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Current Commentary

Magnesium Sulfate TocolysisTime to Quit

David A. Grimes, MD, and Kavita Nanda, MD, MHS

Intravenous magnesium sulfate tocoly-sis remains a North American anomaly.This therapy rose to prominence basedon poor science and the recommenda-tions of authorities. However, a Co-chrane systematic review concludedthat magnesium sulfate is ineffective asa tocolytic. The review found no ben-

efit in preventing preterm or very pre-term birth. Moreover, the risk of totalpediatric mortality was significantlyhigher for infants exposed to magne-sium sulfate (relative risk 2.8; 95% con-fidence interval 1.26.6). Given its lackof benefit, possible harms, and ex-pense, magnesium sulfate should notbe used for tocolysis. Any further use ofmagnesium sulfate for tocolysis shouldbe restricted to formal clinical trialswith approval by an institutional reviewboard and signed informed consent for

participants. Should tocolysis be de-sired, calcium channel blockers, suchas nifedipine, seem preferable.(Obstet Gynecol 2006;108:9869)

Intravenous magnesium sulfate isineffective in stopping premature

labor; that it remains the most com-mon tocolytic in the United Statestoday is unexplained but reflects in-adequate progress toward rational

therapeutics in obstetrics. This com-mentary will describe the scope andpatterns of use, reveal its shaky sci-entific origins, review the evidence ofbenefit, describe harms of therapy,and discuss alternative agents.

SCOPE OF USE

Although precise figures on magne-sium sulfate tocolysis are elusive,the number of pregnant womenand fetuses exposed is large. In2003, 12.3% of all births in theUnited States were preterm. Ofthese approximately one half mil-lion preterm births, a substantialproportion, involved tocolysis(with any agent). The NationalCenter for Health Statistics re-ported that 86,000 women had to-

colysis associated with a live birthin that year. The total number ex-posed one or more times duringpregnancy was larger.

Others have estimated thatabout 150,000 U.S. women receivetocolytic therapy at 34 weeks ofgestation or less each year.1 If 80%1

of these women receive magne-

sium as the tocolytic agent, then theannual number of women exposedwould approximate 120,000. Mag-nesium sulfate has been used fortocolysis by family physicians, gen-eralist obstetricians, and perina-tologists alike.

A SHAKY START: POORSCIENCE AND WORSE ETHICS

As often happens in obstetrics, thistreatment became firmly en-trenched in practice long beforeproper evaluation.2 Based on thepotential ability of magnesium tosuppress smooth-muscle nervetransmission and to quiet myome-trial cells, clinicians began to usethe agent in uncontrolled (and pos-sibly unethical) human experi-

ments. After an early report fromGermany, American investigatorslaunched a study. The first U.S.trial allocated patients to three in-travenous treatment groups: mag-nesium sulfate, ethanol, or dextrose(the placebo). No mention wasmade of approval by an institu-tional review board or informedconsent. The allocation was doneby final digit of hospital number,which is not random and which

prevents allocation concealment.How nine participants were chosenat random to receive dextrose,while 31 women received magne-sium and another 31 got ethanol isunexplained. Imbalances in cervi-cal dilation upon entry into thestudy suggest selection bias. Theoutcome was also inappropriate:

From Family Health International, Research Trian-gle Park, North Carolina.

Corresponding author: David A. Grimes, MD, Fam-ily Health International, P. O. Box 13950, ResearchTriangle Park, North Carolina 27709; e-mail:[email protected].

2006 by The American College of Obstetriciansand Gynecologists. Published by Lippincott Williams& Wilkins.

ISSN: 0029-7844/06

Magnesium sulfate is

ineffective as a

tocolytic . . . , potentially

harmful to infants, and

unpleasant for women.

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stopping contractions and having aperiod of at least one day beforetheir recurrence. No infant out-comes were reported.

No significant difference emergedbetween magnesium and placebo.The relative risk (RR) of successwas 1.7 (95% confidence interval [CI]

0.83.7) for magnesium comparedwith placebo. Despite these method-ologic flaws, the authors claimed that,We have found that delivery can bedelayed with intravenous magnesiumsulfate for the required 48 hours in thevast majority of instances. This state-ment seems all the more peculiar,given that their observation periodended at 24 hours.

This cohort study was followedby studies of even less scientific

rigor. A case-series report of 192women without a comparisongroup concluded that, The presentstudy demonstrates the effective-ness of magnesium sulfate as a to-colytic agent to treat premature la-bor. Another retrospective case-series report on 355 patients(without a control group) reached asimilar untenable conclusion,MgSO4 was found to be a success-ful, inexpensive, and relatively

nontoxic tocolytic agent that hadfew side effects.3 However, studieswithout a comparison group do notallow causal inferences to be made.

