Magnesium Sulfate For Preterm Labor and Preterm Birth

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. Magnesiumsulfate 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;114:65068)
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.
35
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.
68
Given that more than 500,000
preterm births occur annually in the United States
and that approximately half the women treated for
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 MaternalFetal 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
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.
916
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.
1723
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 0.750.95 mmol/L
(1.82.3 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 2030% 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,
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 actinmyosin 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 23 mmol (46 mEq/L), but suprapharma-
cologic levels (410 mmol, 816 mEq/L) have
been required to inhibit agonist mediated cyclic
uterine activity.
2628
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 receptormediated
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 acidinduced damage,
VOL. 114, NO. 3, SEPTEMBER 2009 Mercer and Merlino 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
Gestational
Age (wk) Major Inclusion Criteria
Primary Control
Group Treatment
Compared with control
Cotton et al,
32
1984 2634 Contractions, three or more in 10 min, and
progressive cervical dilatation or 2 or more cm
dilation or 80% or more effaced or SROM
Dextrose placebo
Cox et al,
33
1990 2434 Regular contractions and cervix between 1 and 5 cm Saline placebo
Fox et al,
34
1993 3437 Preterm labor with cervical change Sedation/hydration
How et al,
35
2006 3234 Contractions, six or more per h with progressive
cervical dilatation or effacement
No tocolysis
Compared with -mimetics
Miller et al,
36
1982 Less than 37 Contractions, every 5 min or less for 1 h and
estimated fetal weight less than 2,500 g
Terbutaline
Cotton et al,
32
1984 2634 Contractions, three in 10 min, and progressive
cervical dilatation or 2 or more cm dilation or
80% or more effaced or SROM
Terbutaline
Hollander et al,
37
1987 2035 Contractions, at least two in 10 min, and 30-s
duration, with cervical change or with cervix 2
or more cm in nulliparas
Ritodrine
Wilkins et al,
38
1988 2536 Contractions, every 5 min with cervix 50% or more
effaced or 2 or more cm dilated
Ritodrine
Chau et al,
39
1992 2335 Contractions, three or more in 10 min after initial
measures or with cervix 80% or more effaced or
two or more cm dilated
Terbutaline
Compared with calcium
channel blockers
Floyd et al,
40
1992 2034 Contractions, regular every 10 min or less with
cervix 2 cm or more or with cervical change
from prior examination
Nifedipine
Glock and Morales,
41
1993 2033 Contractions, regular every 10 min or less with
cervical change, or regular contractions with
cervix 2 or more cm
Nifedipine
Haghighi,
42
1999 2336 Contractions, every 10 min or less Nifedipine
652 Mercer and Merlino Magnesium Sulfate for Preterm Labor OBSTETRICS & GYNECOLOGY
Method of Randomization and
Concealment Treatments
Alternative
Rescue Therapy
Three-armed trial, randomization
method unclear
MgSO
4
; 4-g bolus then 2 g/h until quiescence for 12 h
(48 h if SROM)
Dextrose 5% at 125 mL/h
No
Random number table, sealed opaque
envelopes
MgSO
4
; 4-g bolus then 2 g/h, increased to maximum of
3 g/h, continued for 24 h
Saline 80 mL/h
No
envelopes
MgSO
4
4 g/h, until successful
Not stated
envelopes
MgSO
4
5 g/h until quiescence, for 24 h
No
Randomization method unclear, sealed
envelopes
MgSO
4
; 4-g bolus then 2 g/h for 2 h, then 1 g/h for 22 h
Terbutaline, 0.25 mg intravenously then 10 microgram/
min increased to maximum of 25 microgram/min
Not stated
3-armed trial, randomization method
unclear
MgSO
4
; 4-g bolus then 2 g/h until quiescence for 12 h
(48 h if SROM)
Terbutaline 9.2 microgram/min intravenously,
increased to max 25.3 microgram/min
No
Random number table MgSO
4
; 4-g bolus then 2 g/h, increased as needed to
serum level 68 mg/dL, continued for 12 h
Alternate regimen
Ritodrine, 100 microgram/min intravenously, increased
to maximum of 350 microgram/min, continued for
12 h
envelopes
MgSO
4
; 4-g bolus then 2 g/h, increased as needed to
serum level 58 mg/dL, continued for 24 h after
quiescence
Alternate regimen
Ritodrine 100 microgram/min intravenously, increased
to maximum of 350 microgram/min, continued for
12 h after quiescence
Pseudo-randomization by medical
record number
MgSO
4
4 g/h, until quiescence for 12 h or up to 24 h
Mg level maintained between 4 and 7 mg/dL
Alternate regimen
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
envelopes
MgSO
4
; 4-g bolus then 4-6 g/h as needed, continued
for 6 h after quiescence
Nifedipine, 30 mg by mouth then 20 mg every 8 h
until quiescence
Not stated
Randomization method unclear MgSO
4
4 g/h, until quiescence for 24 h
Nifedipine, 10 mg sublingual repeated every 20 min to
maximum of 40 mg, then 20 mg by mouth every
4 h for 48 h
Intravenous
ritodrine
Randomization method unclear MgSO
4
maximum of 40 mg, then 20 mg by mouth every
6 h for 24 h, then 20 mg every 8 h for 24 h
Not stated
(continued)
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 1530 minutes is
followed by a continuous infusion of 2 g/h, and this
infusion may be increased up to 45 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 1012 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 1329%
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-
Table 1. Nineteen Included Randomized Clinical Trials of Intravenous Magnesium Sulfate Tocolysis for
Preterm Labor Published in English-Language Peer-Reviewed Journals (continued)
Study, Year
Gestational
Age (wk) Major Inclusion Criteria
Primary Control
Group Treatment
Larmon et al,
43
1999 2434 Regular contractions, four or more per h for 1 h or
more with cervical change
Nicardipine
Lyell et al,
31
2007 2433 Contractions, two or more every 10 min and
cervical change, or SROM, or 2 or more cm
dilated and 80% or more effaced
Nifedipine
Compared with
cyclooxygenase
inhibitors
Morales and Madhav,
44
1993
Less than 32 Regular contractions, four or more in 20 min and
progressive cervical dilatation or effacement, or
cervix 2 or more cm dilated
Indomethacin
Parilla et al,
45
1997 Less than 30 Regular contractions with progressive cervical
dilatation and effacement
Indomethacin
Schorr et al,
46
1998 2032 Regular contractions 12 or more in 60 min with
cervix 50% or more effaced, 2 or more cm
dilated or cervical change from a recent
examination
Ketolorac
McWhorter et al,
47
2004 2234 Regular contractions with progressive cervical
dilatation or effacement
Rofecoxib
Borna and Saeidi,
48
2008 2434 Contractions, four or more in 20 min or eight in 60
min with progressive cervical change in dilation
or effacement
Celecoxib
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; MgSO
4
, magnesium sulfate.
