Abbreviated (12-hour) versus traditional (24-hour) postpartum magnesium
sulfate therapy in severe pre-eclampsia

Sabina B. Maia, Leila Katz, Carlos Noronha Neto, Bárbara V.R. Ca-
iado, Ana P.R.L. Azevedo, Melania M.R. Amorim

PII: S0020-7292(14)00234-3
DOI: doi: 10.1016/j.ijgo.2014.03.024
Reference: IJG 7968

To appear in: International Journal of Gynecology and Obstetrics

Received date: 7 September 2013

Revised date: 11 March 2014
Accepted date: 30 April 2014

Please cite this article as: Maia Sabina B., Katz Leila, Neto Carlos Noronha, Caiado
Bárbara V.R., Azevedo Ana P.R.L., Amorim Melania M.R., Abbreviated (12-hour) ver-
sus traditional (24-hour) postpartum magnesium sulfate therapy in severe pre-eclampsia,
International Journal of Gynecology and Obstetrics (2014), doi: 10.1016/j.ijgo.2014.03.024

This is a PDF file of an unedited manuscript that has been accepted for publication.
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 ACCEPTED MANUSCRIPT

CLINICAL ARTICLE

Abbreviated (12-hour) versus traditional (24-hour) postpartum magnesium

sulfate therapy in severe pre-eclampsia

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Sabina B. Maia a, Leila Katz a, Carlos Noronha Neto a, Bárbara V.R. Caiado b, Ana

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P.R.L. Azevedo a, Melania M.R. Amorim a,*

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a
Instituto de Medicina Integral Professor Fernando Figueira, Recife, Brazil

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b
Faculdade Pernambucana de Saúde, Recife, Brazil
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* Corresponding author: Melania Maria Ramos de Amorim
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Rua Neuza Borborema de Souza, 300, Bairro Santo Antônio, 58406-120, Campina

Grande, PB, Brazil. Tel.: +55 8388221514; fax: +55 8333424525.

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E-mail address: melania.amorim@gmail.com

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Keywords: Magnesium sulfate therapy; Postpartum; Pre-eclampsia

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Synopsis: Abbreviated (12-hour) treatment with magnesium sulfate in patients with

stable severe pre-eclampsia was associated with less drug exposure, similar

outcomes, and certain benefits.

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ABSTRACT

Objective: To compare the use of magnesium sulfate for 12 hours versus 24 hours in

postpartum women with stable severe pre-eclampsia.

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Methods: In 2011, an open randomized clinical trial was conducted with 120

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postpartum women with severe pre-eclampsia who gave birth at a tertiary hospital in

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Brazil; 60 women received magnesium sulfate for 24 hours and 60 for 12 hours. The

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analysis was by intention-to-treat and the intervention was not masked.

Results: Abbreviated (12-hour) magnesium sulfate therapy was associated with less

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exposure to the drug, and clinical outcomes were similar in both groups. No woman
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developed eclampsia and there was no need to re-initiate treatment after completing

the scheduled magnesium sulfate therapy in either group. Magnesium sulfate

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therapy was extended in only three women in the 12-hour group. In addition, in this

group, significant reductions were found in the duration of postpartum use of an

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indwelling bladder catheter, the time to ambulation, and the time to maternal contact

with the newborn.

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Conclusion: Abbreviated postpartum magnesium sulfate therapy in patients with

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stable severe pre-eclampsia was associated with less drug exposure, similar

outcomes, and benefits such as a reduction in the time to contact with the newborn.

Clinical trials registration: clinicaltrials.gov NCT1408979

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1. Introduction

Pre-eclampsia occurs in 8% of pregnancies [1–3]. An important complication is

eclampsia, which may occur prior to, during, or following delivery and is associated

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with an increased risk of maternal death [4–8].

