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 andPreterm BirthBrian 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 oftocolytics are used in clinical practice, magnesium sulfate remains one of the most commonly usedagents. Magnesium sulfate has also been the focus of recent research for its potential neuroprotectiveeffects for neonates born preterm. Evaluation of 19 randomized clinical trials reveals that magnesiumsulfate tocolysis does not reduce the frequencies of delivery within 48 hours, 7 days, or early/latepreterm birth, and is not associated with improvements in newborn morbidities or mortality. Noother tocolytic class resulted in improved newborn outcomes when compared with magnesiumsulfate tocolysis. We conclude that it is appropriate to withhold tocolysis with magnesium sulfate orother 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, orfor other acute reasons, treatment can be discontinued once these goals have been achieved or iflabor subsides before then. Because brief pregnancy prolongation is unlikely to improve newbornoutcomes after corticosteroid administration has been completed, it is appropriate to withholdmagnesium sulfate tocolysis from women with recurrent preterm labor thereafter. If magnesiumsulfate is given for neuroprotection, a protocol from one of the three major trials that havedemonstrated benefits should be used.(Obstet Gynecol 2009;114:650–68)

Despite considerable clinical and research effortdirected toward the prevention of prematurity,

preterm birth complicated 12.8% of pregnancies inthe United States in 2006, a rise of 36% from the9.4% incidence rate in the 1981.1 Preterm birth iscritically important as it results directly in acuteneonatal 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 complicationsand are particularly more likely among neonatesborn before 32 weeks or under 1,500 grams.3–5

Approximately 75% of preterm births result fromspontaneous preterm labor or preterm prematurerupture of the membranes before labor, with half ormore of these resulting from preterm labor withintact membranes.6 – 8 Given that more than 500,000preterm births occur annually in the United Statesand 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 willvary. This opinion reflects information available at the time of its acceptance forpublication, and is neither designed nor intended to establish an exclusivestandard of perinatal care. This publication is not expected to reflect the opinionsof 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, MetroHealthMedical Center, Suite G240, MetroHealth Medical Center, 2500 MetroHealthDrive, Cleveland, OH 44109.

Financial DisclosureThe authors did not report any potential conflicts of interest.

© 2009 by The American College of Obstetricians and Gynecologists. Publishedby 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 andtreated for preterm labor each year. Tocolytictherapy to prolong pregnancy and reduce newborncomplications continues to be the focus of treat-ment of preterm labor.9 –16 Magnesium sulfate hasbeen one of the most commonly used agents for thisindication. The potential role of magnesium sulfatefor neuroprotection of infants born preterm has alsobeen recently studied.

The purpose of this article is to review thephysiology of magnesium, to evaluate the clinicalutility of magnesium sulfate therapy for treatment ofwomen presenting with preterm labor, and to con-sider the potential role of magnesium sulfate forneuroprotection when preterm birth is anticipated.This review focuses on the currently available peer-reviewed, randomized controlled trials evaluating theeffectiveness of acute tocolysis, as well as those re-garding magnesium sulfate for neuroprotection whenpreterm birth is anticipated.

PHYSIOLOGY OF MAGNESIUM SULFATESeveral recent articles have reviewed the molecularand cellular physiology of magnesium in detail.17–23

Magnesium, a bivalent cation, is the fourth mostcommon cation in the human body after sodium,potassium, and calcium. It is the second most com-mon intracellular cation after potassium. Intracellularmagnesium is found predominantly in bone (53%)and in myocytes (27%)17 and is localized to thenucleus, microsomes, and mitochondria.18 Only 1% oftotal body magnesium is found extracellularly,19 withserum magnesium accounting for 0.3% of total bodymagnesium content.17 Approximately 62% of serummagnesium 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 declinein pregnancy, likely due in part to hemodilution.20,21

Magnesium transport across cell membranes islargely carrier-mediated, is coupled to sodiumtransport, and is energy requiring. Magnesium ex-cretion occurs primarily through the urinary tractwith passive glomerular filtration. Approximately65% of filtered magnesium is actively reabsorbed inthe Loop of Henle, and 20 –30% is passively reab-sorbed in the proximal convoluted tubules.23 Inaddition to serving as a cofactor for numerousreactions, including energy metabolism and nucleicacid synthesis, magnesium is implicated in regula-tion of adenylate cyclase, transmembrane ion flux,muscle contraction and neuronal activity, as wellas control of vasomotor tone, cardiac excitability,

and neurotransmitter release.22 Magnesium sulfateis known to reduce spontaneous and induced myo-metrial contractions.24,25 Magnesium is believed toaffect contractility by competing with calcium inthe 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 intracellularand extracellular mechanisms resulting in de-creased intracellular calcium availability by block-ing channel-dependent influx of extracellular cal-cium and also by blocking agonist-stimulatedrelease of intracellular calcium via inositol 1,4,5-triphosphate receptor/channels.26,27 In vitro, mag-nesium sulfate has been demonstrated to reducespontaneous myometrial contractions at concentra-tions of 2–3 mmol (4 – 6 mEq/L), but suprapharma-cologic levels (4 –10 mmol, 8 –16 mEq/L) havebeen required to inhibit agonist mediated cyclicuterine activity.26 –28 Magnesium has been shownto potentiate neuromuscular blockade from non-depolarizing agents, such as vecuronium andpancuronium.

Potential mechanisms of perinatal brain injuryrelated to ischemia, infection and inflammation,and hemorrhage are described in recent reviews byBerger 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 injuryand magnesium is known to be intricately involvedin numerous cellular processes, the mechanisms bywhich 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 highlevels of magnesium might reduce post-traumaneuronal damage related to increased intracellularcalcium. N-methyl-D-aspartate receptor–mediatedattenuation of the decline in post-traumatic reduc-tion in intracellular magnesium levels has beenassociated with improved neurological outcome inrats. Another potential mechanism is the reductionof inositol 1,4,5-triphosphate receptor binding.Magnesium deficiency has been associated withreductions of antioxidant defenses and is associatedwith oxidative neuronal, myocardial, and endothe-lial death. However, magnesium deficiency has alsobeen associated with both increased and decreasedcellular apoptosis. Thus, while it is plausible thatmagnesium sulfate could provide neuroprotectionthrough mechanisms such as reduced vascular in-stability and hypoxic damage, and/or reductions incytokine/excitatory amino acid–induced 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 forPreterm Labor Published in English-Language Peer-Reviewed Journals

Study, YearGestational

Age (wk) Major Inclusion CriteriaPrimary Control

Group Treatment

Compared with controlCotton et al,32 1984 26–34 Contractions, three or more in 10 min, and

progressive cervical dilatation or 2 or more cmdilation or 80% or more effaced or SROM

Dextrose placebo

Cox et al,33 1990 24–34 Regular contractions and cervix between 1 and 5 cm Saline placebo

Fox et al,34 1993 34–37 Preterm labor with cervical change Sedation/hydration

How et al,35 2006 32–34 Contractions, six or more per h with progressivecervical dilatation or effacement

