Just Accepted by The Journal of Maternal-Fetal & Neonatal Medicine

The Use Of Magnesium Sulphate For Women With Severe

Preeclampsia Or Eclampsia Diagnosed During The Postpartum
Period
Paulino Vigil-De Gracia MD, FACOG, MSPOG, Jack Ludmir, MD, FACOG
doi: 10.3109/14767058.2014.982529
Abstract
This was a systematic review of randomized controlled trials comparing
anticonvulsants with placebo or no anticonvulsant for prevention: a) of
eclampsia in women with severe preeclampsia diagnosed during the
postpartum period or diagnosed before delivery but without previous
treatment and, b) prevention of seizures recurrence in women with
eclampsia postpartum. We do not found study with full inclusion criteria.
However, a total of two RCTs meet inclusion criteria as subgroup analysis;
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one for severe preeclampsia diagnosed during the postpartum period and
one for eclampsia postpartum. For severe preeclampsia diagnosed during
postpartum there was no clear difference between the groups reporting
eclampsia (RR 0.54, 95% CI 0.16 to 1.80). For seizure recurrence
magnesium sulfate was superior to diazepam, but there was no significant difference compared with
phenytoin. This review did not support a beneficial effect of magnesium sulfate in women with diagnosis of
severe preeclampsia during the postpartum.
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 THE USE OF MAGNESIUM SULPHATE FOR WOMEN WITH SEVERE PREECLAMPSIA OR
ECLAMPSIA DIAGNOSED DURING THE POSTPARTUM PERIOD

Paulino Vigil-De Gracia MD, FACOG, MSPOG*

Jack Ludmir, MD, FACOG1

*Corresponding author: Paulino Vigil-De Gracia, MD. Complejo Hospitalario de la Caja de Seguro
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Social, Panama, Panama, FAX: 5073909956, Mobil: 50766143240, e-mail: pvigild@hotmail.com

1- Pennsylvania Hospital, Perelman School of Medicine at the University of Pennsylvania, Philadelphia,

USA
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Conflicts of interest:

The authors report no conflicts of interest.

J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Dicle Univ. on 11/11/14
For personal use only.
 Abstract

This was a systematic review of randomized controlled trials comparing anticonvulsants with placebo or

no anticonvulsant for prevention: a) of eclampsia in women with severe preeclampsia diagnosed during

the postpartum period or diagnosed before delivery but without previous treatment and, b) prevention of

seizures recurrence in women with eclampsia postpartum. We do not found study with full inclusion

criteria. However, a total of two RCTs meet inclusion criteria as subgroup analysis; one for severe
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Dicle Univ. on 11/11/14

preeclampsia diagnosed during the postpartum period and one for eclampsia postpartum. For severe

preeclampsia diagnosed during postpartum there was no clear difference between the groups reporting

eclampsia (RR 0.54, 95% CI 0.16 to 1.80). For seizure recurrence magnesium sulfate was superior to

diazepam, but there was no significant difference compared with phenytoin. This review did not

support a beneficial effect of magnesium sulfate in women with diagnosis of severe preeclampsia during
For personal use only.

the postpartum.
 INTRODUCTION

Pre-eclampsia/eclampsia is one of the most common medical complications of pregnancy and can occur

at any time during the second half of pregnancy; intrapartum or in the first few weeks post partum [1].

About 5% of women with preeclampsia occur for the first time after delivery [2]. A third of eclamptic

patients manifest their first seizure post delivery [3]. In Europe, eclampsia complicate 2 to 3 cases per 10

000 births, however in developing countries the rate is 30 times higher [4].
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The prevention of occurrence and recurrence of seizures is essential in the management of women with

severe preeclampsia. In this respect magnesium sulfate has proven superior to other anticonvulsants in

both the prevention and treatment of eclampsia [5-7].

Usually, the delivery of the fetus and placenta resolves the clinical manifestations of preeclampsia;

however, in some patients the disease process can worsen after delivery, placing them at risk for
For personal use only.

postpartum eclampsia [8]. In other, signs and symptoms of severe preeclampsia can develop for the first

time postpartum [2].

The objective of this review is to assess the effects of magnesium sulfate, and other anticonvulsants in

preventing convulsions in patients with severe preeclampsia or eclampsia diagnosed postpartum not

receiving treatment prior to delivery.

SOURCES

We searched Medline and Lilacs (all from inception through July 31, 2013); the Cochrane central

Register of controlled trial, research registers of ongoing trials (http://www.clinicaltrials.gov, http://

www.controlled-trials.com, http://www. centerwatch.com, http://www.anzctr.org. au,

http://www.nihr.ac.uk, and http:// www.umin.ac.jp/ctr); and Google scholar. No restrictions were placed

on language of publication. We reviewed all randomized studies that compared outcomes for women with

preeclampsia/eclampsia post partum who received magnesium sulfate versus receiving other
 anticonvulsants or placebo in women without treatment prior to delivery.

STUDY SELECTION

We included RCTs in which magnesium sulfate or other anticonvulsants were used to avoid eclampsia o

recurrence of seizures in women with preeclampsia o eclampsia diagnosed for the fist time after delivery.

