Original Research
Alternate Dosing Protocol for Magnesium
Sulfate in Obese Women With Preeclampsia
A Randomized Controlled Trial
Kathleen F. Brookfield, MD, PhD, Kierstyn Tuel, BA, Monica Rincon,
Downloaded from http://journals.lww.com/greenjournal by cobo4WCp0FtOBEI+5j/0yyKguSoIsot9U9oXZg3In86rLm+SqKsDlztGctLKMNvRinLHJazVEu0jrWfRr+CNHPD9Uee/JS4p/6Vp60bT0LoyCZU2+7pCTe4eAfG6xOIG on 12/08/2020
Aaron B. Caughey, MD, PhD, and Brendan Carvalho, MBBCh, FRCA
OBJECTIVE: To evaluate whether obese women need
greater doses of magnesium sulfate to obtain therapeutic
serum concentrations for eclamptic seizure prevention.
METHODS: Women with preeclampsia and a body mass
index (BMI) of 35 or higher were randomly allocated to
either the Zuspan regimen of magnesium sulfate (4-g
intravenous [IV] loading dose, then a 1-g/h infusion) or to
alternate dosing (6-g IV loading dose, then a 2-g/h
infusion). Women had serum magnesium concentrations
obtained at baseline, as well as after administration of
magnesium sulfate at 1 hour, 4 hours, and delivery. The
primary outcome was the proportion of women who had
subtherapeutic serum magnesium concentrations (less
than 4.8 mg/dL) 4 hours after administration. A sample
size of 18 women per group was planned to compare the
From the Department of Obstetrics and Gynecology, Oregon Health & Science
University, Portland, Oregon; and the Department of Anesthesia, Stanford Uni-
versity School of Medicine, Stanford, California.
Supported by the National Institutes of Health Loan Repayment Program and a
Mission Support Award from Oregon Health & Science University (Dr. Brook-
field as recipient and principal investigator) and by the Oregon Clinical &
Translational Research Institute grant. The grant supported the use of REDCap
(Research Electronic Data Capture) for data abstraction (CTSA Award No.:
UL1TR002369). These funding sources were not involved in any aspects of the
research presented in this manuscript.
Presented in part at the Society for Maternal-Fetal Medicine’s 40th Annual
Pregnancy Meeting, February 3–8, 2020, Grapevine, Texas.
Each author has confirmed compliance with the journal’s requirements for
authorship.
Corresponding author: Kathleen F. Brookfield, MD, PhD, Department of
Obstetrics and Gynecology, Oregon Health & Science University, Portland,
OR; email: brookfie@ohsu.edu.
Financial Disclosure
Kathleen Brookfield reports receiving funds from the NIH Loan Repayment
Program Award and an OB/GYN Department Mission Support Award for
sample processing. She also received funds from the World Health Organization.
Aaron Caughey disclosed that he has relationships with Celmatix and Mindchild.
The other authors did not report any potential conflicts of interest.
© 2020 by the American College of Obstetricians and Gynecologists. Published
by Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0029-7844/20
1190 VOL. 136, NO. 6, DECEMBER 2020
© 2020 by the American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
MD, Abbie Vinson, MD,
proportion of women with subtherapeutic serum mag-
nesium concentrations in each group.
RESULTS: From July 12, 2016, to March 14, 2019, 89
women with preeclampsia were screened and 37 were
enrolled: 18 to the Zuspan regimen and 19 to the
alternate regimen. A significantly greater proportion of
women administered the Zuspan regimen had subther-
apeutic serum magnesium concentrations at 4 hours
(100% [95% CI 59–100] vs 63% [95% CI 41–81]; P5.01)
compared with women administered the alternate high-
er dose regimen. At 4 hours, mean concentrations were
significantly higher in the alternate regimen group (3.53
mg/dL60.3 [Zuspan regimen] vs 4.4160.5 [alternate reg-
imen]; P,.01).
CONCLUSION: The alternate dosing regimen of a 6-g IV
loading dose followed by a 2-g/h IV maintenance dose
more reliably achieves therapeutic serum magnesium
concentrations (as defined by a concentration of at least
4.8 mg/dL) in obese women with preeclampsia.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,
NCT02835339.
(Obstet Gynecol 2020;136:1190–4)
DOI: 10.1097/AOG.0000000000004137
R
etrospective studies by Pritchard and Chelsey
evaluated serum magnesium concentrations in
women receiving intramuscular magnesium sulfate
who experienced eclamptic seizures. These studies
suggested a therapeutic range for serum magnesium
of 4.8–8.4 mg/dL.1,2 This therapeutic range was also
supported by a study by Sibai et al.3
In a pharmacokinetic model, we demonstrated that,
in women who received a 4-g intravenous (IV) loading
dose followed by a 2-g/h IV maintenance dose, obese
women take took approximately twice as long as
women of mean body weight in the sample to achieve
these previously accepted therapeutic serum magnesium
concentrations.4 Therefore, the aim of the current study
OBSTETRICS & GYNECOLOGY
was to prospectively validate our pharmacokinetic
model that suggested dosing alterations are needed
based on body mass index (BMI, calculated as weight
in kilograms divided by height in meters squared).
METHODS
In this prospective, randomized controlled trial we