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.
911
The most recent substantial update of the Cochrane
systematic reviewregarding magnesiumsulfate 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 al
10,11
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
Method of Randomization and
Concealment Treatments
Alternative
Rescue Therapy
envelopes
MgSO
4
4 g/h, until quiescence
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
Permitted but
unspecified
envelopes
MgSO
4
maximum of 80 mg, then 20 mg by mouth every 4
to 6 h until quiescence for 12 h
Alternate regimen
envelopes
MgSO
4
Indomethacin, 100 mg rectally, repeated one time as
needed after 1 h, then 25 mg by mouth every 4 h
for 48 h
Alternate regimen
envelopes with cross-over
MgSO
4
; 8 g over 1 h, then 4 g over 4 h, then 2.5 g/h,
until quiescence for 12 h
Permitted but
unspecified
Indomethacin, 50 or 100 mg by mouth or rectally, then
2550 mg by mouth every 46 h for 2448 h
Randomization unclear, sealed opaque
envelopes controlled by pharmacy
MgSO
4
6 g/h, and tapered until discontinued after
quiescence achieved
Not stated
Ketolorac 60 mg intramuscularly then 30 mg
intramuscularly every 6 h as needed for up to 24 h
Random number table controlled by
pharmacy
MgSO
4
; 4- to 6-g bolus then 24 g/h, for up to 48 h if
needed
Permitted but
unspecified
Rofecoxib 50 g by mouth daily for up to 48 h if needed
Random number table controlled by
pharmacy
MgSO
4
; 4- to 6-g bolus then 24 g/h, for up to 48 h if
needed
Celecoxib 100 g by mouth twice daily for up to 48 h if
needed
Permitted but
unspecified
Pseudo-randomization by medical
record number. A saline control
group chosen at random and was
not evaluated
MgSO
4
; 4-g bolus then 2 g/h until labor subsided
9.5% ethanol, 15 mL/kg over 2 h then 1.5 mg/kg until
labor subsided
Not stated
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.
916
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 others determination.
These results were then compared, and all discrepan-
cies were resolved by mutual re-review of the relevant
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.
3235
In 16 trials, magnesium
sulfate tocolysis was compared with an alternate
tocolytic regimen and had outcomes published
relevant to the current analyses.
31,32,3649
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.
3739
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 2. Magnesium Sulfate Tocolysis Studies Not Included in the Current Analysis
Study, Year Reason for Exclusion
Aramayo et al,
50
1990 Magnesium sulfate versus terbutaline, published in Spanish
Armson et al,
51
1992 Magnesium sulfate versus ritodrine, preterm deliveries excluded, no meaningful outcome data
Beall et al,
52
1985 Magnesium sulfate versus -mimetics, outcomes assigned to last therapy rather than to
assigned study group
El-Sayed et al,
53
1999 Magnesium sulfate versus nitroglycerin, randomized by shuffling sealed opaque
envelopes, outcomes specific to this analysis not reported
Ferguson et al,
54
1984 Combination therapy, magnesium sulfate adjuvant to ritodrine
Hatjis et al,
55
1987 Combination therapy, magnesium sulfate adjuvant to ritodrine
How et al,
56
1998 All patients had preterm premature rupture of the membranes and not all were contracting
Ma,
57
1992 Magnesium sulfate versus barbiturates, published in Chinese
Mittendorf et al,
58
2002 Control group received caregivers choice of ritodrine, terbutaline, indomethacin or nifedipine
for acute tocolysis
Newton et al,
59
1991 Magnesium sulfate alone versus magnesium sulfate in combination with indomethacin and
antibiotics
Ogburn et al,
60
1985 Magnesium sulfate as adjuvant for primary tocolytic failure
Sciscione et al,
61
1993 Abstract only, no peer reviewed manuscript
Tchilinguirian et al,
62
1984 Randomization method unclear, outcomes specific to this analysis not reported
Weiner et al,
63
1998 All patients had premature rupture of the membranes, no distinct magnesium sulfate treatment
group
Wischnik et al,
64
1989 Combination therapy with another tocolytic (fenoterol), published in German
Zhu and Fu,
65
1996 Magnesium sulfate versus ritodrine, published in Chinese
Table 3. Pregnancy and Newborn Outcomes After Magnesium Sulfate Treatment Compared With
Control or No Therapy for Preterm Labor (Four Trials
3235
)*
Outcome Studies
Magnesium
Sulfate
[n/N (%)]
Control
[N (%)]
Heterogeneity
P
Summary
Relative
Risk
95%
Confidence
Interval
P for
Overall
Effect
Delivery less than 48 h 3 32/85 (37.6) 46/94 (48.9) .46 0.75 0.541.03 .07
Delivery less than 7 d 3 57/116 (49.1) 52/129 (40.3) .47 1.22 0.941.59 .14
Delivery less than 37 wk 2 32/40 (80.0) 33/49 (67.3) .27 1.18 0.931.51 .17
Birth weight less than 2,500 g 2 61/93 (65.6) 69/98 (70.4) .54 0.94 0.781.14 .53
Respiratory distress 4 22/159 (13.8) 22/173 (12.7) .94 1.10 0.661.85 .71
IVH 4 5/159 (3.1) 7/173 (4.0) .48 0.80 0.262.45 .69
Grade 34 IVH 2 0/69 (0) 0/75 (0) NA
Necrotizing enterocolitis 4 4/159 (2.5) 4/173 (2.3) .49 1.09 0.303.97 .89
Sepsis/infection 1 2/15 (13.3) 0/19 (0) NA 6.25 0.32121.1 .23
Fetal death 4 2/161 (1.2) 0/173 (0) NA 5.13 0.25105.1 .29
Newborn death before
discharge
4 7/159 (4.4) 6/173 (3.5) .08 1.33 0.453.92 .61
Fetal or newborn death before
discharge
4 9/161 (5.6) 6/173 (3.5) .05 1.68 0.604.70 .33
IVH, intraventricular hemorrhage; NA, not applicable.