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Eclampsia can be prevented with magnesium sulfate, which decreases the risk of

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seizures by 50%, paralleled by a reduction in maternal mortality [6,9]. Although

magnesium sulfate administration is recommended for all women with severe pre-

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eclampsia [1,9–11], consensus has yet to be reached on the ideal duration of
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prophylactic postpartum anticonvulsant therapy [9,12].
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Traditionally, the use of magnesium sulfate has been recommended for 24 hours

following delivery, the period of greatest risk for the occurrence of eclampsia [1,13].
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Nonrandomized studies have used clinical criteria for stopping magnesium sulfate

earlier in some women with pre-eclampsia [14,15]. By reducing the duration of

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therapy, the frequency of monitoring maternal blood pressure and urinary output may
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be curtailed and the possibility for the woman to ambulate and care for her newborn

may be increased. However, a systematic review [16] found that some women who

received a short-duration magnesium treatment regimen required a prolongation or

re-institution of therapy, although this finding was not statistically significant.

In economically developing nations, the use of magnesium sulfate is also effective

[1]. However, unnecessarily prolonged use of magnesium seizure prophylaxis in

resource-constrained regions might delay a mother’s return to normality and thus

preclude such recommended practices as kangaroo care [17].

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The present study was undertaken to compare the use of intravenous magnesium

sulfate for 12 hours versus 24 hours postpartum on the process of care for women

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with stable severe pre-eclampsia.

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2. Materials and methods

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The present study was an open-label, randomized clinical trial of 12 hours versus 24

hours of intravenous magnesium sulfate administered immediately postpartum to

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women with stable severe pre-eclampsia. The study was conducted at the Instituto
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de Medicina Integral Professor Fernando Figueira in Recife, Pernambuco,

northeastern Brazil, between July 1 and October 31, 2011, and approved by the
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internal Institutional Review Board.

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Severe pre-eclampsia was defined as a systolic blood pressure of 160 mm Hg or

more and/or a diastolic blood pressure of 110 mm Hg or more, persisting at rest in

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the left lateral decubitus position for 30 minutes or more, as well as the presence of
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at least 2 g of urinary protein over 24 hours or a urinary dipstick value of 3+ [18].

Pre-eclampsia was deemed to be “stable” in the absence of visual signs or

symptoms (scotomata or blurred vision), frontal and/or occipital headache,

hyperreflexia, and either epigastric or right hypochondrium pain.

Women with eclampsia were excluded from the study, as were those with evident

hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome [11],

pre-existing diabetes mellitus, epilepsy, renal disease, a contraindication to the use

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of magnesium sulfate such as known hypersensitivity to the drug, or anuric or

oliguric urinary output under 25 mL/hour.

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All women were already receiving magnesium sulfate before and during delivery

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(loading dose 6 g; maintenance dose 1 g/hour). Postpartum, all participants received

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a 12-hour infusion of magnesium sulfate at 1 g/hour. Approximately 6–8 hours after

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delivery, eligible women were invited to participate in the trial. Those who provided

written informed consent were enrolled and assigned a randomization number.

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The participants were randomized 1:1 to receive an ongoing (24-hour) or

abbreviated (12-hour) magnesium sulfate infusion at 1 g/hour. Randomization was

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achieved using a sequential list of random numbers ranging from 1 to 120,

generated by Random Allocation Software version 1.0 (M. Saghaei, Isfahan

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University of Medical Sciences, Isfahan, Iran). The group allocation was concealed in

opaque, sequentially numbered envelopes, which remained sealed until

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randomization.
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At 12 hours, after completion of the initial period of intravenous magnesium sulfate

infusion, each woman’s study envelope was opened. If she was assigned to 24

hours of treatment, her infusion was continued at 1 g/hour for another 12 hours. If

she was assigned to 12 hours of treatment, her infusion was stopped.

As a safety measure, in the rare situation where a woman was assigned to the

abbreviated magnesium protocol and she had very high blood pressure (systolic

blood pressure of 180 mm Hg or more and/or a diastolic blood pressure of 120 mm

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Hg or more), her urine output was under 25 mL/hour, and/or she had signs of

imminent eclampsia, she was maintained on magnesium sulfate for the duration

deemed necessary by her attending physician. These women were described as

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“need to continue magnesium sulfate treatment after 12 hours” and were considered

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to belong to the abbreviated treatment group. In the 24-hour treatment group, the

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attending physician was also permitted to extend magnesium therapy if he/she

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deemed this to be necessary.

