Elsevier

The Lancet

Volume 359, Issue 9321, 1 June 2002, Pages 1877-1890
The Lancet

Articles
Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial

https://doi.org/10.1016/S0140-6736(02)08778-0Get rights and content

Summary

Background

Anticonvulsants are used for pre-eclampsia in the belief they prevent eclamptic convulsions, and so improve outcome. Evidence supported magnesium sulphate as the drug to evaluate.

Methods

Eligible women (n=10 141) had not given birth or were 24 h or less postpartum; blood pressure of 140/90 mm Hg or more, and proteinuria of 1+ (30 mg/dL) or more; and there was clinical uncertainty about magnesium sulphate. Women were randomised in 33 countries to either magnesium sulphate (n=5071) or placebo (n=5070). Primary outcomes were eclampsia and, for women randomised before delivery, death of the baby. Follow up was until discharge from hospital after delivery. Analyses were by intention to treat.

Findings

Follow-up data were available for 10 110 (99·7%) women, 9992 (99%) of whom received the allocated treatment. 1201 of 4999 (24%) women given magnesium sulphate reported side-effects versus 228 of 4993 (5%) given placebo. Women allocated magnesium sulphate had a 58% lower risk of eclampsia (95% CI 40–71) than those allocated placebo (40, 0·8%, vs 96, 1·9%; 11 fewer women with eclampsia per 1000 women). Maternal mortality was also lower among women allocated magnesium sulphate (relative risk 0·55, 0·26–1·14). For women randomised before delivery, there was no clear difference in the risk of the baby dying (576, 12·7%, vs 558, 12·4%; relative risk 1·02, 99% CI 0·92–1·14). The only notable difference in maternal or neonatal morbidity was for placental abruption (relative risk 0·67, 99% CI 0·45–0·89).

Interpretation

Magnesium sulphate halves the risk of eclampsia, and probably reduces the risk of maternal death. There do not appear to be substantive harmful effects to mother or baby in the short term.

Introduction

Pre-eclampsia, a multisystem disorder of pregnancy usually associated with raised blood pressure and proteinuria, complicates 2–8% of pregnancies.1 Although outcome is often good, pre-eclampsia is a major cause of morbidity and mortality for the woman and her child.2 Eclampsia is defined as the occurrence of one or more convulsions superimposed on pre-eclampsia. In developed countries eclampsia is rare, affecting around one in 2000 deliveries3, while in developing countries estimates vary from one in 100 to one in 1700.4, 5 Worldwide an estimated 600 000 women die each year of pregnancy-related causes6, with 99% of these deaths occurring in developing countries. Pre-eclampsia and eclampsia probably account for more than 50 000 maternal deaths a year.7 In places where maternal mortality is high, most of these deaths are associated with eclampsia. Where maternal mortality is lower, a higher proportion will be due to pre-eclampsia. For example, in the UK pre-eclampsia and eclampsia together account for 15% of direct maternal deaths, and two-thirds were related to pre-eclampsia.2

For decades anticonvulsant drugs have been given to women with pre-eclampsia, in the belief that they reduce the risk of seizure, and so improve outcome.8 However, there has been little reliable evidence to support that belief. In 1998, a systematic review9 of anticonvulsants for women with pre-eclampsia identified four trials (total 1249 women) comparing an anticonvulsant with no anticonvulsant or placebo. This review concluded that magnesium sulphate was the most promising choice for pre-eclampsia, and the priority for further evaluation. Additionally, magnesium sulphate is now the drug of choice for women with eclampsia, with strong evidence that it is better than either diazepam10, phenytoin11, or lytic cocktail.12

The use of magnesium sulphate for pre-eclampsia is increasing13, although a range of other anticonvulsant drugs continue to be used, including diazepam and other benzodiazepines, phenytoin, barbiturates, and lytic cocktail. There is also substantial variation in the severity of pre-eclampsia for which a prophylactic anticonvulsant is used. In the USA, for example, magnesium sulphate is given to an estimated 5% of pregnant women before delivery.14 By contrast, a quarter of UK obstetricians never use any prophylactic anticonvulsants13, and those who do often restrict their use to women with severe pre-eclampsia, which is around 1% of deliveries.

