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Magnesium For Preeclampsia2005
Magnesium For Preeclampsia2005
Magnesium Sulfate
Prophylaxis in
Preeclampsia:
Evidence From
Randomized Trials
BAHA M. SIBAI, MD
Department of Obstetrics and Gynecology, University of Cincinnati,
Cincinnati, Ohio
478
Magnesium Sulfate Prophylaxis 479
TABLE 1. Randomized Trials Comparing Magnesium Sulfate (MgSO4) Therapy With Other
Anticonvulsant Agents for Eclampsia
Recurrent Seizures
MgSO4 Other
Antihypertensive
Author Therapy No. (%) No. (%) RR (95% CI)
3
Dommisse Dihydralazine 0/11 (0) 4/11 (36.7)
Crowther4 Dihydralazine 5/24 (20.8) 7/27 (26) 0.8 (0.292.2)
Bhalla et al5 Nifedipine 1/45 (2.2) 11/45 (24.4) 0.09 (0.010.68)
Friedman et al6 Nifedipine, labetalol 0/11 (0) 2/13 (15.4)*
Collaborative Trial2 NR 60/453 (13.2) 126/452 (27.9) 0.48 (0.360.63)
NR 22/388 (5.7) 66/387 (17.1) 0.33 (0.210.53)
All studies 88/922 (9.4) 216/935 (23.1) 0.41 (0.320.51)
* Phenytoin.
Diazepam.
Lytic cocktail.
CI, confidence interval; NR, not reported; RR, relative risk.
Odendaal and Hall8 studied 1001 women with obvious regarding decision to use magne-
severe preeclampsia; 510 received magne- sium sulfate in these studies.
sium sulfate prophylaxis based on the clinical There are 4 large randomized, controlled
impression of impending eclampsia and 491 trials comparing the use of magnesium sul-
women did not receive magnesium sulfate. fate to prevent convulsions in patients with
Five patients (0.5%) developed eclampsia, severe preeclampsia (Table 3).1013 Two of
2 (0.4%) in the magnesium group (both oc- the trials were single center,10,11 and the
curred before delivery) and 3 (0.6%) in the other 2 were multicenter with large sample
no magnesium group (all 3 developed post- sizes.12,13 Two of the trials were placebo-
partum). Interestingly, 2 of the 3 with post- controlled,11,12 one trial used a no treatment
partum seizures occurred beyond 48 hours group,10 and the remaining trial compared
and thus would not have been eligible for magnesium sulfate to a cerebral vasodilator
their standard magnesium sulfate regimen. (nimodipine).13 All 4 trials allowed the use
In a subsequent report, Hall and associates9 of various antihypertensive agents to control
reported on 318 women with preeclampsia hypertension. The Magpie trial12 included
(mostly severe and remote from term and 10,110 women with preeclampsia and was
not in labor) who were managed expectantly conducted in 175 hospitals in 33 countries
with antihypertensive drugs and without with considerable heterogeneity of clinical
magnesium sulfate. Twenty-six of the wom- characteristics, obstetric care, and availabil-
en subsequently received magnesium sulfate ity of maternal and neonatal intensive care
during labor or because of antepartum seiz- units. In addition, many aspects of clinical
ures (n = 4). Five (1.5%) developed eclamp- characteristics or management were poorly
sia; 2 (0.7%) developed within 24 hours of defined or controlled at time of randomiza-
hospitalization, 2 (0.7%) at 8 and 14 days tion. Some of these women received study
after hospitalization, and 1 developed 4 days medications antepartum during expectant
postpartum. Therefore, only 2 would have management for 24 hours only (no subse-
been prevented by their standard magnesium quent magnesium sulfate in labor or post-
sulfate prophylaxis regimen. In addition, partum), some were discharged home, others
none of the 5 women had serious morbidity received drug during labor and delivery, and
because of seizures. The authors of these some were randomized only during the post-
studies therefore questioned the need for partum period.12 Fifty percent of patients
magnesium sulfate prophylaxis in patients received antihypertensives before randomi-
with severe preeclampsia.8,9 However, it is zation and 75% received antihypertensives
important to note that selection bias was after randomization. Moreover, 9% received
anticonvulsants before randomization and these women. This study did not include
6% received magnesium sulfate or other anti- intention-to-treat analysis. The overall re-
convulsants after randomization; 17 women sults of the 4 trials listed in Table 3 demons-
had eclampsia before randomization.8 This trate that magnesium sulfate prophylaxis
trial revealed a significant reduction in the in severe preeclampsia is associated with a
rate of eclampsia in women assigned to mag- significantly lower rate of eclampsia (RR =
nesium sulfate (Table 3). This benefit was 0.39, 95% CI, 0.280.55).