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Clinical and laboratory measures were assessed in both groups until at least 24
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hours following delivery.
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The women were evaluated every 2 hours for heart rate, respiratory rate, blood

pressure, and urine output. Deep tendon reflexes were evaluated every 6 hours and
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laboratory tests to screen for the HELLP syndrome were evaluated every 24 hours.
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At approximately 24 hours after delivery, each woman’s satisfaction with her care
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was evaluated on a scale of 1–5 (1 = very satisfied, 2 = satisfied, 3 = not very

satisfied, 4 = dissatisfied, and 5 = very dissatisfied) [19].

The primary study outcome was the duration of anticonvulsant therapy postpartum.

Secondary outcomes included patient satisfaction at 24 hours after delivery, clinical

measures such as blood pressure, time to return to ambulation (in hours), duration of

indwelling urinary catheter use (in hours), and time until contact with the newborn

infant (in hours). Additional outcomes included eclampsia, oliguria (urine output <25

mL/hour), postpartum hemorrhage, urinary tract infection, thromboembolic

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complications, liver failure, kidney failure, disseminated intravascular coagulation,

cerebrovascular accident, acute pulmonary edema, discontinuation of magnesium

treatment because of adverse effects (heat, flushing, hypersensitivity reaction,

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nausea, or vomiting), and the presence of any associated complication occurring

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prior to the woman’s discharge from hospital.

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The analysis was by intention to treat. The t test and the Mann–Whitney U test were

used for the comparison of continuous variables as appropriate, and the χ2 and

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Fisher exact tests were used for the comparison of categorical variables. All P values
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were two-tailed; P<0.05 was considered statistically significant.
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To compare the total durations of magnesium sulfate use and postpartum urinary

catheter use and the total times between delivery and the beginning of
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ambulation/the mother’s contact with her newborn infant, risk ratios (RR) and their

95% confidence intervals (CI) were calculated as measures of relative risk. The
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numbers needed to treat (NNT) to obtain a benefit were also calculated using the
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Evidence-Based Calculator (http://moosenose.com/EBCalculator.htm).

The analysis was conducted using Epi Info version 7 (Centers for Disease Control

and Prevention, Atlanta, GA, USA). The sample size was calculated using OpenEpi

version 2.3 (www.openepi.com). Based on previous data [15], it was assumed that

the mean duration of magnesium sulfate treatment in the abbreviated group would

be 18 ± 9 hours, whereas women in the 24-hour treatment group would receive

therapy for 24 ± 6 hours. To detect this 6-hour difference in the duration of treatment

with a statistical power of 80% and a two-sided P value 0.05, 50 women were
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needed per group. Considering possible drop-outs, the sample size was increased

by 20%, resulting in a total of 60 women per group.

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3. Results

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During the study period, 140 of 157 women with severe pre-eclampsia were

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approached, but 20 women were excluded (Figure 1). Of the remaining 120 women

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who fulfilled the eligibility criteria, 60 were randomized to receive magnesium sulfate

for 12 hours and 60 to receive magnesium sulfate for 24 hours. During the first 12

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hours of magnesium sulfate treatment, four women in each group were excluded.
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Therefore, data for 56 women were analyzed in each group.
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With respect to the baseline characteristics of the women, no significant differences

were found between the groups (Table 1). Most clinical and laboratory parameters at
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admission were similar, with no differences in the severity of the disease. However,

the median platelet count was lower in the 12-hour group than in the 24-hour group
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(178 500/mm3 vs 219 500/mm3; P=0.01).

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During the first 12 hours, no statistically significant differences were found between

the groups with respect to blood pressure or urine output (Table 2). However, there

was a difference in the mean urine output during the period of 12–24 hours following

treatment initiation (12-hour group, 128.3 mL/hour; 24-hour group, 159.8 mL/hour;

P=0.008).

There was no difference between the two groups in the number of women with

episodes of very high blood pressure (Table 2). Magnesium sulfate therapy was
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extended in three women in the 12-hour group; in the 24-hour group, there was no

need to prolong the duration of therapy.

