Clinical Expert Series

Continuing medical education is available online at www.greenjournal.org

Magnesium Sulfate for Preterm Labor and

Preterm Birth
Brian M. Mercer, MD, and Amy A. Merlino, MD, for the Society for Maternal-Fetal Medicine

Approximately half of the more than 500,000 preterm births each year result from preterm labor.
Tocolytic therapy continues to be the focus of treatment of these women. Although a variety of
tocolytics are used in clinical practice, magnesium sulfate remains one of the most commonly used
agents. Magnesium sulfate has also been the focus of recent research for its potential neuroprotective
effects for neonates born preterm. Evaluation of 19 randomized clinical trials reveals that magnesium
sulfate tocolysis does not reduce the frequencies of delivery within 48 hours, 7 days, or early/late
preterm birth, and is not associated with improvements in newborn morbidities or mortality. No
other tocolytic class resulted in improved newborn outcomes when compared with magnesium
sulfate tocolysis. We conclude that it is appropriate to withhold tocolysis with magnesium sulfate or
other agents from women presenting in preterm labor as newborn benefit has not been demon-
strated with such treatment. If initiated to achieve time for antenatal corticosteroid administration, or
for other acute reasons, treatment can be discontinued once these goals have been achieved or if
labor subsides before then. Because brief pregnancy prolongation is unlikely to improve newborn
outcomes after corticosteroid administration has been completed, it is appropriate to withhold
magnesium sulfate tocolysis from women with recurrent preterm labor thereafter. If magnesium
sulfate is given for neuroprotection, a protocol from one of the three major trials that have
demonstrated benefits should be used.
(Obstet Gynecol 2009;114:650–68)

See related editorial on page 500.

From the Department of Obstetrics & Gynecology, MetroHealth Medical Center,
Cleveland, Ohio.
Continuing medical education for this article is available at http://links.lww.
com/AOG/A120.
The practice of medicine continues to evolve and individual circumstances will
vary. This opinion reflects information available at the time of its acceptance for
publication, and is neither designed nor intended to establish an exclusive
standard of perinatal care. This publication is not expected to reflect the opinions
of all members of the Society for Maternal–Fetal Medicine.
Corresponding author: Brian M. Mercer, MD, Professor, Reproductive Biology,
Case Western Reserve University, Vice-Chair, Director of Obstetrics & Mater-
nal-Fetal Medicine, Department of Obstetrics & Gynecology, MetroHealth
Medical Center, Suite G240, MetroHealth Medical Center, 2500 MetroHealth
Drive, Cleveland, OH 44109.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2009 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/09
D espite considerable clinical and research effort
directed toward the prevention of prematurity,
preterm birth complicated 12.8% of pregnancies in
the United States in 2006, a rise of 36% from the
9.4% incidence rate in the 1981.1 Preterm birth is
critically important as it results directly in acute
neonatal morbidities and mortality.2 Long-term se-
quelae, including neurologic handicap, blindness,
deafness, and chronic respiratory disease are di-
rectly linked to preterm birth and its complications
and are particularly more likely among neonates
born before 32 weeks or under 1,500 grams.3–5
Approximately 75% of preterm births result from
spontaneous preterm labor or preterm premature
rupture of the membranes before labor, with half or
more of these resulting from preterm labor with
intact membranes.6 – 8 Given that more than 500,000
preterm births occur annually in the United States
and that approximately half the women treated for

