Magnesium sulphate and pre-eclampsia

Magnesium sulphate has been used for treating eclampsia in the United States for much of the 20th century.¹ The international collaborative eclampsia trial confirmed that this anticonvulsant is indeed more effective, and safer, than alternative drugs.² British obstetric practice has changed rapidly in response to these findings,³ and standard treatment of eclampsia in the United Kingdom now much more closely corresponds to that of the United States, although some controversies remain about optimal dosage.

Is treatment of pre-eclampsia also better in the United States? As many as 5% of all pregnant women in some US centres receive magnesium sulphate in the belief that this prevents eclampsia and thus improves the outcome of pregnancy.⁴ In contrast, some UK experts advocate never using anticonvulsants for pre-eclampsia⁵; many clinicians would use anticonvulsants only in women with severe pre-eclampsia.³ Such enormous differences in attitude are mirrored by practice in other countries⁶ and reflect uncertainty about the best treatment of “the disease of theories.”⁷

The central issues are:

• Even for women with severe pre-eclampsia, the risk of eclampsia is low—around 1%.³

• The risk of eclampsia is probably reduced by magnesium sulphate, but, even if this reduction is by as much as 50%, very large numbers of women will need to be treated to prevent a single fit.

• Therefore, if prophylaxis with magnesium sulphate is to do more good than harm it must be very safe for both the woman and her child and should have few side effects.

Pre-eclampsia is a complex, multisystem disorder and how magnesium sulphate may prevent eclamptic convulsions is unclear. Magnesium may have localised effects, producing cerebral vasodilatation with subsequent reduction of cerebral ischaemia,⁸ or blocking of neuronal damage associated with ischaemia.⁹ However, magnesium sulphate also affects many other organs,¹⁰ and it would be implausibly fortuitous if these effects were exclusively beneficial.

For example, magnesium sulphate is known to relax smooth muscle and in many parts of the world is widely used as a tocolytic agent for preterm labour (despite little evidence from randomised trials to support this use¹¹). However, if the tocolytic effect is significant at doses used for pre-eclampsia, magnesium sulphate administration could increase the length of labour—and the risks of caesarean section and of postpartum haemorrhage. These effects, if they exist, would be especially important in resource poor settings, where pre-eclampsia may be particularly common.¹²

The fetus is also not immune to potential effects, beneficial or harmful, because magnesium readily crosses the placenta. Hypermagnesaemia in the neonate is associated with flaccidity, hyporeflexia, and respiratory depression.¹³ It has been suggested that prenatal magnesium administration may reduce the risk of cerebral palsy for very low birthweight babies.¹⁴ This observation comes from several high quality case-control studies; but a small randomised trial evaluating magnesium sulphate as a tocolytic agent reported an increased paediatric mortality in the magnesium arm.¹⁵ Whatever the true effects for these low birthweight preterm babies, reassurance is also required about the short and long term effects of in utero exposure to magnesium sulphate on term babies.

Determining the best care for women with pre-eclampsia is an important common problem in obstetrics. In a recent survey of obstetricians in Britain and Ireland over half the respondents expressed interest in collaborating in a trial to evaluate magnesium sulphate for women with pre-eclampsia.³ To be clinically worthwhile, treatment with magnesium sulphate would probably need to reduce the risk of eclampsia by at least 50%, and this seems a realistic expectation based on currently available evidence.⁶ To show such a halving in risk with reasonable certainty requires a trial of 14 000 women (α=0.05, β=0.1). This is the challenge taken up by the Magpie Trial Collaborative Group. The magpie trial aims, for the reasons discussed above, to evaluate other possible and important effects on women and their children of magnesium sulphate for pre-eclampsia. The trial is now recruiting, and new collaborators are very welcome.*