Clinical Review

Judicious use of magnesium sulfate for eclampsia

OBG Manag. 2003 June;15(6):38-56

The landmark Magpie study confirmed magnesium’s effectiveness in treating and preventing pregnancy-related seizures. Some Ob/Gyns fear side effects and toxicity, however. This practical guide tells how to assess risk and select the appropriate regimen.

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References

1. 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;359:1877-1890.

2. Coetzee EJ, Dommisse J, Anthony J. A randomized controlled trial of intravenous magnesium sulphate versus placebo in the management of women with severe pre-eclampsia. Br J Obstet Gynecol. 1998;105:300-303.

3. Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. 1998;92:883-889.

4. Belfort MA, Anthony J, Saade GR, Allen JC. for the Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003;348:304-311.

5. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med. 1995;333:201-205.

6. The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet. 1995;345:1455-1463

7. Belfort M, Moise KJ. Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: A randomized, placebo-controlled study. Am J Obstet Gynecol. 1992;167:661-666.

8. Naidu S, Payne AJ, Moodley J, Hoffmann M, Gouws E. Randomized study assessing the effect of phenytoin and magnesium sulphate on maternal cerebral circulation in eclampsia using transcranial Doppler ultrasound. Br J Obstet Gynaecol. 1996;103:111-116.

9. Fawcett WJ, Haxby EJ, Male DA. Magnesium: Physiology and pharmacology. Br J Anaesthesia. 1999;83:302-320.

10. Yang Z-W, Gebrewold A, Nowakowski M, Altura BT, Altura BM. Mg²⁺ -induced endothelium-dependent relaxation of blood vessels and blood pressure lowering: role of NO. Am J Physiol. 2000;R628-R639.

11. Sipes SL, Weiner CP, Gellhaus TM, Goodspeed JD. Effects of magnesium sulfate infusion upon plasma prostaglandins in preeclampsia and preterm labor. Hypertens Pregnancy. 1994;13:293-302.

12. Richards A, Graham D, Bullock R. Clinicopathological study of neurological complications due to hypertensive disorders of pregnancy. J. Neurol Neurosurg Psych. 1988;51:416-421.

13. Pritchard JA. The use of magnesium sulfate in preeclampsia-eclampsia. J Reprod Med. 1979;23:107-114.

14. Lu JF, Nightingale CH. Magnesium sulfate in eclampsia and pre-eclampsia. Clin Pharmacokinet. 2000;38:305-314.

15. Sibai BM, Spinnato JA, Watson DL, Lewis JA, Anderson GD. Effect of magnesium sulfate on electroencephalographic findings in preeclampsia-eclampsia. Obstet Gynecol. 1984;64:261-266.

16. Sibai BM, Spinnato JA, Watson DL, Lewis JA, Anderson GD. Eclampsia. IV. Neurological findings and future outcome. Am J Obstet Gynecol. 1985;152:184-192.

17. Douglas KA, Redman CWG. Eclampsia in the United Kingdom. BMJ. 1994;309:1395-1400.

18. Sibai BM. Eclampsia. VI. Maternal-perinatal outcome in 254 consecutive cases. Am J Obstet Gynecol. 1990;163:1049-1055.

19. Sibai BM, Lipshitz J, Anderson GD, Dilts PV. Reassessment of intravenous MgSO⁴ therapy in preeclampsia-eclampsia. Obstet Gynecol. 1981;57:199.-

20. Katz VL, Farmer R, Kuller JA. Preeclampsia into eclampsia: Toward a new paradigm. Am J Obstet Gynecol. 2000;182:1389-1396.

21. Pritchard JA. The use of the magnesium ion in the management of eclamptogenic toxemias. Surg Gynecol Obstet. 1955;100:131-140.

22. Zuspan FP. Problems encountered in the treatment of pregnancy-induced hypertension. A point of view. Am J Obstet Gynecol. 1978;131:591-597.

23. Pritchard JA, Cunningham FG, Pritchard SA. The Parkland Memorial Hospital protocol for treatment of eclampsia: Evaluation of 245 cases. Am J Obstet Gynecol. 1984;148:951-960.

24. Usta IM, Sibai BM. Emergent management of puerperal eclampsia. Obstet Gynecol Clin N Am. 1995;22:315-333.

25. Ascarelli MH, Johnson V, May WL, Martin RW, Martin JN. Individually determined postpartum magnesium sulfate therapy with clinical parameters to safely and cost-effectively shorten treatment for pre-eclampsia. Am J Obstet Gynecol. 1998;179:952-956.

26. Isler CM, Barrilleaux PS, Rinehart BK, Magann EF, Martin JN, Jr. Postpartum seizure prophylaxis: Using maternal clinical parameters to guide therapy. Obstet Gynecol. 2003;101:66-69.

27. Atkinson MW, Guinn D, Owen J, Hauth JC. Does magnesium sulfate affect the length of labor induction in women with pregnancy-associated hypertension? Am J Obstet Gynecol. 1995;173:1219-1222.

28. Witlin AG, Friedman SA, Sibai BM. The effect of magnesium sulfate therapy on the duration of labor in women with mild preeclampsia at term: A randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol. 1997;177:623-627.

