Introduction
Preeclampsia is a multisystem disorder affecting mother and fetus that
complicates 2-8% of pregnancies and causes 10-15% of direct maternal
mortality worldwide.1,2 Eclampsia is diagnosed when a
woman with preeclampsia experiences generalized convulsions and further
increases the risk for maternal and neonatal
mortality.3 In 72-86% of cases eclampsia occurs
antepartum or intrapartum, but can occur at any time, including
postpartum.3 In order to decrease the risk of
eclampsia, magnesium sulfate is administered to women with pre-eclampsia
with severe features through continuous intravenous (IV) infusion or
intramuscular (IM) injections intrapartum, and may be continued
postpartum. The American College of Obstetricians and Gynecologists
(ACOG) has recommended that magnesium continue for 24 hours postpartum
for women with preeclampsia with severe features.4Notably, magnesium infusion has been shown to have multiple side effects
including maternal flushing, and sedation. Occasionally more severe side
effects are noted in the case of magnesium toxicity, for example 1.3%
of women receiving magnesium infusion can experience maternal
respiratory depression.5,6 Given these side effects
and risks as well as the lower rate of eclampsia in the postpartum
period (14% of all episodes of eclampsia3,6)
consideration has been given to early discontinuation of magnesium
during the postpartum period in several randomized controlled trials
(RCTs).
Our objective was to investigate the effect that early magnesium
discontinuation has on the rates of postpartum eclampsia when compared
to the standard 24-hour regimen by performing a systematic review and
meta-analysis. Our secondary objective was to assess postpartum
patient-care parameters for each group by examining time to ambulation,
time to initiation of breastfeeding, and length of maternal stay.
Methods The systematic review and meta-analysis was reported following the
Preferred Reporting Item for Systematic Reviews and Meta-analyses
(PRISMA) statement standards.7 The research protocol
was designed a priori , defining methods for searching the
literature, assessing studies for inclusion, and extracting and
analyzing data. The research protocol was registered with the PROSPERO
International Prospective Register of Systematic Reviews
(CRD42019127167). Searches were performed in MEDLINE, OVID, Scopus,
World Health Organization (WHO) International Clinical Trials Registry
Platform (ICTRP), ClinicalTrials.gov and the Cochrane Central Register
of Controlled Trials with the use of a combination of keywords and text
words related to “magnesium,” “magnesium sulfate,” and
“preeclampsia” from inception of each database until March 2019
(Appendix S1 contains search strategy). To locate additional
publications, we reviewed bibliographies of identified studies and
review articles. No restrictions for language or geographic location
were applied.
Study Selection We included all RCTs studying women with preeclampsia and receiving
magnesium prior to delivery that were subsequently randomized to a
shorter duration (<24 hours) of magnesium administration
postpartum or to the standard 24-hour duration. Notably, the
intervention group (shorter duration) included studies where no
magnesium was administered postpartum as well as when magnesium was
continued for less than 24 hours. In the control group for all included
studies, the women received the standard 24-hour regimen administration
postpartum. Exclusion criteria were studies involving medications other
than magnesium for seizure prophylaxis, preeclampsia diagnosed in the
postpartum period, studies examining only women with eclampsia and
studies where the control group received less than 24 hours of
magnesium.Assessment of included trial
quality Trial registration number, ethics approval and trial protocolFor each included trial, registration numbers were obtained from
searching the WHO ICTRP and Clinicaltrials.gov by two authors (JQN and
AdR) and timing of trial registration was recorded (prospectively or
retrospectively). If no trial registration number could be found,
trialists were contacted to confirm registration. All included studies
were asked for a statement confirming ethics approval and a trial
protocol. If trials were registered retrospectively, trialists were
contacted to confirm ethics approval and a pre-specified trial protocol
before start of recruitment and were asked to explain reasons for
retrospective trial registration. If no response, at least two more
attempts were made to contact trialists.
