Magnesium sulfate is not used for pre-eclampsia and eclampsia in Mexico and Thailand as much as it should be
Pisake Lumbiganon a, A Metin Gülmezoglu b, Gilda Piaggio c, Ana Langer c, Jeremy Grimshaw d
Pre-eclampsia is a multiple organ disorder of unknown etiology usually associated with raised blood pressure and proteinuria. Eclampsia, the occurrence of one or more convulsions (fits), is a rare but serious complication in patients with pre-eclampsia. Pre-eclampsia/eclampsia remains one of the leading problems that threaten safe motherhood, particularly in developing countries. It was estimated that hypertension complicates approximately 5% of all pregnancies and 11% of all first pregnancies.1 Based on these estimations and case fatality rates, up to 40 000 women could die from pre-eclampsia and eclampsia each year.1
In a systematic review involving six trials (11 444 women) magnesium sulfate significantly reduced the risk of eclampsia (relative risk, RR 0.41; 95% confidence interval, CI: 0.29–0.58) and the risk of maternal death (RR 0.54; 95% CI: 0.26–1.10) among patients with pre-eclampsia although the latter was not statistically significant.2,3 Magnesium sulfate was more effective than phenytoin for reducing the risk of eclampsia among patients with pre-eclampsia (two trials, 2241 women; RR 0.05; 95% CI: 0.00–0.84).2
Magnesium sulfate appears to be substantially more effective than phenytoin (six trials, 897 women)4 or diazepam (seven trials, 1441 women)5 for the treatment of eclampsia. Magnesium sulfate is therefore the anticonvulsant of choice for both prevention and treatment of eclampsia.1
Implementing magnesium sulfate for the prevention and treatment of eclampsia in low- and middle-income countries could potentially benefit hundreds of thousands of women.6 This study aims to evaluate the use of magnesium sulfate for women with pre-eclampsia and eclampsia in Mexico and Thailand, where a cluster randomized trial to evaluate an educational strategy to change obstetric practices was conducted. The study methodology was published in detail elsewhere.7 The main results related to the effects of the intervention was published separately.8
The study was conducted in two countries: the Mexico City municipal area, Mexico, and the north-east region of Thailand. Maternity units of hospitals with > 1000 deliveries/year that were not associated directly with a university or other academic/research department were eligible to participate. In Mexico, all state and social security hospitals in the Mexico City municipal area were approached. Twenty-two out of 34 hospitals approached were eligible and agreed to participate in the trial. In Thailand, 18 hospitals out of 19 in the north-east region agreed to participate. There were therefore 40 hospitals in this study. The objective of the main trial was to evaluate the improvement in obstetric practices using an active dissemination strategy to promote uptake of recommendations contained in the WHO Reproductive Health Library (RHL).9
A multifaceted intervention addressing potential barriers to evidence-based practice was conducted over a period of six months following baseline data collection on clinical practices. Three interactive workshops focusing on principles of evidence-based medicine, the RHL and how to implement change formed the core intervention. The use of magnesium sulfate and other effective practices were not specifically addressed during the workshops.
The data on the occurrences of pre-eclampsia and eclampsia and the use of anticonvulsants were collected as part of measuring the rate of evidence-based practices in the main trial. The data were collected at baseline (September 2000) and 10 to 12 months after implementation of the intervention (September 2002). We collected data from 1000 women or for six months, whichever was reached first in each unit. Field workers not involved in the implementation of the trial collected the data. The data collection forms were completed in the postnatal wards mostly from hospital records. The mothers were consulted if information was missing from the records.
We report crude prevalence rates of pre-eclampsia and eclampsia. The rates of magnesium sulfate use and their 95% confidence intervals were considered at cluster (hospital) level.
The study was approved by the Scientific and Ethical Review Group of the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP) and the ethics review committees of the participating institutions.
The overall prevalence of pre-eclampsia in Mexico and Thailand was 5.5% (2320/41 828) and 1.9% (699/35 923), respectively. There was no statistically and clinically significant difference between the rate of magnesium sulfate use for women with pre-eclampsia (and eclampsia) at baseline and at the end of the study, in both intervention and control hospitals. We therefore combined the data collected during these two periods for each hospital. Only eight out of 22 hospitals in Mexico used magnesium sulfate for pre-eclampsia, and for those using magnesium sulfate the rate of use ranged from 0.8% (95% CI: 0–4.5) to 8.5% (95% CI: 4.8–13.6) among women with pre-eclampsia (Fig. 1). In Thailand, all 18 hospitals used magnesium sulfate for pre-eclampsia; the rates of use ranged from 18.6% (95% CI: 8.4–33.9) to 63.6% (95% CI: 50.9–75.1) in the intervention group and 12.5% (95% CI: 1.6–38.3) to 79.2% (95% CI: 65.0–89.5) in the control group (Fig. 1). In Mexico, phenytoin was more commonly used than magnesium sulfate but it was not used at all in Thailand. Diazepam was not used in either country for women with pre-eclampsia.