Trials were excluded if they were quasi randomized of if they included women randomized before

delivery.
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Two reviewers (P.V-D. and J.L.) independently reviewed all potentially relevant articles for eligibility.

Disagreements regarding trail eligibility were resolved by consensus. Reviewers extracted data on

participants, study characteristics, primary and secondary outcome from each study

Statistical analysis was performed using Epi Info software version 7 (Centers for Disease Control and
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Prevention, Atlanta, GA), under the intention to treat principle.

For dichotomous data, the summary relative risk (RR) with 95% confidence interval (CI) was calculated.

The p values for all hypotheses were two sided, and p values of less than 0·05 were judged to be

significant.

RESULTS

The search yielded 145 citations, of which 35 were RCTs considered potentially eligible. 33 studies were

excluded, because these studies dealt with women with severe preeclampsia or eclampsia diagnosed prior

to labor or intrapartum receiving treatment. We do not found study with full inclusion criteria. However, a

total of two RCTs meet inclusion criteria as subgroup analysis. One included 1335 women with criteria

for severe preeclampsia postpartum and the second study had 419 women diagnosed with postpartum
 eclampsia. Both studies included women randomized after delivery, however these studies were not

exclusive for postpartum patients, and the randomization of postpartum patients represented one arm of

the studied population (subgroup analysis).

Severe preeclampsia diagnosed during the postpartum period or diagnosed before delivery but

without treatment at trail entry.

Only one trial of high quality, the MAGPIE trial fulfilled the above criteria as subgroup analysis [5]. In
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this study [5], 10 141 women with severe preeclampsia were randomized at 175 secondary and tertiary

levels hospitals in 33 countries. Information and follow-up data were available for 10 110 women. Of the

total number of patients involved 1335 women were randomized after delivery (639 to magnesium sulfate

and 696 to placebo). In the group of magnesium sulfate group, approximately half the women received

magnesium sulfate maintenance therapy by the intravenous route (1 g/hour), and half by the intramuscular
For personal use only.

route. In this postpartum arm trial [5,9] (postpartum) four (0.62%) women had seizures in the magnesium

sulfate group and eight (1.14%) in the placebo group. There were no statistical differences between the

groups in the rate of eclampsia (RR 0.54, 95% CI 0.16 to 1.80), the risk of serious maternal morbidity

(RR 0.92. 95% CI 0.48 to 1.77) and the risk of maternal deaths (RR 0.36, 95% CI 0.04 to 3.48), (10),

Table 1. Despite the 95% CI of the RR for women with postpartum preeclampsia includes 1, there is

overlap of the 95% CIs with interaction p value >0.10.

Eclampsia diagnosed during the postpartum period.

One high quality trial fulfilled the above criteria as subgroup analysis, the Collaborative Eclampsia Trial

[8]. This study involved a total of 1687 women with clinical diagnosis of eclampsia, 910 women were

randomized to magnesium sulfate versus diazepam (mag-diazepam group), and 777 women were

randomized to magnesium sulfate versus phenytoin (mag-phenytoin group). The trial included 419

postpartum eclamptic randomized either to magnesium sulfate versus diazepam (272 patients) or

magnesium sulfate versus phenytoin in 147 patients [9].

 In this Trial [9], Magnesium sulfate was given as a loading dose of 4 g IV over 5 min and was to be

followed by 5 g into each buttock intramuscularly, then 5 g IM every 4 h for 24 h. Or 4 g were given

intravenously over 5 min, followed by an infusion of 1 g/h for 24 h. For both regimen, a further 2-4 g was

given IV over 5 min if convulsions recurred. Diazepam was given as a loading dose of 10 mg iv over 2

min, repeated if convulsions recurred, was to be followed by an intravenous infusion of 40 mg/500 ml

normal saline for 24 h, the rate titrated against conscious level. During the next 24 h an infusion of 20 mg

diazepam in 500 mL normal saline was to be given and slowly reduced. Phenytoin was given as an initial
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loading doses of 1 g intravenous by slow infusion over 20 min, then 100 mg every 6 h for the next 24 h.

In the postpartum arm study, 128 women were randomized to magnesium sulfate and 144 to diazepam

(mag-diazepam group). In addition 79 women were randomized to magnesium sulfate and 68 women to

phenytoin (mag-phenytoin group), Table 1. In the mag-diazepam group the recurrent convulsion was:

magnesium sulfate 14/128 (10.9%) versus diazepam 43/144 (29.9%), RR 0.37, 95% CI 0.21 to 0.64. In
For personal use only.

the mag-phenytoin group the recurrent risk of seizures was 5/79 (6.3%) for the magnesium sulfate group

and 10/68 (14.7%) for the phenytoin group, RR 0.43, 95% CI 0.15 to 1.20, This difference was not

significant. Maternal mortality and serious maternal morbidity were no reported in these patients.

