- Email: [email protected]
Use of magnesium sulphate in obstetrics
THE LANCET
COMMENTARY
Use of magnesium sulphate in obstetrics See page 1517 Magnesium sulphate has been used as a tocolytic in American obstetric practice since the 1960s, but it has hardly been used in Britain. The evidence that supports its use for tocolysis is weak. Magnesium ions do inhibit myometrial contractility in vitro, probably by inhibition of myometrial calcium channels. However randomised trials show that it is no better than placebo at delaying preterm delivery,1 and when used in pre-eclampsia magnesium has no effect on the length of spontaneous2 or induced labour.3 In 1993, after a comprehensive review of the efficacy and safety of a range of tocolytic agents, Higby et al4 recommended that magnesium sulphate be abandoned as a tocolytic. Nevertheless magnesium remains in widespread use in the USA. There is better evidence that magnesium sulphate is an effective anticonvulsant. In the USA it has been in use as an anticonvulsant in severe pre-eclampsia for the past 6 decades. Chlormethiazole was widely used in the UK but no clinical trials were done. In the 1980s there were moves towards phenytoin or diazepam until two large trials, published in 1995,5,6 showed that magnesium sulphate was better than phenytoin or diazepam at reducing the risk of seizures and improved both maternal and neonatal outcome. There is still no proof that the routine use of anticonvulsants in pre-eclampsia is beneficial, but where an anticonvulsant is to be used, magnesium sulphate seems to be the best choice. Recently another possible indication for giving magnesium to women in preterm labour has been suggested. In a retrospective epidemiological study Nelson and Grether7 found that antenatal exposure of very low birthweight (<1500 g) infants to magnesium reduced the incidence of cerebral palsy at age 3 or more. This report was exciting because magnesium blocks the n-methyl-d-aspartate (NMDA) receptor responsible for a considerable amount of neuronal death during hypoxicischaemic injury, and in cell culture high concentrations of magnesium protect neurons from hypoxic-ischaemic death. Considerable research effort has gone into investigating whether magnesium sulphate given perinatally is truly cerebroprotective. Further epidemiological work produced conflicting results.8,9 Most studies found no protective effect and instead suggested confounding factors that might have accounted for the apparent effect in the earlier studies. Magnesium was unlikely to have been given to mothers who presented in rapid, or advanced, preterm labour, or had clinical evidence of infection or fetal distress, all of which are risk factors for neurological injury. Conversely the widespread use of magnesium to treat pre-eclampsia in the USA meant that such mothers would have received the drug, and preeclampsia before 32 weeks independently reduces the risk of cerebral palsy. Magnesium protects newborn rats against brain injury caused by intracerebral injection of NMDA. However, administration of magnesium to fetal lambs and newborn sheep did not protect against hypoxia-ischaemia,10,11 and there have been suggestions that magnesium might disrupt fetal haemodynamic responses. In the light of this body of circumstantial evidence, a
Vol 350 • November 22, 1997
randomised controlled double-blind trial was established in Chicago specifically to examine the Nelson and Grether hypothesis. The discontinuation of this trial is reported in today’s Lancet. Interim analysis showed that magnesium sulphate given to mothers in preterm labour before 34 weeks is associated with a significant increase in neonatal mortality. This trial tilts the balance of evidence firmly away from magnesium use as a tocolytic or cerebroprotectant in preterm labour. Magnesium should probably also be restricted to only the most severe forms of pre-eclampsia or to eclampsia, where its value may outweigh the neonatal risks.