Review statistical methods of included studiesThe statistical methods described and used in each included trials were
reviewed by two authors (JQN, AdR). The following issues were assessed:
1) consistency between the (pre)specified statistical methods in the
trial protocol (or pre-specified data analysis plan) (if available) and
the statistical methods used in the published manuscript, 2) a clear and
detailed description of the statistical methods used (making trial
results reproducible) (if available), 3) consistency between the
specified method and what is presented in the results section (including
tables and figures), 4) use of the appropriate statistical methods given
the data type (e.g. possible errors that could be identified: use of a
paired sample t-test, to determine whether the mean difference between
two sets of observations is zero in two independent treatment arms).
Judgments were categorized as “yes”, “no” or “unclear
risk”.
Trialists of included studies were contacted in case of any lack of
clarity regarding trial methods or results, inconsistency in rates of
reported outcome events, or results that contained number patterns
unlikely to be randomly resulted, or improper interim analyses. If no
response, at least two more attempts were made to contact trialists.Risk of biasThe risk of bias in each included trial was assessed by two authors (JQN
and AdR) using the criteria outlined in the Cochrane Handbook for
Systematic Reviews of Interventions.8 Seven domains
related to risk of bias were assessed in each included trial since there
is evidence that these issues are associated with biased estimates of
treatment effect: 1) random sequence generation; 2) allocation
concealment; 3) blinding of participants and personnel; 4) blinding of
outcome assessment; 5) incomplete outcome data; 6) selective reporting;
and 7) other bias. Review authors’ judgments were categorized as “low
risk”, “high risk” or “unclear risk” of bias.
Outcomes The primary outcome was the rate of postpartum eclampsia, occurring up
until six weeks postpartum, with time frame as reported by study.
Secondary maternal postpartum outcomes were maternal respiratory
depression, severe hypertension, maternal death, need to extend
magnesium therapy, amount of magnesium sulfate (grams) received, time to
ambulation (hours), time to initiation of breastfeeding (hours),
duration of urinary catheter (hours), postpartum medications for
hypertension, antihypertensive therapy at discharge, postpartum hospital
stay (days) by mode of delivery, and maternal satisfaction.
We planned subgroup analyses for the primary outcome for studies
allocating women to no postpartum magnesium, as well as 6 and 12 hours
of postpartum magnesium. Additionally, we planned a sensitivity analysis
for preeclampsia without severe features (identified as mild
preeclampsia in some studies) and preeclampsia with severe features.
Furthermore, we planned a sensitivity analysis for studies judged to be
at low risk of bias based off Cochrane handbook
assessment.Statistical analysis Data abstraction was completed by two independent investigators (JQN
and AdR). Each investigator independently abstracted data from each
study and analyzed data separately using Review Manager 5.3 (The Nordic
Cochrane Centre, Cochrane Collaboration, 2014, Copenhagen, Denmark). The
completed analyses were then compared, and any difference was resolved
with review of the entire data and independent analysis. Additional
discrepancies were settled by discussion with a third author (VB).
Data from each eligible study were extracted without modification of
original data. A 2 by 2 table was assessed for the relative risk (RR);
for continuous outcomes means and standard deviations were extracted and
imported into Review Manager v. 5.3 (The Nordic Cochrane Centre,
Cochrane Collaboration, 2014, Copenhagen, Denmark).
Meta-analysis was performed using the random effects model of
DerSimonian and Laird, to produce summary treatment effects in terms of
RR or mean difference (MD) with a 95% confidence interval (CI).
Heterogeneity was measured using I-squared (Higgins
I2). Potential publication biases were assessed
statistically by using Begg’s and Egger’s tests when more than 10
publications with the primary outcome were available on the topic. A p
value <0.05 was considered statistically significant.
Results Eight trials met the inclusion criteria for this meta-analysis with a
total of 2,183 participants (1,088 in early magnesium group versus 1,095
in 24-hour regimen) (Table 1).9-16 Figure 1 shows the
flow diagram (PRISMA template) of records reviewed. Table S1 has
characteristics of excluded studies. Table S2 reports on trial
registration number, trial protocol, and ethical approval. Five of the
trials were registered; only one trial underwent trial registration in a
prospective fashion.16 Contact was made with seven
trials and the authors of four of the included trials provided
additional study information on request.12, 13,15,16 A
review of the statistical methods used by the included studies did not
reveal any discrepancies (Table S3). Three studies had an overall low
risk of bias for all key domains as assessed by the Cochrane
Collaboration’s tool (Figure 2).13,15,16 Four studies
had unclear or high risk of bias in allocation concealment and selective
reporting.9,11,12,14 None of the studies were
double-blinded, thus all were judged to be at high risk of performance
bias as assessed by the Cochrane Collaboration’s tool. Publication bias
was not assessed as less than 10 publications with the primary outcome
were included.
