Magpie: Magnesium Sulphate for Pre-eclampsia (2002)

“Magnesium sulphate is a safe and effective treatment for women with pre-eclampsia. It more than halves the risk of eclampsia and probably reduces the risk of maternal death.”

  • The Magpie Trial Collaborative Group

1. Publication Details

  • Trial Title: Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial
  • Citation: The Magpie Trial Collaborative Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet. 2002;359(9321):1877-1890. DOI: 10.1016/s0140-6736(02)08778-0
  • Published: June 1, 2002, in The Lancet
  • Author: The Magpie Trial Collaborative Group
  • Funding: UK Medical Research Council; UK Department for International Development; and others.

2. Keywords

  • Pre-eclampsia, Eclampsia, Magnesium Sulphate, Seizure Prophylaxis, Obstetrics, Randomized Controlled Trial

3. The Clinical Question

  • In pregnant women with pre-eclampsia (Population), does treatment with magnesium sulphate (Intervention) compared to placebo (Comparison) reduce the risk of developing eclampsia (seizures) (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Pre-eclampsia is a common and dangerous complication of pregnancy that can lead to eclampsia (life-threatening seizures) and maternal death. Magnesium sulphate was used for the treatment of established eclamptic seizures, but its role in preventing the first seizure in women with pre-eclampsia was highly uncertain.
  • Knowledge Gap: Despite its use in some centers, there was no high-quality evidence from a large, definitive randomized controlled trial to determine if prophylactic magnesium sulphate was effective and safe for women with pre-eclampsia.
  • Proposed Hypothesis: The authors hypothesized that magnesium sulphate would be superior to placebo in reducing the risk of eclampsia in women with pre-eclampsia.

5. Study Design and Methods

  • Design: A very large, international, multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 175 hospitals in 33, mostly low- and middle-income, countries.
  • Trial Period: Enrollment ran from November 1995 to September 2001.
  • Population:
    • Inclusion Criteria: Pregnant women with a clinical diagnosis of pre-eclampsia (hypertension and proteinuria).
    • Exclusion Criteria: Included a clear indication for or contraindication to magnesium sulphate.
  • Intervention: Patients received a loading dose of magnesium sulphate (4g IV over 10-15 minutes) followed by a maintenance infusion of 1g per hour for 24 hours.
  • Control: Patients received a matching intravenous placebo.
  • Management Common to Both Groups: All patients received standard care for pre-eclampsia, including antihypertensive therapy as needed.
  • Power and Sample Size: The authors planned to enroll 10,000 women, which would provide very high power to detect a clinically meaningful difference in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: The development of eclampsia.
    • Secondary Outcomes: Included maternal mortality, major maternal morbidity, and perinatal outcomes for the baby.

6. Key Results

  • Enrollment and Baseline: 10,141 women were randomized (5071 to magnesium sulphate and 5070 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The risk of eclampsia was dramatically and significantly lower in the magnesium sulphate group. Eclampsia occurred in 40 of 4999 women (0.8%) in the magnesium sulphate group, compared with 96 of 4993 women (1.9%) in the placebo group (p<0.0001).
  • Secondary Outcomes: Maternal mortality was also lower in the magnesium sulphate group, although this difference was not statistically significant. There were no significant differences in perinatal outcomes for the baby.
  • Adverse Events: Side effects, primarily flushing, were more common in the magnesium sulphate group, but there was no significant difference in the rate of serious adverse events.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of women who developed eclampsia between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for eclampsia: 0.42 (95% CI, 0.29 to 0.60).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the result as 0.42.
      • Clinical Meaning: The RR of 0.42 means that women in the magnesium sulphate group had a 58% lower relative risk of developing eclampsia compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.29 to 0.60.
      • Clinical Meaning: Since this entire range is well below the line of no effect (1.0), it confirms that the result is highly statistically significant and demonstrates a large and precise benefit.
    • P-value: The p-value of <0.0001 is extremely low, indicating the result is highly statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 1.9% – 0.8% = 1.1%.
      • Clinical Meaning: For every 100 women with pre-eclampsia treated with magnesium sulphate, about 1 additional case of eclampsia was prevented.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.011 = 91.
      • Clinical Meaning: You would need to treat 91 women with pre-eclampsia with magnesium sulphate to prevent one case of eclampsia.
  • Subgroup Analyses: The benefit was consistent across all pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard and provided a massive amount of high-quality data.
  • Generalizability: The pragmatic design and inclusion of a very large, global population of women, particularly from low- and middle-income countries where the disease burden is highest, makes the findings highly generalizable.
  • Statistical Power: The enormous sample size provided definitive power to detect a clinically important difference.
  • Patient-Centered Outcomes: The primary outcome of eclampsia and the secondary outcome of maternal mortality are the most important patient-centered endpoints.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a very low risk of bias.
  • External Validity (Generalizability): The findings are highly generalizable to a broad population of women with pre-eclampsia.
  • Other: The NNT of 91 may seem high, but given the devastating consequences of eclampsia, preventing even one case is a major clinical success.

10. Conclusion of the Authors

  • The authors concluded that magnesium sulphate is a safe and effective prophylactic treatment that more than halves the risk of eclampsia in women with pre-eclampsia.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided the definitive evidence that established magnesium sulphate as the global standard of care for the prevention of eclampsia in women with pre-eclampsia.
  • Specific Recommendations:
    • Patient Selection: For pregnant women with a diagnosis of pre-eclampsia.
    • Actionable Intervention: Administer prophylactic magnesium sulphate according to the trial protocol.
    • Expected Benefit: This intervention can be expected to prevent approximately one case of eclampsia for every 91 women treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that magnesium sulphate is a cure for pre-eclampsia; it is a prophylactic treatment for its most severe complication.
  • Implementation Caveats: The key is the timely administration of magnesium sulphate to all women diagnosed with pre-eclampsia to prevent the progression to eclampsia.

12. Context and Related Studies

  • Building on Previous Evidence: The Magpie trial (2002) was designed to definitively answer a question that had been debated for decades, based on smaller, less conclusive studies.
  • Influence on Subsequent Research: The definitive positive result of this trial has been highly influential in shaping international obstetric and critical care guidelines.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question.
  • Future Directions: Subsequent research has focused on optimizing the management of pre-eclampsia, including the timing of delivery and the treatment of associated hypertension.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was of the highest relevance, addressing a leading cause of maternal mortality worldwide with a simple, inexpensive intervention.
  • Methods: The very large, multicenter, double-blind RCT design was of the highest quality and was essential for providing a definitive answer. The pragmatic design ensured high external validity.
  • Results: The study reported a statistically significant and clinically profound benefit for its primary outcome. The finding of safety was also a critical result.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in evidence-based medicine and global health, demonstrating that a simple, low-cost intervention can save lives and prevent severe morbidity on a global scale. Its findings are highly applicable worldwide.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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