fetal exposures to tocolytic MgSO4, and two after 118 fetal exposures to normal saline or other tocolytics. In the Leveno trial,3 MgSO4 proved no more effective as a tocolytic than physiological saline. We believe the significance of the
THE LANCET • Vol 351 • January 24, 1998
intent-to-treat analysis to be fairly robust. Even if 30% (three of ten) deaths related to MgSO4 are excluded, the association remains marginally significant (p=0·064). However, it is a violation of methodological rigor to exclude outcomes retrospectively since the patients met the original inclusion criteria. Crossing over is common in randomised trials of tocolytics. All the exposure deaths in MAGnet were in those who were originally randomised to MgSO4. Mortality in MAGnet controls was low (1·4%). However, Leveno’s data3 showed a similar low mortality in the controls—2·2% (two of 89). All our unexplained deaths happened in the first 6 months of infant life (corrected for gestational age at birth). Analysis of US linked birth-death files with preeclampsia as a surrogate measure of MgSO4 exposure would not be helpful since the pathophysiology of preeclampsia and preterm labour are different. Our meta-analysis was based on the only two published trials of MgSO4 tocolytic that included information on total paediatric mortality, the most appropriate endpoint. ACTOMgSO4 and the Beneficial Effects of Antenatal Magnesium Trial (BEAM) alluded to by Grether and colleagues are preventive—not tocolytic—trials, in which the dose of prophylactic MgSO4 is 28 g and 30 g, respectively. The median dose of tocolytic MgSO4 given in MAGnet was 49·8 g, and the minimum dose received in Leveno’s trial3 was 50 g. If there is a dose-response relation between exposure to MgSO4 and mortality,5 lower preventive doses, such as those in ACTOMgSO4 and BEAM, might prove to reduce the frequency of cerebral palsy, while not being associated with excess total paediatric deaths.
5
utero. Teratol 1995; 51: 435–45. Reynolds JD, Chestnut DH, Dexter F, McGrath J, Penning DH. Magnesium sulfate adversely affects fetal lamb survival and blocks fetal cerebral blood flow response during maternal hemorrhage. Anesth Analg 1996; 83: 493–99.
SIR—Clinicians have a responsibility to ensure relevant research findings are put into practice within their own sphere of influence, but this is not always straightforward. For example, in 1995, The Lancet published strong evidence, from a large randomised controlled trial,1 that MgSO4 is better than either diazepam or phenytoin for women with eclampsia. Although fairly cheap, MgSO4 is still not available for women presenting with eclampsia, especially in African countries. This is even the situation in some centres that collaborated in the original research, where clinicians are forced to continue to use diazepam. WHO have recently added MgSO4 to their essential drugs list. It is thus imperative that policy makers now urgently address this issue of poor supplies of the drug. In this respect, governments and international agencies could also help to ensure that effective drugs are made available to those that need them, and that patients and clinicians are not held hostage by whether or not pharmaceutical companies make profit from supplying such life-saving drugs. *Kassam Mahomed, Paul Garner, Lelia Duley *Department of Obstetrics, University of Zimbabwe Medical School, PO Box A178, Avondale, Harare, Zimbabwe; Liverpool School of Tropical Medicine, Liverpool, UK; and Institute of Health Sciences, Oxford, UK 1
The Eclampsia Trial Collaborative Group. Which anticonvulsant for which women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 1995; 345: 1455–63.
We thank Theodore Karrison for assistance with additional statistical analyses.
*Robert Mittendorf, Nancy Roizen, Mark Siegler, Babak Khoshnood, Kwang-Sun Lee Departments or *Obstetrics and Gynaecology and Paediatrics, and MacLean Centre for Clinical Medical Ethics, Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA 1 2
3
4
Stata Corporation. 1997. Stata Statistical Software: Release 5.0. College Station, TX. Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986; 42: 121–30. Cox SM, Sherman ML, Leveno KJ. Randomized investigation of magnesium sulfate for prevention of preterm birth. Am J Obstet Gynecol 1990; 163; 767–72. Mittendorf R. Teratogen update: Carcinogenesis and teratogenesis associated with exposure to diethylstilbestrol (DES) in
Jet-lag SIR—I wish to add to the comments made by Jim Waterhouse and colleagues (Nov 29, p 1611)1 about the efficacy and mechanism of action of melatonin in alleviating jet-lag. There is substantial evidence in laboratory and field studies that melatonin acts by increasing sleepiness and by hastening adjustment of the body clock.2 In the largest controlled study reported to date,3 320 people received 5 mg fast-release melatonin after the flight at bedtime for 4 days. Melatonin improved sleep latency, sleep quality, daytime sleepiness, and fatigue, compared with placebo. A lower dose (0·5 mg) of fast-release preparation was
293