650 VOL. 114, NO. 3, SEPTEMBER 2009 OBSTETRICS & GYNECOLOGY

preterm labor will ultimately deliver at term, hun-
dreds of thousands of women are evaluated and
treated for preterm labor each year. Tocolytic
therapy to prolong pregnancy and reduce newborn
complications continues to be the focus of treat-
ment of preterm labor.9 –16 Magnesium sulfate has
been one of the most commonly used agents for this
indication. The potential role of magnesium sulfate
for neuroprotection of infants born preterm has also
been recently studied.
The purpose of this article is to review the
physiology of magnesium, to evaluate the clinical
utility of magnesium sulfate therapy for treatment of
women presenting with preterm labor, and to con-
sider the potential role of magnesium sulfate for
neuroprotection when preterm birth is anticipated.
This review focuses on the currently available peer-
reviewed, randomized controlled trials evaluating the
effectiveness of acute tocolysis, as well as those re-
garding magnesium sulfate for neuroprotection when
preterm birth is anticipated.
PHYSIOLOGY OF MAGNESIUM SULFATE
Several recent articles have reviewed the molecular
and cellular physiology of magnesium in detail.17–23
Magnesium, a bivalent cation, is the fourth most
common cation in the human body after sodium,
potassium, and calcium. It is the second most com-
mon intracellular cation after potassium. Intracellular
magnesium is found predominantly in bone (53%)
and in myocytes (27%)17 and is localized to the
nucleus, microsomes, and mitochondria.18 Only 1% of
total body magnesium is found extracellularly,19 with
serum magnesium accounting for 0.3% of total body
magnesium content.17 Approximately 62% of serum
magnesium circulates in its ionized form.17 The nor-
mal serum magnesium level is 0.75– 0.95 mmol/L
(1.8 –2.3 mg/dL).19 Serum magnesium levels decline
in pregnancy, likely due in part to hemodilution.20,21
Magnesium transport across cell membranes is
largely carrier-mediated, is coupled to sodium
transport, and is energy requiring. Magnesium ex-
cretion occurs primarily through the urinary tract
with passive glomerular filtration. Approximately
65% of filtered magnesium is actively reabsorbed in
the Loop of Henle, and 20 –30% is passively reab-
sorbed in the proximal convoluted tubules.23 In
addition to serving as a cofactor for numerous
reactions, including energy metabolism and nucleic
acid synthesis, magnesium is implicated in regula-
tion of adenylate cyclase, transmembrane ion flux,
muscle contraction and neuronal activity, as well
as control of vasomotor tone, cardiac excitability,
VOL. 114, NO. 3, SEPTEMBER 2009 Mercer and Merlino
and neurotransmitter release.22 Magnesium sulfate
is known to reduce spontaneous and induced myo-
metrial contractions.24,25 Magnesium is believed to
affect contractility by competing with calcium in
the sarcoplasmic reticulum, reducing the availabil-
ity of calcium to participate in actin–myosin inter-
action and in myometrial repolarization. Magne-
sium is thought to act through both intracellular
and extracellular mechanisms resulting in de-
creased intracellular calcium availability by block-
ing channel-dependent influx of extracellular cal-
cium and also by blocking agonist-stimulated
release of intracellular calcium via inositol 1,4,5-
triphosphate receptor/channels.26,27 In vitro, mag-
nesium sulfate has been demonstrated to reduce
spontaneous myometrial contractions at concentra-
tions of 2–3 mmol (4 – 6 mEq/L), but suprapharma-
cologic levels (4 –10 mmol, 8 –16 mEq/L) have
been required to inhibit agonist mediated cyclic
uterine activity.26 –28 Magnesium has been shown
to potentiate neuromuscular blockade from non-
depolarizing agents, such as vecuronium and
pancuronium.
Potential mechanisms of perinatal brain injury
related to ischemia, infection and inflammation,
and hemorrhage are described in recent reviews by
Berger et al,29 Fawcett et al,22 and Wolfe et al.18
Although animal studies have suggested that mag-
nesium can reduce ischemia-induced cellular injury
and magnesium is known to be intricately involved
in numerous cellular processes, the mechanisms by
which magnesium might reduce or prevent neuro-
nal damage have not been fully elucidated. Magne-
sium has been shown to antagonize N-methyl-D-
aspartate regulated receptor activity, and thus high
levels of magnesium might reduce post-trauma
neuronal damage related to increased intracellular
calcium. N-methyl-D-aspartate receptor–mediated
attenuation of the decline in post-traumatic reduc-
tion in intracellular magnesium levels has been
associated with improved neurological outcome in
rats. Another potential mechanism is the reduction
of inositol 1,4,5-triphosphate receptor binding.
Magnesium deficiency has been associated with
reductions of antioxidant defenses and is associated
with oxidative neuronal, myocardial, and endothe-
lial death. However, magnesium deficiency has also
been associated with both increased and decreased
cellular apoptosis. Thus, while it is plausible that
magnesium sulfate could provide neuroprotection
through mechanisms such as reduced vascular in-
stability and hypoxic damage, and/or reductions in
cytokine/excitatory amino acid–induced damage,
Magnesium Sulfate for Preterm Labor 651
Table 1. Nineteen Included Randomized Clinical Trials of Intravenous Magnesium Sulfate Tocolysis for
Preterm Labor Published in English-Language Peer-Reviewed Journals
Study, Year
Compared with control
Cotton et al,32 1984
Cox et al,33 1990
Fox et al,34 1993
How et al,35 2006
Compared with ␤-mimetics
Miller et al,36 1982
Cotton et al,32 1984
Hollander et al,37 1987
Wilkins et al,38 1988
Chau et al,39 1992
Compared with calcium
channel blockers
Floyd et al,40 1992
Glock and Morales,41 1993
Haghighi,42 1999
652 Mercer and Merlino Magnesium Sulfate for Preterm Labor
Gestational Primary Control
Age (wk) Major Inclusion Criteria Group Treatment
26–34 Contractions, three or more in 10 min, and Dextrose placebo
progressive cervical dilatation or 2 or more cm
dilation or 80% or more effaced or SROM
24–34 Regular contractions and cervix between 1 and 5 cm Saline placebo
34–37 Preterm labor with cervical change Sedation/hydration
32–34 Contractions, six or more per h with progressive No tocolysis
cervical dilatation or effacement
Less than 37 Contractions, every 5 min or less for 1 h and Terbutaline
estimated fetal weight less than 2,500 g
26–34 Contractions, three in 10 min, and progressive Terbutaline
cervical dilatation or 2 or more cm dilation or
80% or more effaced or SROM
20–35 Contractions, at least two in 10 min, and 30-s Ritodrine
duration, with cervical change or with cervix 2
or more cm in nulliparas
25–36 Contractions, every 5 min with cervix 50% or more Ritodrine
effaced or 2 or more cm dilated
23–35 Contractions, three or more in 10 min after initial Terbutaline
measures or with cervix 80% or more effaced or
two or more cm dilated
20–34 Contractions, regular every 10 min or less with Nifedipine
cervix 2 cm or more or with cervical change
from prior examination
20–33 Contractions, regular every 10 min or less with Nifedipine
cervical change, or regular contractions with
cervix 2 or more cm
23–36 Contractions, every 10 min or less Nifedipine
OBSTETRICS & GYNECOLOGY
 Method of Randomization and
Concealment
Three-armed trial, randomization
method unclear
Random number table, sealed opaque
envelopes
Random number table, sealed opaque
envelopes
Random number table, sealed opaque
envelopes
Randomization method unclear, sealed
envelopes
3-armed trial, randomization method
unclear
Random number table
Random number table, sealed opaque
envelopes
Pseudo-randomization by medical
record number
Random number table, sealed opaque
envelopes
Randomization method unclear
Randomization method unclear
VOL. 114, NO. 3, SEPTEMBER 2009
Alternative
Treatments Rescue Therapy
MgSO4; 4-g bolus then 2 g/h until quiescence for 12 h No
(48 h if SROM)
Dextrose 5% at 125 mL/h
MgSO4; 4-g bolus then 2 g/h, increased to maximum of No
3 g/h, continued for 24 h
Saline 80 mL/h
MgSO4; 4-g bolus then 2 g/h, increased to maximum of Not stated
4 g/h, until successful
MgSO4; 6-g bolus then 2 g/h, increased to maximum of No
5 g/h until quiescence, for 24 h
MgSO4; 4-g bolus then 2 g/h for 2 h, then 1 g/h for 22 h Not stated
Terbutaline, 0.25 mg intravenously then 10 microgram/
min increased to maximum of 25 microgram/min
MgSO4; 4-g bolus then 2 g/h until quiescence for 12 h No
(48 h if SROM)
Terbutaline 9.2 microgram/min intravenously,
increased to max 25.3 microgram/min
MgSO4; 4-g bolus then 2 g/h, increased as needed to Alternate regimen
serum level 6–8 mg/dL, continued for 12 h
Ritodrine, 100 microgram/min intravenously, increased
to maximum of 350 microgram/min, continued for
12 h
MgSO4; 4-g bolus then 2 g/h, increased as needed to Alternate regimen
serum level 5–8 mg/dL, continued for 24 h after
quiescence
Ritodrine 100 microgram/min intravenously, increased
to maximum of 350 microgram/min, continued for
12 h after quiescence
MgSO4; 4-g bolus then 2 g/h, increased to maximum of Alternate regimen
4 g/h, until quiescence for 12 h or up to 24 h
Mg level maintained between 4 and 7 mg/dL
Terbutaline, 0.25 mg subcutaneously every 30 min for
three doses, then every 4 h until quiescence for 12 h
or up to 24 h
MgSO4; 4-g bolus then 4-6 g/h as needed, continued Not stated
for 6 h after quiescence
Nifedipine, 30 mg by mouth then 20 mg every 8 h
until quiescence
MgSO4; 6-g bolus then 2 g/h, increased to maximum of Intravenous
4 g/h, until quiescence for 24 h ritodrine
Nifedipine, 10 mg sublingual repeated every 20 min to
maximum of 40 mg, then 20 mg by mouth every
4 h for 48 h
MgSO4; 6-g bolus then 2 g/h, increased to maximum of Not stated
4 g/h, until quiescence for 12 h
Nifedipine, 10 mg sublingual repeated every 20 min to
maximum of 40 mg, then 20 mg by mouth every
6 h for 24 h, then 20 mg every 8 h for 24 h
(continued)
Mercer and Merlino Magnesium Sulfate for Preterm Labor 653
Table 1. Nineteen Included Randomized Clinical Trials of Intravenous Magnesium Sulfate Tocolysis for
Preterm Labor Published in English-Language Peer-Reviewed Journals (continued)
Gestational Primary Control
Study, Year Age (wk) Major Inclusion Criteria Group Treatment
Larmon et al,43 1999 24–34 Regular contractions, four or more per h for 1 h or Nicardipine
more with cervical change

Lyell et al,31 2007 24–33 Contractions, two or more every 10 min and Nifedipine
cervical change, or SROM, or 2 or more cm
dilated and 80% or more effaced
Compared with
cyclooxygenase
inhibitors
Morales and Madhav,44 Less than 32 Regular contractions, four or more in 20 min and Indomethacin
1993 progressive cervical dilatation or effacement, or
cervix 2 or more cm dilated

Parilla et al,45 1997 Less than 30 Regular contractions with progressive cervical Indomethacin
dilatation and effacement

Schorr et al,46 1998 20–32 Regular contractions 12 or more in 60 min with Ketolorac
cervix 50% or more effaced, 2 or more cm
dilated or cervical change from a recent
examination

McWhorter et al,47 2004 22–34 Regular contractions with progressive cervical Rofecoxib
dilatation or effacement

Borna and Saeidi,48 2008 24–34 Contractions, four or more in 20 min or eight in 60 Celecoxib
min with progressive cervical change in dilation
or effacement

Compared with alcohol

Steer and Petrie,49 1977 Less than 37 Painful contractions every 5 min or less Ethanol

SROM, spontaneous rupture of the membranes; MgSO4, magnesium sulfate.

further study is needed to clarify its role in these
processes.
TOCOLYSIS FOR TREATMENT OF PRETERM
LABOR
Magnesium sulfate has been evaluated and used for
its tocolytic properties for nearly 50 years.25,30 Typ-
ically a 4- to 6-g loading dose over 15–30 minutes is
followed by a continuous infusion of 2 g/h, and this
infusion may be increased up to 4 –5 g/h as needed
in the absence of significant clinical side effects or
oliguria. Magnesium toxicity is rarely seen with
serum levels below 10 mg/dL, but respiratory
depression and subsequent arrest can occur at
levels above 10 –12 mg/dL. Although serious com-
plications rarely occur during magnesium sulfate
tocolysis, other side effects, including lethargy,
flushing, nausea and vomiting, blurred vision and
dizziness, are not uncommon, occurring in 13–29%
of patients in one report.31
Magnesium sulfate has been the subject of
numerous clinical trials regarding its efficacy for the
treatment of preterm labor. Individual studies have
been marked by inadequate power to evaluate the
impact of treatment on neonatal outcomes, the
primary reason for which pregnancy prolongation
is attempted. Other than ␤-mimetics, most tocolytic
agents have not been tested extensively against a
placebo or control group, and magnesium sulfate is
not an exception in this regard. Magnesium sulfate
has been compared with a wide variety of agents,
including alcohol, ␤-mimetic agents, cyclooxygen-
ase inhibitors, calcium channel blockers, and nitric
oxide donors. Like other tocolytic agents, compar-