* Comparison of magnesium sulfate with placebo from Cotton et al
32
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.
5065
Results of
analyses from the included trials are presented in
Tables 310 and Figures 15.
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).
3235
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 [0.541.03]) (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-
siumsulfate 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 4. Gestational Age, Latency, and Birth Weight Outcomes After Magnesium Sulfate Treatment
Compared With Control or No Therapy for Preterm Labor (Four Trials
3235
)*
Outcome Studies
Magnesium
(N)
Control
(N)
Heterogeneity
P
Mean
Difference
95% Confidence
Interval
P for
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 al
32
-mimetics for Preterm Labor (Five Trials
32,3639
)*
Outcome Studies
Magnesium
Sulfate
[n/N (%)]
Control
[n/N (%)]
Heterogeneity
P
Summary
Relative
Risk
95% Confidence
Interval
P for
Overall
Effect
Delivery less than 7 d 5 40/176 (22.7) 44/176 (25.0) .32 0.94 0.681.31 .73
IVH 1 1/15 (6.7) 2/19 (10.5) NA 0.63 0.066.34 .70
Necrotizing enterocolitis 1 0/15 (0) 1/19 (5.3) NA 0.42 0.029.55 .58
Sepsis/infection 1 2/15 (13.3) 7/19 (36.8) NA 0.36 0.091.49 .16
Fetal death 1 0/15 (0) 0/19 (0) NA
discharge
1 1/15 (6.7) 1/19 (5.3) NA 1.27 0.0918.6 .86
Fetal or newborn death before
discharge
1 1/15 (6.7) 1/19 (5.3) NA 1.27 0.0918.6 .86
IVH, intraventricular hemorrhage; NA, not applicable.
* Comparison of magnesium sulfate with terbutaline from Cotton et al
32
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 pretermbirth.
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%, N65).
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. 35).
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 510. Data available from
individual trials for selected outcomes are presented
in Figs. 15. 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).
32,3639
Compared with magnesium sulfate, calcium channel
blocker therapy did not improve any marker of
latency, prematurity, or gestational age at delivery
Table 6. Gestational Age, Latency and Birth Weight Outcomes After Magnesium Sulfate Treatment
Compared With -mimetics for Preterm Labor (Five Trials
32,3639
)*
Outcome Studies
Magnesium
(N)
Control
(N)
Heterogeneity
P
Mean
Difference
95% Confidence
Interval
P for
Overall Effect
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 al
32
Table 7. Analysis of Pregnancy and Newborn Outcomes After Magnesium Sulfate Treatment Compared
With Calcium Channel Blockers for Preterm Labor (Five Trials
31,4043
)
Outcome Studies
Magnesium
Sulfate
[n/N (%)]
Control
[n/N (%)]
Heterogeneity
P
Summary
Relative
Risk
95% Confidence
Interval
P for
Overall
Effect
Delivery less than 32 wk 1 10/92 (10.9) 7/100 (7.0) NA 1.55 0.623.91 .35
IVH 1 3/106 (2.8) 2/110 (1.8) NA 1.56 0.279.13 .62
Necrotizing enterocolitis 1 0/106 (0) 0/110 (0) NA
Fetal death 3 0/146 (0) 1/146 (0.7) NA 0.41 0.029.91 .59
discharge
4 1/252 (0.4) 3/256 (1.2) .44 0.59 0.132.70 .49
Fetal or newborn death
before discharge
3 0/146 (0) 3/146 (2.1) .73 0.27 0.032.29 .23
NA, not applicable; IVH, intraventricular hemorrhage.
and did not prevent adverse newborn outcomes in
studies totaling more than 550 pregnancies (Tables 7
and 8).
31,4043
Similarly, treatment with cyclooxygen-
ase inhibitors did not appear to confer any benefits
over magnesium sulfate therapy (Tables 9 and
10).
4448
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 al
62
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 [1.206.62]). However, there was no con-
sistent pattern between studies. We found no in-
creases in fetal or newborn death before discharge
(RR 1.08 [0.472.46) with magnesium sulfate therapy
compared with any alternative regimen. We did not
include the trial by Mittendorf et al
58
because of the
lack of a distinct control intervention (caregivers
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 [0.863.70]).
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.
9,1216
In the
preceding analyses, individual classes of tocolytic
Compared With Calcium Channel Blockers for Preterm Labor (Five Trials
31,4043
)
Outcome Studies
Magnesium
(N)
Control
(N)
Heterogeneity
P
Mean
Difference
95% Confidence
Interval
P for
Overall Effect
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
Cyclooxygenase Inhibitors for Preterm Labor (Five Trials
4448
)
Outcome Studies
Magnesium
Sulfate
[n/N (%)]
Control
[n/N (%)]
Heterogeneity
P
Summary
Relative
Risk
95% Confidence
Interval
P for
Overall
Effect
Delivery less than 37 wk 1 7/43 (16.3) 4/45 (8.9) NA 1.83 0.585.81 .30
IVH 4 17/215 (7.9) 15/200 (7.5) .91 0.99 0.521.88 .98
Grade 34 IVH 2 2/70 (2.9) 1/63 (1.6) .66 1.44 0.1910.8 .72
Necrotizing enterocolitis 2 0/120 (0) 3/106 (2.8) .86 0.21 0.021.87 .16
Fetal death 1 0/52 (0) 0/49 (0) NA
discharge
3 6/172 (1.8) 2/155 (1.3) .42 2.28 0.559.55 .26
before discharge
1 1/52 (1.9) 1/49 (2.0) NA 0.94 0.0614.7 .97
NA, not applicable; IVH, intraventricular hemorrhage.
