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Clinical Reviews


Judicious use of magnesium sulfate for eclampsia

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.

June 2003 · Vol. 15, No. 6

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 nimodipine 4 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

Placebo

1.9

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

Placebo

3.2

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

Nimodipine

2.6

Lucas et al5

Magnesium

0

BP 140/90 mm Hg

n = 2,138, P<.004

Phenytoin

0.9

TREATMENT

STUDY

THERAPY

RECURRENT SEIZURES (%)

STUDY CHARACTERISTICS

Eclampsia Trial Collaborative Group6

Magnesium

13.2

n = 905, P<.0005

Diazepam

27.9

Eclampsia Trial Collaborative Group6

Magnesium

5.7

n = 775, P<.0005

Phenytoin

17.1

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.

Quick facts on eclampsia

Incidence

  • The maternal death rate for eclampsia varies geographically, according to the quality of the area’s health-care system. In developed countries, the rate ranges from 1.8% to 7.2%, while in countries with less available medical care, it can exceed 25%.1-3
  • Although the maternal mortality rate for preeclampsia is lower (approximately 0.34% in the United States) than for eclampsia, preeclampsia still accounts for more than half of the maternal deaths linked to pregnancy “toxemia.”3,4
  • Eclampsia-associated perinatal mortality remains high—about 10%—even in developed countries.

Risk of eclampsia

  • Eclampsia usually involves reversible cerebral edema and endangers the mother principally through seizure-related aspiration (2%) or underlying disturbances such as acute renal failure (5%), pulmonary edema (4%), cardiorespiratory arrest (3%), and abruptio placentae.5,6
  • Eclamptic seizures also carry the risk of permanent brain injury or death when they are associated with hemorrhagic or ischemic stroke or with tentorial herniation.
  • Recurrent seizures—in which prolonged activation of N-methyl-D-aspartate receptors can produce toxic brain levels of calcium—also may lead to permanent injury and death.
  • About 7% of eclamptic women develop significant neurologic sequelae, including aphasia, psychosis, cortical blindness, weakness, coma, or cerebrovascular accident.7
  • More than half of eclamptic women who die within 48 hours after the onset of convulsions have cerebral petechiae, hemorrhage, or ischemic softening (nonhemorrhagic) of the brain,8 which may result from thrombosis of cerebral vessels9 or other complications of cerebral vasospasm.8,10
  • Necrosis of the walls and endothelium of precapillary arterioles also can occur.
  • Cerebral edema in gross specimens has not been a consistent finding at autopsy.8,11 Although this seems to run counter to expectations, a detailed microscopic analysis of the brain would be necessary to identify focal edema affecting a small brain sector.

REFERENCES

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

2. Majoko F, Mujaji C. Maternal outcome in eclampsia at Harare Maternity Hospital. Cent Afr J Med. 2001;47:123-128.

3. MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol. 2001;97:533-538.

4. 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.

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

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

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

8. Sheehan JL, Lynch JB. Pathology of Toxaemia of Pregnancy. London: Churchill Livingston; 1973;524-582.

9. McKay DG. Clinical significance of the pathology of toxemia of pregnancy. Circulation. 1964;30(suppl 2):66-75.

10. Will AD, Lewis KL, Hinshaw DB, Jr, et al. Cerebral vasoconstriction in toxemia. Neurology. 1987;37:1555-1557.

11. Hibbard LT. Maternal mortality due to acute toxemia. Obstet Gynecol. 1973;42:263-270.

Give magnesium to all preeclamptic patients to be delivered

Clinical symptoms and signs are unreliable predictors of which pregnant women will develop seizures. For example, eclampsia can occur in gravidas without hypertension or proteinuria. When these conditions are present, the risk of eclampsia is not proportional to their severity.1,17-20 Thus, given the relative safety of magnesium therapy with appropriate monitoring, a reasonable approach is to initiate therapy at the time of diagnosis in all preeclamptic patients who are to be delivered.

If all clinicians followed this management approach, about 5% of gravidas would receive therapy to prevent a rare but potentially injurious event, although for most (more than 97%) the treatment would be unnecessary.

Pregnancy-induced hypertension. The administration of magnesium sulfate to women with new-onset hypertension (arterial blood pressure of 140/90 mm Hg or more) without proteinuria is controversial. Some physicians do not give magnesium to these patients because the risk of eclampsia is lower than in those with preeclampsia (as characterized by hypertension and proteinuria).

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