654 Mercer and Merlino Magnesium Sulfate for Preterm Labor OBSTETRICS & GYNECOLOGY
 Method of Randomization and
Concealment
Random number table, sealed opaque
envelopes
Random number table, sealed opaque
envelopes
Random number table, sealed opaque
envelopes
Random number table, sealed opaque
envelopes with cross-over
Randomization unclear, sealed opaque
envelopes controlled by pharmacy
Random number table controlled by
pharmacy
Random number table controlled by
pharmacy
Alternative
Treatments Rescue Therapy
MgSO4; 6-g bolus then 2 g/h, increased to maximum of Permitted but
4 g/h, until quiescence unspecified
Nicardipine, 40 mg by mouth, repeated every 2 h as
required to maximum of 80 mg, then sustained
release nicardipine 45 mg every 12 h
MgSO4; 4-g bolus then 2 g/h, increased to maximum of Alternate regimen
4 g/h, until quiescence for 12 h
Nifedipine, 10 mg sublingual repeated every 20 min to
maximum of 80 mg, then 20 mg by mouth every 4
to 6 h until quiescence for 12 h
MgSO4; 6-g bolus then 2 g/h, increased to maximum of Alternate regimen
5 g/h, until quiescence for 12 h
Indomethacin, 100 mg rectally, repeated one time as
needed after 1 h, then 25 mg by mouth every 4 h
for 48 h
MgSO4; 8 g over 1 h, then 4 g over 4 h, then 2.5 g/h, Permitted but
until quiescence for 12 h unspecified
Indomethacin, 50 or 100 mg by mouth or rectally, then
25–50 mg by mouth every 4–6 h for 24–48 h
MgSO4; 6-g bolus then 2 g/h, increased to maximum of Not stated
6 g/h, and tapered until discontinued after
quiescence achieved
Ketolorac 60 mg intramuscularly then 30 mg
intramuscularly every 6 h as needed for up to 24 h
MgSO4; 4- to 6-g bolus then 2–4 g/h, for up to 48 h if Permitted but
needed unspecified
Rofecoxib 50 g by mouth daily for up to 48 h if needed
MgSO4; 4- to 6-g bolus then 2–4 g/h, for up to 48 h if Permitted but
needed unspecified
Celecoxib 100 g by mouth twice daily for up to 48 h if
needed

Pseudo-randomization by medical MgSO4; 4-g bolus then 2 g/h until labor subsided Not stated
record number. A saline control 9.5% ethanol, 15 mL/kg over 2 h then 1.5 mg/kg until
group chosen “at random” and was labor subsided
not evaluated

ison of individual studies regarding magnesium
sulfate is made difficult by varying inclusion re-
quirements (eg, diagnostic criteria for preterm la-
bor, gestational age, the presence or absence of
intact membranes), concurrent interventions, dif-
fering criteria for successful treatment, and therapy
for initial treatment failures, as well as selective
reporting of maternal and newborn outcomes.
These trials have been the subject of several re-
views and meta-analyses, which provide detailed
descriptions of the individual study designs and
outcomes.9 –11
The most recent substantial update of the Cochrane
systematic review regarding magnesium sulfate tocolysis
for preterm labor was published by Crowther et al in
2002.9 Published and unpublished data from 23 trials in
peer-reviewed journals and abstracts were evaluated
and included more than 2,000 pregnancies. The authors
concluded that “there was no evidence of a clinically
important tocolytic effect for magnesium sulphate; it did
not have any substantial effect on the proportion of
women delivering within 48 hours, either overall, or in
any subgroup analysis. Moreover, there was no evi-
dence of any substantial improvements in neonatal
morbidity.” Alternatively, in an evidence report on the
management of preterm labor, Berkman et al10,11 eval-
uated 18 randomized controlled trials and observational
and retrospective studies. Regarding magnesium as a
first-line treatment, this group determined that “signifi-
cant differences were not found between magnesium
sulfate and placebo,” but regarding comparisons among
different classes of tocolytics, “␤-mimetics, calcium

VOL. 114, NO. 3, SEPTEMBER 2009 Mercer and Merlino Magnesium Sulfate for Preterm Labor 655
channel blockers, and magnesium sulfate nearly dou-
bled the odds of term births, relative to control, with
potentially small differences in effect sizes between
classes.” These authors concluded that “Overall, the
evidence supports the notion that first-line treatment
with ␤-mimetics, calcium channel blockers, magnesium
sulfate, or [nonsteroidal antiinflammatory drugs] offers
small improvements in prolonging pregnancy.” Due to
the publication of an additional four trials regarding
magnesium sulfate as a first-line tocolytic agent for
preterm labor since the most recent Cochrane review,
an additional analysis was performed for this review.
METHODS OF SYSTEMATIC REVIEW
Data Sources
All English-language randomized clinical trials of
magnesium sulfate tocolysis compared with an alter-
nate tocolytic regimen or control therapy for preterm
labor were identified through literature review. For
this analysis, PubMed (U.S. National Library of Med-
icine) was searched for English-language randomized
controlled trials including the terms “tocolysis” and
any of “magnesium,” “indomethacin,” “prostaglan-
din,” “COX,” “cyclo-oxygenase,” “nitric oxide,”
“NO,” “calcium,” “oxytocin receptor antagonist,”
“atosiban,” “betamimetic,” and “␤-agonist” that were
published between January 1, 1966, and December
31, 2008. The most recent Cochrane reviews regard-
ing acute tocolysis with magnesium sulfate, tocolysis
with other agents, and the above mentioned Agency
for Healthcare Research and Quality report were
reviewed for additional studies.9 –16
Study Selection and Data Abstraction
Studies were excluded if magnesium was given in
addition to or following failure of another tocolytic
agent, was compared with a control group which
included more than one agent, was compared with
unspecified treatments at the discretion of the care-
giver, or was given only to women with ruptured
membranes. Studies of chronic “prophylactic” toco-
lysis administered for the purpose of preventing,
rather than treating, preterm labor were also ex-
cluded. Data abstraction was performed only from the
original peer-reviewed publications. The authors of
the original articles were not contacted. Unpublished
data used in other meta-analyses were not included.
Each data point for all included articles was evaluated
separately by two independent reviewers (B.M. and
A.M.) who were masked to the other’s determination.
These results were then compared, and all discrepan-
cies were resolved by mutual re-review of the relevant
656 Mercer and Merlino Magnesium Sulfate for Preterm Labor
manuscript. Subsequently, the results of our data
review were compared with those from the most
recent Cochrane analysis for those studies that were
included in both, and each manuscript for which
there was a discrepancy was again reviewed to make
a final determination for each outcome.
Selection of Outcomes
Pregnancy latency characteristics, including gesta-
tional age at randomization and delivery, latency to
delivery, and various markers of early delivery and
preterm birth (before 48 hours and 7 days, before
32, 34, and 37 weeks) and low birth weight (below
2,500 g) were evaluated for each included article
where available. Perinatal outcomes (fetal and/or
newborn mortality before discharge, major acute
morbidities before discharge) were also analyzed.
Statistical Analyses
Statistical analyses were performed using Review
Manager (RevMan) 5.0 (Copenhagen: The Nordic
Cochrane Centre, The Cochrane Collaboration,
2008) and figures were adapted from Forest plots
obtained using this software (forest plots are available
online at http://links.lww.com/AOG/A121). Mantel
Haenszel ␹2 analyses, using a fixed effects model,
were performed for categorical data. The DerSimo-
nian-Laird random effects model was used for contin-
uous data. Data are presented as summary relative
risks (RRs) (95% confidence intervals [CIs]) for cate-
gorical outcomes and as mean differences (95% CIs)
for continuous variables. Where significant heteroge-
neity was identified using the Q statistic, P values for
the summary RRs and mean differences were not
evaluated. Separate analyses were performed for tri-
als comparing magnesium sulfate with a control/
placebo or no treatment, for trials comparing mag-
nesium sulfate with alternate classes of tocolytic
agents, and for all studies combined. Where a
specific outcome was not evaluated in any of the
compared trials, this outcome was excluded from
the corresponding table. No sensitivity analyses
were prespecified.
Summary of Included and Excluded Articles
Table 1 summarizes those published peer-reviewed
studies regarding magnesium sulfate as a first-line
tocolytic agent that were selected for inclusion. In
four of these trials, magnesium sulfate was com-
pared with a control/placebo or no additional
tocolytic treatment.32–35 In 16 trials, magnesium
sulfate tocolysis was compared with an alternate
OBSTETRICS & GYNECOLOGY
Table 2. Magnesium Sulfate Tocolysis Studies Not Included in the Current Analysis
Study, Year
50
Aramayo et al, 1990
Armson et al,51 1992
Beall et al,52 1985
El-Sayed et al,53 1999
Ferguson et al,54 1984
Hatjis et al,55 1987
How et al,56 1998
Ma,57 1992
Mittendorf et al,58 2002
Newton et al,59 1991
Ogburn et al,60 1985
Sciscione et al,61 1993
Tchilinguirian et al,62 1984
Weiner et al,63 1998
Wischnik et al,64 1989
Zhu and Fu,65 1996
Reason for Exclusion
Magnesium sulfate versus terbutaline, published in Spanish
Magnesium sulfate versus ritodrine, preterm deliveries excluded, no meaningful outcome data
Magnesium sulfate versus ␤-mimetics, outcomes assigned to last therapy rather than to
assigned study group
Magnesium sulfate versus nitroglycerin, randomized by shuffling sealed opaque
envelopes, outcomes specific to this analysis not reported
Combination therapy, magnesium sulfate adjuvant to ritodrine
Combination therapy, magnesium sulfate adjuvant to ritodrine
All patients had preterm premature rupture of the membranes and not all were contracting
Magnesium sulfate versus barbiturates, published in Chinese
Control group received caregivers’ choice of ritodrine, terbutaline, indomethacin or nifedipine
for acute tocolysis
Magnesium sulfate alone versus magnesium sulfate in combination with indomethacin and
antibiotics
Magnesium sulfate as adjuvant for primary tocolytic failure
Abstract only, no peer reviewed manuscript
Randomization method unclear, outcomes specific to this analysis not reported
All patients had premature rupture of the membranes, no distinct magnesium sulfate treatment
group
Combination therapy with another tocolytic (fenoterol), published in German
Magnesium sulfate versus ritodrine, published in Chinese