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. 15).
31,32,3649
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 al
16
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 [0.530.75]) and 7 days (RR 0.78
[0.680.90]), but no significant reductions in pre-
term birth, respiratory distress, or other neonatal
morbidities were evident. The only U.S. Food and
Drug Administrationapproved 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 al
12
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-
Control or placebo
Cotton 1984
Fox 1993
How 2006
Subtotal (95% CI)
10
19
3
32
16
45
24
85
12
29
5
46
19
45
30
94
10.2
27.1
4.1
41.4
0.99 (0.591.65)
0.66 (0.440.98)
0.75 (0.202.83)
0.75 (0.541.03)
Heterogeneity: df=2, P=.46 Test for overall effect: P=.07
Magnesium
Events Total
Control
Events Total
Weight
(%)
Risk ratio
(95% CI)
Delivery within 48 hours
0.05 0.2 1 5 20
Compared with
other tocolytics
Compared with
any control
Heterogeneity: df=9, P=.88
Test for overall effect: P=.95
64 571 63 562 58.6 1.01 (0.741.38)
96 656 109 656 100.0 0.90 (0.721.13)
0.05 0.2 1 5 20
Betamimetics
Cotton 1984
Wilkins 1988
Chau 1992
Subtotal (95% CI)
10
5
2
17
16
66
46
128
9
2
4
15
19
54
52
125
7.7
2.1
3.5
13.2
1.32 (0.722.42)
2.05 (0.4110.13)
0.57 (0.112.94)
1.23 (0.702.17)
Calcium channel blockers
Glock 1993
Larmon 1999
Haghighi 1999
Lyell 2007
Subtotal (95% CI)
3
4
12
7
26
41
65
40
92
238
3
4
8
8
23
39
57
34
100
230
2.9
4.0
8.1
7.2
22.1
0.95 (0.204.43)
0.88 (0.233.35)
1.27 (0.592.75)
0.95 (0.362.52)
1.06 (0.631.78)
Cyclooxygenase inhibitors
Morales 1993
McWhorter 2004
Borna 2008
Subtotal (95% CI)
8
6
7
21
52
101
52
205
5
10
10
25
49
106
52
207
4.8
9.1
9.3
23.2
1.51 (0.534.30)
0.63 (0.241.67)
0.70 (0.291.70)
0.84 (0.491.45)
Fig. 1. Comparison of magnesium
sulfate tocolysis and other regimens
(control/no therapy, individual toco-
lytic classes, any tocolytic agent, and
any other regimen) for delivery within
48 hours. Modified from figures gen-
erated by Review Manager 5.0.
Copenhagen: The Nordic Cochrane
Centre, The Cochrane Collaboration,
2008. CI, confidence interval; df, de-
grees of freedom.
Mercer. Magnesium Sulfate for Preterm
Labor. Obstet Gynecol 2009.
Versus Cyclooxygenase Inhibitors for Preterm Labor (Five Trials
4448
)
Outcome Studies
Magnesium
(N)
Control
(N)
Heterogeneity
P
Mean
Difference
95% Confidence
Interval
P for
Overall Effect
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.
ing nitric oxide donors and oxytocin receptor an-
tagonists have failed to demonstrate improved
pregnancy or neonatal outcomes with these classes
of tocolytic agents.
14,15
Finally, calcium channel
blocker treatment for preterm labor has garnered
significant attention in recent years; however no
Control or placebo
Cotton 1984
How 2006
Subtotal (95% CI)
14
18
32
16
24
40
16
17
33
19
30
49
7.4
7.6
15.0
1.04 (0.791.36)
1.32 (0.901.95)
1.18 (0.931.51)
Magnesium
Events Total
Control
Events Total
Weight
(%)
Risk ratio
(95% CI)
Delivery before 37 weeks
Betamimetics
Miller 1982
Cotton 1984
Wilkins 1988
Chau 1992
Subtotal (95% CI)
6
14
35
12
67
14
16
66
46
142
7
15
29
25
76
15
19
54
52
140
3.4
6.9
16.0
11.8
38.1
0.92 (0.412.07)
1.11 (0.821.49)
0.99 (0.711.38)
0.54 (0.310.95)
0.87 (0.691.08)
Glock 1993
Floyd 1995
Lyell 2007
Subtotal (95% CI)
24
18
50
92
41
40
92
173
23
18
52
93
39
50
100
189
11.9
8.0
25.1
45.0
0.99 (0.691.43)
1.25 (0.762.07)
1.05 (0.801.36)
1.07 (0.881.30)
Schorr 1998
Subtotal (95% CI)
7
7
43
43
4
4
45
45
2.0
2.0
1.83 (0.585.81)
1.83 (0.585.81)
Heterogeneity: Not applicable Test for overall effect: P=.30
Compared with
other tocolytics
Compared with
any control
166 358 173 374 85.0 0.99 (0.861.15)
198 398 206 423 100.0 1.02 (0.901.17)
0.2 0.5 1 2 5
0.2 0.5 1 2 5
any other regimen) for preterm deliv-
ery before 37 weeks of gestation.
Modified from figures generated by
Review Manager 5.0. Copenhagen:
The Nordic Cochrane Centre, The
Cochrane Collaboration, 2008. CI,
confidence interval; df, degrees of
freedom.