No tocolysis

Compared with �-mimeticsMiller et al,36 1982 Less than 37 Contractions, every 5 min or less for 1 h and

estimated fetal weight less than 2,500 gTerbutaline

Cotton et al,32 1984 26–34 Contractions, three in 10 min, and progressivecervical dilatation or 2 or more cm dilation or80% or more effaced or SROM

Terbutaline

Hollander et al,37 1987 20–35 Contractions, at least two in 10 min, and 30-sduration, with cervical change or with cervix 2or more cm in nulliparas

Ritodrine

Wilkins et al,38 1988 25–36 Contractions, every 5 min with cervix 50% or moreeffaced or 2 or more cm dilated

Ritodrine

Chau et al,39 1992 23–35 Contractions, three or more in 10 min after initialmeasures or with cervix 80% or more effaced ortwo or more cm dilated

Terbutaline

Compared with calciumchannel blockers

Floyd et al,40 1992 20–34 Contractions, regular every 10 min or less withcervix 2 cm or more or with cervical changefrom prior examination

Nifedipine

Glock and Morales,41 1993 20–33 Contractions, regular every 10 min or less withcervical change, or regular contractions withcervix 2 or more cm

Nifedipine

Haghighi,42 1999 23–36 Contractions, every 10 min or less Nifedipine

652 Mercer and Merlino Magnesium Sulfate for Preterm Labor OBSTETRICS & GYNECOLOGY

Method of Randomization andConcealment Treatments

AlternativeRescue Therapy

Three-armed trial, randomizationmethod unclear

MgSO4; 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 opaqueenvelopes

MgSO4; 4-g bolus then 2 g/h, increased to maximum of3 g/h, continued for 24 h

Saline 80 mL/h

No


MgSO4; 4-g bolus then 2 g/h, increased to maximum of4 g/h, until successful

Not stated


MgSO4; 6-g bolus then 2 g/h, increased to maximum of5 g/h until quiescence, for 24 h

No

Randomization method unclear, sealedenvelopes

MgSO4; 4-g bolus then 2 g/h for 2 h, then 1 g/h for 22 hTerbutaline, 0.25 mg intravenously then 10 microgram/

min increased to maximum of 25 microgram/min

Not stated

3-armed trial, randomization methodunclear

MgSO4; 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 MgSO4; 4-g bolus then 2 g/h, increased as needed toserum level 6–8 mg/dL, continued for 12 h

Alternate regimen

Ritodrine, 100 microgram/min intravenously, increasedto maximum of 350 microgram/min, continued for12 h


MgSO4; 4-g bolus then 2 g/h, increased as needed toserum level 5–8 mg/dL, continued for 24 h afterquiescence

Alternate regimen

Ritodrine 100 microgram/min intravenously, increasedto maximum of 350 microgram/min, continued for12 h after quiescence

Pseudo-randomization by medicalrecord number

MgSO4; 4-g bolus then 2 g/h, increased to maximum of4 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 forthree doses, then every 4 h until quiescence for 12 hor up to 24 h


MgSO4; 4-g bolus then 4-6 g/h as needed, continuedfor 6 h after quiescence

Nifedipine, 30 mg by mouth then 20 mg every 8 huntil quiescence

Not stated

Randomization method unclear MgSO4; 6-g bolus then 2 g/h, increased to maximum of4 g/h, until quiescence for 24 h

Nifedipine, 10 mg sublingual repeated every 20 min tomaximum of 40 mg, then 20 mg by mouth every4 h for 48 h

Intravenousritodrine

Randomization method unclear MgSO4; 6-g bolus then 2 g/h, increased to maximum of4 g/h, until quiescence for 12 h

Nifedipine, 10 mg sublingual repeated every 20 min tomaximum of 40 mg, then 20 mg by mouth every6 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 theseprocesses.

TOCOLYSIS FOR TREATMENT OF PRETERMLABORMagnesium sulfate has been evaluated and used forits tocolytic properties for nearly 50 years.25,30 Typ-ically a 4- to 6-g loading dose over 15–30 minutes isfollowed by a continuous infusion of 2 g/h, and thisinfusion may be increased up to 4 –5 g/h as neededin the absence of significant clinical side effects oroliguria. Magnesium toxicity is rarely seen withserum levels below 10 mg/dL, but respiratorydepression and subsequent arrest can occur atlevels above 10 –12 mg/dL. Although serious com-plications rarely occur during magnesium sulfatetocolysis, other side effects, including lethargy,

flushing, nausea and vomiting, blurred vision anddizziness, are not uncommon, occurring in 13–29%of patients in one report.31

Magnesium sulfate has been the subject ofnumerous clinical trials regarding its efficacy for thetreatment of preterm labor. Individual studies havebeen marked by inadequate power to evaluate theimpact of treatment on neonatal outcomes, theprimary reason for which pregnancy prolongationis attempted. Other than �-mimetics, most tocolyticagents have not been tested extensively against aplacebo or control group, and magnesium sulfate isnot an exception in this regard. Magnesium sulfatehas been compared with a wide variety of agents,including alcohol, �-mimetic agents, cyclooxygen-ase inhibitors, calcium channel blockers, and nitricoxide donors. Like other tocolytic agents, compar-

Table 1. Nineteen Included Randomized Clinical Trials of Intravenous Magnesium Sulfate Tocolysis forPreterm Labor Published in English-Language Peer-Reviewed Journals (continued)

Study, YearGestational

Age (wk) Major Inclusion CriteriaPrimary Control

Group Treatment

Larmon et al,43 1999 24–34 Regular contractions, four or more per h for 1 h ormore with cervical change

Nicardipine

Lyell et al,31 2007 24–33 Contractions, two or more every 10 min andcervical change, or SROM, or 2 or more cmdilated and 80% or more effaced

Nifedipine

Compared withcyclooxygenaseinhibitors

Morales and Madhav,44

1993Less than 32 Regular contractions, four or more in 20 min and

progressive cervical dilatation or effacement, orcervix 2 or more cm dilated

Indomethacin

Parilla et al,45 1997 Less than 30 Regular contractions with progressive cervicaldilatation and effacement

Indomethacin

Schorr et al,46 1998 20–32 Regular contractions 12 or more in 60 min withcervix 50% or more effaced, 2 or more cmdilated or cervical change from a recentexamination

Ketolorac

McWhorter et al,47 2004 22–34 Regular contractions with progressive cervicaldilatation or effacement

Rofecoxib

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

Celecoxib

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

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


ison of individual studies regarding magnesiumsulfate is made difficult by varying inclusion re-quirements (eg, diagnostic criteria for preterm la-bor, gestational age, the presence or absence ofintact membranes), concurrent interventions, dif-fering criteria for successful treatment, and therapyfor initial treatment failures, as well as selectivereporting of maternal and newborn outcomes.These trials have been the subject of several re-views and meta-analyses, which provide detaileddescriptions of the individual study designs andoutcomes.9 –11