Seven trials9,11-15 included only women with
preeclampsia with severe features, and two trials of 1,397 patients
included in this meta-analysis used the definition of preeclampsia with
severe features by ACOG criteria.14,15 There were five
different time frames for early magnesium discontinuation (Table 1): 1).
Loading dose of magnesium only, one trial,14 2). No
magnesium given postpartum, one trial,16 3). Magnesium
administration until diuresis, one trial,11 4). Six
hours of postpartum magnesium, two studies,9,15 5).
Twelve hour postpartum regimen of magnesium, three
studies.10,12,13 Table S4 details inclusion/exclusion
criteria and magnesium dosing used in each study and Table S5 details
maternal characteristics at randomization.
Average maternal age at time of randomization was 25.8 versus 26.3
years. The majority of women were nulliparous; twin pregnancies (when
reported) constituted a small proportion of studied women (0.7 – 3.6%,
3 studies) (Table S5).13,15,16 Only two
studies12,16 reported on the use of antihypertensive
medication antepartum (187/637 (29.4%) versus 197/646 (30.5%), 2
studies) or during labor (24/154 (15.6%) versus 31/166 (18.7%), 2
studies).9,12 The mean gestational age (GA) at
delivery was 36.3 versus 36.5 weeks (Table 2) with a large percentage of
women were delivered via cesarean delivery (571/1011 (56.5%) versus
562/1,002 (56.9%), 8 studies).9-16 Eclampsia rates were no different between the two groups (5/1,088
(0.5%), versus 2/1,095 (0.2%); RR 2.3, 95% CI 0.5-9.9,
I2=0%, 8 studies, 2,183 participants) (Table
3).9-16 The details of the seven women with eclampsia
are presented in Table 4. One women was being treated with magnesium
when she experienced eclampsia; three were not being treated with
magnesium at the time of her eclampsia. For all other women the details
were not reported and were unavailable when additional data was sought
from the authors. Further detail on women with eclampsia including the
number of episodes, the pre-existing symptoms and the amount of
magnesium received prior to eclampsia were not reported.
Regarding secondary outcomes (Tables 3 and 5), there was a significant
decrease in time to ambulation in the early discontinuation group (MD
-9.1 hours, 95% CI -14.7-(-3.6), I2=98%, 3 studies,
1,509 participants)13,15,16 and in time to initiation
of breastfeeding (MD -8.4 hours, 95% CI -12.0-(-4.8),
I2=60%, 2 studies, 1,397
participants).15,16 Only one study reported on the
duration of the urinary catheter, and demonstrated a shorter duration in
the early discontinuation group.13 Magnesium therapy
was extended past planned duration more commonly in the early magnesium
discontinuation group, (15/961 (1.6%) versus 3/954 (0.3%), RR 3.7,
95% CI 1.2-11.5, I2=0%, 7 studies, 2,006
participants).9,10,12-16 Length of stay in the
hospital, reported in three studies, was only available for combined
modes of delivery, and was not different between groups (Table
5).10,11,14 A total of four studies reported on severe
consequences of magnesium toxicity such as respiratory or cardiac
arrest, and death and no differences were seen between study
groups.13-16 The more commonly reported maternal
adverse effects such as flushing, nausea, vomiting, and headaches, were
also not reported by any of the included trials.
Robust data was not available for antihypertensive therapy during
hospitalization postpartum (1 study, 300/558 (53.7%) versus 283/555
(51.0%))16 or at discharge (1 study, 30/48 (63%)
versus 23/50 (46%)).11 Only one study with 112 women
reported on maternal satisfaction and noted a higher satisfaction with
early discontinuation of magnesium, but this finding was not
statistically significant.13 Subgroup analyses and
sensitivity analyses, which were conducted for the primary outcome, did
not reveal any increased risk of eclampsia, including discontinuing
magnesium immediately postpartum or at 6 or 12 hours (Figure S1).