primarily found in women enrolled in devel-
oping countries, and no significant reduction
in eclampsia was found in women enrolled in
Effects of Magnesium Sulfate
the Western world (RR = 0.67; 95% CI, on Maternal Mortality
0.192.37).12 However, the number of women and Morbidities
enrolled in the Western world was too few. The trials mentioned here provided informa-
Based on the rate of eclampsia found in this tion regarding maternal mortality, and some
group, with an a of 0.05 and a b of 0.2, of the studies provided information about ma-
11,263 women from the Western world need ternal morbidities such as abruptio placen-
to be enrolled in each group to find a signif- tae,10,12,13 respiratory depression,1013 and ce-
icant reduction in rate of eclampsia in wom- rebrovascular accidents.1013 There were no
en treated with magnesium sulfate. maternal deaths reported in 2 of the trials10,13
The trial by Belfort et al13 compared the and 1 trial reported 1 death among 340 women
use of magnesium sulfate with nimodipine, assigned to placebo.11 This woman pre-
a calcium channel blocker with cerebral vas- sented 10 days after discharge from the hos-
odilatory effects. In this trial, the authors en- pital with signs of pelvic sepsis.11 In the
rolled women at 14 sites in 8 countries who Magpie trial, there were 11 maternal deaths
were given study drugs during labor and for in the magnesium group and 20 deaths in the
24 hours postpartum. All study women had placebo group (RR = 0.55; 95% CI, 0.26
well-defined clinical characteristics before 1.14).12 However, 3 of the deaths in the pla-
randomization.13 The authors found a signif- cebo group were the result of renal failure, 3
icant reduction in the rate of eclampsia in the were attributed to pulmonary embolism, and
magnesium sulfate group (Table 3); most of 2 because of infection. These 8 deaths can
the difference was the result of a lower hardly be ascribed to magnesium whose
eclampsia rate in the postpartum period actions are to prevent status epilepticus
among group assigned to magnesium sulfate and aspiration. In addition, the deaths result-
(0 of 831 vs. 9 of 819 in nimodipine; P = ing from pulmonary embolism and infection
0.01).13 The trial by Coetzee et al11 included could not be attributed to cesarean section
822 randomized women; however, 137 because the rate of cesarean was similar be-
(17%) were excluded after randomization. tween the 2 groups (50% in magnesium and
There were no cases of eclampsia among 48% in placebo).12 Moreover, it is not clear
from this trial how many women had renal ing neonatal morbidities.12,13 The use of
failure before randomization. Overall, the magnesium sulfate in severe preeclampsia
results of these trials demonstrate no benefit does not affect the rates of Apgar ,7 at 5
of magnesium sulfate on maternal mortality. minutes, respiratory distress, need for intu-
Nevertheless, the numbers are too small to bation, hypotonia, or days in a special care
draw any certain conclusions. baby unit.12,13
Table 4 summarizes the data from ran-
domized trials regarding the effects of
magnesium sulfate on the rate of abruptio Magnesium Sulfate in
placentae.10,12,13 Magnesium sulfate is
not associated with a significant reduction Mild Preeclampsia
in the rate of abruptio placentae (RR = There are only 2 double-blind, placebo-
0.67; 95% CI, 0.381.19). controlled trials evaluating the use of mag-
Randomized, controlled trials evaluating nesium sulfate in patients with mild pre-
the effects of magnesium sulfate on the fre- eclampsia (Table 7).14,15 In both trials,
quency of respiratory depression are sum- patients with well-defined mild preeclamp-
marized in Table 5. The use of magnesium sia were randomized during labor or post-
sulfate in severe preeclampsia is associated partum, and there was no difference in the
with a significant increase in the rate of percentage of women who progressed to
respiratory depression (RR = 2.06; 95% severe preeclampsia (12.5% vs. 13.8%;
CI, 1.333.18). There were 3 cases of cere- RR = 0.90; 95% CI, 0.521.54). There were
brovascular accidents among 6343 women no instances of eclampsia among 181 pa-
(0.05%) assigned to magnesium sulfate and tients assigned to placebo. In one of these
6 cases among 6330 women (0.09%) as- trials,14 there was higher rates of postpartum
signed to placebo.1013 The power regarding hemorrhage and 2 instances of magnesium
this outcome is too low for valid conclusions. toxicity among those assigned to magne-
sium sulfate.
Because the number of patients studied
in the 2 placebo trials is limited,10,11 a larger
Effects of Magnesium Sulfate number of patients needs to be studied be-
on Perinatal Deaths and fore the effectiveness or safety of magne-
Neonatal Morbidities sium sulfate can be stated with certainty.