Phillip Bennett, David Edwards Division of Paediatrics, Obstetrics, and Gynaecology, Imperial College School of Medicine, Hammersmith Hospital Campus, London W12 0HS, UK 1
Cotton DB, Strassner T, Hill LM, Schifrin BS, Paul RH. A comparison of magnesium sulfate, terbutaline and a placebo for the inhibition of preterm labour. J Reprod Med 1984; 29: 92-97. 2 Witlin AG, Friedman SA, Sibai BM. The effect of magnesium sulfate therapy on the duration of labor in women with mild pre-eclampsia at term: a randomised, double blind, placebo controlled trial. Am J Obstet Gynecol 1997; 176: 623-27. 3 Atkinson MW, Guinn D,Owen J, Hauth JC. Does magnesium sulfate affect the length of labor induction in women with pregnancyassociated hypertension? Am J Obstet Gynecol 1995; 173: 1219-22. 4 Higby K, Xenakis EMJ, Pauerstein CJ. Do tocolytic agents stop preterm labor? A critical and comprehensive review of efficacy and safety. Am J Obstet Gynecol 1993; 168:1247-59. 5 The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the collaborative eclampsia trial. Lancet 1995; 345: 1455-63. 6 Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med 1995; 333: 201-05. 7 Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995; 95: 26369. 8 Schendel DE, Berg CJ,Yeargin-Allsopp M, Boyla C A, Decoufle P. Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 years. JAMA 1996; 276: 1805-11. 9 Paneth N, Jetton J, Pintomartin J, et al. Magnesium sulfate in labor and risk of neonatal brain lesions and cerebral palsy in low birthweight infants. Pediatrics 1997; 99: E11-E16. 10 Penrice J, Amess PN, Punwani S, et al. Magnesium sulfate after transient hypoxia-ischemia fails to prevent delayed cerebral energy failure in the newborn piglet. Ped Res 1997; 41: 1-5. 11 Dehaan HH, Gunn AJ, Williams CE, Heyman MA, Gluckman PD. Magnesium sulfate therapy during asphyxia in near term fetal lambs does not compromise the fetus but does not reduce cerebral injury. Am J Obstet Gynecol 1997; 176:18-27.
From antiphospholipid syndrome to antibody-mediated thrombosis Over the past decade the association of antibodies having an apparent specificity for anionic phospholipids with thrombosis, fetal loss, and thrombocytopenia has become widely recognised as the antiphospholipid (aPL) syndrome. In addition to affecting a subset of patients with systemic lupus erythematosus, the aPL syndrome is an important cause of thromboembolic disease and fetal loss in the general population. The aPL syndrome may account for 15-20% of all episodes of deep venous thrombosis,1 a third of new strokes occurring in patients under the age of 50,2 and 5-15% of women with recurrent fetal losses.3 Recent research has significantly advanced our understanding of the autoantibodies associated with the aPL syndrome and the mechanisms by which these 1491
COMMENTARY
Use of magnesium sulphate in obstetrics See page 1517 Magnesium sulphate has been used as a tocolytic in American obstetric practice since the 1960s, but it has hardly been used in Britain. The evidence that supports its use for tocolysis is weak. Magnesium ions do inhibit myometrial contractility in vitro, probably by inhibition of myometrial calcium channels. However randomised trials show that it is no better than placebo at delaying preterm delivery,1 and when used in pre-eclampsia magnesium has no effect on the length of spontaneous2 or induced labour.3 In 1993, after a comprehensive review of the efficacy and safety of a range of tocolytic agents, Higby et al4 recommended that magnesium sulphate be abandoned as a tocolytic. Nevertheless magnesium remains in widespread use in the USA. There is better evidence that magnesium sulphate is an effective anticonvulsant. In the USA it has been in use as an anticonvulsant in severe pre-eclampsia for the past 6 decades. Chlormethiazole was widely used in the UK but no clinical trials were done. In the 1980s there were moves towards phenytoin or diazepam until two large trials, published in 1995,5,6 showed that magnesium sulphate was better than phenytoin or diazepam at reducing the risk of seizures and improved both maternal and neonatal outcome. There is still no proof that the routine use of anticonvulsants in pre-eclampsia is beneficial, but where an anticonvulsant is to be used, magnesium sulphate seems to be the best choice. Recently another possible indication for giving magnesium to women in preterm labour has been suggested. In a retrospective epidemiological study Nelson and Grether7 found that antenatal exposure of very low birthweight (<1500 g) infants to magnesium reduced the incidence of cerebral palsy at age 3 or more. This report was exciting because magnesium blocks the n-methyl-d-aspartate (NMDA) receptor responsible for a considerable amount of