The most recent substantial update of the Cochranesystematic review regarding magnesium sulfate tocolysisfor preterm labor was published by Crowther et al in2002.9 Published and unpublished data from 23 trials in

peer-reviewed journals and abstracts were evaluatedand included more than 2,000 pregnancies. The authorsconcluded that “there was no evidence of a clinicallyimportant tocolytic effect for magnesium sulphate; it didnot have any substantial effect on the proportion ofwomen delivering within 48 hours, either overall, or inany subgroup analysis. Moreover, there was no evi-dence of any substantial improvements in neonatalmorbidity.” Alternatively, in an evidence report on themanagement of preterm labor, Berkman et al10,11 eval-uated 18 randomized controlled trials and observationaland retrospective studies. Regarding magnesium as afirst-line treatment, this group determined that “signifi-cant differences were not found between magnesiumsulfate and placebo,” but regarding comparisons amongdifferent classes of tocolytics, “�-mimetics, calcium

Method of Randomization andConcealment Treatments

AlternativeRescue Therapy


MgSO4; 6-g bolus then 2 g/h, increased to maximum of4 g/h, until quiescence

Nicardipine, 40 mg by mouth, repeated every 2 h asrequired to maximum of 80 mg, then sustainedrelease nicardipine 45 mg every 12 h

Permitted butunspecified


MgSO4; 4-g bolus then 2 g/h, increased to maximum of4 g/h, until quiescence for 12 h

Nifedipine, 10 mg sublingual repeated every 20 min tomaximum of 80 mg, then 20 mg by mouth every 4to 6 h until quiescence for 12 h

Alternate regimen


MgSO4; 6-g bolus then 2 g/h, increased to maximum of5 g/h, until quiescence for 12 h

Indomethacin, 100 mg rectally, repeated one time asneeded after 1 h, then 25 mg by mouth every 4 hfor 48 h

Alternate regimen

Random number table, sealed opaqueenvelopes with cross-over

MgSO4; 8 g over 1 h, then 4 g over 4 h, then 2.5 g/h,until quiescence for 12 h


Indomethacin, 50 or 100 mg by mouth or rectally, then25–50 mg by mouth every 4–6 h for 24–48 h

Randomization unclear, sealed opaqueenvelopes controlled by pharmacy

MgSO4; 6-g bolus then 2 g/h, increased to maximum of6 g/h, and tapered until discontinued afterquiescence achieved

Not stated

Ketolorac 60 mg intramuscularly then 30 mgintramuscularly every 6 h as needed for up to 24 h

Random number table controlled bypharmacy

MgSO4; 4- to 6-g bolus then 2–4 g/h, for up to 48 h ifneeded


Rofecoxib 50 g by mouth daily for up to 48 h if neededRandom number table controlled by

pharmacyMgSO4; 4- to 6-g bolus then 2–4 g/h, for up to 48 h if

neededCelecoxib 100 g by mouth twice daily for up to 48 h if

needed


Pseudo-randomization by medicalrecord number. A saline controlgroup chosen “at random” and wasnot evaluated

MgSO4; 4-g bolus then 2 g/h until labor subsided9.5% 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, withpotentially small differences in effect sizes betweenclasses.” These authors concluded that “Overall, theevidence supports the notion that first-line treatmentwith �-mimetics, calcium channel blockers, magnesiumsulfate, or [nonsteroidal antiinflammatory drugs] offerssmall improvements in prolonging pregnancy.” Due tothe publication of an additional four trials regardingmagnesium sulfate as a first-line tocolytic agent forpreterm labor since the most recent Cochrane review,an additional analysis was performed for this review.

METHODS OF SYSTEMATIC REVIEWData SourcesAll English-language randomized clinical trials ofmagnesium sulfate tocolysis compared with an alter-nate tocolytic regimen or control therapy for pretermlabor were identified through literature review. Forthis analysis, PubMed (U.S. National Library of Med-icine) was searched for English-language randomizedcontrolled trials including the terms “tocolysis” andany of “magnesium,” “indomethacin,” “prostaglan-din,” “COX,” “cyclo-oxygenase,” “nitric oxide,”“NO,” “calcium,” “oxytocin receptor antagonist,”“atosiban,” “betamimetic,” and “�-agonist” that werepublished between January 1, 1966, and December31, 2008. The most recent Cochrane reviews regard-ing acute tocolysis with magnesium sulfate, tocolysiswith other agents, and the above mentioned Agencyfor Healthcare Research and Quality report werereviewed for additional studies.9–16

Study Selection and Data AbstractionStudies were excluded if magnesium was given inaddition to or following failure of another tocolyticagent, was compared with a control group whichincluded more than one agent, was compared withunspecified treatments at the discretion of the care-giver, or was given only to women with rupturedmembranes. 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 theoriginal peer-reviewed publications. The authors ofthe original articles were not contacted. Unpublisheddata used in other meta-analyses were not included.Each data point for all included articles was evaluatedseparately by two independent reviewers (B.M. andA.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

manuscript. Subsequently, the results of our datareview were compared with those from the mostrecent Cochrane analysis for those studies that wereincluded in both, and each manuscript for whichthere was a discrepancy was again reviewed to makea final determination for each outcome.

Selection of Outcomes

Pregnancy latency characteristics, including gesta-tional age at randomization and delivery, latency todelivery, and various markers of early delivery andpreterm birth (before 48 hours and 7 days, before32, 34, and 37 weeks) and low birth weight (below2,500 g) were evaluated for each included articlewhere available. Perinatal outcomes (fetal and/ornewborn mortality before discharge, major acutemorbidities before discharge) were also analyzed.

Statistical AnalysesStatistical analyses were performed using ReviewManager (RevMan) 5.0 (Copenhagen: The NordicCochrane Centre, The Cochrane Collaboration,2008) and figures were adapted from Forest plotsobtained using this software (forest plots are availableonline at http://links.lww.com/AOG/A121). MantelHaenszel �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 relativerisks (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 forthe summary RRs and mean differences were notevaluated. 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 tocolyticagents, and for all studies combined. Where aspecific outcome was not evaluated in any of thecompared trials, this outcome was excluded fromthe corresponding table. No sensitivity analyseswere prespecified.