tocolytic regimen and had outcomes published
relevant to the current analyses.31,32,36 – 49 In one
trial, magnesium sulfate was compared with both a
placebo group and a specific alternative tocolytic
regimen.32 Twelve studies utilized random number
tables for study group assignment, while two studies
used medical record numbers, and five did not
specify the method of randomization (Table 1).
Study group assignment was concealed by sealed
opaque envelopes in nine studies. In three trials, the
envelopes or random number table list was con-
trolled by the study pharmacy. In the remaining
seven studies, the concealment method was un-
clear. Three of the trials included evaluation of
maternal serum magnesium levels to determine
adequacy of dosing.37–39 The included studies were
inconsistent regarding the inclusion of twin preg-
nancies and the method of presentation of their
newborns’ outcomes. Some presented data for both
twins while others presented only one set of new-
born outcomes for each pregnancy, and these did
not clarify whether the data were those for the first

Table 3. Pregnancy and Newborn Outcomes After Magnesium Sulfate Treatment Compared With
Control or No Therapy for Preterm Labor (Four Trials32–35)*
Magnesium Summary 95% P for
Sulfate Control Heterogeneity Relative Confidence Overall
Outcome Studies [n/N (%)] [N (%)] P Risk Interval Effect
Delivery less than 48 h 3 32/85 (37.6) 46/94 (48.9) .46 0.75 0.54–1.03 .07
Delivery less than 7 d 3 57/116 (49.1) 52/129 (40.3) .47 1.22 0.94–1.59 .14
Delivery less than 37 wk 2 32/40 (80.0) 33/49 (67.3) .27 1.18 0.93–1.51 .17
Birth weight less than 2,500 g 2 61/93 (65.6) 69/98 (70.4) .54 0.94 0.78–1.14 .53
Respiratory distress 4 22/159 (13.8) 22/173 (12.7) .94 1.10 0.66–1.85 .71
IVH 4 5/159 (3.1) 7/173 (4.0) .48 0.80 0.26–2.45 .69
Grade 3–4 IVH 2 0/69 (0) 0/75 (0) NA — — —
Necrotizing enterocolitis 4 4/159 (2.5) 4/173 (2.3) .49 1.09 0.30–3.97 .89
Sepsis/infection 1 2/15 (13.3) 0/19 (0) NA 6.25 0.32–121.1 .23
Fetal death 4 2/161 (1.2) 0/173 (0) NA 5.13 0.25–105.1 .29
Newborn death before 4 7/159 (4.4) 6/173 (3.5) .08 1.33 0.45–3.92 .61
discharge
Fetal or newborn death before 4 9/161 (5.6) 6/173 (3.5) .05 1.68 0.60–4.70 .33
discharge
IVH, intraventricular hemorrhage; NA, not applicable.
* Comparison of magnesium sulfate with placebo from Cotton et al32 used for this analysis.

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Table 4. Gestational Age, Latency, and Birth Weight Outcomes After Magnesium Sulfate Treatment
Compared With Control or No Therapy for Preterm Labor (Four Trials32–35)*
Magnesium Control Heterogeneity Mean 95% Confidence P for
Outcome Studies (N) (N) P Difference Interval Overall Effect
Gestation at enrollment (wk) 4 161 174 .05 ⫺0.02 ⫺0.28 to 0.25 .91
Latency (wk) 4 161 174 ⬍.001 ⫺0.29 ⫺1.21 to 0.63 —
Gestation at delivery (wk) 4 160 174 ⬍.001 ⫺0.48 ⫺1.81 to 0.86 —
Birth weight (g) 4 161 173 .09 ⫺28.6 ⫺179.1 to 121.8 .71
* Comparison of magnesium sulfate with placebo from Cotton et al32 used for this analysis.

twin, the second twin, a randomly selected twin, or
for the worst outcome for either twin. Newborn
outcome data were analyzed as published in the
primary papers. Postrandomization exclusion and
loss to follow-up were uncommon (less than 5%) in
all studies with the exception of one in which 13 of
114 recruited patients were excluded after random-
ization.44 Sixteen additional studies were consid-
ered but were excluded from further analysis based
on criteria delineated in Table 2.50 – 65 Results of
analyses from the included trials are presented in
Tables 3–10 and Figures 1–5.
SUMMARY OF RESULTS
Magnesium Sulfate Compared With Control or
No Therapy
A major purported benefit of acute tocolysis for
preterm labor is brief pregnancy prolongation to
allow administration of antenatal corticosteroids for
fetal maturation. Data in this regard were frequently
available in published trials, with 12 of 19 evaluated
studies reporting the outcome of “delivery within 48
hours” for a total of 1,281 pregnancies. However, only
three of four studies that compared magnesium sulfate
with a placebo/control or no therapy evaluated the
impact of such treatment on delivery within 48 hours
or within 7 days (Table 3).32–35 These trials appeared to
include higher-risk populations than the trials compar-
ing magnesium sulfate with an alternative tocolytic
regimen, with more frequent early delivery and preterm
birth. Overall, magnesium sulfate tocolysis did not re-
duce the frequency of delivery within 48 hours when
compared with placebo/control or no tocolytic treat-
ment (RR 0.75 [0.54 –1.03]) (Table 3 and Fig. 1). No
significant reductions in delivery within 7 days or before
37 weeks of gestation were evident with magnesium
sulfate tocolysis, and no trend toward reduction in the
outcome of newborn birth weight below 2,500 g was
seen (Table 3 and Fig. 2). No individual study demon-
strated improvements in these outcomes with magne-
sium sulfate tocolysis. Significant heterogeneity was seen
regarding latency to delivery and delivery gestation, but
no improvement in newborn birth weight was seen with
magnesium treatment (Table 4).

Table 5. Pregnancy and Newborn Outcomes After Magnesium Sulfate Treatment Compared With
␤-mimetics for Preterm Labor (Five Trials32,36 –39)*
Magnesium Summary P for
Sulfate Control Heterogeneity Relative 95% Confidence Overall
Outcome Studies [n/N (%)] [n/N (%)] P Risk Interval Effect
Delivery less than 48 h 3 17/128 (13.3) 15/125 (12.0) .52 1.23 0.70–2.17 .47
Delivery less than 7 d 5 40/176 (22.7) 44/176 (25.0) .32 0.94 0.68–1.31 .73
Delivery less than 37 wk 4 67/142 (47.2) 76/140 (54.3) .12 0.87 0.69–1.08 .21
Birth weight less than 2,500 g 2 23/31 (74.2) 27/35 (77.1) .85 0.98 0.76–1.25 .84
Respiratory distress 2 9/30 (30.0) 6/35 (17.1) .86 1.79 0.73–4.41 .20
IVH 1 1/15 (6.7) 2/19 (10.5) NA 0.63 0.06–6.34 .70
Necrotizing enterocolitis 1 0/15 (0) 1/19 (5.3) NA 0.42 0.02–9.55 .58
Sepsis/infection 1 2/15 (13.3) 7/19 (36.8) NA 0.36 0.09–1.49 .16
Fetal death 1 0/15 (0) 0/19 (0) NA — — —
Newborn death before 1 1/15 (6.7) 1/19 (5.3) NA 1.27 0.09–18.6 .86
discharge
Fetal or newborn death before 1 1/15 (6.7) 1/19 (5.3) NA 1.27 0.09–18.6 .86
discharge
IVH, intraventricular hemorrhage; NA, not applicable.
* Comparison of magnesium sulfate with terbutaline from Cotton et al32 used for this analysis.

