Preventing and treating eclamptic seizures

Ninety nine percent of all maternal deaths occur in developing countries. Pre-eclampsia or eclampsia is responsible for many of these, accounting for 50 000 deaths annually. Large randomised trials in developing countries and systematic reviews have shown the usefulness of magnesium sulphate in treating recurrent eclamptic seizures and in the prophylaxis of eclampsia.^1–3 Despite this evidence magnesium sulphate remains underused.

In 1995 the Eclampsia Trial Collaborative Group did an impressive study in developing countries and showed unequivocally that magnesium sulphate given intramuscularly or intravenously is superior to phenytoin or diazepam in reducing recurrent eclamptic seizures.¹ Seizures were a half or a third less likely to recur after treatment with magnesium. Maternal mortality was also lower in women allocated magnesium rather than phenytoin or diazepam, although this did not achieve statistical significance. Recent Cochrane reviews, however, indicated a significant reduction in maternal mortality with magnesium.² Magnesium was also associated with less maternal and neonatal morbidity than phenytoin.

Recently the findings of this study were extended to indicate the value of magnesium as prophylaxis for eclampsia.³ In the Magpie study, 10 000 women with pre-eclampsia were randomised to receive magnesium sulphate before or during labour, or after giving birth. About two thirds of the women in this study were from developing countries with high or moderate perinatal mortality. The results were again impressive. Magnesium was effective, reducing seizures by more than half. Treatment was also safe in this setting, without any excess of serious maternal morbidity. There was no reduction in deaths due to eclampsia. Total maternal mortality was, however, lower in treated women, although this did not achieve statistical significance (mortality for treated women was 55% of controls (95% confidence intervals 26 to 114)).

It is counterintuitive that magnesium, which is used as an anticonvulsant, should reduce deaths from renal failure, pulmonary embolism, and infection (the causes of mortality that were reduced in the group treated with magnesium). But the significant reduction of placental abruption in treated women suggests alternative mechanisms of action of magnesium.

Is magnesium safe to use in developing countries? Magnesium was used safely in both the eclampsia trial and the Magpie trial. None the less, as indicated in the Magpie study, magnesium is associated with side effects, and some of these (for example, respiratory and cardiac arrest) can be life threatening. For safety in developing countries it is important to assess in which patients the benefit from being given magnesium is sufficient to justify this risk. Treatment is certainly justified in women with eclampsia, in whom evidence from meta-analysis indicates that magnesium reduces mortality. A quarter of the women in the Magpie study had severe pre-eclampsia—very high blood pressure (>170 mm Hg systolic or 110 mm Hg diastolic) with very high proteinuria, or lower blood pressure (150 mm Hg systolic or 100 mm Hg diastolic) with two or more signs of imminent eclampsia such as hyperreflexia, frontal headache, blurred vision, or epigastric tenderness). In this group it was necessary to treat 63 women to prevent one seizure. In women who did not have such severe pre-eclampsia 109 patients had to be treated to prevent a seizure. Even the women without severe pre-eclampsia were probably quite ill in this study, as almost 75% of them were given antihypertensive treatment. Thus, the Magpie study indicates a very favourable ratio of benefit to risk for magnesium, given according to the protocol, in women with severe pre-eclampsia or requiring antihypertensive treatment.

The safety of magnesium in this study was facilitated by limiting the loading dose of magnesium to 4 g and restricting intravenous administration to 1 g/hour, whereas the intramuscular dose was at 10 g, followed by 5 g every 4 hours. For the loading and intravenous doses this is considerable lower than has been recommended by some, and the safety of higher doses is not assured by this study.⁴ In addition, some instruction was undoubtedly provided to the participants in the trial. None the less, as carried out in this protocol with simple clinical assessment and without determining magnesium concentration, treatment with magnesium was safe.

Despite the evidence, this effective treatment has not been used widely. We have few examples in obstetric practice of treatments that have been tested in randomised controlled trials to show efficacy and even fewer that address treatment in the field. Why has this treatment not become part of the armamentarium of providers of obstetric care throughout the world? The answer is complex, but at least part of the explanation is that this inexpensive generic treatment has no industrial advocate to facilitate licensing, production, and distribution. Another factor is the reluctance of care providers and administrators to change healthcare practice. On behalf of the World Health Organization, Fédération Internationale de Gynécologie et d'Obstétrique, and the International Society for the Study of Hypertension in Pregnancy we advocate the use of magnesium sulphate in the treatment and prevention of eclampsia. We urge nations in which eclampsia has a major impact on maternal mortality to institute policies to ensure that this inexpensive and life saving treatment is made available and that care providers are trained to use it safely.