enrolled women who met the following criteria: aged
15–45 years with preeclampsia or at high-risk of
developing preeclampsia, BMI of 35 or higher, and
at least 32 weeks of gestation. We excluded women
with serum creatinine levels greater than 1.1 mg/dL.
The study was approved by the Oregon Health and
Science University Institutional Review Board, and
the trial was registered at ClinicalTrials.gov
(NCT02835339).
After consent, women were randomized in 1:1
allocation to one of two magnesium sulfate treatment
groups: a 4-g IV loading dose administered over
20 minutes followed by a 1-g/h IV maintenance dose
(the Zuspan regimen, which is standard at our
institution), or a 6-g IV loading dose administered
over 20 minutes followed by a 2-g/h IV maintenance
dose. Simple randomization was performed using the
random number generator function in OpenEpi 3.01
(open-source software for epidemiologic statistics) by
a member of the research team not involved with
recruitment or data entry. Magnesium was adminis-
tered only if criteria for preeclampsia with severe
features were met.5
Neither the managing clinicians nor the patients
were blinded to the treatment group. Serum magne-
sium concentrations were obtained at baseline, and at
1 hour, 4 hours and at the time of delivery after
magnesium sulfate administration. The primary out-
come was the proportion of women with serum
magnesium concentrations of less than 4.8 mg/dL 4
hours after magnesium administration. The main
secondary outcome of interest was the proportion of
women who had subtherapeutic serum magnesium
concentrations at the time of delivery.
Data on demographic, obstetric, and neonatal
covariates were collected and included maternal age,
race, serum creatinine concentration, time to delivery
after administration, BMI, mode of delivery, parity,
gestational age, Apgar scores, neonatal respiratory
distress syndrome, and neonatal intensive care admis-
sion. Self-reported maternal side effect data were
collected prospectively by nursing staff during mag-
nesium administration, including flushing, sedation,
nausea, vomiting, and pain at IV site. Objective
evaluation for magnesium toxicity was performed
every 4 hours during magnesium administration,
VOL. 136, NO. 6, DECEMBER 2020 Brookfield et al Magnesium Dosing in Obese Women With Preeclampsia
© 2020 by the American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
which included urine output, patellar tendon reflexes,
respiratory rate, and blood pressure evaluation.
Sample size estimates were based on Brookfield4
and Tudela6 data, considering their estimates of the
proportion of women with subtherapeutic serum mag-
nesium concentrations less than 4.8 mg/dL in these
studies. We used a BMI threshold of 35 because the
Brookfield study suggests that the most profound
changes in magnesium disposition occur in women
with this level of obesity.4
We assumed that 80% of women in the standard
group with the 4-g IV loading dose followed by the 1-
g/h IV maintenance dose would have subtherapeutic
concentrations and that 35% of women in the alter-
nate group with the 6-g IV loading dose followed by
the 2-g/h IV maintenance dose would have sub-
therapeutic concentrations 4 hours after magnesium
sulfate administration. Assuming alpha50.05 and
power of 80%, a sample size of 18 women per group
was planned to be able demonstrate a risk ratio of
greater than two for subtherapeutic serum magnesium
concentrations in the standard Zuspan dosing group.
Traditional univariate analysis with Fisher exact
test or x2 for categorical variables and t test for com-
parison of means or Mann-Whitney U test for com-
parison of medians for continuous data were used
where appropriate. Normality was assessed using the
Shapiro-Wilk test. P,.05 was considered statistically
significant for our primary outcome measure and
P,.01 for secondary outcomes.
RESULTS
Between July 12, 2016, and March 14, 2019, 89
women were approached for participation; ultimately,
37 were enrolled (Fig. 1). There were no baseline dif-
ferences between the two groups (Table 1). A signifi-
cantly greater proportion of women administered the
Zuspan regimen had subtherapeutic serum magne-
sium concentrations at 4 hours (100% [95% CI 59–
100] vs 63% [95% CI 41–81]; P5.01) compared with
women administered the higher dose regimen
(Table 2). Similarly, at time of delivery, a significantly
greater proportion of women administered the Zu-
span regimen had subtherapeutic concentrations
(92% [95% CI 66–100] vs 27% [95% CI 12–51];
P,.01) compared with women administered the alter-
nate regimen. Women in the alternate higher dose
group (6-g IV loading followed by 2-g/h IV mainte-
nance) had significantly higher serum magnesium
concentrations at 4 hours and at time of delivery com-
pared with women in the Zuspan group (Table 2).
There were no statistically significant differences
in maternal side effects between the two groups;
1191
Fig. 1. Flow diagram. IV, intravenous.
Brookfield. Magnesium Dosing in Obese Women With Preeclampsia. Obstet Gynecol 2020.