658 Mercer and Merlino Magnesium Sulfate for Preterm Labor OBSTETRICS & GYNECOLOGY
Table 6. Gestational Age, Latency and Birth Weight Outcomes After Magnesium Sulfate Treatment
Compared With ␤-mimetics for Preterm Labor (Five Trials32,36 –39)*
Magnesium Control Heterogeneity Mean 95% Confidence P for
Outcome Studies (N) (N) P Difference Interval Overall Effect
Gestation at enrollment (wk) 4 142 140 .55 ⫺0.30 ⫺0.89 to 0.29 .32
Latency (wk) 2 61 71 .37 1.57 0.74 to 2.41 ⬍.001
Gestation at delivery (wk) 1 15 19 NA ⫺2.10 ⫺3.87 to ⫺0.33 .02
Birth weight (g) 2 61 71 .07 76.4 385.6 to 538.5 .75
NA, not applicable.
* Comparison of magnesium sulfate versus terbutaline from Cotton et al32 used for this analysis.

The 2002 Cochrane review regarding this issue also
found that magnesium sulfate tocolysis did not signifi-
cantly prolong pregnancy at 48 hours or 7 days or
prevent preterm birth.9 That analysis included data from
a study of magnesium sulfate compared with sedation
alone, which found delivery at 48 hours to be less
common with magnesium sulfate therapy (23.3% com-
pared with 91.4%, N⫽65).57 However, inclusion of this
trial into our analysis would have led to a result with
significant heterogeneity (data not shown).
Consistent with lack of evident benefit of magne-
sium sulfate tocolysis for pregnancy prolongation, we
found no improvements in perinatal mortality (fetal
death and/or newborn death before discharge) or the
most common perinatal morbidities (respiratory dis-
tress, intraventricular hemorrhage, severe intraventricu-
lar hemorrhage, necrotizing enterocolitis, newborn sep-
sis) when magnesium sulfate was compared with a
placebo/control or no therapy (Table 3 and Figs. 3–5).
No individual study demonstrated improved outcomes
with magnesium sulfate for any of the newborn
outcomes.
Magnesium Sulfate Compared With Other
Tocolytic Classes
Given the above findings, the question remains as to
whether alternative tocolytic classes might be more
effective than magnesium sulfate. Separate evalua-
tions were performed for head-to-head trials in which
magnesium was compared with a distinct alternative
tocolytic class. Magnesium sulfate was compared with
␤-mimetics in five studies, calcium channel blockers
in five studies, and cyclooxygenase inhibitors in five
studies. (Table 1). The results of these analyses are
summarized in Tables 5–10. Data available from
individual trials for selected outcomes are presented
in Figs. 1–5. Compared with magnesium sulfate,
␤-mimetic treatment was not associated with reduc-
tions in delivery at 48 hours, 7 days, preterm birth, or
low birth weight, despite an apparent improvement in
overall latency in two studies (Tables 5 and 6).32,36 –39
Compared with magnesium sulfate, calcium channel
blocker therapy did not improve any marker of
latency, prematurity, or gestational age at delivery

Table 7. Analysis of Pregnancy and Newborn Outcomes After Magnesium Sulfate Treatment Compared
With Calcium Channel Blockers for Preterm Labor (Five Trials31,40 – 43)
Magnesium Summary P for
Sulfate Control Heterogeneity Relative 95% Confidence Overall
Outcome Studies [n/N (%)] [n/N (%)] P Risk Interval Effect
Delivery less than 48 h 4 26/238 (10.9) 23/230 (10.0) .95 1.06 0.63–1.78 .84
Delivery less than 37 wk 3 92/173 (53.2) 93/189 (49.2) .76 1.07 0.88–1.30 .52
Delivery less than 34 wk 2 21/81 (25.9) 25/89 (28.1) .71 0.89 0.55–1.45 .64
Delivery less than 32 wk 1 10/92 (10.9) 7/100 (7.0) NA 1.55 0.62–3.91 .35
Birth weight less than 2,500 g 2 71/146 (48.6) 60/160 (37.5) .25 1.29 0.99–1.67 .06
Respiratory distress 2 28/146 (19.2) 26/159 (16.4) .78 1.15 0.71–1.86 .57
IVH 1 3/106 (2.8) 2/110 (1.8) NA 1.56 0.27–9.13 .62
Necrotizing enterocolitis 1 0/106 (0) 0/110 (0) NA — — —
Sepsis/infection 1 5/106 (4.7) 3/110 (2.7) NA 1.73 0.42–7.06 .45
Fetal death 3 0/146 (0) 1/146 (0.7) NA 0.41 0.02–9.91 .59
Newborn death before 4 1/252 (0.4) 3/256 (1.2) .44 0.59 0.13–2.70 .49
discharge
Fetal or newborn death 3 0/146 (0) 3/146 (2.1) .73 0.27 0.03–2.29 .23
before discharge
NA, not applicable; IVH, intraventricular hemorrhage.

VOL. 114, NO. 3, SEPTEMBER 2009 Mercer and Merlino Magnesium Sulfate for Preterm Labor 659
Table 8. Gestational Age, Latency, and Birth Weight Outcomes After Magnesium Sulfate Treatment
Compared With Calcium Channel Blockers for Preterm Labor (Five Trials31,40 – 43)
Magnesium Control Heterogeneity Mean 95% Confidence P for
Outcome Studies (N) (N) P Difference Interval Overall Effect
Gestation at enrollment (wk) 3 173 189 .26 ⫺0.25 ⫺0.82 to 0.31 .38
Latency (wk) 2 105 107 .44 0.23 ⫺0.79 to 1.26 .66
Gestation at delivery (wk) 3 198 196 .52 0.05 ⫺0.59 to 0.69 .88
Birth weight (g) 4 252 240 .73 ⫺10.4 ⫺134.6 to 113.9 .87

and did not prevent adverse newborn outcomes in
studies totaling more than 550 pregnancies (Tables 7
and 8).31,40 – 43 Similarly, treatment with cyclooxygen-
ase inhibitors did not appear to confer any benefits
over magnesium sulfate therapy (Tables 9 and
10).44 – 48 Comparison of perinatal morbidities accord-
ing to tocolytic classes was limited in some cases
because these results were not included in all studies
and/or the frequency of adverse outcomes was low.
No individual tocolytic class was more effective than
magnesium sulfate in preventing any of the evaluated
newborn morbidities or fetal/newborn mortality be-
fore discharge (Tables 5, 7, and 9).
Review of trials not included in the statistical
analyses found more frequent successful tocolysis at
12 hours with magnesium sulfate than with nitroglyc-
erin (78.6 compared with 37.5%, P⫽.03) and frequent
hypotension requiring discontinuation of nitroglyc-
erin (25%), but other outcomes relevant to this anal-
ysis were not published.53 In a comparison of magne-
sium sulfate and ritodrine in 67 women,
Tchilinguirian et al62 identified failed tocolysis within
48 hours to be similarly common between groups
(25% compared with 35.5%, P⫽.35), but data regard-
ing timing of delivery and other outcomes specific to
this analysis were not provided.
In an evaluation of seven studies, the Cochrane
review found an increased risk of total fetal, neonatal,
and/or neonatal deaths with magnesium tocolysis
(RR 2.82 [1.20 – 6.62]). However, there was no con-
sistent pattern between studies. We found no in-
creases in fetal or newborn death before discharge
(RR 1.08 [0.47–2.46) with magnesium sulfate therapy
compared with any alternative regimen. We did not
include the trial by Mittendorf et al58 because of the
lack of a distinct control intervention (caregiver’s
choice). Had we included this study in our analysis,
our finding of no evident increase in total death
before discharge would not have been altered (18 of
414 magnesium sulfate versus 10 of 420 control in
nine trials, RR 1.78 [0.86 –3.70]).
Efficacy of Other Tocolytic Agents
Detailed evaluation of the literature regarding the
efficacy other classes of tocolytic agents is beyond the
scope of this article, and recent reviews regarding
these have been published elsewhere.9,12–16 In the
preceding analyses, individual classes of tocolytic

Table 9. Pregnancy and Newborn Outcomes After Magnesium Sulfate Treatment Compared With
Cyclooxygenase Inhibitors for Preterm Labor (Five Trials44 – 48)
Magnesium Summary P for
Sulfate Control Heterogeneity Relative 95% Confidence Overall
Outcome Studies [n/N (%)] [n/N (%)] P Risk Interval Effect
Delivery less than 48 h 3 21/205 (10.2) 25/207 (12.1) .43 0.84 0.49–1.45 .53
Delivery less than 37 wk 1 7/43 (16.3) 4/45 (8.9) NA 1.83 0.58–5.81 .30
Respiratory distress 4 33/215 (15.3) 30/200 (15.0) .79 0.99 0.63–1.55 .96
IVH 4 17/215 (7.9) 15/200 (7.5) .91 0.99 0.52–1.88 .98
Grade 3–4 IVH 2 2/70 (2.9) 1/63 (1.6) .66 1.44 0.19–10.8 .72
Necrotizing enterocolitis 2 0/120 (0) 3/106 (2.8) .86 0.21 0.02–1.87 .16
Sepsis/infection 1 7/102 (6.9) 5/92 (5.4) NA 1.26 0.42–3.84 .68
Fetal death 1 0/52 (0) 0/49 (0) NA — — —
Newborn death before 3 6/172 (1.8) 2/155 (1.3) .42 2.28 0.55–9.55 .26
discharge
Fetal or newborn death 1 1/52 (1.9) 1/49 (2.0) NA 0.94 0.06–14.7 .97
before discharge
NA, not applicable; IVH, intraventricular hemorrhage.