29. Riaz M, Porat R, Brodsky NL, Hurt J. The effects of maternal magnesium sulfate treatment on newborns: A prospective controlled study. Perinatology. 1998;18:449-454.

KEY POINTS

Give magnesium sulfate at the time of diagnosis to all preeclamptic patients who are to be delivered.
Administration of magnesium sulfate for new-onset hypertension and preeclampsia remote from term is controversial.
Even with therapeutic serum concentrations of magnesium, convulsions are possible.
Magnesium sulfate should be administered for 24 hours after delivery or after the last postpartum seizure.
Safe administration requires vigilant monitoring of reflexes, respiratory status, and urine output.

Although magnesium sulfate has been used to treat eclampsia since the 1920s, the most compelling evidence of its effectiveness has come in the past year. Yet some Ob/Gyns hesitate to use this agent because of potential side effects and the risk of toxicity.

Last year’s headline-grabbing Magpie Trial¹ confirmed a previous, smaller randomized study² as well as a number of small controlled trials³ indicating that magnesium sulfate is better than placebo^1,2 for seizure prophylaxis. Other large, randomized trials have demonstrated the drug’s superiority to nimodipine⁴ and phenytoin⁵ in preventing convulsions and to diazepam and phenytoin⁶ as therapy for eclampsia (TABLE 1).

As a result, magnesium sulfate remains a reliable tool for preventing eclampsia.³ Because clinical symptoms and signs are notoriously unreliable in predicting which gravidas will develop seizures, it is reasonable to administer magnesium at the time of diagnosis to all preeclamptic patients who are to be delivered.

This article reviews the practical implications of recent findings on prophylactic and therapeutic use, patient selection and risk assessment, and administration and monitoring protocols.

TABLE 1

Incidence of seizures according to therapy

PROPHYLAXIS
STUDY	THERAPY GROUPS	SEIZURES (%)	PREECLAMPSIA DEFINED AS …	STUDY CHARACTERISTICS
Magpie Trial¹	Magnesium	0.8	BP 140/90 mm Hg, proteinuria, nulliparity	n = 10,110, P<.0001>
Magpie Trial¹	Placebo	1.9	BP 140/90 mm Hg, proteinuria, nulliparity	n = 10,110, P<.0001>
Coetzee et al²	Magnesium	0.3	Presence of 2 or more of the following: diastolic BP 110 mm Hg, proteinuria, prodromal symptoms	n = 699, P<.003>
Coetzee et al²	Placebo	3.2		n = 699, P<.003>
Belfort et al⁴	Magnesium	0.8	BP 140/90 mm Hg and proteinuria with 1 or more of the following: headache, clonus, visual disturbances, epigastric/right upper quadrant pain, oliguria, pulmonary edema, elevated liver enzymes, elevated creatinine, hemolysis, thrombocytopenia, intrauterine growth retardation, oligohydramnios	n = 1,650, P.01
Belfort et al⁴	Nimodipine	2.6		n = 1,650, P.01
Lucas et al⁵	Magnesium	0	BP 140/90 mm Hg	n = 2,138, P<.004>
Lucas et al⁵	Phenytoin	0.9	BP 140/90 mm Hg	n = 2,138, P<.004>
TREATMENT
STUDY	THERAPY	RECURRENT SEIZURES (%)	STUDY CHARACTERISTICS
Eclampsia Trial Collaborative Group⁶	Magnesium	13.2	n = 905, P<.0005>
Eclampsia Trial Collaborative Group⁶	Diazepam	27.9	n = 905, P<.0005>
Eclampsia Trial Collaborative Group⁶	Magnesium	5.7	n = 775, P<.0005>
Eclampsia Trial Collaborative Group⁶	Phenytoin	17.1	n = 775, P<.0005>
BP = blood pressure

Magnesium increases vasodilatation

The prophylactic and therapeutic benefits of magnesium likely derive from its ability to counteract vasospasm; the mechanism by which magnesium protects against seizures has not been established.

Transcranial Doppler ultrasound studies indicate that magnesium increases cerebral blood flow in preeclamptic⁷ and eclamptic women.⁸ Magnesium-induced vasodilatation involves a number of factors,⁹ such as blockade of calcium entry into vascular smooth muscle, antagonism of intracellular calcium activity, and release of nitric oxide¹⁰ and prostacyclin.¹¹

In addition, magnesium inhibits platelet aggregation and protects endothelial cells from injury by free radicals. This action, along with stabilization of vascular tone, can potentially reduce the risk of cerebral thrombosis.^9,12 The anticonvulsant effects of magnesium in clinically relevant doses do not involve depression of the neuromuscular junction.¹³

Magnesium also can directly affect the central nervous system by antagonizing N-methyl-D-aspartate receptor activation, which inhibits calcium influx and subsequent neuronal injury.⁹ This mechanism of action requires that plasma magnesium pass freely into the interstitial fluid of the brain. (Magnesium has already been shown to readily enter the cerebrospinal fluid after intravascular injection.¹⁴) The extent to which blockade of N-methyl-D-aspartate receptors contributes to magnesium prophylaxis and therapy remains to be established.