CONCLUSION

Research in preeclampsia and eclampsia has focused on the antenatal complications, for both mother and

baby, and the risks and benefits of administering anticonvulsive therapy prior to delivery [5-7,9]. There is

very little information on how best to manage postpartum severe preeclampsia or postpartum eclampsia

diagnosed for the first time after delivery or in patients not receiving treatment before delivery. This

review provides reasonable reassurance that there is no or little effect on developing eclampsia in patients

with severe preeclampsia or recurrent convulsions in patients with eclampsia with the use of magnesium

sulfate when the diagnosis of preeclampsia/eclampsia is made postpartum.

 In our analysis of the MAGPIE trial (subgroup analysis), in women with severe preeclampsia diagnosed

during the postpartum period or diagnosed before delivery but not being treated, the risk of eclampsia

(convulsions) was very small (1%) and not reduced by the use of magnesium sulfate. Based on this

properly conduced randomized study, but without enough power to make definitive conclusions, there is

no evidence to support the use of magnesium sulfate for the prevention of postpartum eclampsia in

women with diagnosis of severe preeclampsia during the postpartum period if the diagnosis was made

before delivery and the patient was not receiving magnesium sulfate prophylaxis. In the absence of
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reliable evidence from randomized trials to justify the use of magnesium sulfate to prevent seizures in

women with severe preeclampsia diagnosed in the postpartum period, it is necessary an adequate powered

RCT will be needed to establish definitively whether magnesium sulfate is the better for this group of

women.
For personal use only.

Based in our subgroup analysis of The Collaborative Eclampsia trial, in women with eclampsia diagnosed

during the postpartum period, the use of magnesium sulfate compared to diazepam resulted in decrease

number recurrent seizure; however, even with magnesium sulfate the recurrent risk for convulsion was in

the order of 6 to 11%. Compared to phenytoin, magnesium sulfate did not show benefit. Although the

evidence for these comparative findings is based in a small number of patients with the possibility of not

enough power to make definite conclusions; in our opinion, the use of diazepam for women with

diagnosis of eclampsia during the postpartum period should be abandoned. Whether magnesium sulfate is

better that phenytoin to prevent recurrent seizures in women diagnosed with eclampsia postpartum will

require a properly powered RCT comparing both modalities in this setting.

An interesting question is: are severe preeclampsia antepartum and post partum similar?. In general, pre-

eclampsia is cured by delivery of the placenta, although in some women the disease process could worsen

during the first 24-72 h postpartum, placing these women at a small risk for postpartum eclampsia [2].

Then, there is difference in women with antepartum preeclampsia that postpartum or with ante o

postpartum eclampsia. In the Magpie study [5] the eclampsia incidence (placebo group) for women
 randomized before delivery was 2.01% and in the group randomized after delivery was 1.14%. Thus, the

partum reduce the eclampsia in about 50%. In other word, antepartum pre-eclampsia is management with

two treatment: magnesium sulfate and delivery; however post partum pre-eclampsia only receive one

treatment. Therefore, there is doubt if that patients with postpartum preeclampsia benefit more or less

from the use of magnesium sulfate than patients with antepartum/intrapartum preeclampsia.

In summary, based in the analysis of this review there is insufficient data to guarantee that for patients
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with severe preeclampsia (diagnosed postpartum), magnesium sulfate should be used. For women that

develop postpartum eclampsia the recommendation to use magnesium sulfate to prevent recurrent

seizures is based on very low quality of evidence.

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enzymes and low platelets syndrome: what is new? Women´s Health, 2011;7(5):555-69.

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preeclampsia: an experience of 151 cases. American Journal of Obstetrics and

Gynecology 2004;90:1464–6.
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3- Knight M, on behalf of UKOSS. Eclampsia in the United Kingdom 2005. BJOG: an

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7- Duley L, Henderson-Smart DJ, Chou D. Magnesium sulphate versus phenytoin for

eclampsia. Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.:

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8- The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with

eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 1995;345: 1455–63

9- Duley L, Gülmezoglu AM, Henderson-Smart DJ, Chou D. Magnesium sulphate and other
 anticonvulsants for women with pre-eclampsia. Cochrane Database of Systematic

Reviews 2010, Issue 11. Art. No.: CD000025. DOI: 10.1002/14651858.CD000025.pub2.

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Table 1.
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Magnesium Sulfate compared to placebo/diazepam/phenytoin. Severe pre-eclampsia or eclampsia

management only during postpartum.

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STUDY Randomized Primary Magnesium Placebo Diazepam Phenytoin RR P

Postpartum (N) Outcome sulfate N-% N(%) N(%) N(%)
Magpie 1335 Eclampsia 4(0.62) 8(1.1) --- ---- 0.69(0.31-1.5) 0.39
5
M=639;P=696
Col 272 Seizure 14(10.9) --- 43(29.9) --- 0.46(0.29-0.7) 0.001
Trial9 M=128;D=144 Recurrence
Col 147 Seizure 5(6.3) --- --- 10(14.7) 0.59(0.29-1.2) 0.10
Trial9 M=79;Ph=68 Recurrence

M = Magnesium sulfate; P = Placebo; D = Diazepam; Ph = Phenytoin