Summary of Included and Excluded Articles

Table 1 summarizes those published peer-reviewedstudies regarding magnesium sulfate as a first-linetocolytic agent that were selected for inclusion. Infour of these trials, magnesium sulfate was com-pared with a control/placebo or no additionaltocolytic treatment.32–35 In 16 trials, magnesiumsulfate tocolysis was compared with an alternate


tocolytic regimen and had outcomes publishedrelevant to the current analyses.31,32,36 – 49 In onetrial, magnesium sulfate was compared with both aplacebo group and a specific alternative tocolyticregimen.32 Twelve studies utilized random numbertables for study group assignment, while two studiesused medical record numbers, and five did notspecify the method of randomization (Table 1).Study group assignment was concealed by sealedopaque envelopes in nine studies. In three trials, theenvelopes or random number table list was con-

trolled by the study pharmacy. In the remainingseven studies, the concealment method was un-clear. Three of the trials included evaluation ofmaternal serum magnesium levels to determineadequacy of dosing.37–39 The included studies wereinconsistent regarding the inclusion of twin preg-nancies and the method of presentation of theirnewborns’ outcomes. Some presented data for bothtwins while others presented only one set of new-born outcomes for each pregnancy, and these didnot 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 SpanishArmson et al,51 1992 Magnesium sulfate versus ritodrine, preterm deliveries excluded, no meaningful outcome dataBeall et al,52 1985 Magnesium sulfate versus �-mimetics, outcomes assigned to last therapy rather than to

assigned study groupEl-Sayed et al,53 1999 Magnesium sulfate versus nitroglycerin, randomized by shuffling sealed opaque

envelopes, outcomes specific to this analysis not reportedFerguson et al,54 1984 Combination therapy, magnesium sulfate adjuvant to ritodrineHatjis et al,55 1987 Combination therapy, magnesium sulfate adjuvant to ritodrineHow et al,56 1998 All patients had preterm premature rupture of the membranes and not all were contractingMa,57 1992 Magnesium sulfate versus barbiturates, published in ChineseMittendorf et al,58 2002 Control group received caregivers’ choice of ritodrine, terbutaline, indomethacin or nifedipine

for acute tocolysisNewton et al,59 1991 Magnesium sulfate alone versus magnesium sulfate in combination with indomethacin and

antibioticsOgburn et al,60 1985 Magnesium sulfate as adjuvant for primary tocolytic failureSciscione et al,61 1993 Abstract only, no peer reviewed manuscriptTchilinguirian et al,62 1984 Randomization method unclear, outcomes specific to this analysis not reportedWeiner et al,63 1998 All patients had premature rupture of the membranes, no distinct magnesium sulfate treatment

groupWischnik et al,64 1989 Combination therapy with another tocolytic (fenoterol), published in GermanZhu and Fu,65 1996 Magnesium sulfate versus ritodrine, published in Chinese

Table 3. Pregnancy and Newborn Outcomes After Magnesium Sulfate Treatment Compared WithControl or No Therapy for Preterm Labor (Four Trials32–35)*

Outcome Studies

MagnesiumSulfate

[n/N (%)]Control[N (%)]

HeterogeneityP

SummaryRelative

Risk

95%Confidence

Interval

P forOverallEffect

Delivery less than 48 h 3 32/85 (37.6) 46/94 (48.9) .46 0.75 0.54–1.03 .07Delivery less than 7 d 3 57/116 (49.1) 52/129 (40.3) .47 1.22 0.94–1.59 .14Delivery less than 37 wk 2 32/40 (80.0) 33/49 (67.3) .27 1.18 0.93–1.51 .17Birth weight less than 2,500 g 2 61/93 (65.6) 69/98 (70.4) .54 0.94 0.78–1.14 .53Respiratory distress 4 22/159 (13.8) 22/173 (12.7) .94 1.10 0.66–1.85 .71IVH 4 5/159 (3.1) 7/173 (4.0) .48 0.80 0.26–2.45 .69Grade 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 .89Sepsis/infection 1 2/15 (13.3) 0/19 (0) NA 6.25 0.32–121.1 .23Fetal death 4 2/161 (1.2) 0/173 (0) NA 5.13 0.25–105.1 .29Newborn death before

discharge4 7/159 (4.4) 6/173 (3.5) .08 1.33 0.45–3.92 .61

Fetal or newborn death beforedischarge

4 9/161 (5.6) 6/173 (3.5) .05 1.68 0.60–4.70 .33

IVH, intraventricular hemorrhage; NA, not applicable.* Comparison of magnesium sulfate with placebo from Cotton et al32 used for this analysis.


twin, the second twin, a randomly selected twin, orfor the worst outcome for either twin. Newbornoutcome data were analyzed as published in theprimary papers. Postrandomization exclusion andloss to follow-up were uncommon (less than 5%) inall studies with the exception of one in which 13 of114 recruited patients were excluded after random-ization.44 Sixteen additional studies were consid-ered but were excluded from further analysis basedon criteria delineated in Table 2.50 – 65 Results ofanalyses from the included trials are presented inTables 3–10 and Figures 1–5.

SUMMARY OF RESULTSMagnesium Sulfate Compared With Control orNo TherapyA major purported benefit of acute tocolysis forpreterm labor is brief pregnancy prolongation toallow administration of antenatal corticosteroids forfetal maturation. Data in this regard were frequentlyavailable in published trials, with 12 of 19 evaluatedstudies reporting the outcome of “delivery within 48

hours” for a total of 1,281 pregnancies. However, onlythree of four studies that compared magnesium sulfatewith a placebo/control or no therapy evaluated theimpact of such treatment on delivery within 48 hoursor within 7 days (Table 3).32–35 These trials appeared toinclude higher-risk populations than the trials compar-ing magnesium sulfate with an alternative tocolyticregimen, with more frequent early delivery and pretermbirth. Overall, magnesium sulfate tocolysis did not re-duce the frequency of delivery within 48 hours whencompared with placebo/control or no tocolytic treat-ment (RR 0.75 [0.54–1.03]) (Table 3 and Fig. 1). Nosignificant reductions in delivery within 7 days or before37 weeks of gestation were evident with magnesiumsulfate tocolysis, and no trend toward reduction in theoutcome of newborn birth weight below 2,500 g wasseen (Table 3 and Fig. 2). No individual study demon-strated improvements in these outcomes with magne-sium sulfate tocolysis. Significant heterogeneity was seenregarding latency to delivery and delivery gestation, butno improvement in newborn birth weight was seen withmagnesium treatment (Table 4).

Table 4. Gestational Age, Latency, and Birth Weight Outcomes After Magnesium Sulfate TreatmentCompared With Control or No Therapy for Preterm Labor (Four Trials32–35)*

Outcome StudiesMagnesium

(N)Control

(N)Heterogeneity

PMean

Difference95% Confidence

IntervalP for

Overall Effect

Gestation at enrollment (wk) 4 161 174 .05 �0.02 �0.28 to 0.25 .91Latency (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.

Table 5. Pregnancy and Newborn Outcomes After Magnesium Sulfate Treatment Compared With�-mimetics for Preterm Labor (Five Trials32,36–39)*

Outcome Studies

MagnesiumSulfate

[n/N (%)]Control

[n/N (%)]Heterogeneity

P

SummaryRelative

Risk95% Confidence

Interval

P forOverallEffect

Delivery less than 48 h 3 17/128 (13.3) 15/125 (12.0) .52 1.23 0.70–2.17 .47Delivery less than 7 d 5 40/176 (22.7) 44/176 (25.0) .32 0.94 0.68–1.31 .73Delivery less than 37 wk 4 67/142 (47.2) 76/140 (54.3) .12 0.87 0.69–1.08 .21Birth weight less than 2,500 g 2 23/31 (74.2) 27/35 (77.1) .85 0.98 0.76–1.25 .84Respiratory distress 2 9/30 (30.0) 6/35 (17.1) .86 1.79 0.73–4.41 .20IVH 1 1/15 (6.7) 2/19 (10.5) NA 0.63 0.06–6.34 .70Necrotizing enterocolitis 1 0/15 (0) 1/19 (5.3) NA 0.42 0.02–9.55 .58Sepsis/infection 1 2/15 (13.3) 7/19 (36.8) NA 0.36 0.09–1.49 .16Fetal death 1 0/15 (0) 0/19 (0) NA — — —Newborn death before

discharge1 1/15 (6.7) 1/19 (5.3) NA 1.27 0.09–18.6 .86

Fetal or newborn death beforedischarge

1 1/15 (6.7) 1/19 (5.3) NA 1.27 0.09–18.6 .86

IVH, intraventricular hemorrhage; NA, not applicable.* Comparison of magnesium sulfate with terbutaline from Cotton et al32 used for this analysis.