Control or placebo
Cotton 1984a
Cox 1990
Fox 1993
How 2006
Subtotal (95% CI)
1
8
0
0
9
15
77
45
24
161
4
2
0
0
6
19
79
45
30
173
31.2
17.5
48.6
0.32 (0.042.55)
4.10 (0.9018.71)
Not estimable
Not estimable
1.68 (0.604.70)
Magnesium
Events Total
Control
Events Total
Weight
(%)
Risk ratio
(95% CI)
before discharge
Betamimetics
Cotton 1984b
Subtotal (95% CI)
Heterogeneity: Not applicable
1
1
15
15
1
1
19
19
7.8
7.8
1.27 (0.0918.62)
1.27 (0.0918.62)
Glock 1993
Floyd 1995
Larmon 1999
Subtotal (95% CI)
0
0
0
0
41
40
65
146
2
1
0
3
39
50
57
146
22.6
11.8
34.5
0.19 (0.013.85)
0.41 (0.029.91)
Not estimable
0.27 (0.032.29)
Morales 1993
Subtotal (95% CI)
1
1
52
52
1
1
49
49
9.1
9.1
0.94 (0.0614.65)
0.94 (0.0614.65)
Heterogeneity: Not applicable Test for overall effect: P=.97
Compared with
other tocolytics
Compared with
any control
2 213 5 214 51.4 0.54 (0.142.09)
11 374 11 387 100.0 1.09 (0.502.41)
0.01 0.1 1 10 100
0.01 0.1 1 10 100
any other regimen) for fetal or new-
born death before discharge. Modi-
fied fromfigures generated by Review
Manager 5.0. Copenhagen: The Nor-
dic Cochrane Centre, The Cochrane
Collaboration, 2008. CI, confidence
interval; df, degrees of freedom.
placebo-controlled studies or comparisons with no
treatment have been published. In a 2003 Co-
chrane meta-analysis of 12 trials, King et al
13
re-
ported improved latency and reductions in neona-
tal morbidities including respiratory distress,
intraventricular hemorrhage, and necrotizing en-
terocolitis with calcium channel blocker therapy.
However, these improvements were largely due to
Control or placebo
Cotton 1984
Cox 1990
Fox 1993
How 2006
Subtotal (95% CI)
6
15
1
0
22
15
75
45
24
159
6
15
1
0
22
19
79
45
30
173
6.4
17.6
1.2
25.1
1.27 (0.513.14)
1.05 (0.552.00)
1.00 (0.0615.50)
Not estimable
1.10 (0.661.85)
Magnesium
Events Total
Control
Events Total
Weight
(%)
Risk ratio
(95% CI)
Respiratory distress
0.05 0.2 1 5 20
Betamimetics
Miller 1982
Cotton 1984
Subtotal (95% CI)
3
6
9
15
15
30
2
4
6
16
19
35
2.3
4.2
6.6
1.60 (0.318.29)
1.90 (0.655.53)
1.79 (0.734.41)
Floyd 1995
Lyell 2007
Subtotal (95% CI)
4
24
28
40
106
146
5
21
26
49
110
159
5.4
24.8
30.2
0.98 (0.283.41)
1.19 (0.702.00)
1.15 (0.711.86)
Morales 1993
Parilla 1997
Schorr 1998
McWhorter 2004
Subtotal (95% CI)
5
5
4
19
33
52
18
43
102
215
5
5
2
18
30
49
14
45
92
200
6.2
6.8
2.4
22.8
38.1
0.94 (0.293.06)
0.78 (0.282.17)
2.09 (0.4010.85)
0.95 (0.531.70)
0.99 (0.631.55)
Compared with
other tocolytics
Compared with
any control
70 391 62 394 74.9 1.12 (0.831.53)
92 550 84 567 100.0 1.12 (0.861.46)
0.05 0.2 1 5 20
Fig. 4. Comparison of magnesium sul-
fate tocolysis and other regimens (con-
trol/no therapy, individual tocolytic
classes, any tocolytic agent, and any
other regimen) for respiratory distress.
Modified from figures generated by Re-
view Manager 5.0. Copenhagen: The
Nordic Cochrane Centre, The Co-
chrane Collaboration, 2008. CI, confi-
dence interval; df, dgrees of freedom.
Control or placebo
Cotton 1984
Cox 1990
Fox 1993
How 2006
Subtotal (95% CI)
1
4
0
0
5
15
75
45
24
159
3
4
0
0
7
19
79
45
30
173
9.9
14.6
24.5
0.42 (0.053.66)
1.05 (0.274.06)
Not estimable
Not estimable
0.80 (0.262.45)
Magnesium
Events Total
Control
Events Total
Weight
(%)
Risk ratio
(95% CI)
Intraventricular hemorrhage
0.05 0.2 1 5 20
Betamimetics
Cotton 1984
Subtotal (95% CI)
1
1
15
15
2
2
19
19
6.6
6.6
0.63 (0.066.34)
0.63 (0.066.34)
Lyell 2007
Subtotal (95% CI)
3
3
106
106
2
2
110
110
7.4
7.4
1.56 (0.279.13)
1.56 (0.279.13)
Morales 1993
Parilla 1997
Schorr 1998
McWhorter 2004
Subtotal (95% CI)
4
6
0
7
17
52
18
43
102
215
4
4
1
6
15
49
14
45
92
200
15.4
16.9
5.5
23.7
61.5
0.94 (0.253.56)
1.17 (0.413.35)
0.35 (0.018.33)
1.05 (0.373.02)
0.99 (0.521.88)
Compared with
other tocolytics
Compared with
any control
21 336 19 329 75.5 1.02 (0.571.81)
26 495 26 502 100.0 0.96 (0.581.61)
0.05 0.2 1 5 20
Fig. 5. Comparison of magnesium sul-
fate tocolysis and other regimens (con-
trol/no therapy, individual tocolytic
classes, any tocolytic agent, and any
other regimen) for intraventricular hem-
orrhage. Modified from figures gener-
ated by Review Manager 5.0. Copenha-
gen: The Nordic Cochrane Centre, The
Cochrane Collaboration, 2008. CI, con-
fidence interval; df, degrees of freedom.
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.
7074
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.
7781
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 [0.290.91]) and death or substantial motor
gross motor dysfunction (17.0% compared with
22.7%; RR 0.75 [0.590.96]) with magnesium sulfate
treatment. Marret et al
81
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 [0.410.93]) and in death and/or motor or
cognitive dysfunction (34.9% compared with 40.5%;
odds ratio 0.68 [0.470.99]) at 2-year follow-up. Rouse
et al
80
studied women at 2431 6/7 weeks of gestation in
whom spontaneous or indicated preterm birth was
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 [0.320.95]) 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
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 whomattempts 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
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.
REFERENCES
1. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F,
Kirmeyer S, et al. Births: final data for 2006. National vital
statistics reports. Vol 57. Hyattsville, MD: National Center for
Health Statistics; 2009. p.1104.