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None of the women had to interrupt anticonvulsant therapy because of adverse

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effects of the drug or to re-initiate magnesium sulfate treatment following suspension

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of the drug. There were no occurrences of eclampsia, acute pulmonary edema,

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thromboembolic complications, kidney failure, liver failure, disseminated

intravascular coagulation, cerebrovascular accident, or maternal death. One woman

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had oliguria and one woman had a urinary tract infection in the 12-hour group, and
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one woman in the 12-hour group and two women in the 24-hour group had

postpartum hemorrhage. Even when the presence of any complication was used as
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an outcome measure, no difference was found between the groups. The degree of

satisfaction was also similar (Table 2).

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The duration of anticonvulsant therapy was significantly shorter in the 12-hour group
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(12.5 hours vs 24.0 hours; P<0.001) (Table 3), resulting in a reduction of the total
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dose of magnesium sulfate. The total time of indwelling urinary catheter use was

also significantly shorter in the 12-hour group (14.3 hours vs 25.3 hours; P<0.001).

Overall, 98.2% of the women in the 24-hour group used an indwelling urinary

catheter for more than 12 hours compared with 62.5% of the women in the 12-hour

group, reflecting a significant reduction in its use (RR, 0.63; 95% CI, 0.51–0.78;

NNT=3). Similar results were obtained for the time from delivery to ambulation (18.8

hours vs 25.8 hours in the 12-hour and 24-hour groups, respectively; P<0.001)

(Table 3).
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A reduction in the time between delivery and contact with the newborn infant was

found (29.6 vs 35.0 hours in the 12-hour and 24-hour groups; P=0.03). In the

abbreviated treatment group, there was a 38% reduction in the risk of late (after 24

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hours of delivery) contact with the neonate (NNT=3) (Table 3).

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4. Discussion

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In women with stable severe pre-eclampsia, a shorter duration of magnesium sulfate

therapy was associated with less exposure to the drug, both in terms of treatment

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duration and in terms of total dose, and the clinical outcomes were similar to those
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among women who had received the traditionally recommended 24-hour regimen of

magnesium sulfate therapy.

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The shorter regimen was found to be safe for this particular group of women,
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although the study did not have sufficient power to evaluate the frequency of

eclampsia. However, in a systematic review on magnesium sulfate for the prevention

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of eclampsia available in the Cochrane Library [9], convulsions occurred in only

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1.45% of women with pre-eclampsia receiving magnesium sulfate; therefore, to

determine any difference in the frequency of eclampsia with the shorter regimen, a

sample of approximately 18 000 women would have been required. Perhaps a future

meta-analysis of randomized clinical trials will have sufficient power to determine

whether there is any difference in the incidence of eclampsia.

Previous nonrandomized studies [14,15] used clinical parameters (for example

absence of symptoms of the imminence of eclampsia, re-establishment of diuresis)

as criteria for interrupting magnesium sulfate use in postpartum women with pre-
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eclampsia, with the result that a significant reduction in the duration of treatment was

achieved.

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In a randomized clinical trial [20] comparing an abbreviated 6-hour magnesium

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sulfate regimen versus 24-hour treatment in postpartum women with pre-eclampsia

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considered to be at a low risk for eclampsia, only one woman in the 6-hour

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magnesium sulfate group needed to reinitiate therapy because of worsening

hypertension nine hours following delivery.

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In another study [21] comparing 12-hour versus 24-hour magnesium sulfate therapy

in postpartum women with mild pre-eclampsia, clinical conditions such as chronic

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hypertension and type I diabetes were also found to be factors that would increase

the risk of aggravating the condition, requiring postpartum anticonvulsant therapy to

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be extended.
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Another randomized clinical trial [22] that used the evaluation of urine output as the
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criterion for interrupting magnesium sulfate therapy in postpartum women with

severe pre-eclampsia reported results similar to those found in the present study, in

particular a reduction in the duration of treatment.

The mean urine output during the period of 12–24 hours after delivery was

approximately 30 mL/hour higher when magnesium sulfate therapy was used for 24

hours compared with the shorter treatment duration. The higher level of diuresis

found in the 24-hour group may be attributable to the longer duration of treatment

and the volume of fluid administered together with the anticonvulsant.

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A significant reduction was found in the duration of postpartum indwelling urinary

catheter use, which may account for the reduction in the risk of urinary tract infection

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[23] and the decrease in postpartum discomfort reported by the women; these

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outcomes remain to be evaluated in future studies.