The initial question about magnesium sulphate, as a prophylactic anticonvulsant for women with pre-eclampsia, is whether it reduces the risk of eclampsia. Even if it does, reliable information is required before magnesium sulphate can be safely recommended for clinical practice; in particular about the size of any risk reduction, effects on other important outcomes for the woman and child, and disease severity at which benefits outweigh the risks. The Magpie Trial (MAGnesium sulphate for Prevention of Eclampsia) was a large international trial designed to evaluate the effects of magnesium sulphate on women and their babies. The aim was to find out if, overall, women with pre-eclampsia or their children, or both, do better if they are given magnesium sulphate rather than placebo, regardless of whether treatment is started before or after delivery and irrespective of any previous anticonvulsant therapy.

Section snippets

Trial organisation

Overall coordination of the trial was from the Resource Centre for Randomised Trials at the Institute of Health Sciences in Oxford, UK. Spanish speaking centres in Latin America were coordinated from the Centro Rosarino de Estudios Perinatales in Rosario, Argentina, and from the Instituto Argentino de Medicina Basada en las Evidencias in Buenos Aires, Argentina. Centres in South Africa were coordinated from the MRC Pregnancy Hypertension Unit in Durban. Throughout recruitment, a 24-h on-call

Subgroup and sensitivity analyses

Definition of severe pre-eclampsia

All women

Diastolic blood pressure ≥110 mm Hg on two occasions, or systolic blood pressure ≥170 mm Hg on two occasions and proteinuria ≥3+

or

Diastolic blood pressure ≥100 mm Hg on two occasions, or systolic blood pressure ≥150 mm Hg on two occasions and proteinuria ≥2+ and at least two signs or symptoms of imminent eclampsia

Or, for women who had an antihypertensive in the 48 h before randomisation

In 48 h before trial entry, highest diastolic blood pressure

≥110

Statistical analysis

We initially estimated that the risk of convulsions for women allocated placebo might be around 1%, and that to have 90% power to show a 50% decrease in this risk would require 14 000 women (α=0·05). In February, 2000, the sample size estimate was revisited, because the overall risk of eclampsia among trial participants was 1·2%. After consultation with the chair of the data monitoring committee, target recruitment was revised to between 10 800 and 12 750 women. We expected that most women

Role of the funding source

The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Results

Overall, 10 141 women were randomised at 175 secondary and tertiary level hospitals in 33 countries. Recruitment of 101 women in the pilot occurred from Feb 23, to July 14, 1998, and of the remaining women from July 15, 1998, to Nov 29, 2001. Altogether, 2037 women were recruited through the telephone service and 8104 through the local pack system. 4762 (47%) women were recruited in Africa, 2735 (27%) in the Americas, 1583 (15%) in the Asia-Pacific region, and 1061 (10%) in Europe. Of these,

Discussion

The Magpie Trial was designed to assess the effects, on women and their babies, of magnesium sulphate when used for women with pre-eclampsia. To provide reliable evidence to guide the care of women with pre-eclampsia the trial needed to recruit very large numbers of women. The study also aimed to provide results that would be generalisable to a wide range of clinical settings, in both rich and poor countries. In order to achieve our target recruitment, and to include collaborators from

Implications for clinical practice

The results of this trial should be made available to women with pre-eclampsia, and those responsible for their care. Magnesium sulphate should be considered for women with pre-eclampsia for whom there is concern about the risk of eclampsia. As it is an inexpensive drug, it is especially suitable for use in low-income countries, iv administration is preferable, where there are appropriate resources, as side-effects and injection-site problems seem lower. Duration of treatment should not

Implications for research

Remaining questions about the use of magnesium sulphate include: what is the minimum effective dose? When is the optimal time to give it? Should it be used at primary-care level for women being transferred for secondary of tertiary care? What are the long-term consequences of exposure for the mother and her child? Many clinicians reserve magnesium sulphate for women for whom delivery is planned in the next 24 h. In the Magpie Trial some women were given 24-h treatment and the pregnancy was

Conclusions

Magnesium sulphate reduces the risk of eclampsia, and it is likely that it also reduces the risk of maternal death. At the dosage used in this trial it does not have any substantive harmful effects on the mother or child, although a quarter of women will have side-effects.

Magpie Trial Collaborative Group

Central Coordinating Team –Lelia Duley (clinical coordinator), Barbara Farrell (trial manager), Patsy Spark (trial programmer), Barbara Roberts (trial secretary), Karen Watkins (research fellow,

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