neuronal death during hypoxicischaemic injury, and in cell culture high concentrations of magnesium protect neurons from hypoxic-ischaemic death. Considerable research effort has gone into investigating whether magnesium sulphate given perinatally is truly cerebroprotective. Further epidemiological work produced conflicting results.8,9 Most studies found no protective effect and instead suggested confounding factors that might have accounted for the apparent effect in the earlier studies. Magnesium was unlikely to have been given to mothers who presented in rapid, or advanced, preterm labour, or had clinical evidence of infection or fetal distress, all of which are risk factors for neurological injury. Conversely the widespread use of magnesium to treat pre-eclampsia in the USA meant that such mothers would have received the drug, and preeclampsia before 32 weeks independently reduces the risk of cerebral palsy. Magnesium protects newborn rats against brain injury caused by intracerebral injection of NMDA. However, administration of magnesium to fetal lambs and newborn sheep did not protect against hypoxia-ischaemia,10,11 and there have been suggestions that magnesium might disrupt fetal haemodynamic responses. In the light of this body of circumstantial evidence, a
Vol 350 • November 22, 1997
randomised controlled double-blind trial was established in Chicago specifically to examine the Nelson and Grether hypothesis. The discontinuation of this trial is reported in today’s Lancet. Interim analysis showed that magnesium sulphate given to mothers in preterm labour before 34 weeks is associated with a significant increase in neonatal mortality. This trial tilts the balance of evidence firmly away from magnesium use as a tocolytic or cerebroprotectant in preterm labour. Magnesium should probably also be restricted to only the most severe forms of pre-eclampsia or to eclampsia, where its value may outweigh the neonatal risks.
Phillip Bennett, David Edwards Division of Paediatrics, Obstetrics, and Gynaecology, Imperial College School of Medicine, Hammersmith Hospital Campus, London W12 0HS, UK 1
Cotton DB, Strassner T, Hill LM, Schifrin BS, Paul RH. A comparison of magnesium sulfate, terbutaline and a placebo for the inhibition of preterm labour. J Reprod Med 1984; 29: 92-97. 2 Witlin AG, Friedman SA, Sibai BM. The effect of magnesium sulfate therapy on the duration of labor in women with mild pre-eclampsia at term: a randomised, double blind, placebo controlled trial. Am J Obstet Gynecol 1997; 176: 623-27. 3 Atkinson MW, Guinn D,Owen J, Hauth JC. Does magnesium sulfate affect the length of labor induction in women with pregnancyassociated hypertension? Am J Obstet Gynecol 1995; 173: 1219-22. 4 Higby K, Xenakis EMJ, Pauerstein CJ. Do tocolytic agents stop preterm labor? A critical and comprehensive review of efficacy and safety. Am J Obstet Gynecol 1993; 168:1247-59. 5 The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the collaborative eclampsia trial. Lancet 1995; 345: 1455-63. 6 Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med 1995; 333: 201-05. 7 Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995; 95: 26369. 8 Schendel DE, Berg CJ,Yeargin-Allsopp M, Boyla C A, Decoufle P. Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 years. JAMA 1996; 276: 1805-11. 9 Paneth N, Jetton J, Pintomartin J, et al. Magnesium sulfate in labor and risk of neonatal brain lesions and cerebral palsy in low birthweight infants. Pediatrics 1997; 99: E11-E16. 10 Penrice J, Amess PN, Punwani S, et al. Magnesium sulfate after transient hypoxia-ischemia fails to prevent delayed cerebral energy failure in the newborn piglet. Ped Res 1997; 41: 1-5. 11 Dehaan HH, Gunn AJ, Williams CE, Heyman MA, Gluckman PD. Magnesium sulfate therapy during asphyxia in near term fetal lambs does not compromise the fetus but does not reduce cerebral injury. Am J Obstet Gynecol 1997; 176:18-27.
From antiphospholipid syndrome to antibody-mediated thrombosis Over the past decade the association of antibodies having an apparent specificity for anionic phospholipids with thrombosis, fetal loss, and thrombocytopenia has become widely recognised as the antiphospholipid (aPL) syndrome. In addition to affecting a subset of patients with systemic lupus erythematosus, the aPL syndrome is an important cause of thromboembolic disease and fetal loss in the general population. The aPL syndrome may account for 15-20% of all episodes of deep venous thrombosis,1 a third of new strokes occurring in patients under the age of 50,2 and 5-15% of women with recurrent fetal losses.3 Recent research has significantly advanced our understanding of the autoantibodies associated with the aPL syndrome and the mechanisms by which these 1491