2. Lemons JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll
BJ, et al. Very low birth weight outcomes of the National
Institute of Child Health and Human Development Neonatal
Research Network, January 1995 through December 1996.
NICHD Neonatal Research Network. Pediatrics 2001;107:E1.
3. Vohr BR, Wright LL, Poole WK, McDonald SA. Neurodevel-
opmental outcomes of extremely low birth weight infants 32
weeks gestation between 1993 and 1998. Pediatrics 2005;116:
63543.
4. Hack M, Flannery DJ, Schluchter M, Cartar L, Borawski E,
Klein N. Outcomes in young adulthood for very-low-birth-
weight infants. N Engl J Med 2002;346:14957.
5. Hintz SR, Kendrick DE, Vohr BR, Poole WK, Higgins RD.
National Institute of Child Health and Human Development
Neonatal Research Network. Changes in neurodevelopmental
outcomes at 18 to 22 months corrected age among infants of
less than 25 weeks gestational age born in 1993-1999. Pediat-
rics 2005;115:164551.
6. Meis PJ, Ernest JM, Moore ML. Causes of low birth weight
births in public and private patients. Am J Obstet Gynecol
1987;156:11658.
7. Tucker JM, Goldenberg RL, Davis RO, Copper RL, Winkler
CL, Hauth JC. Etiologies of preterm birth in an indigent
population: is prevention a logical expectation? Obstet
Gynecol 1991;77:3437.
8. Mercer BM, Goldenberg RL, Moawad AH, Meis PJ, Iams JD,
Das AF, et al. The preterm prediction study: effect of gesta-
tional age and cause of preterm birth on subsequent obstetric
outcome. Am J Obstet Gynecol 1999;181:121621.
9. Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for
preventing preterm birth in threatened preterm labour.
Cochrane Database of Systematic Reviews 2002, Issue 4. Art.
No.: CD001060. DOI: 10.1002/14651858.CD001060.
10. Berkman ND, Thorp Jr, JM Hartmann KE, Lohr KN, Anjolie
E, Idicula AE, et al. Management of preterm labor. Evidence
Report/Technology Assessment No. 18. Research Triangle
Institute. AHRQ Publication No. 01-E021. Rockville (MD):
Agency for Healthcare Research and Quality; 2000.
11. Berkman ND, Thorp JM Jr, Lohr KN, Carey TS, Hartmann
KE, Gavin NI, et al. Tocolytic treatment for the management
of preterm labor: a review of the evidence. Am J Obstet
Gynecol 2003;188:164859.
12. King J, Flenady V, Cole S, Thornton S. Cyclo-oxygenase
(COX) inhibitors for treating preterm labour. Cochrane Data-
base of Systematic Reviews 2005, Issue 2. Art. No.: CD001992.
DOI: 10.1002/14651858.CD001992.pub2.
13. King JF, Flenady VJ, Papatsonis DNM, Dekker GA, Carbonne
B. Calcium channel blockers for inhibiting preterm labour.
Cochrane Database of Systematic Reviews 2003, Issue 1. Art.
No.: CD002255. DOI: 10.1002/14651858.CD002255.
14. Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin receptor
antagonists for inhibiting preterm labour. Cochrane Database
of Systematic Reviews 2005, Issue 3. Art. No.: CD004452.
DOI: 10.1002/14651858.CD004452.pub2.
15. Duckitt K, Thornton S. Nitric oxide donors for the treatment of
preterm labour. Cochrane Database of Systematic Reviews
2002, Issue 3. Art. No.: CD002860. DOI: 10.1002/
14651858.CD002860.
16. Anotayanonth S, Subhedar NV, Neilson JP, Harigopal S.
Betamimetics for inhibiting preterm labour. Cochrane Data-
base of Systematic Reviews 2004, Issue 4. Art. No.: CD004352.
DOI: 10.1002/14651858.CD004352.pub2.
17. Elin RJ. Magnesium: the fifth but forgotten electrolyte. Am
J Clin Pathol 1994;102:61622.
18. Wolfe FI, Torsello A, Fasanella S, Cittadini A. Cell physiology
of magnesium. Mol Aspects Med 2003;24:1126.
19. Standing committee on the scientific evaluation of dietary
reference intakes, Food and Nutrition Board, Institute of
Medicine. Dietary reference intakes for calcium, phosphorous,
magnesium, vitamin D, and Fluoride. Washington, DC:
National Academies Press; 1997. p. 190249.
20. Kurzel RB. Serum magnesium levels in pregnancy and pre-
term labor. Am J Perinatol 1991;8:11927.
21. Weissberg N, Schwartz G, Shemesh O, Brooks BA, Algur N,
Eylath U, et al. Serum and mononuclear cell potassium,
magnesium, sodium and calcium in pregnancy and labour and
their relation to uterine muscle contraction. Magnes Res
1992;5:1737.
22. Fawcett WJ, Haxby EJ, Male DA. Magnesium: physiology and
pharmacology. Br J Anesthes 1999;83:30220.
23. Quamme GA, Dirks JH. The physiology of renal magnesium
handling. Ren Physiol 1986;9:25769.
24. Kumar D, Zourlas PA, Barnes AC. In vitro and in vivo effects
of magnesium sulfate on human uterine contractility. Am J
Obstet Gynecol 1963;86:103640.
25. Hall DG, Mcgaughey Jr, HS Corey EL, Thornton WN. The
effects of magnesium therapy on the duration of labor. Am J
26. Fomin VP, Gibbs SG, Vanam R, Morimiya A, Hurd WW.
Effect of magnesium sulfate on contractile force and intracel-
lular calcium concentration in pregnant human myometrium.
Am J Obstet Gynecol 2006;194:138490.
27. Phillippe M. Cellular mechanisms underlying magnesium sul-
fate inhibition of phasic myometrial contractions. Biochem
Biophys Res Commun 1998;252:5027.
28. Tica VI, Tica AA, Carlig V, Banica OS. Magnesium ion
inhibits spontaneous and induced contractions of isolated
uterine muscle. Gynecol Endocrinol 2007;23:36872.