Women with preeclampsia or eclampsia often have electroencephalogram abnormalities that typically involve diffuse slowing (delta waves). These nonspecific electroencephalogram changes develop independently of arterial pressure and are not suppressed by intravenous (IV) magnesium.^15,16

Mistaken identity: Tracing the etiology of eclampsia through time

Eclamptic women have undergone renal decapsulation, spinal fluid drainage, implantation of the ureters into the colon, mastectomy, and oophorectomy. Each of these treatments was once considered rational based on hypotheses about the cause of eclampsia.

Although descriptions of convulsions in pregnancy date to antiquity, it was not until the 18th century that eclampsia was distinguished from tonic-clonic seizures in the nonpregnant state.

Eventually eclampsia was thought to be one of the pregnancy toxemias caused by a circulating toxin that acted on “nerve centers.”¹ Thus, in the 1920s, a popular treatment for eclampsia involved eliminative measures, such as stomach lavage and high colonic flushings, as well as phlebotomy. Later, sedation with morphine sulfate and chloral hydrate without bleeding, popularized by Stroganoff in the 1930s, became prominent.^2,3

Magnesium enters the picture. In 1924, an intern at Los Angeles General Hospital suggested using intravenous magnesium sulfate to treat eclamptic seizures, knowing that it controlled tetanic convulsions and had mild sedative effects. As a result, intravenous magnesium sulfate was added to the elimination protocol for eclampsia. In the initial trial, which included 17 eclamptic women, all seizures were controlled by magnesium, and maternal mortality was only 6%, compared with the historical average of 30%.⁴

By the 1960s, magnesium therapy combined with antihypertensive medication and delivery had been adopted in the United States as frontline therapy for eclamptic seizures—an approach that reduced maternal mortality to 5% or less.^5-8 The associated perinatal mortality, which was due largely to abruptio placentae, prematurity, and complications of fetal growth restriction, also was substantially reduced—from 30% to about 10%.^5-8

Criticism of this therapy has centered on 2 perceptions of the pharmacology of magnesium: It acted only at the neuromuscular junction, and it did not penetrate the blood-brain barrier.^9,10 These effects seemed less than optimal when compared to those of newly developed antiepileptic medications, which had well-described mechanisms of action involving rapid transfer from blood to brain and stabilization of neuronal membranes.

Newer findings. In the 1990s, however, small controlled studies suggested that magnesium is surprisingly effective in preventing seizures in both preeclampsia and eclampsia.¹¹ Recurrent seizures occurred in 9% of eclamptic women who received magnesium, which was about 40% less than in those given the anticonvulsants diazepam or phenytoin. In patients with severe preeclampsia, magnesium prophylaxis reduced the risk of seizures to 0.9% from 2.8% in women who received antihypertensive agents but no anticonvulsants. Large randomized trials confirmed these findings.^12-16

REFERENCES

1. Loudan I. Some historical aspects of toxaemia of pregnancy. A review. Br J Gynecol. 1991;98:853-858.

2. Lawson J. Complications of eclampsia: Abruptio placentae, cardiac failure, renal failure, hyperpyrexia, uncontrollable fits, prolonged coma. Clinics Obstet Gynaecol. 1982;9:711-721.

3. O’Dowd MJ, Philipp EE. The History of Obstetrics and Gynecology. New York: Parthenon; 1994:23.

4. Lazard EM. A preliminary report on the intravenous use of magnesium sulphate in puerperal eclampsia. Am J Obstet Gynecol. 1925;9:178-188.

5. Zuspan FP, Ward MC. Improved fetal salvage in eclampsia. Obstet Gynecol. 1965;26:893-897.

6. Pritchard JA, Stone SR. Clinical and laboratory observations on eclampsia. Am J Obstet Gynecol. 1967;99:754-762.

7. Pritchard JA, Cunningham FG, Pritchard SA. The Parkland Memorial Hospital protocol for treatment of eclampsia: Evaluation of 245 cases. Am J Obstet Gynecol. 1984;148:951-960.

8. Sibai BM. Eclampsia. VI. Maternal-perinatal outcome in 254 consecutive cases. Am J Obstet Gynecol. 1990;63:1049-1055.

9. Kaplan PW, Lesser RP, Fisher RS, Repke JT, Hanley DF. No, magnesium sulfate should not be used in treating eclamptic seizures. Arch Neurol. 1988;45:1361-1364.

10. Donaldson JO. The case against magnesium sulfate for eclamptic convulsions. Int J Obstet Anesth. 1992;1:159-166.

11. Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. 1998;92:883-889.

12. Coetzee EJ, Dommisse J, Anthony J. A randomized controlled trial of intravenous magnesium sulphate versus placebo in the management of women with severe preeclampsia. Br J Obstet Gynecol. 1998;105:300-303.

13. 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;359:1877-1890.

14. Belfort MA, Anthony J, Saade GR, Allen JC. for the Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003;348:304-311.

15. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med. 1995;333:201-205.

16. The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet. 1995;345:1455-1463.