Discussion This meta-analysis demonstrates that early discontinuation of magnesium
postpartum does not significantly increase the rates of eclampsia when
compared to a 24-hour regimen. Though only reported by three trials, in
the early discontinuation group there is a significant improvement in
postpartum quality indicators such as decrease in time to ambulation,
time to initiation of breastfeeding, as well as duration of urinary
catheter. The rate of cesarean delivery was high in included studies,
likely related to geographic variation. Subgroup analyses, conducted for
the primary outcome, did not reveal any increased risk of eclampsia in
any subgroups including discontinuing magnesium immediately postpartum
or at six or 12 hours.
While not significant, there was a higher incidence of eclampsia in the
early discontinuation group (5/1,088 (0.5%) early discontinuation, vs
2/1,095 (0.2%) 24-hour group). When using this rate (absolute risk
reduction of -0.0027) to calculate a number needed to treat (NNT), 370
women would need to receive the standard 24-hr regimen to prevent one
episode of eclampsia. This is similar to the notable NNT is the rate of
1/400 in preeclampsia without severe features for which magnesium is not
routinely recommended.19 Table 6 provides additional
scenarios where clinicians could consider early discontinuation of
magnesium as well as patients who would benefit from continuation for
the standard 24-hour regimen. Notably, as neurologic symptoms have the
highest correlation with risk of eclampsia with a NNT of
1/36,19 providers may want to consider the standard
24-hour regimen in women with such symptoms.
The strengths of this meta-analysis are that it follows the PRISMA
guidelines and includes studies without restriction to publication date
or language. This study examined not only the risk of bias but also
closely examined trial methodology, such as trial registration timing,
confirmation of ethics approval, and a review of statistical methods.
This provides the reader additional information to assess methodological
quality, and evaluate data integrity and transparency. All included
studies reported on the primary outcome, the risk of eclampsia.
This meta-analysis is not without limitations; many of which are
inherent to those limitations of any meta-analysis as well as the
included trials. For example the included trials use five different time
frames to administer magnesium postpartum (loading dose only, no
postpartum magnesium, six hours, 12 hours, or until diuresis took
place). With such heterogeneity in study design, the results may be
interpreted with caution, as the optimal timing of postpartum magnesium
administration has not been established by this meta-analysis.
Additionally, a large proportion of these women come from two large
trials located in Latin America and thus the external validity of these
data may be questioned. Lastly, the lack of difference between groups
may be secondary to a lack of power. If the eclampsia rates of 0.5% in
the early discontinuation group vs 0.2% in the 24-hour group were used
to perform a sample size calculation with power of 0.8 and alpha of
0.05, then a total of 12,164 women would need to be randomized, with
6,082 in each group. Until a larger trial is performed, this
meta-analysis remains the most comprehensive review of the literature.
Our results reflect the results of each of
the included individual studies, that the rate of eclampsia is not
significantly different when magnesium is discontinued early. The
Cochrane Review by Duley et al published in 2010 examined alternative
regimens for women with preeclampsia as well as
eclampsia.6 They included a total of four studies, two
of the studies included in this review, and concluded that there were
too few published data to make any reliable conclusions regarding
duration of treatment postpartum.10,11 We have
expanded upon the Cochrane Review by including a total of eight
randomized controlled studies. Eclampsia rates remain low, with a total
of seven eclamptic events, which is a total rate of 0.3%. Given this
low rate of eclampsia, it is clear that the administration of magnesium
remains clinically effective and the standard of care for treatment of
preeclampsia with severe features.6,17 This study
expands on the information available in the Cochrane review by including
the secondary postpartum outcomes, including time to ambulation, time to
breastfeeding, duration of urinary catheter placement, and length of
time in the hospital. This review shows that all of these findings were
significantly improved by the shorter magnesium regimen. These quality
measures call into question the recommendation to continue magnesium for
24 hours postpartum.18