Correspondence

Magnesium Sulfate versus Phenytoin for the Prevention of Eclampsia

N Engl J Med 1995; 333:1638-1639December 14, 1995

Article

To the Editor:

The study by Lucas et al. (July 27 issue)1 offered an opportunity to resolve a controversy in patient care that has divided neurologists and obstetricians for decades. However, their conclusion regarding the superiority of magnesium sulfate over phenytoin may have been influenced by several methodologic flaws. First, the loading dose of phenytoin was lower than the typical recommended dose of 18 to 20 mg per kilogram of body weight, and the reported serum levels when seizures occurred (<12.2 μg per milliliter in 8 of the 10 patients in whom eclampsia subsequently developed) are evidence of this less aggressive approach. Although decreased serum albumin levels during pregnancy may permit a greater fraction of unbound phenytoin to be available, the increased volume of distribution and increased clearance (hepatic and placental) associated with pregnancy are likely to mandate an increase in the dose. Second, none of the patients had electroencephalographic monitoring. Fisher et al. reported2 that persistent ictal electroencephalographic abnormalities could be seen when neuromuscular blockade had been achieved with magnesium sulfate and no clinical seizures were observable.

Raman Sankar, M.D., Ph.D.
UCLA School of Medicine, Los Angeles, CA 90024-1752

Eliot A. Licht, M.D.
1945 Glendon Ave., Los Angeles, CA 90025

2 References

1
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
Full Text | Web of Science | Medline

2
Fisher RS, Kaplan PW, Krumholz A, Lesser RP, Rosen SA, Wolff MR. Failure of high-dose intravenous magnesium sulfate to control myoclonic status epilepticus. Clin Neuropharmacol 1988;11:537-544
CrossRef | Web of Science | Medline

To the Editor:

Among the 10 women in whom eclampsia developed despite prophylaxis with phenytoin, it appears that 6 did not receive a maintenance dose, at least not within the first 10 hours after the initial loading dose (i.e., “eclampsia occurred before the oral dose was given”), since the protocol stipulated that women with eclampsia would be treated intravenously with magnesium sulfate, regardless of their initial treatment assignment. Does this mean that magnesium therapy was administered concurrently with phenytoin? Also, I question how long phenytoin therapy was continued in women in whom eclampsia did not develop.

With respect to the 10 patients with eclampsia, 9 had serum phenytoin levels no higher than 13.1 μg per milliliter at the time of seizures, and although such values may be within the “therapeutic” range in patients who are not pregnant, they may well have been subtherapeutic in this group because of the effects of decreased protein binding and volume expansion.

I was also concerned by the lack of electroencephalographic follow-up in the patients who had seizures. It is possible that some of these patients would have had persistently abnormal electroencephalograms after delivery, despite appearing clinically well.

I agree that magnesium sulfate should still be considered an effective therapy in the prevention of eclamptic seizures in pregnant women with hypertension. However, I do not believe we can conclude, on the basis of this study, that phenytoin therapy is any less effective than magnesium. Consequently, phenytoin may still well be an effective alternative therapy for eclamptic seizures.

Mark N. Friedman, D.O.
Pennsylvania Hospital, Philadelphia, PA 19107

To the Editor:

Unfortunately, the study by Lucas et al. was not blinded, despite the fact that both agents used were administered intravenously, which would have made blinding possible. This lack of blinding appears to have biased the outcome, as reflected by the markedly different rates of cesarean section in the two groups. Forty-two more cesarean sections were performed in the magnesium group before the onset or induction of labor than in the group that received phenytoin. Although this difference was statistically significant (P = 0.047), it was not discussed by the authors. Preemptive delivery is a treatment that is often used to prevent convulsions if there are signs of worsening cerebral irritation or if eclampsia is judged to be imminent. Were the 42 patients so treated to avert convulsions because a clinical judgment of imminent eclampsia had been made?

Karen Duggan, M.D.
Graham Macdonald, M.D.
Prince Henry Hospital, Sydney, NSW 2036, Australia

Author/Editor Response

The authors reply:

To the Editor: We can clarify for Dr. Friedman that eclampsia occurred in phenytoin-treated women before the scheduled maintenance dose was due. With regard to the implication that women treated with phenytoin who did not have a seizure may have been effectively treated, we reported the distribution of levels in the entire group and found that the occurrence of eclampsia seemed to be independent of the phenytoin level. The points raised about the volume of distribution in pregnancy seem ill considered. We reported the concentration per milliliter of serum, which is presumably the same in the subject's entire blood volume. We reiterate that free phenytoin levels are increased because of decreased albumin concentrations in pregnancy, and this effect is exaggerated in preeclampsia.

With regard to electroencephalographic monitoring, Drs. Sankar and Licht resurrect the concept that women with eclampsia who are treated with magnesium sulfate are convulsing on the inside but not on the outside. This concept is flawed: the serum magnesium levels that prevent eclampsia are too low to produce neuromuscular blockade. Dr. Friedman suggests that electroencephalography might prove useful during long-term follow-up of women with eclampsia. We cannot dispute this suggestion.

Drs. Duggan and Macdonald criticize our investigation because it was not double-blinded. Unfortunately, use of this preferred method was precluded by differences in dosing frequency, route of administration, and monitoring requirements between the two agents. Cesarean section was not used in the magnesium sulfate group to preempt eclamspsia. The overall statistical difference in the rates of cesarean section was due to small, statistically insignificant increases in various indications for cesarean delivery among the women randomly assigned to the magnesium sulfate group.

This has been a noteworthy year for our understanding of the treatment of eclampsia. In June, magnesium sulfate was reported to be clearly superior to either diazepam or phenytoin in the treatment of women with eclampsia.1 In July, we reported that magnesium sulfate was superior to phenytoin in preventing the disorder. These two studies were recently described to have “signaled the victory of pragmatism over theory,”2 since there is now conclusive evidence that magnesium sulfate is an effective drug in both the treatment and prevention of eclampsia. We agree.

Michael J. Lucas, M.D.
Kenneth J. Leveno, M.D.
F. Gary Cunningham, M.D.
University of Texas Southwestern Medical Center, Dallas, TX 75235-9032

2 References