The 2002 Cochrane review regarding this issue alsofound that magnesium sulfate tocolysis did not signifi-cantly prolong pregnancy at 48 hours or 7 days orprevent preterm birth.9 That analysis included data froma study of magnesium sulfate compared with sedationalone, which found delivery at 48 hours to be lesscommon with magnesium sulfate therapy (23.3% com-pared with 91.4%, N�65).57 However, inclusion of thistrial into our analysis would have led to a result withsignificant heterogeneity (data not shown).

Consistent with lack of evident benefit of magne-sium sulfate tocolysis for pregnancy prolongation, wefound no improvements in perinatal mortality (fetaldeath and/or newborn death before discharge) or themost common perinatal morbidities (respiratory dis-tress, intraventricular hemorrhage, severe intraventricu-lar hemorrhage, necrotizing enterocolitis, newborn sep-sis) when magnesium sulfate was compared with aplacebo/control or no therapy (Table 3 and Figs. 3–5).No individual study demonstrated improved outcomeswith magnesium sulfate for any of the newbornoutcomes.

Magnesium Sulfate Compared With OtherTocolytic ClassesGiven the above findings, the question remains as towhether alternative tocolytic classes might be moreeffective than magnesium sulfate. Separate evalua-tions were performed for head-to-head trials in whichmagnesium was compared with a distinct alternativetocolytic class. Magnesium sulfate was compared with�-mimetics in five studies, calcium channel blockersin five studies, and cyclooxygenase inhibitors in fivestudies. (Table 1). The results of these analyses aresummarized in Tables 5–10. Data available fromindividual trials for selected outcomes are presentedin Figs. 1–5. Compared with magnesium sulfate,�-mimetic treatment was not associated with reduc-tions in delivery at 48 hours, 7 days, preterm birth, orlow birth weight, despite an apparent improvement inoverall latency in two studies (Tables 5 and 6).32,36–39

Compared with magnesium sulfate, calcium channelblocker therapy did not improve any marker oflatency, prematurity, or gestational age at delivery

Table 6. Gestational Age, Latency and Birth Weight Outcomes After Magnesium Sulfate TreatmentCompared With �-mimetics for Preterm Labor (Five Trials32,36–39)*


(N)Control

(N)Heterogeneity

PMean


IntervalP for

Overall Effect

Gestation at enrollment (wk) 4 142 140 .55 �0.30 �0.89 to 0.29 .32Latency (wk) 2 61 71 .37 1.57 0.74 to 2.41 �.001Gestation at delivery (wk) 1 15 19 NA �2.10 �3.87 to �0.33 .02Birth 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.

Table 7. Analysis of Pregnancy and Newborn Outcomes After Magnesium Sulfate Treatment ComparedWith Calcium Channel Blockers for Preterm Labor (Five Trials31,40–43)

Outcome Studies

MagnesiumSulfate

[n/N (%)]Control


P

SummaryRelative

Risk95% Confidence

Interval

P forOverallEffect

Delivery less than 48 h 4 26/238 (10.9) 23/230 (10.0) .95 1.06 0.63–1.78 .84Delivery less than 37 wk 3 92/173 (53.2) 93/189 (49.2) .76 1.07 0.88–1.30 .52Delivery less than 34 wk 2 21/81 (25.9) 25/89 (28.1) .71 0.89 0.55–1.45 .64Delivery less than 32 wk 1 10/92 (10.9) 7/100 (7.0) NA 1.55 0.62–3.91 .35Birth weight less than 2,500 g 2 71/146 (48.6) 60/160 (37.5) .25 1.29 0.99–1.67 .06Respiratory distress 2 28/146 (19.2) 26/159 (16.4) .78 1.15 0.71–1.86 .57IVH 1 3/106 (2.8) 2/110 (1.8) NA 1.56 0.27–9.13 .62Necrotizing 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 .45Fetal death 3 0/146 (0) 1/146 (0.7) NA 0.41 0.02–9.91 .59Newborn death before

discharge4 1/252 (0.4) 3/256 (1.2) .44 0.59 0.13–2.70 .49

Fetal or newborn deathbefore discharge

3 0/146 (0) 3/146 (2.1) .73 0.27 0.03–2.29 .23

NA, not applicable; IVH, intraventricular hemorrhage.


and did not prevent adverse newborn outcomes instudies totaling more than 550 pregnancies (Tables 7and 8).31,40–43 Similarly, treatment with cyclooxygen-ase inhibitors did not appear to confer any benefitsover magnesium sulfate therapy (Tables 9 and10).44–48 Comparison of perinatal morbidities accord-ing to tocolytic classes was limited in some casesbecause these results were not included in all studiesand/or the frequency of adverse outcomes was low.No individual tocolytic class was more effective thanmagnesium sulfate in preventing any of the evaluatednewborn morbidities or fetal/newborn mortality be-fore discharge (Tables 5, 7, and 9).

Review of trials not included in the statisticalanalyses found more frequent successful tocolysis at12 hours with magnesium sulfate than with nitroglyc-erin (78.6 compared with 37.5%, P�.03) and frequenthypotension 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 within48 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 tothis analysis were not provided.

In an evaluation of seven studies, the Cochranereview 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 therapycompared with any alternative regimen. We did notinclude the trial by Mittendorf et al58 because of thelack of a distinct control intervention (caregiver’schoice). Had we included this study in our analysis,our finding of no evident increase in total deathbefore discharge would not have been altered (18 of414 magnesium sulfate versus 10 of 420 control innine trials, RR 1.78 [0.86–3.70]).