however, the absolute rates of nausea and flushing
were higher in the alternate dosing group. Nausea was
reported in 10.5% of women who received the
alternate 6-g IV loading dose followed by the 2-g/h
IV maintenance dose and in 5.5% of women who
received the Zuspan regimen. Flushing was reported
by 5.2% of women who received the higher dose,
compared with 0% in those who received the standard
Zuspan regimen. The only magnesium toxicity re-
ported was a loss of patellar tendon reflexes, where
this was noted once in each of the dosing groups. The
highest serum magnesium concentration achieved by
any woman was 7.4 mg/dL. There were no significant
differences observed in neonatal outcomes between
the two dosing groups (Appendix 1, available online
at http://links.lww.com/AOG/C83).
DISCUSSION
We found that a significantly greater proportion of
obese women with preeclampsia have therapeutic
serum magnesium concentrations (defined as serum
magnesium concentration of 4.8 mg/dL or higher) for
eclamptic seizure prophylaxis when administered a
magnesium sulfate regimen of a 6-g IV loading dose
followed by a 2-g/h IV maintenance dose, compared
with women who receive a 4-g IV loading dose
followed by a 1-g/h IV maintenance dose.
There has been an increasing research effort to
tailor magnesium sulfate dosing administered to
pregnant and postpartum women to maximize
benefits, minimize side effects, and address chal-
lenges in resource limited settings.4–12 Interestingly,
recent data published by Du et al8 that apply phar-
macokinetic data to women with preeclampsia from
the Magpie trial13 suggest that the therapeutic serum
concentration to prevent the first seizure is likely
closer to 3.6 mg/dL, with multiple regimens avail-
able to achieve this concentration.7,8 When we used
3.6 mg/dL as the threshold for a therapeutic serum
concentration in the participants from the current
study, we still found that, 4 hours after administra-
tion, 95% of women in the alternate dosing group
had therapeutic concentrations, compared with 31%
of women in the standard Zuspan group; by the time
of delivery, 100% of women receiving the 6-g IV
loading dose followed by 2-g/h maintenance dose
had therapeutic concentrations, compared with 50%