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A reduction was found in the time to ambulation with the shorter regimen of

postpartum magnesium sulfate. Early ambulation is important for the prophylaxis of

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deep vein thrombosis [24]. The shorter, 12-hour magnesium sulfate therapy enables
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women to benefit from this prophylactic practice.
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Another benefit associated with shorter magnesium sulfate therapy was the

possibility of earlier contact with the newborn, improving the likelihood of establishing
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breastfeeding. It is common practice during magnesium sulfate administration for the

woman to remain in an intermediate or intensive care unit, which may contribute

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toward keeping the mother apart from her infant, with all resulting disadvantages. In
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the present study, a significant reduction was found in the time from delivery until

contact with the newborn in the 12-hour group. We believe that this difference would

have been greater if these women had been discharged from the intensive care unit

to a rooming-in environment immediately after discontinuation of the anticonvulsant

medication. However, because the abbreviated therapy protocol represented a

change from the routine management protocol at the study institution, the

participants were kept in intensive care for safety and ethical reasons, to guarantee

more rigorous surveillance for at least 24 hours. In a systematic review [16],

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postpartum hospital stay was not evaluated because the data (obtained from only

three clinical trials) were heterogeneous.

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As a future perspective, shorter magnesium sulfate therapy may permit the mother to

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be released earlier from intensive care, freeing up hospital beds. The available beds

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would benefit other postpartum women with more severe clinical conditions, and

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there would also be a reduction in the total time of postpartum hospitalization.

Although further studies are indispensable before this practice can be incorporated,

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there is evidence of real benefits, both for the users and for the public healthcare
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system, which would translate into savings on the costs of improvements in tertiary

care.
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It should be emphasized that postpartum women with other more severe

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hypertensive syndromes (exacerbation of chronic hypertension, HELLP syndrome,

eclampsia) and those with associated clinical conditions were excluded from the
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present study, and the available evidence in relation to the shorter regimen of
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magnesium sulfate therapy in these woman is incipient and sparse. Therefore, we do

not recommend early discontinuation of postpartum anticonvulsant therapy in this

group of women. Moreover, well-designed studies should be conducted with larger

sample sizes to avoid hasty conclusions based on a single study.

In conclusion, in ideal conditions (when the surveillance of postpartum women can

be guaranteed), women with stable severe pre-eclampsia can be re-evaluated

clinically and through laboratory tests after 12 hours of postpartum magnesium

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sulfate use and the magnesium sulfate infusion can be stopped, allowing other

possible benefits derived from this practice.

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Conflict of interest

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The authors have no conflicts of interest.

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Figure 1 Selection and follow-up of participants (CONSORT flow chart).

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Table 1 Baseline characteristics among women with stable severe pre-eclampsia who received
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magnesium sulfate for 12 versus 24 hours after delivery.
Characteristic 12 hours 24 hours P value
(n=56) (n=56)
Age, y 24.7 ± 6.3 26.3 ± 7.6 0.26
Number of pregnancies 2.1 (1–3) 2.0 (1–2) 0.57
Parity 1.8 (1–2.5) 1.8 (1–2) 0.73

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Gestational age at delivery, wk 36.8 ± 3.0 37.2 ± 4.9 0.14

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Route of delivery

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Cesarean delivery 36 (64.3) 33 (58.9) 0.28
Clinical parameters at inclusion in the study
SBP, mm Hg 142.4 ± 16.4 142.1 ± 15.1 0.91

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DBP, mm Hg 92.4 ± 11.9 95.4 ± 10.8 0.17
Heart rate, bpm 88.1 (80–94) 86.1 (80–92) 0.38
Respiratory rate, breaths/min 19.0 (18–20) 18.8 (18–20) 0.60

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Urine output, mL/h 117.2 ± 77.6 112.5 ± 79.6 0.76
Laboratory parameters at diagnosis
Hematocrit, % 34.9 ± 15.1 35.3 ± 13.6 0.53
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3 178 500 (158 000– 219 500 (176 000–
Platelets, mm 0.01
228 500) 268 000)
Creatinine, mg/dL 0.6 ± 0.1 0.6 ± 0.1 0.63
Uric acid, mg/dL 5.2 ± 1.4 5.8 ± 1.6 0.26
LDH, U/l 280.0 ± 110.7 278.1 ± 97.6 0.92
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AST, U/l 24.0 ± 16.5 25.2 ± 16.5 0.99