The overall prevalence of eclampsia was 0.6% (232/41 828) and 0.3% (122/35 923) in Mexico and Thailand, respectively. Only 11 out of 22 hospitals in Mexico used magnesium sulfate for eclampsia; for those using it the rates of use ranged from 9.1% (95% CI: 0.2–41.3) to 60.0% (95% CI: 14.7–94.7) in the intervention group and 3.8% (95% CI: 0.5–13.2) to 60.0% (95% CI: 14.7–94.7) in the control group (Fig. 2). In Thailand, there was one hospital that did not have patients with eclampsia at both baseline and at the end of the study; it was excluded from the analysis. The remaining 17 hospitals used magnesium sulfate for eclampsia. The rates of use ranged from 25.0% (95% CI: 0.6–80.6) to 100% (95% CI: 29.2–100) in the intervention group, and 25.0% (95% CI: 0.6–80.6) to 80.0% (95% CI: 44.4–97.5) in the control group (Fig. 2). Phenytoin was more commonly used than magnesium sulfate in Mexico but was not used at all in Thailand for eclampsia. Diazepam was rarely used in both countries.
The prevalence of pre-eclampsia and eclampsia in Mexico was 5.5% and 0.6% respectively, which is quite similar to the overall global picture.1 However, the corresponding rates in Thailand were 1.8% and 0.3%, which are lower. The uses of magnesium sulfate for pre-eclampsia and eclampsia were surprisingly low in Mexico. In Thailand, magnesium sulfate was used more frequently for both pre-eclampsia and eclampsia.
A report on the management of eclampsia from Sweden shows the remarkably increased use of magnesium sulfate: from 8% during 1980–1989 to 83% during 1990–1999.10 A questionnaire survey of obstetricians in the United Kingdom and Ireland in 1996 indicated that 40% and 60% of respondents would use magnesium sulfate for pre-eclampsia and eclampsia, respectively.11
The very low rate of magnesium use particularly in Mexico is alarming. Magnesium sulfate is reasonably cheap and its effectiveness when used in pre-eclampsia and eclampsia has been clearly shown by evidence from randomized controlled trials and systematic reviews.2,12,13 Although magnesium sulfate use for pre-eclampsia and eclampsia in Thailand is much higher than in Mexico, there is still room for improvement. Magnesium sulfate has been in the National Essential Drug List of Thailand since 1999. As of 2002, there were only 45 countries that had magnesium sulfate in their essential drug list (WHO unpublished data). As of 16 October 2006, the Mexican National Essential Drug List did not include magnesium sulfate (Edición 2005 del Cuadro Básico y Catálogo de Medicamentos, available at: http://www.salud.gob.mx). Responsible persons and organizations in these two countries should take immediate actions to ensure wider use of this effective and inexpensive drug for these conditions. Researchers and responsible persons in other low- to middle-income countries should also evaluate the situation regarding this issue and take appropriate actions.
Why has magnesium sulfate not become the treatment of choice particularly for eclampsia throughout the world? There are two possible hypotheses. First, magnesium sulfate is too cheap to motivate mass manufacturing, licensing, production and distribution. Second, health-care providers and administrators may be reluctant to adopt a practice that requires intensive monitoring for a condition (eclampsia) that is relatively infrequent.14 Not having experience with magnesium sulfate administration has been proposed as a reason for not using it in the United Kingdom.15 International organizations have advocated the use of magnesium sulfate in the treatment and prevention of eclampsia.14 There are often systematic gaps between evidence of effectiveness and what is actually practiced. Failure in the registration, procurement and distribution mechanisms for magnesium sulfate contribute to its poor availability in Mozambique and Zimbabwe.16 A survey of WHO drug information officers, regulatory officials and obstetricians in 12 countries was undertaken to identify barriers and facilitators to knowledge translation on the use of magnesium sulfate to treat pre-eclampsia. The perceived barriers include drug licensing and availability, inadequate and poorly implemented clinical guidelines, and the lack of political support for policy change.17 There were significant regional and national differences in the importance of specific barriers.17
Our report is unique in that we measured actual practices of using magnesium sulfate in pre-eclampsia and eclampsia by extracting data from medical records of a large number of women from 22 hospitals in Mexico and 18 hospitals in Thailand. Based on anecdotal evidence before data collection, we had assumed that magnesium sulfate would be routinely used in both Mexico and Thailand. For pre-eclampsia we anticipated some variation because the evidence was not strong at the time. The Magpie trial was published in June 2002.18 However, the use of phenytoin for pre-eclampsia and eclampsia in Mexico was surprising. These data highlight the importance of collecting actual practice data rather than reported behaviour, which can often overestimate the quality of care.