Efficacy of Other Tocolytic AgentsDetailed evaluation of the literature regarding theefficacy other classes of tocolytic agents is beyond thescope of this article, and recent reviews regardingthese have been published elsewhere.9,12–16 In thepreceding analyses, individual classes of tocolytic

Table 8. Gestational Age, Latency, and Birth Weight Outcomes After Magnesium Sulfate TreatmentCompared With Calcium Channel Blockers for Preterm Labor (Five Trials31,40–43)


(N)Control

(N)Heterogeneity

PMean


IntervalP for

Overall Effect

Gestation at enrollment (wk) 3 173 189 .26 �0.25 �0.82 to 0.31 .38Latency (wk) 2 105 107 .44 0.23 �0.79 to 1.26 .66Gestation at delivery (wk) 3 198 196 .52 0.05 �0.59 to 0.69 .88Birth weight (g) 4 252 240 .73 �10.4 �134.6 to 113.9 .87

Table 9. Pregnancy and Newborn Outcomes After Magnesium Sulfate Treatment Compared WithCyclooxygenase Inhibitors for Preterm Labor (Five Trials44–48)

Outcome Studies

MagnesiumSulfate

[n/N (%)]Control


P

SummaryRelative

Risk95% Confidence

Interval

P forOverallEffect

Delivery less than 48 h 3 21/205 (10.2) 25/207 (12.1) .43 0.84 0.49–1.45 .53Delivery less than 37 wk 1 7/43 (16.3) 4/45 (8.9) NA 1.83 0.58–5.81 .30Respiratory distress 4 33/215 (15.3) 30/200 (15.0) .79 0.99 0.63–1.55 .96IVH 4 17/215 (7.9) 15/200 (7.5) .91 0.99 0.52–1.88 .98Grade 3–4 IVH 2 2/70 (2.9) 1/63 (1.6) .66 1.44 0.19–10.8 .72Necrotizing enterocolitis 2 0/120 (0) 3/106 (2.8) .86 0.21 0.02–1.87 .16Sepsis/infection 1 7/102 (6.9) 5/92 (5.4) NA 1.26 0.42–3.84 .68Fetal death 1 0/52 (0) 0/49 (0) NA — — —Newborn death before

discharge3 6/172 (1.8) 2/155 (1.3) .42 2.28 0.55–9.55 .26

Fetal or newborn deathbefore discharge

1 1/52 (1.9) 1/49 (2.0) NA 0.94 0.06–14.7 .97

NA, not applicable; IVH, intraventricular hemorrhage.


agents were not superior to magnesium sulfate. Whenevaluated in aggregate, other tocolytic therapy wasnot 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 substantiveCochrane meta-analysis updates and subsequentlypublished randomized controlled trials are gener-ally supportive of the findings obtained in thecurrent analysis. In 2004, Anotayanonth et al16

reported on 16 trials in which a �-mimetic wascompared with placebo or another �-mimetic toinhibit preterm labor. Compared with placebo,�-mimetic treatment reduced delivery within 48hours (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 neonatalmorbidities were evident. The only U.S. Food andDrug Administration–approved tocolytic agent (in-travenous ritodrine; Yutopar, AstraZeneca, Lon-don, UK; NDA #018580) is no longer marketed inthe United States. In a 2005 Cochrane review of 13trials, King et al12 found no improvements in neo-natal outcomes when cyclooxygenase inhibitorswere compared with placebo (three trials) or withother agents, although cyclooxygenase treatmentwas associated with less frequent preterm birth,delivery within 48 hours, and delivery within 7days, as well as improvements in gestational age atdelivery and birth weight.66,67 Meta-analysis regard-

Control or placeboCotton 1984Fox 1993How 2006Subtotal (95% CI)

10193

32

16452485

12295

46

19453094

10.227.1

4.141.4

0.99 (0.59–1.65)0.66 (0.44–0.98)0.75 (0.20–2.83)0.75 (0.54–1.03)

Heterogeneity: df=2, P=.46 Test for overall effect: P=.07

MagnesiumEvents Total

ControlEvents Total

Weight(%)

Risk ratio(95% CI)

Delivery within 48 hours0.05 0.2 1 5 20

Compared with other tocolytics

Compared with any control

Heterogeneity: df=9, P=.88


Test for overall effect: P=.9564 571 63 562 58.6 1.01 (0.74–1.38)


0.05 0.2 1 5 20

BetamimeticsCotton 1984Wilkins 1988Chau 1992Subtotal (95% CI)

1052

17

166646

128

924

15

195452

125

7.72.13.5

13.2

1.32 (0.72–2.42) 2.05 (0.41–10.13)

0.57 (0.11–2.94)1.23 (0.70–2.17)


Calcium channel blockersGlock 1993Larmon 1999Haghighi 1999Lyell 2007Subtotal (95% CI)

34

127

26

41654092

238

3488

23

395734

100230

2.94.08.17.2

22.1

0.95 (0.20–4.43)0.88 (0.23–3.35)1.27 (0.59–2.75)0.95 (0.36–2.52)1.06 (0.63–1.78)

Heterogeneity: df=3, P=.95 Test for overall effect: P=.84Cyclooxygenase inhibitorsMorales 1993McWhorter 2004Borna 2008Subtotal (95% CI)

867

21

5210152

205

5101025

4910652

207

4.89.19.3

23.2

1.51 (0.53–4.30)0.63 (0.24–1.67)0.70 (0.29–1.70)0.84 (0.49–1.45)


Fig. 1. Comparison of magnesiumsulfate tocolysis and other regimens(control/no therapy, individual toco-lytic classes, any tocolytic agent, andany other regimen) for delivery within48 hours. Modified from figures gen-erated by Review Manager 5.0.Copenhagen: The Nordic CochraneCentre, The Cochrane Collaboration,2008. CI, confidence interval; df, de-grees of freedom.Mercer. Magnesium Sulfate for PretermLabor. Obstet Gynecol 2009.

Table 10. Gestational Age, Latency, and Birth Weight Outcomes After Magnesium Sulfate TreatmentVersus Cyclooxygenase Inhibitors for Preterm Labor (Five Trials44–48)


(N)Control

(N)Heterogeneity

PMean


IntervalP for

Overall Effect

Gestation at enrollment (wk) 5 268 263 .10 0.50 0.02 to 0.98 .04Latency (wk) 1 52 49 NA �0.03 �0.72 to 0.66 .93Gestation at delivery (wk) 4 209 201 .74 �0.13 �0.78 to 0.51 .68Birth 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 improvedpregnancy or neonatal outcomes with these classes

of tocolytic agents.14,15 Finally, calcium channelblocker treatment for preterm labor has garneredsignificant attention in recent years; however no

Control or placeboCotton 1984How 2006Subtotal (95% CI)

141832

162440

161733

193049

7.47.6

15.0

1.04 (0.79–1.36)1.32 (0.90–1.95)1.18 (0.93–1.51)



ControlEvents Total

Weight(%)

Risk ratio(95% CI)

Delivery before 37 weeks

BetamimeticsMiller 1982Cotton 1984Wilkins 1988Chau 1992Subtotal (95% CI)


614351267

14166646142

715292576

15195452140

3.46.9

16.011.838.1

0.92 (0.41–2.07)1.11 (0.82–1.49)0.99 (0.71–1.38)0.54 (0.31–0.95)0.87 (0.69–1.08)

Test for overall effect: P=.21

Calcium channel blockersGlock 1993Floyd 1995Lyell 2007Subtotal (95% CI)


24185092

414092173

23185293

3950100189

11.98.0

25.145.0

0.99 (0.69–1.43)1.25 (0.76–2.07)1.05 (0.80–1.36)1.07 (0.88–1.30)


Cyclooxygenase inhibitorsSchorr 1998Subtotal (95% CI)

77

4343

44

4545

2.02.0

1.83 (0.58–5.81)1.83 (0.58–5.81)

Heterogeneity: Not applicable Test for overall effect: P=.30







0.2 0.5 1 2 5

0.2 0.5 1 2 5

Fig. 2. Comparison of magnesiumsulfate tocolysis and other regimens(control/no therapy, individual toco-lytic classes, any tocolytic agent, andany other regimen) for preterm deliv-ery before 37 weeks of gestation.Modified from figures generated byReview Manager 5.0. Copenhagen:The Nordic Cochrane Centre, TheCochrane Collaboration, 2008. CI,confidence interval; df, degrees offreedom.Mercer. Magnesium Sulfate for PretermLabor. Obstet Gynecol 2009.