660 Mercer and Merlino Magnesium Sulfate for Preterm Labor OBSTETRICS & GYNECOLOGY
Table 10. Gestational Age, Latency, and Birth Weight Outcomes After Magnesium Sulfate Treatment
Versus Cyclooxygenase Inhibitors for Preterm Labor (Five Trials44 – 48)
Magnesium Control Heterogeneity Mean 95% Confidence P for
Outcome Studies (N) (N) P Difference Interval Overall Effect
Gestation at enrollment (wk) 5 268 263 .10 0.50 0.02 to 0.98 .04
Latency (wk) 1 52 49 NA ⫺0.03 ⫺0.72 to 0.66 .93
Gestation at delivery (wk) 4 209 201 .74 ⫺0.13 ⫺0.78 to 0.51 .68
Birth weight (g) 4 224 207 .34 83.1 ⫺53.2 to 219.4 .23
NA, not applicable.

agents were not superior to magnesium sulfate. When
evaluated in aggregate, other tocolytic therapy was
not superior to magnesium sulfate regarding latency,
preterm birth, perinatal mortality, respiratory distress,
or intraventricular hemorrhage. (Figs. 1–5).31,32,36 – 49
Data available from the most recent substantive
Cochrane meta-analysis updates and subsequently
published randomized controlled trials are gener-
ally supportive of the findings obtained in the
current analysis. In 2004, Anotayanonth et al16
reported on 16 trials in which a ␤-mimetic was
compared with placebo or another ␤-mimetic to
inhibit preterm labor. Compared with placebo,
␤-mimetic treatment reduced delivery within 48
hours (RR 0.63 [0.53– 0.75]) and 7 days (RR 0.78
[0.68 – 0.90]), but no significant reductions in pre-
term birth, respiratory distress, or other neonatal
morbidities were evident. The only U.S. Food and
Drug Administration–approved tocolytic agent (in-
travenous ritodrine; Yutopar, AstraZeneca, Lon-
don, UK; NDA #018580) is no longer marketed in
the United States. In a 2005 Cochrane review of 13
trials, King et al12 found no improvements in neo-
natal outcomes when cyclooxygenase inhibitors
were compared with placebo (three trials) or with
other agents, although cyclooxygenase treatment
was associated with less frequent preterm birth,
delivery within 48 hours, and delivery within 7
days, as well as improvements in gestational age at
delivery and birth weight.66,67 Meta-analysis regard-

Magnesium Control Weight Risk ratio Delivery within 48 hours

Events Total Events Total (%) (95% CI) 0.05 0.2 1 5 20
Control or placebo
Cotton 1984 10 16 12 19 10.2 0.99 (0.59–1.65)
Fox 1993 19 45 29 45 27.1 0.66 (0.44–0.98)
How 2006 3 24 5 30 4.1 0.75 (0.20–2.83)
Subtotal (95% CI) 32 85 46 94 41.4 0.75 (0.54–1.03)
Heterogeneity: df=2, P=.46 Test for overall effect: P=.07
Betamimetics
Cotton 1984 10 16 9 19 7.7 1.32 (0.72–2.42)
Wilkins 1988 5 66 2 54 2.1 2.05 (0.41–10.13)
Chau 1992 2 46 4 52 3.5 0.57 (0.11–2.94)
Subtotal (95% CI) 17 128 15 125 13.2 1.23 (0.70–2.17)
Heterogeneity: df=2, P=.52 Test for overall effect: P=.47
Calcium channel blockers
Glock 1993 3 41 3 39 2.9 0.95 (0.20–4.43)
Larmon 1999 4 65 4 57 4.0 0.88 (0.23–3.35)
Haghighi 1999 12 40 8 34 8.1 1.27 (0.59–2.75)
Lyell 2007 7 92 8 100 7.2 0.95 (0.36–2.52)
Subtotal (95% CI) 26 238 23 230 22.1 1.06 (0.63–1.78)
Heterogeneity: df=3, P=.95 Test for overall effect: P=.84
Fig. 1. Comparison of magnesium
Cyclooxygenase inhibitors
sulfate tocolysis and other regimens
Morales 1993 8 52 5 49 4.8 1.51 (0.53–4.30)
McWhorter 2004 6 101 10 106 9.1 0.63 (0.24–1.67) (control/no therapy, individual toco-
Borna 2008 7 52 10 52 9.3 0.70 (0.29–1.70) lytic classes, any tocolytic agent, and
Subtotal (95% CI) 21 205 25 207 23.2 0.84 (0.49–1.45) any other regimen) for delivery within
Heterogeneity: df=2, P=.43 Test for overall effect: P=.53
48 hours. Modified from figures gen-
Compared with
other tocolytics 64 571 63 562 58.6 1.01 (0.74–1.38)
erated by Review Manager 5.0.
Heterogeneity: df=9, P=.88 Test for overall effect: P=.95 Copenhagen: The Nordic Cochrane
Centre, The Cochrane Collaboration,
Compared with
any control 96 656 109 656 100.0 0.90 (0.72–1.13) 2008. CI, confidence interval; df, de-
Heterogeneity: df=12, P=.79 Test for overall effect: P=.37 grees of freedom.
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 Magnesium Control Weight Risk ratio Delivery before 37 weeks
Events Total Events Total (%) (95% CI) 0.2 0.5 1 2 5
Control or placebo
Cotton 1984 14 16 16 19 7.4 1.04 (0.79–1.36)
How 2006 18 24 17 30 7.6 1.32 (0.90–1.95)
Subtotal (95% CI) 32 40 33 49 15.0 1.18 (0.93–1.51)
Heterogeneity: df=1, P=.27 Test for overall effect: P=.17
Betamimetics
Miller 1982 6 14 7 15 3.4 0.92 (0.41–2.07)
Cotton 1984 14 16 15 19 6.9 1.11 (0.82–1.49)
Wilkins 1988 35 66 29 54 16.0 0.99 (0.71–1.38)
Chau 1992 12 46 25 52 11.8 0.54 (0.31–0.95)
Subtotal (95% CI) 67 142 76 140 38.1 0.87 (0.69–1.08)
Heterogeneity: df=3, P=.12 Test for overall effect: P=.21
Calcium channel blockers
Glock 1993 24 41 23 39 11.9 0.99 (0.69–1.43)
Floyd 1995 18 40 18 50 8.0 1.25 (0.76–2.07) Fig. 2. Comparison of magnesium
Lyell 2007 50 92 52 100 25.1 1.05 (0.80–1.36)
Subtotal (95% CI) 92 173 93 189 45.0 1.07 (0.88–1.30)
sulfate tocolysis and other regimens
Heterogeneity: df=2, P=.76 Test for overall effect: P=.52 (control/no therapy, individual toco-
Cyclooxygenase inhibitors
lytic classes, any tocolytic agent, and
Schorr 1998 7 43 4 45 2.0 1.83 (0.58–5.81)
any other regimen) for preterm deliv-
Subtotal (95% CI) 7 43 4 45 2.0 1.83 (0.58–5.81) ery before 37 weeks of gestation.
Heterogeneity: Not applicable Test for overall effect: P=.30 Modified from figures generated by
Compared with Review Manager 5.0. Copenhagen:
other tocolytics 166 358 173 374 85.0 0.99 (0.86–1.15) The Nordic Cochrane Centre, The
Heterogeneity: df=7, P=.43 Test for overall effect: P=.95 Cochrane Collaboration, 2008. CI,
Compared with confidence interval; df, degrees of
any control 198 398 206 423 100.0 1.02 (0.90–1.17) freedom.
Heterogeneity: df=9, P=.47 Test for overall effect: P=.73
Mercer. Magnesium Sulfate for Preterm
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ing nitric oxide donors and oxytocin receptor an- of tocolytic agents.14,15 Finally, calcium channel
tagonists have failed to demonstrate improved blocker treatment for preterm labor has garnered
pregnancy or neonatal outcomes with these classes significant attention in recent years; however no