29. Berger R, Garnier Y, Jensen A. Perinatal brain damage:
underlying mechanisms and neuroprotective strategies. J Soc
Gynecol Investig 2002;9:31928.
30. Hutchison HT, Nichols MM, Kuhn CR, Vasicka A. Effects of
magnesium sulphate on uterine contractility, intrauterine fetus,
and infant. Am J Obstet Gynecol 1964;88:74758.
31. Lyell DJ, Pullen K, Campbell L, Ching S, Druzin ML, Chitkara
U, Burrs D, Caughey AB, El-Sayed YY. Magnesium sulfate
compared with nifedipine for acute tocolysis of preterm labor:
a randomized controlled trial. Obstet Gynecol 2007;110:617.
32. Cotton DB, Strassner HT, Hill LM, Schifrin BS, Paul RH.
Comparison of magnesium sulfate, terbutaline and a placebo
for inhibition of preterm labor. A randomized study. J Reprod
Med 1984;29:927.
33. Cox SM, Sherman ML, Leveno KJ. Randomized investigation
of magnesium sulfate for prevention of preterm birth. Am J
34. Fox MD, Allbert JR, McCaul JF, Martin RW, McLaughlin BN,
Morrison JC. Neonatal morbidity between 34 and 37 weeks
gestation. J Perinatol 1993;13:34953.
35. How HY, Zafaranchi L, Stella CL, Recht K, Maxwell RA, Sibai
BM, et al. Tocolysis in women with preterm labor between 32
0/7 and 34 6/7 weeks of gestation: a randomized controlled
pilot study. Am J Obstet Gynecol 2006;194:97681.
36. Miller JM, Keane MWD, Horger EO. Comparison of magne-
sium sulfate and terbutaline for the arrest of premature labor.
J Reprod Med 1982;27:34851.
37. Hollander DI, Nagey DA, Pupkin MJ. Magnesium sulfate and
ritodrine hydrochloride: a randomized comparison. Am J
38. Wilkins IA, Lynch L, Mehalek KE, Berkowitz GS, Berkowitz
RL. Efficacy and side effects of magnesium sulfate and rito-
drine as tocolytic agents. Am J Obstet Gynecol 1988;159:
6859.
39. Chau AC, Gabert HA, Miller JM. A prospective comparison of
terbutaline and magnesium for tocolysis. Obstet Gynecol
1992;80:84751.
40. Floyd RC, McLauglin BN, Perry Jr, KG Martin RW, Sullivan
CA, Morrison JC. Magnesium sulfate or nifedipine hydrochlo-
ride for acute tocolysis of preterm labor: efficacy and side
effects. J Matern Fetal Invest 1995;5:259.
41. Glock JL, Morales WJ. Efficacy and safety of nifedipine versus
magnesium sulfate in the management of preterm labor: A
randomized study. Am J Obstet Gynecol 1993;169:9604.
42. Haghighi L. Prevention of preterm delivery: nifedipine or
magnesium sulfate. Int J Gynecol Obstet 1999;66:2978.
43. Larmon JE, Ross BS, May WL, Dickerson GA, Fischer RG,
Morrison JC. Oral nicardipine versus intravenous magnesium
sulfate for the treatment of preterm labor. Am J Obstet
Gynecol 1999;181:14327.
44. Morales WJ, Madhav H. Efficacy and safety of indomethacin
compared with magnesium sulfate in the management of
preterm labor: a randomized study. Am J Obstet Gynecol
1993;169:97102.
45. Parilla BV, Tamura RK, Cohen LS, Clark E. Lack of effect of
antenatal indomethacin on fetal cerebral blood flow. Am J
46. Schorr SJ, Ascarelli MH, Rust OA, Ross EL, Calfee EL, Perry
KG, et al. A Comparative study of ketorolac (toradol) and
magnesium sulfate for arrest of preterm labor. South Med J
1998;91:102832.
47. McWhorter J, Carlan S, OLeary T, Richici K, OBrien W.
Rofecoxib versus magnesium sulfate to arrest preterm labour:
a randomized trial. Obstet Gynecol 2004;103:92330.
48. Borna S, Saeidi FM. Celecoxib versus magnesium sulfate to
arrest preterm labor: randomized trial. J Obstet Gynaecol Res
2007;33:6314.
49. Steer CM, Petrie RH. A comparison of magnesium sulfate and
alcohol for the prevention of premature labor. Am J Obstet
Gynecol 1977;129:14.
50. Aramayo FJ, Martinez FJ, Rosales CL. Tocolytic therapy with
magnesium sulfate and terbutaline for inhibition of premature
labor [Terapia tocolitica con sulfato de magnesio y terbutalina
para la inhibicion del trabajo de parto pretermino]. Ginecol y
Obstet de Mexico 1990;58:2659.
51. Armson BA, Samuels P, Miller F, Verbalis J, Main EK.
Evaluation of maternal fluid dynamics during tocolytic therapy
with ritodrine hydrochloride and magnesium sulfate. Am J
52. Beall MH, Edgar BW, Paul RM, Smith-Wallace T. A compar-
ison of ritodrine, terbutaline, and magnesium sulfate for the
suppression of preterm labor. Am J Obstet Gynecol 1985;153:
8549.
53. El-Sayed YY, Riley ET, Holbrook RH, Cohen SE, Chitkara U,
Druzin ML. Randomized comparison of intravenous nitroglyc-
erin and magnesium sulfate for treatment of preterm labor.
54. Ferguson JE, Hensleigh PA, Kredenster D. Adjunctive use of
magnesium sulfate with ritodrine for preterm labour. Am J
55. Hatjis CG, Swain M, Nelson LH, Meis PJ, Ernest JM. Efficacy
of combined administration of magnesium sulfate and rito-
drine in the treatment of premature labor. Obstet Gynecol
1987;69:31722.
56. How HY, Cook CR, Cook VD, Miles DE, Spinnato JA.
Preterm premature rupture of membranes: aggressive tocolysis
versus expectant management. J Matern Fetal Med 1998;7:
812.
57. Ma L. Magnesium sulfate in prevention of preterm labor.
Chung Hua I Hsueh Tsa Chih Taipei 1992;72:15861.