Control or placeboCotton 1984aCox 1990Fox 1993How 2006Subtotal (95% CI)

18009

15774524

161

42006

19794530

173

31.217.5

48.6

0.32 (0.04–2.55)4.10 (0.90–18.71) Not estimable Not estimable1.68 (0.60–4.70)



ControlEvents Total

Weight(%)

Risk ratio(95% CI)

Fetal or newborn death before discharge

BetamimeticsCotton 1984bSubtotal (95% CI)

Heterogeneity: Not applicable

11

1515

11

1919

7.87.8

1.27 (0.09–18.62)1.27 (0.09–18.62)

Test for overall effect: P=.86Calcium channel blockersGlock 1993Floyd 1995Larmon 1999Subtotal (95% CI)


0000

414065146

2103

395057146

22.611.8

34.5

0.19 (0.01–3.85)0.41 (0.02–9.91) Not estimable0.27 (0.03–2.29)


Cyclooxygenase inhibitorsMorales 1993Subtotal (95% CI)

11

5252

11

4949

9.19.1

0.94 (0.06–14.65)0.94 (0.06–14.65)

Heterogeneity: Not applicable Test for overall effect: P=.97







0.01 0.1 1 10 100

0.01 0.1 1 10 100

Fig. 3. Comparison of magnesiumsulfate tocolysis and other regimens(control/no therapy, individual toco-lytic classes, any tocolytic agent, andany other regimen) for fetal or new-born death before discharge. Modi-fied from figures generated by ReviewManager 5.0. Copenhagen: The Nor-dic Cochrane Centre, The CochraneCollaboration, 2008. CI, confidenceinterval; df, degrees of freedom.Mercer. Magnesium Sulfate for PretermLabor. Obstet Gynecol 2009.


placebo-controlled studies or comparisons with notreatment have been published. In a 2003 Co-chrane meta-analysis of 12 trials, King et al13 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 placeboCotton 1984Cox 1990Fox 1993How 2006Subtotal (95% CI)

61510

22

15754524159

61510

22

19794530

173

6.417.6

1.2

25.1

1.27 (0.51–3.14)1.05 (0.55–2.00)1.00 (0.06–15.50) Not estimable1.10 (0.66–1.85)



ControlEvents Total

Weight(%)

Risk ratio(95% CI)

Respiratory distress0.05 0.2 1 5 20

BetamimeticsMiller 1982Cotton 1984Subtotal (95% CI)


369

151530

246

161935

2.34.26.6

1.60 (0.31–8.29)1.90 (0.65–5.53)1.79 (0.73–4.41)

Test for overall effect: P=.20Calcium channel blockersFloyd 1995Lyell 2007Subtotal (95% CI)


42428

40106146

52126

49110159

5.424.830.2

0.98 (0.28–3.41)1.19 (0.70–2.00)1.15 (0.71–1.86)


Cyclooxygenase inhibitorsMorales 1993Parilla 1997Schorr 1998McWhorter 2004Subtotal (95% CI)

554

1933

521843

102215

552

1830

49144592

200

6.26.82.4

22.838.1

0.94 (0.29–3.06)0.78 (0.28–2.17)2.09 (0.40–10.85)0.95 (0.53–1.70)0.99 (0.63–1.55)








0.05 0.2 1 5 20

Fig. 4. Comparison of magnesium sul-fate tocolysis and other regimens (con-trol/no therapy, individual tocolyticclasses, any tocolytic agent, and anyother regimen) for respiratory distress.Modified from figures generated by Re-view Manager 5.0. Copenhagen: TheNordic Cochrane Centre, The Co-chrane Collaboration, 2008. CI, confi-dence interval; df, dgrees of freedom.Mercer. Magnesium Sulfate for PretermLabor. Obstet Gynecol 2009.

Control or placeboCotton 1984Cox 1990Fox 1993How 2006Subtotal (95% CI)

14005

15754524

159

34007

19794530

173

9.914.6

24.5

0.42 (0.05–3.66)1.05 (0.27–4.06)

Not estimableNot estimable

0.80 (0.26–2.45)Heterogeneity: df=1, P=.48 Test for overall effect: P=.69


ControlEvents Total

Weight(%)

Risk ratio(95% CI)

Intraventricular hemorrhage0.05 0.2 1 5 20

BetamimeticsCotton 1984Subtotal (95% CI)


11

1515

22

1919

6.66.6

0.63 (0.06–6.34)0.63 (0.06–6.34)

Test for overall effect: P=.70Calcium channel blockersLyell 2007Subtotal (95% CI)


33

106106

22

110110

7.47.4

1.56 (0.27–9.13)1.56 (0.27–9.13)


Cyclooxygenase inhibitorsMorales 1993Parilla 1997Schorr 1998McWhorter 2004Subtotal (95% CI)

4607

17

521843

102215

4416

15

49144592

200

15.416.9

5.523.761.5

0.94 (0.25–3.56)1.17 (0.41–3.35)0.35 (0.01–8.33)1.05 (0.37–3.02)0.99 (0.52–1.88)








0.05 0.2 1 5 20

Fig. 5. Comparison of magnesium sul-fate tocolysis and other regimens (con-trol/no therapy, individual tocolyticclasses, any tocolytic agent, and anyother regimen) for intraventricular hem-orrhage. Modified from figures gener-ated by Review Manager 5.0. Copenha-gen: The Nordic Cochrane Centre, TheCochrane Collaboration, 2008. CI, con-fidence interval; df, degrees of freedom.Mercer. Magnesium Sulfate for PretermLabor. Obstet Gynecol 2009.


the results of only one trial.68 No consistent patternregarding improved outcomes was seen in theremaining 11 studies, and no significant improve-ments in latency or newborn morbidities are evi-dent with calcium channel blocker tocolysis if thisstudy is excluded from that analysis (data notshown). Two subsequently published trials haverevealed conflicting results regarding the potentialbenefits of calcium channel blockers.31,69 Sublingualadministration of nifedipine, the usual initial modeof administration in the published tocolysis trials,has been associated with serious cardiovasculareffects when given for hypertension, and this modeof administration is not recommended in preg-nancy or U.S. Food and Drug Administration–approved for treatment of preterm labor.