Fetal or newborn death

Magnesium Control Weight Risk ratio before discharge
Events Total Events Total (%) (95% CI) 0.01 0.1 1 10 100
Control or placebo
Cotton 1984a 1 15 4 19 31.2 0.32 (0.04–2.55)
Cox 1990 8 77 2 79 17.5 4.10 (0.90–18.71)
Fox 1993 0 45 0 45 Not estimable
How 2006 0 24 0 30 Not estimable
Subtotal (95% CI) 9 161 6 173 48.6 1.68 (0.60–4.70)
Heterogeneity: df=1, P=.05 Test for overall effect: P=.33
Betamimetics
Cotton 1984b 1 15 1 19 7.8 1.27 (0.09–18.62)
Subtotal (95% CI) 1 15 1 19 7.8 1.27 (0.09–18.62)
Heterogeneity: Not applicable Test for overall effect: P=.86
Calcium channel blockers
Glock 1993 0 41 2 39 22.6 0.19 (0.01–3.85)
Floyd 1995 0 40 1 50 11.8 0.41 (0.02–9.91)
Larmon 1999 0 65 0 57 Not estimable
Subtotal (95% CI) 0 146 3 146 34.5 0.27 (0.03–2.29) Fig. 3. Comparison of magnesium
Heterogeneity: df=1, P=.73 Test for overall effect: P=.23 sulfate tocolysis and other regimens
Cyclooxygenase inhibitors (control/no therapy, individual toco-
Morales 1993 1 52 1 49 9.1 0.94 (0.06–14.65) lytic classes, any tocolytic agent, and
Subtotal (95% CI) 1 52 1 49 9.1 0.94 (0.06–14.65) any other regimen) for fetal or new-
Heterogeneity: Not applicable Test for overall effect: P=.97 born death before discharge. Modi-
Compared with fied from figures generated by Review
other tocolytics 2 213 5 214 51.4 0.54 (0.14–2.09)
Manager 5.0. Copenhagen: The Nor-
Heterogeneity: df=3, P=.79 Test for overall effect: P=.37
dic Cochrane Centre, The Cochrane
Compared with
any control 11 374 11 387 100.0 1.09 (0.50–2.41)
Collaboration, 2008. CI, confidence
Heterogeneity: df=5, P=.31 Test for overall effect: P=.83 interval; df, degrees of freedom.
Mercer. Magnesium Sulfate for Preterm
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662 Mercer and Merlino Magnesium Sulfate for Preterm Labor OBSTETRICS & GYNECOLOGY
 Magnesium Control Weight Risk ratio Respiratory distress
Events Total Events Total (%) (95% CI) 0.05 0.2 1 5 20
Control or placebo
Cotton 1984 6 15 6 19 6.4 1.27 (0.51–3.14)
Cox 1990 15 75 15 79 17.6 1.05 (0.55–2.00)
Fox 1993 1 45 1 45 1.2 1.00 (0.06–15.50)
How 2006 0 24 0 30 Not estimable
Subtotal (95% CI) 22 159 22 173 25.1 1.10 (0.66–1.85)
Heterogeneity: df=2, P=.94 Test for overall effect: P=.71
Betamimetics
Miller 1982 3 15 2 16 2.3 1.60 (0.31–8.29)
Cotton 1984 6 15 4 19 4.2 1.90 (0.65–5.53)
Subtotal (95% CI) 9 30 6 35 6.6 1.79 (0.73–4.41)
Heterogeneity: df=1, P=.86 Test for overall effect: P=.20
Calcium channel blockers
Floyd 1995 4 40 5 49 5.4 0.98 (0.28–3.41)
Lyell 2007 24 106 21 110 24.8 1.19 (0.70–2.00)
Subtotal (95% CI) 28 146 26 159 30.2 1.15 (0.71–1.86)
Heterogeneity: df=1, P=.78 Test for overall effect: P=.57
Cyclooxygenase inhibitors
Morales 1993 5 52 5 49 6.2 0.94 (0.29–3.06)
Fig. 4. Comparison of magnesium sul-
Parilla 1997 5 18 5 14 6.8 0.78 (0.28–2.17) fate tocolysis and other regimens (con-
Schorr 1998 4 43 2 45 2.4 2.09 (0.40–10.85) trol/no therapy, individual tocolytic
McWhorter 2004 19 102 18 92 22.8 0.95 (0.53–1.70)
Subtotal (95% CI) 33 215 30 200 38.1 0.99 (0.63–1.55)
classes, any tocolytic agent, and any
Heterogeneity: df=3, P=.79 Test for overall effect: P=.96 other regimen) for respiratory distress.
Compared with
Modified from figures generated by Re-
other tocolytics 70 391 62 394 74.9 1.12 (0.83–1.53) view Manager 5.0. Copenhagen: The
Heterogeneity: df=7, P=.92 Test for overall effect: P=.45 Nordic Cochrane Centre, The Co-
Compared with chrane Collaboration, 2008. CI, confi-
any control 92 550 84 567 100.0 1.12 (0.86–1.46)
Heterogeneity: df=10, P=.99 Test for overall effect: P=.40
dence interval; df, dgrees of freedom.
Mercer. Magnesium Sulfate for Preterm
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placebo-controlled studies or comparisons with no tal morbidities including respiratory distress,

treatment have been published. In a 2003 Co- intraventricular hemorrhage, and necrotizing en-
chrane meta-analysis of 12 trials, King et al13 re- terocolitis with calcium channel blocker therapy.
ported improved latency and reductions in neona- However, these improvements were largely due to

Magnesium Control Weight Risk ratio Intraventricular hemorrhage

Events Total Events Total (%) (95% CI) 0.05 0.2 1 5 20
Control or placebo
Cotton 1984 1 15 3 19 9.9 0.42 (0.05–3.66)
Cox 1990 4 75 4 79 14.6 1.05 (0.27–4.06)
Fox 1993 0 45 0 45 Not estimable
How 2006 0 24 0 30 Not estimable
Subtotal (95% CI) 5 159 7 173 24.5 0.80 (0.26–2.45)
Heterogeneity: df=1, P=.48 Test for overall effect: P=.69
Betamimetics
Cotton 1984 1 15 2 19 6.6 0.63 (0.06–6.34)
Subtotal (95% CI) 1 15 2 19 6.6 0.63 (0.06–6.34)
Heterogeneity: Not applicable Test for overall effect: P=.70
Calcium channel blockers
Lyell 2007 3 106 2 110 7.4 1.56 (0.27–9.13)
Subtotal (95% CI) 3 106 2 110 7.4 1.56 (0.27–9.13)
Heterogeneity: Not applicable Test for overall effect: P=.62
Cyclooxygenase inhibitors
Fig. 5. Comparison of magnesium sul-
Morales 1993 4 52 4 49 15.4 0.94 (0.25–3.56)
Parilla 1997 6 18 4 14 16.9 1.17 (0.41–3.35) fate tocolysis and other regimens (con-
Schorr 1998 0 43 1 45 5.5 0.35 (0.01–8.33) trol/no therapy, individual tocolytic
McWhorter 2004 7 102 6 92 23.7 1.05 (0.37–3.02) classes, any tocolytic agent, and any
Subtotal (95% CI) 17 215 15 200 61.5 0.99 (0.52–1.88)
Heterogeneity: df=3, P=.91 Test for overall effect: P=.98 other regimen) for intraventricular hem-
Compared with
orrhage. Modified from figures gener-
other tocolytics 21 336 19 329 75.5 1.02 (0.57–1.81) ated by Review Manager 5.0. Copenha-
Heterogeneity: df=5, P=.97 Test for overall effect: P=.96 gen: The Nordic Cochrane Centre, The
Compared with Cochrane Collaboration, 2008. CI, con-
any control 26 495 26 502 100.0 0.96 (0.58–1.61) fidence interval; df, degrees of freedom.
Heterogeneity: df=7, P=.98 Test for overall effect: P=.89
Mercer. Magnesium Sulfate for Preterm
0.05 0.2 1 5 20 Labor. Obstet Gynecol 2009.