Three of the 4 trials mentioned here provid- Thus, there is a definite need for a multicen-
ed adequate information regarding perinatal ter trial to address the value of magnesium
deaths (Table 6).1012 The use of magnesium sulfate prophylaxis in mild preeclampsia.
sulfate in severe preeclampsia does not Based on a rate of eclampsia of 0.5% and
affect the rate of perinatal deaths (RR = assuming 50% reduction by magnesium sul-
1.03; 95% CI, 0.871.22). Only 2 of the ran- fate (0.25% rate), with an a of 0.05 and
domized trials provided information regard- a b of 0.2, 9383 women would need to be
TABLE 5. Effects of Magnesium Sulfate on the Proportion With Respiratory Depression
in Women With Severe Preeclampsia
Authors Magnesium Sulfate No. (%) Control No. (%) RR (95% CI)
10
Moodley and Moodley 0/112 0/116 NA
Coetzee et al11 1/345 (0.3) 0/340 NA
Magpie Trial Group12 51/4999 (1.0) 26/4993 (0.5) 1.96 (1.223.14)
Belfort et al13 11/831 (1.3) 3/819 (0.4) 3.61 (1.0112.90)
Total 63/6287 (1.0) 29/6268 (0.46) 2.06 (1.333.18)
NA, not applicable; RR, relative risk; CI, confidence interval.
Magnesium Sulfate Prophylaxis 483
TABLE 6. Effects of Magnesium Sulfate on the Rate of Perinatal Deaths in Severe Preeclampia
Authors Magnesium Sulfate No. (%) Control No. (%) RR (95% CI)
10
Moodley and Moodley 20/117 (17) 25/118 (21) 0.81 (0.471.37)
Coetzee et al11 38/348 (11) 38/354 (8.0) 1.38 (0.872.20)
Magpie Trial Group12 576/4538 (13) 558/4486 (12) 1.02 (0.921.14)
Total 634/5003 (13) 601/4958 (13) 1.03 (0.871.22)
RR, relative risk; CI; confidence interval.
enrolled in each group to find a significant with severe preeclampsia. This study sug-
reduction in eclampsia in women with mild gests that the rate of seizures in women
preeclampsia treated with magnesium sulfate. with mild hypertension or mild preeclamp-
There are 4 randomized trials compar- sia receiving phenytoin is 0.6% (6 of 1000
ing magnesium sulfate with phenytoin in women).
women with various hypertensive disor-
ders of pregnancy (Table 8).1619 Only
one of these trials had an adequate sample Side Effects and Toxicity of
size to evaluate development of convul- Magnesium Sulfate
sions.19 The results of these studies reveal The use of magnesium sulfate is associated
that magnesium sulfate is superior to phe- with a high rate of minor side effects such as
nytoin to prevent eclamptic seizures in these feeling warm, flushed, nausea or vomiting,
women (Table 8).1619 muscle weakness, dizziness, and irritation
The largest randomized trial was at the site of injections. The reported rates
reported by Lucas et al.19 The trial com- of these effects in randomized trials ranged
pared the use of intramuscular magnesium from 15% to 67%.1214 These side effects
sulfate to phenytoin in women with vari- were the most common reason for the wom-
ous hypertensive disorders (hypertension ans request to stop treatment early in the
only, mild preeclampsia, and a small per- Magpie trial.12 In addition, the use of mag-
centage with severe preeclampsia). The nesium sulfate is associated with major side
phenytoin group included 178 women effects such as respiratory depression1214
who were given either no phenytoin (n = and postpartum hemorrhage.13,14 However,
139) or only a partial loading dose (n = postpartum hemorrhage was not increased
39). There were no cases of seizures with magnesium sulfate use in the Magpie
among 1049 women assigned to magne- trial.12
sium sulfate as compared with 10 (0.9%) Life-threatening magnesium toxicity is
among 1089 women assigned to phenytoin extremely rare with correct dosing and proper
(P = 0.004). Four of the 10 women with monitoring of the patient during magnesium
seizures had clinical findings consistent sulfate therapy. Nevertheless, maternal
Evidence from the Collaborative Eclampsia 14. Witlin AG, Friedman SA, Sibai BM. The
Trial. Lancet. 1995;345:14551463. effect of magnesium sulfate therapy on the
3. Dommisse J. Phenytoin sodium and magne- duration of labor in women with mild
sium sulfate in the management of eclampsia. preeclampsia at term: a randomized, double-
Br J Obstet Gynaecol. 1990;97:104109. blind, placebo-controlled trial. Am J Obstet
4. Crowther C. Magnesium sulfate versus diaz- Gynecol. 1997;176:623627.
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