Our data has the limitation of being retrospective. The quality of data might be somewhat limited to the standards of patient records in the two countries. However, both pre-eclampsia and eclampsia are serious conditions where women are hospitalized, and it is unlikely that magnesium sulfate would have been used but not recorded.
We conclude that magnesium sulfate is not as widely used for preventing and treating eclampsia as it should be, in spite of its inexpensiveness and the very clear evidence about its effectiveness. Immediate actions are necessary to promote its use in all countries around the world, including insertion in National Essential Drug Lists. Organizations, such as the International Federation of Gynecology and Obstetrics (FIGO) and the International Confederation of Midwives (ICM), their national counterparts and other professional organizations should advocate for the availability and use of magnesium sulfate, assist in the development of local treatment protocols to follow and training of health-care workers in the use of magnesium sulfate. Given the paucity of evidence to select appropriate strategies for implementation, research projects to evaluate innovative approaches to implement magnesium sulfate treatment are of high priority in low- and middle-income countries. ■
- J Villar, L Say, A Shennan, M Lindheimer, L Duley, A Conde-Agudelo, et al., et al. Methodological and technical issues related to the diagnosis, screening, prevention, and treatment of pre-eclampsia and eclampsia. Int J Gynaecol Obstet 2004; 85: S28-41.
- L Duley, AM Gulmezoglu, DJ Henderson-Smart. Magnesium sulfate and other anticonvulsants for women with pre-eclampsia. Cochrane Database Syst Rev 2003; ▪▪▪: CD000025-.
- L Duley. Pre-eclampsia and the hypertensive disorders of pregnancy. Br Med Bull 2003; 67: 161-76.
- L Duley, D Henderson-Smart. Magnesium sulfate versus phenytoin for eclampsia. Cochrane Database Syst Rev 2003; ▪▪▪: CD000128-.
- L Duley, D Henderson-Smart. Magnesium sulfate versus diazepam for eclampsia. Cochrane Database Syst Rev 2003; ▪▪▪: CD000127-.
- SS Sheth, I Chalmers. Magnesium for preventing and treating eclampsia: time for international action. Lancet 2002; 359: 1872-3.
- AM Gülmezoglu, J Villar, J Grimshaw, G Piaggio, P Lumbiganon, A Langer. Cluster randomized trial of an active, multifaceted information dissemination intervention based on the WHO Reproductive Health Library to change obstetric practices: methods and design issues. BMC Med Res Methodol 2004; 4: 2-.
- Gülmezoglu A, Langer A, Piaggio G, Lumbiganon P, Villar J, Grimshaw J. Cluster randomised trial of an active, multifaceted educational intervention based on the WHO Reproductive Health Library to improve obstetric practices. BJOG 2006; article published online 27-Sep-2006.
- The WHO Reproductive Health Library. Geneva: WHO. http://www.rhlibrary.com
- O Rugarn, S Carling Moen, G Berg. Eclampsia at a tertiary hospital 1973-99. Acta Obstet Gynecol Scand 2004; 83: 240-5.
- AM Gülmezoglu, L Duley. Use of anticonvulsants in eclampsia and pre-eclampsia: survey of obstetricians in the United Kingdom and Republic of Ireland. BMJ 1998; 316: 975-6.
- L Duley. Magnesium sulfate in eclampsia. Eclampsia Trial Collaborative Group. Lancet 1998; 352: 67-8.
- Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 1995; 345: 1455-63.
- JM Roberts, J Villar, S Arulkumaran. Preventing and treating eclamptic seizures. Magnesium sulfate is effective and recommended for use. BMJ 2002; 325: 609-10.
- R Fox, T Draycott. Prefer diazepam for initial control of pre-eclamptic fit. BMJ 1995; 311: 1433-.
- E Sevene, S Lewin, A Mariano, G Woelk, A Oxman, S Matinhure, et al., et al. System and market failures: the unavailability of magnesium sulphate for the treatment of eclampsia and pre-eclampsia in Mozambique and Zimbabwe. BMJ 2005; 331: 765-9.
- M Aaserud, S Lewin, S Innvaer, E Paulsen, AT Dahlgren, M Trommald, et al., et al. Translating research into policy and practice in developing countries: a case study of magnesium sulphate for pre-eclampsia. BMC Health Serv Res 2005; 5: 68-.
- Duley L and the Magpie Trial Collaborative Group. Do women with pre- eclampsia, and their babies, benefit from magnesium sulfate? The Magpie Trial: a randomized placebo-controlled trial. Lancet 2002; 359: 1877-90.
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
- UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research, World Health Organization, 20 avenue Appia, 1211 Geneva 27, Switzerland.
- Population Council, Regional Office for Latin America and the Caribbean, Mexico City, Mexico.
- Ottawa Health Research Institute, Clinical Epidemiology Program, Ottawa, Canada.