58. Mittendorf R, Dambrosia J, Pryde PG, Lee KS, Gianopoulos
JG, Besinger RE, et al. Association between the use of antenatal
magnesium sulfate in preterm labor and adverse health out-
comes in infants. Am J Obstet Gynecol 2002;186:11118.
59. Newton ER, Shields L, Ridgway LE, Berkus MD, Elliott BD.
Combination antibiotics and indomethacin in idiopathic pre-
term labor: a randomized double-blind clinical trial. Am J
60. Ogburn PL, Hansen CA, Williams PP, Butler JC, Joseph MS,
Julian TM. Magnesium sulfate and B-mimetic dual-agent toco-
lysis in preterm labor after single-agent failure. J Reprod Med
1985;30:5837.
61. Sciscione A, Gorman R, Schlossman P, Colmorgen G. A
randomized prospective study of intravenous magnesium sul-
fate, ritodrine, and subcutaneous terbutaline as treatments for
preterm labor. Am J Obstet Gynecol 1993;168:376.
62. Tchilinguirian NG, Najem R, Sullivan GB, Craparo FJ. The
use of ritodrine and magnesium sulfate in the arrest of prema-
ture labor. Int J Gynaecol Obstet 1984;22:11723.
63. Weiner CP, Renk K, Klugman M. The therapeutic efficacy and
cost-effectiveness of aggressive tocolysis for premature labor
associated with premature rupture of the membranes. Am J
64. Wischnik A, Hettenbach A, Schmidt R, Zieger W, Hug G,
Melchert F. The effect of magnesium sulfate on volume
balance in tocolysis with the betamimetic agent fenoterol. Z
Geburtshilfe Perinatol 1989;193:2515.
65. Zhu B, Fu Y. Treatment of preterm labor with ritodrine
(translation). Chung Hua Fu Chan Ko Tsa Chih 1996;31:
7213.
66. Zuckerman H, Shalev E, Gilad G, Katzuni E. Further study of
the inhibition of premature labor by indomethacin. Part II
double-blind study. J Perinat Med 1984;12:259.
67. Panter KR, Hannah ME, Amankwah KS, Ohlsson A, Jefferies
AL, Farine D. The effect of indomethacin tocolysis in preterm
labour on perinatal outcome: a randomised placebo-controlled
trial. Br J Obstet Gynaecol 1999;106:46773.
68. Papatsonis DN, Van Geijn HP, Ade` r HJ, Lange FM, Bleker
OP, Dekker GA. Nifedipine and ritodrine in the management
of preterm labor: a randomized multicenter trial. Obstet
Gynecol 1997;90:2304.
69. Rayamajhi R, Pratap K. A comparative study between nifedi-
pine and isoxsuprine in the suppression of preterm labour.
Kathmandu Univ Med J 2003;1:18590.
70. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk
of cerebral palsy in very low birthweight infants? Pediatrics
1995;95:2639.
71. Schendel DE, Berg CJ, Yeargin-Allsopp M, Boyle CA, Dec-
oufle P. Prenatal magnesium sulfate exposure and the risk for
cerebral palsy or mental retardation among very low-birth-
weight children aged 3 to 5 years. JAMA 1996;276:180510.
72. Paneth N, Jetton J, Pinto-Martin J, Susser M. Magnesium
sulfate in labor and risk of neonatal brain lesions and cerebral
palsy in low birth weight infants. The Neonatal Brain Hemor-
rhage Study Analysis Group. Pediatrics 1997;99:E1.
73. Grether JK, Hoogstrate J, Walsh-Greene E, Nelson KB. Mag-
nesium sulfate for tocolysis and risk of spastic cerebral palsy in
premature children born to women without preeclampsia.
Am J Obstet Gynecol 2000;183:71725.
74. Boyle CA, Yeargin-Allsopp M, Schendel DE, Holmgreen P,
Oakley GP. Tocolytic magnesium sulfate exposure and risk of
cerebral palsy among children with birth weights less than
1,750 grams. Am J Epidemiol 2000;152:1204.
75. Altman D, Carroli G, Duley L, Farrell B, Moodley J, Neilson
J, et al. Do women with pre-eclampsia, and their babies, benefit
from magnesium sulphate? The Magpie Trial: a randomised
placebo-controlled trial. Lancet 2002;359:187790.
76. Magpie Trial Follow-Up Study Collaborative Group. The
Magpie Trial: a randomised trial comparing magnesium sul-
phate with placebo for pre-eclampsia. Outcome for children at
18 months. BJOG 2007;114:28999.
77. Mittendorf R, Covert R, Boman J, Khoshnood B, Lee KS,
Siegler M. Is tocolytic magnesium sulphate associated with
increased total paediatric mortality? Lancet 1997;350:
15178.
78. Crowther CA, Hiller JE, Doyle LW, Haslam RR. Effect of
magnesium sulfate given for neuroprotection before preterm
birth: a randomized controlled trial. JAMA 2003;290:
266976.
79. Marret S, Marpeau L, Zupan-Simunek V, Eurin D, Le ve que
Hellot MF, et al. Magnesium sulphate given before very-
preterm birth to protect infant brain: the randomised con-
trolled PREMAG trial. BJOG 2007;114:3108.
80. Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY,
Mercer BM, et al. A randomized, controlled trial of magne-
sium sulfate for the prevention of cerebral palsy. N Engl J Med
2008;359:895905.
81. Marret S, Marpeau L, Be nichou J. Benefit of magnesium
sulfate given before very preterm birth to protect infant brain.
Pediatrics 2008;121:2256.
82. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D.
Magnesium sulphate for women at risk of preterm birth for
neuroprotection of the fetus. Cochrane Database of Systematic
Reviews 2009, Issue 1. Art. No.: CD004661. DOI: 10.1002/
14651858.CD004661.pub3.

Magnesium Sulfate For Preterm Labor and Preterm Birth

Enviado por

Dados do documento

Título original

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

Magnesium Sulfate For Preterm Labor and Preterm Birth

Enviado por

Direitos autorais:

Formatos disponíveis

Clinical Expert Series

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

Você também pode gostar