Total bilirubin, mg/dL 0.5 ± 0.4 0.4 ± 0.2 0.13
Abbreviations: AST, aspartate aminotransferase; DBP, diastolic blood pressure; LDH, lactate
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dehydrogenase; SBP, systolic blood pressure.

a
Values are given as mean ± SD, median (interquartile range), or number (percentage).
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Table 2 Outcomes of magnesium sulfate use for 12 versus 24 hours: need to prolong treatment,
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clinical parameters, complications, and treatment satisfaction.
Outcome measure 12 hours 24 hours P value
(n=56) (n=56)
b
Need to prolong treatment 3 (5.4) 0 (0.0) 0.50
Blood pressure and urinary
output at 0–12 hours

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Highest SBP, mm Hg 151.3 ± 15.8 152.3 ± 16.6 0.75

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Highest DBP, mm Hg 102.2 ± 11.3 100.7 ± 12.5 0.51
Urinary output, mL/h 107.0 ± 46.7 119.7 ± 76.5 0.29

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Blood pressure and urinary
output at 12–24 hours

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Highest SBP, mm Hg 148.8 ± 15.7 151.5 ± 16.4 0.38

Highest DBP, mm Hg 98.6 ± 11.4 100.3 ± 10.4 0.40

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Urinary output, mL/h 128.3 ± 50.9 159.8 ± 61.6 0.008
Presence of very high blood 12 (21.4) 12 (21.4) >0.99
pressure episodes (0–24
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hours)
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d
Complications
b
Urinary tract infection 1 (1.8) 0 (0.0) 0.50
b
Oliguria 1 (1.8) 0 (0.0) 0.50
b
Postpartum hemorrhage 1 (1.8) 2 (3.6) 0.50
ED

Any complication 13 (23.3) 15 (26.8) 0.66

Satisfaction
Very satisfied or satisfied 41 (73.2) 36 (64.3) 0.30
Abbreviations: CI, confidence interval; DBP, diastolic blood pressure; RR, relative risk; SBP, systolic
PT

blood pressure.
a
Values are given as mean ± SD or number (percentage).
b
Fisher exact test.
CE

c
“Very high blood pressure” defined as systolic blood pressure of 180 mm Hg or more and/or a
diastolic blood pressure of 120 mm Hg or more.
d
Participants may have had more than one complication.
AC
 ACCEPTED MANUSCRIPT

Table 3 Outcomes of magnesium sulfate use for 12 versus 24 hours: total duration of magnesium
a
sulfate use, duration of catheterization, time to ambulation, and time to contact with the newborn.
Outcome measure 12 hours 24 hours RR (95% P NNT
(n=56) (n=56) CI) value
Total duration of magnesium sulfate use, h 12.5 ± 2.3 24.0 ± 3.6 — <0.001 -
Total duration of postpartum use of an 14.3 ± 3.7 25.3 ± 3.5 — <0.001 -
indwelling urinary catheter, h

T
Postpartum use of an indwelling urinary 35 (62.5) 55 (98.2) 0.63 <0.001 3

P
catheter for >12 hours (0.51–
0.78)

RI
Time from delivery to beginning of 18.8 ± 4.9 25.8 ± 6.9 — <0.001 —
ambulation, h
Time from delivery to beginning of 36 (64.3) 51 (91.1) 0.57 <0.001 3

SC
ambulation >15 hours (0.42–
0.77)
Time from delivery to contact with newborn, h 29.6 ± 14.0 35.0 ± 10.6 — 0.03 —
b

NU
Time from delivery to contact with newborn 30 (55.6) 49 (89.1) 0.62 <0.001 3
b
>24 hours (0.48–
0.80)
Abbreviations: CI, confidence interval; NNT, number needed to treat; RR, relative risk.
MA
a
Values are given as mean ± SD or number (percentage).
b
Time until contact with the newborn infant was not evaluated in one woman in the 24-hour group
(stillbirth) and in two women in the 12-hour group (one stillbirth and one early neonatal death).
ED
PT
CE
AC