VOL. 114, NO. 3, SEPTEMBER 2009 Mercer and Merlino Magnesium Sulfate for Preterm Labor 663
the results of only one trial.68 No consistent pattern
regarding improved outcomes was seen in the
remaining 11 studies, and no significant improve-
ments in latency or newborn morbidities are evi-
dent with calcium channel blocker tocolysis if this
study is excluded from that analysis (data not
shown). Two subsequently published trials have
revealed conflicting results regarding the potential
benefits of calcium channel blockers.31,69 Sublingual
administration of nifedipine, the usual initial mode
of administration in the published tocolysis trials,
has been associated with serious cardiovascular
effects when given for hypertension, and this mode
of administration is not recommended in preg-
nancy or U.S. Food and Drug Administration–
approved for treatment of preterm labor.
Magnesium Sulfate for Neuroprotection
A number of observational studies in humans and
animal studies have evaluated the potential that pre-
natal exposure to magnesium sulfate might reduce
neurologic morbidities.70 –74 In addition to studies of
magnesium sulfate for seizure prophylaxis in preg-
nancies complicated by preeclampsia,75,76 four ran-
domized trials have been specifically designed to
evaluate magnesium sulfate for neuroprotection.77– 81
Although each of these four neuroprotection trials
failed to demonstrate significant improvements in the
designated primary outcome, none found increased
pediatric morbidities or mortality with magnesium
sulfate treatment given for this indication. Addition-
ally, these studies did find improvements in other
important outcomes with prenatal magnesium sulfate
exposure. Crowther et al,78 in a placebo controlled
trial of women considered likely to deliver within 24
hours and before 30 weeks of gestation (4-g intrave-
nous magnesium sulfate bolus over 20 minutes fol-
lowed by an infusion at 1 g/h until delivery or for up
to 24 hours), found less frequent “substantial gross
motor dysfunction” (3.4% compared with 6.6%; RR
0.51 [0.29 – 0.91]) and “death or substantial motor
gross motor dysfunction” (17.0% compared with
22.7%; RR 0.75 [0.59 – 0.96]) with magnesium sulfate
treatment. Marret et al81 compared magnesium sulfate
(4-g intravenous bolus over 30 minutes) with placebo
for women in preterm labor before 33 weeks of gesta-
tion and demonstrated reductions in death and/or gross
motor dysfunction (25.6% compared with 30.8%; odds
ratio 0.62 [0.41– 0.93]) and in death and/or motor or
cognitive dysfunction (34.9% compared with 40.5%;
odds ratio 0.68 [0.47– 0.99]) at 2-year follow-up. Rouse
et al80 studied women at 24 –31 6/7 weeks of gestation in
whom spontaneous or indicated preterm birth was
664 Mercer and Merlino Magnesium Sulfate for Preterm Labor
anticipated within 24 hours. Treatment included a 6-g
intravenous bolus of magnesium sulfate over 20 to 30
minutes followed by an infusion of 2 g/h, which was
discontinued if delivery was not considered imminent
after 12 hours. Retreatment was given for threatened
delivery before 34 weeks of gestation. Using this ap-
proach, these investigators demonstrated less frequent
moderate or severe cerebral palsy (1.9% compared with
3.5%; RR 0.55 [0.32– 0.95]) and overall cerebral palsy
(4.2% compared with 7.3%, P⫽.004) in the magnesium
sulfate arm. Comparisons between the published trials
are made difficult by differences in inclusion criteria,
study interventions, and evaluated outcomes. Although
a 2009 meta-analysis was supportive of magnesium
sulfate for neuroprotection before preterm birth, the
optimal treatment indication(s), gestational age range,
and therapeutic regimen remain to be determined.82
SUMMARY
Magnesium sulfate has been incorporated widely into
obstetric practice as a tocolytic agent for preterm
labor. Like other tocolytic agents, there is biologic
plausibility to suggest that magnesium might act to
interfere with uterine contractions by interference
with intracellular calcium directly or via membrane
calcium channels, and there is evidence that mag-
nesium can reduce spontaneous and induced myo-
metrial contractions. However, review of random-
ized clinical trials, including four comparing
magnesium sulfate with placebo/control or no ther-
apy and 16 comparing magnesium sulfate with an
alternate tocolytic regimen, has failed to demon-
strate that magnesium sulfate is effective in prevent-
ing preterm birth or reducing newborn morbidities
or mortality as compared with alternative or no
tocolytic treatments. Alternatively, ␤-mimetics, cal-
cium channel blockers, and cyclooxygenase inhib-
itors were not found to be superior when compared
with magnesium sulfate treatment. Recent meta-
analyses and randomized controlled trials do not
provide consistent evidence of a reduction in new-
bornmorbidities or mortality with these other toco-
lytic classes. Although it has been suggested that
tocolytic therapy might improve short-term preg-
nancy prolongation to facilitate antenatal cortico-
steroid administration, we did not find improve-
ments in delivery at 48 hours, respiratory distress
syndrome, or intraventricular hemorrhage with
magnesium sulfate, and we did not find any other
tocolytic class to be superior to magnesium sulfate
regarding these. It is disappointing that tocolytic
treatment with magnesium sulfate and other agents
has been so widely accepted in practice despite the
OBSTETRICS & GYNECOLOGY
relatively small number of patients studied and lack
of evident benefits.
Currently available data suggest that magnesium
sulfate administration does not increase the risk of
fetal and/or newborn mortality. Alternatively, accu-
mulating evidence indicates that magnesium sulfate
treatment before anticipated early preterm birth may
be protective against long-term neurologic morbidi-
ties including cerebral palsy. Because the potential
benefits of antenatal magnesium sulfate were identi-
fied only in secondary analyses from the recent major
prospective trials, caution is warranted in incorporat-
ing such treatment into clinical practice. The issues of
tocolysis and neuroprotection should be treated as
distinct entities. Magnesium sulfate should not be
given as a tocolytic solely because it might offer
neuroprotective benefits. Ultimately, it may be that
magnesium sulfate neuroprotection may be most ef-
fective for those who are not candidates for pregnancy
prolongation as these are the pregnancies at highest
risk for early delivery and newborn morbidities.
Controlled trials and dose-response studies are
needed to determine if magnesium sulfate tocolysis can
result in significant improvements in perinatal out-
comes. Similar studies are needed for the other classes of
tocolytic agents. Future research regarding tocolytic
therapies for preterm labor should include comparisons
with a control group that is not treated, optimally a
masked placebo regimen, and should be adequately
powered to evaluate improvements in significant new-
born morbidities and/or mortality, the primary reason
for attempted pregnancy prolongation in the setting of
preterm labor. Studies of magnesium sulfate tocolysis
should include assessment of magnesium levels to iden-
tify a clinically relevant therapeutic range, if any. Further
research is needed to determine if tocolytic administra-
tion concurrent with antenatal corticosteroid therapy,
treatment of acute risk factors for preterm birth, or
during maternal transport to a tertiary-care facility actu-
ally improves outcomes related to these interventions.
These studies may also help identify individuals who
will respond differently to specific tocolytic regimens
and those for whom attempts at pregnancy prolongation
may be futile. In the meantime, practitioners should
reconsider their current practices regarding tocolysis with
magnesium sulfate and other classes of tocolytic agents.
In light of the current evidence, the following
treatment options are offered for consideration. Local
practices, specific circumstances, and findings may
alter the approach to any individual patient.
1. It is appropriate to withhold magnesium sulfate
tocolysis from women presenting in preterm
VOL. 114, NO. 3, SEPTEMBER 2009 Mercer and Merlino
labor as neonatal benefit has not been demon-
strated with such treatment.
2. If initiated to achieve time to accrue the benefits
of antenatal corticosteroid administration, to
facilitate patient transport, or during treatment
of reversible causes of preterm labor, magne-
sium sulfate treatment can be discontinued once
these goals have been achieved or if labor
subsides before then.
3. It is appropriate to withhold magnesium sulfate
treatment from women with recurrent preterm
labor after the above benefits have been ac-
crued, as brief pregnancy prolongation is un-
likely to improve neonatal outcomes once these
goals have been achieved.
4. Because ␤-mimetic, calcium channel blocker,
and cyclooxygenase inhibitor therapies are not
clearly superior to magnesium sulfate tocolysis,
it is also appropriate to withhold tocolysis with
these agents from women in presenting in pre-
term labor. If used, discontinuation of treatment
should be considered once the short-term ther-
apeutic goal has been achieved.
5. Caregivers are encouraged to monitor for new
information and guidelines regarding antenatal
magnesium sulfate administration for neuropro-
tection when early preterm birth is anticipated.
6. If magnesium sulfate is given for neuroprotec-
tion, caregivers should follow a protocol used in
one of the three major trials that have demon-
strated benefits from this treatment.
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