Magnesium Sulfate for NeuroprotectionA number of observational studies in humans andanimal studies have evaluated the potential that pre-natal exposure to magnesium sulfate might reduceneurologic morbidities.70–74 In addition to studies ofmagnesium sulfate for seizure prophylaxis in preg-nancies complicated by preeclampsia,75,76 four ran-domized trials have been specifically designed toevaluate magnesium sulfate for neuroprotection.77–81

Although each of these four neuroprotection trialsfailed to demonstrate significant improvements in thedesignated primary outcome, none found increasedpediatric morbidities or mortality with magnesiumsulfate treatment given for this indication. Addition-ally, these studies did find improvements in otherimportant outcomes with prenatal magnesium sulfateexposure. Crowther et al,78 in a placebo controlledtrial of women considered likely to deliver within 24hours 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 upto 24 hours), found less frequent “substantial grossmotor dysfunction” (3.4% compared with 6.6%; RR0.51 [0.29–0.91]) and “death or substantial motorgross motor dysfunction” (17.0% compared with22.7%; RR 0.75 [0.59–0.96]) with magnesium sulfatetreatment. Marret et al81 compared magnesium sulfate(4-g intravenous bolus over 30 minutes) with placebofor women in preterm labor before 33 weeks of gesta-tion and demonstrated reductions in death and/or grossmotor dysfunction (25.6% compared with 30.8%; oddsratio 0.62 [0.41–0.93]) and in death and/or motor orcognitive dysfunction (34.9% compared with 40.5%;odds ratio 0.68 [0.47–0.99]) at 2-year follow-up. Rouseet al80 studied women at 24–31 6/7 weeks of gestation inwhom spontaneous or indicated preterm birth was

anticipated within 24 hours. Treatment included a 6-gintravenous bolus of magnesium sulfate over 20 to 30minutes followed by an infusion of 2 g/h, which wasdiscontinued if delivery was not considered imminentafter 12 hours. Retreatment was given for threateneddelivery before 34 weeks of gestation. Using this ap-proach, these investigators demonstrated less frequentmoderate or severe cerebral palsy (1.9% compared with3.5%; RR 0.55 [0.32–0.95]) and overall cerebral palsy(4.2% compared with 7.3%, P�.004) in the magnesiumsulfate arm. Comparisons between the published trialsare made difficult by differences in inclusion criteria,study interventions, and evaluated outcomes. Althougha 2009 meta-analysis was supportive of magnesiumsulfate for neuroprotection before preterm birth, theoptimal treatment indication(s), gestational age range,and therapeutic regimen remain to be determined.82

SUMMARYMagnesium sulfate has been incorporated widely intoobstetric practice as a tocolytic agent for pretermlabor. Like other tocolytic agents, there is biologicplausibility to suggest that magnesium might act tointerfere with uterine contractions by interferencewith intracellular calcium directly or via membranecalcium 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 comparingmagnesium sulfate with placebo/control or no ther-apy and 16 comparing magnesium sulfate with analternate tocolytic regimen, has failed to demon-strate that magnesium sulfate is effective in prevent-ing preterm birth or reducing newborn morbiditiesor mortality as compared with alternative or notocolytic treatments. Alternatively, �-mimetics, cal-cium channel blockers, and cyclooxygenase inhib-itors were not found to be superior when comparedwith magnesium sulfate treatment. Recent meta-analyses and randomized controlled trials do notprovide consistent evidence of a reduction in new-bornmorbidities or mortality with these other toco-lytic classes. Although it has been suggested thattocolytic 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 distresssyndrome, or intraventricular hemorrhage withmagnesium sulfate, and we did not find any othertocolytic class to be superior to magnesium sulfateregarding these. It is disappointing that tocolytictreatment with magnesium sulfate and other agentshas been so widely accepted in practice despite the


relatively small number of patients studied and lackof evident benefits.

Currently available data suggest that magnesiumsulfate administration does not increase the risk offetal and/or newborn mortality. Alternatively, accu-mulating evidence indicates that magnesium sulfatetreatment before anticipated early preterm birth maybe protective against long-term neurologic morbidi-ties including cerebral palsy. Because the potentialbenefits of antenatal magnesium sulfate were identi-fied only in secondary analyses from the recent majorprospective trials, caution is warranted in incorporat-ing such treatment into clinical practice. The issues oftocolysis and neuroprotection should be treated asdistinct entities. Magnesium sulfate should not begiven as a tocolytic solely because it might offerneuroprotective benefits. Ultimately, it may be thatmagnesium sulfate neuroprotection may be most ef-fective for those who are not candidates for pregnancyprolongation as these are the pregnancies at highestrisk for early delivery and newborn morbidities.

Controlled trials and dose-response studies areneeded to determine if magnesium sulfate tocolysis canresult in significant improvements in perinatal out-comes. Similar studies are needed for the other classes oftocolytic agents. Future research regarding tocolytictherapies for preterm labor should include comparisonswith a control group that is not treated, optimally amasked placebo regimen, and should be adequatelypowered to evaluate improvements in significant new-born morbidities and/or mortality, the primary reasonfor attempted pregnancy prolongation in the setting ofpreterm labor. Studies of magnesium sulfate tocolysisshould include assessment of magnesium levels to iden-tify a clinically relevant therapeutic range, if any. Furtherresearch is needed to determine if tocolytic administra-tion concurrent with antenatal corticosteroid therapy,treatment of acute risk factors for preterm birth, orduring maternal transport to a tertiary-care facility actu-ally improves outcomes related to these interventions.These studies may also help identify individuals whowill respond differently to specific tocolytic regimensand those for whom attempts at pregnancy prolongationmay be futile. In the meantime, practitioners shouldreconsider their current practices regarding tocolysis withmagnesium sulfate and other classes of tocolytic agents.

In light of the current evidence, the followingtreatment options are offered for consideration. Localpractices, specific circumstances, and findings mayalter the approach to any individual patient.

1. It is appropriate to withhold magnesium sulfatetocolysis 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 benefitsof antenatal corticosteroid administration, tofacilitate patient transport, or during treatmentof reversible causes of preterm labor, magne-sium sulfate treatment can be discontinued oncethese goals have been achieved or if laborsubsides before then.

3. It is appropriate to withhold magnesium sulfatetreatment from women with recurrent pretermlabor after the above benefits have been ac-crued, as brief pregnancy prolongation is un-likely to improve neonatal outcomes once thesegoals have been achieved.

4. Because �-mimetic, calcium channel blocker,and cyclooxygenase inhibitor therapies are notclearly superior to magnesium sulfate tocolysis,it is also appropriate to withhold tocolysis withthese agents from women in presenting in pre-term labor. If used, discontinuation of treatmentshould be considered once the short-term ther-apeutic goal has been achieved.

5. Caregivers are encouraged to monitor for newinformation and guidelines regarding antenatalmagnesium 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 inone of the three major trials that have demon-strated benefits from this treatment.

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Magnesium Sulfate for Preterm Labor and Preterm Birth