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Table 1. Baseline Demographics and Clinical Features

Dosing Protocol
Variable 4 g Then 1 g/h (n518) 6 g Then 2 g/h (n519)

Maternal age (y) 30.966.6 31.667.1

Race*
White 15 (83) 15 (79)
Black 0 (0) 1 (5)
Non-White, non-Black 3 (17) 3 (16)
BMI (kg/m2) 41 (37–46) 42 (37–45)
Multiparity 11 (61) 11 (58)
Baseline creatinine concentration (mg/dL) 0.60 (0.56–0.65) 0.67 (0.54–0.73)
Time to delivery (h) 14.7 (10.3–27.2) 22.0 (13.1–39.0)
Severe feature of preeclampsia†
Blood pressure 160/110 or higher 12 (67) 17 (89)
Symptoms of end-organ damage 8 (44) 10 (52)
Laboratory abnormalities 4 (22) 4 (21)
BMI, body mass index.
Data are mean6SD, n (%), or median (interquartile range).
* Race was self-identified by participants at the time of admission. Non-White, non-Black in our study describes participants who self-
identified as Asian or Pacific Islander. It is unknown whether or not race plays a role in metabolism of magnesium sulfate.
†
Women may have had more than one severe feature (column does not add to 100%).

of women receiving the 4-g IV loading followed by
the 1-g/h IV maintenance dose. The findings from
our study support the previous retrospective trials
and prospective pharmacokinetic modelling that
show dosing requirements increase with BMI to
achieve serum magnesium concentrations on par
with women of the mean body weight in pregnancy,
regardless of which threshold is used to define a ther-
apeutic serum magnesium concentration.4,6,7
An unanswered question from this study is
whether the increased alternate dose of magnesium
sulfate actually decreases rates of seizures in the obese
population. This study was not powered to examine
eclampsia as an outcome and there is no evidence to
date to suggest women in the United States with
higher BMIs are more likely to experience eclampsia
as a result of lower serum magnesium concentra-
tions.14 No woman in our trial experienced eclampsia.
Therefore, we caution against universally applying the
study findings to obese women without also consider-
ing the potential for increased toxicity with higher
dosing regimens.
Strengths of the study include the fact that dosing
selection was based on prospective pharmacokinetic
data and the alternate higher dosing regimen selected for
the trial is one that has been used clinically and in other
trials for preeclampsia and other indications. This was a
randomized trial, and, although there was no blinding of
clinicians or participating women, we used a concrete
objective outcome of serum magnesium concentrations.
It is unlikely that the unblinded nature of the trial would
have an effect on the primary outcome.

Table 2. Study Outcomes

Dosing Protocol
4 g Then 1 g/h (n518) 6 g Then 2 g/h (n519) P

Serum magnesium concentration (mg/dL)

4 h after administration 3.5360.3 4.4160.5 ,.01
At delivery 3.7360.7 5.4461.0 ,.01
Subtherapeutic level*
4 h after administration† 100 (78–100) 63 (41–81) .01
At delivery‡ 92 (66–100) 27 (12–51) ,.01
Data are mean6SD or % (95% CI).
* Serum magnesium concentration of less than 4.8 mg/dL.
†
By Fisher exact test, Taylor method.
‡
By x2 test, Taylor method (n533 for women with serum magnesium concentration data at time of delivery).

VOL. 136, NO. 6, DECEMBER 2020 Brookfield et al Magnesium Dosing in Obese Women With Preeclampsia 1193

© 2020 by the American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
 Limitations of the trial include those of general-
izability to the most extremely obese patients seen in
obstetric settings today and, as mentioned, limited
statistical power to evaluate clinical outcomes. We
also acknowledge that magnesium sulfate regimens
vary greatly within the United States and internation-
ally, and many institutions did not adopt the Zuspan
regimen as the standard after the Magpie trial was
published.13,15 This may limit the generalizability of
the findings where the alternate higher dose regimen
used in this trial is already administered as standard
treatment.
Women with BMIs of 35 or higher are signifi-
cantly more likely to achieve therapeutic serum
magnesium concentrations (defined as serum magne-
sium concentration of 4.8 mg/dL or higher) for
eclampsia prophylaxis when administered a 6-g IV
loading dose followed by a 2-g/h IV maintenance
dose, compared with women who received a 4-g IV
loading dose followed by a 1-g/h IV maintenance
dose.
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© 2020 by the American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
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Authors’ Data Sharing Statement
Will individual participant data be available (including
data dictionaries)? Individual deidentified participant
data (including data dictionaries) will be shared at the
request of other researchers.
What data in particular will be shared? All data used in
the production of this manuscript will be shared.
What other documents will be available? Study related
documents, including the study protocol, will be
available upon request.
When will data be available (start and end dates)? Data
will become available upon publication of the manu-
script for 12 months.
By what access criteria will data be shared (including
with whom, for what types of analyses, and by what
mechanism)? Criteria to access sharing data include
inquiries directly to the Principal Investigator, to
inform future research planning, by password-
protected files.
PEER REVIEW HISTORY
Received June 10, 2020. Accepted August 21, 2020. Peer reviews
and author correspondence are available at http://links.lww.com/
AOG/C84.
OBSTETRICS & GYNECOLOGY