RECOMMENDATIONS OF

AUTHORITIES

Pronouncements, often in presti-gious journals or from famous med-ical institutions, reinforced the effi-cacy of magnesium in cliniciansminds. Like the early investigators,

recent commentators have laudedmagnesium. A review article in theNew England Journal of Medicineclaimed that, Magnesium sulfate issafe and has become the first-linetreatment for preterm labor in NorthAmerica.4 (No evidence was pro-vided as to why this should be so.) Arecent Canadian medical newsletter

proclaimed that according to theMayo Clinic and the Medical Uni-versity of South Carolina, Magne-sium tocolysis stops preterm labor inits tracks (Dent E. Magnesium toco-lysis stops preterm labor in its tracks.National Review of Medicine. Avail-able at: http://www.nationalreview

ofmedicine.com/issue/2005/02_28/2_clinical11_04.html. Retrieved

January 18, 2006). The study in ques-tion was an unpublished retrospec-tive case series of 172 patients. TheMarch of Dimes also suggests mag-nesium is an effective tocolytic agent.

SYSTEMATIC REVIEWS OF

THE EVIDENCE

A Cochrane review of the worldsrandomized controlled trials, en-

compassing more than 2,000women in 23 trials, concluded thatmagnesium sulfate tocolysis is notonly ineffective but also harmful toinfants.5 Magnesium sulfate wascompared with no tocolytic inthree trials (saline, sedation plushydration, or sedation), beta mi-metics in ten, calcium channelblockers in four, prostaglandin syn-thetase inhibitors in two, nitroglyc-erin in one, ethanol in one, and

other combinations of agents intwo. Whether compared with notocolytic drug or with an alterna-tive tocolytic agent, magnesiumsulfate had no clinical benefit.Methodologic problems with thesetrials included inadequate descrip-tions of allocation concealment andhandling of losses to follow-up.5

No difference emerged in therisk of delivery within 48 hourswhen magnesium was compared

with the controls. No reduction inrisk of preterm (less than 37weeks) or very preterm (less than34 weeks) delivery occurred.Ironically, the risk of fetal andpediatric death was increased sig-nificantly for infants exposed tomagnesium sulfate (RR 2.8, 95%CI 1.26.6), based on seven stud-

ies encompassing 727 infants.These trials all featured an intra-venous loading dose of magne-sium sulfate (4 to 6 g), followed bycontinuous infusion (1.5 to 5 g/h).A test of statistical heterogeneityin these seven trials was insignifi-cant (P.21).5 No infant benefit in

respiratory distress syndrome, in-traventricular hemorrhage, infec-tion, or necrotizing enterocolitiswas evident. Magnesium sulfatewas less likely than betamimeticsto cause maternal adverse effectsrequiring discontinuation, butwas more likely than other treat-ments to cause unpleasant ad-verse effects.

An independent review fromCanada found the North American

preference for magnesium sulfateunexplained: Despite the lack ofclear tocolytic effects, magnesiumsulfate is one of the most populartocolytics in North America.6 A sys-tematic review commissioned by theU.S. Agency for Healthcare Re-search and Quality evaluated ran-domized controlled trials publishedbetween 1966 and 1999. This reviewfound two trials that compared mag-nesium sulfate with placebo. One

found that women receiving magne-sium were less likely to deliver in 48hours, but infants of the placebogroup had a higher estimated gesta-tional age at birth. The other trialfound similar birth outcomes withmagnesium sulfate and placebo.Birth weights were similar in bothgroups in both trials.

RECOMMENDATIONS OF

PROFESSIONAL

ORGANIZATIONS

Neither the American College ofObstetricians and Gynecologists northe Royal College of Obstetriciansand Gynaecologists endorses use ofmagnesium sulfate tocolysis. For ex-ample, the American College of Ob-stetricians and Gynecologists notesthat, . . .all [tocolytic agents] have

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demonstrated only limited benefit.Hence, there is no clear first-linetocolytic drug. The Royal Collegestates that, In view of the currentlack of evidence for any substantivebenefit for the baby from tocolysis,and the possibility of hazard for themother, the available evidence

should be discussed with the womanand her partner and their prefer-ences taken into account in deter-mining her care. The Scottish Pro-gramme for Clinical Effectiveness inReproductive Health guideline spe-cifically states Magnesium sulfate isone of the most popular tocolytics inNorth America despite lack of cleartocolytic effects. . ..

HARMS

Risks of magnesium therapyrange from unpleasant to fatal. Ofmost concern is the link betweenmagnesium and total pediatricmortality.1 Evidence comes bothfrom randomized controlled tri-als7,8 and an observational study.9

The Magnesium and NeurologicEndpoints Trial was designed totest the ability of magnesium toprevent cerebral palsy, and thefinding of increased total pediat-

ric mortality (fetal, neonatal, andpostneonatal) was unexpected.1

However, in retrospect, the ear-lier randomized controlled trial atParkland Hospital in Dallas alsoshowed a significant increase infetal and pediatric mortality asso-ciated with magnesium tocolysis.

A casecontrol study of perina-tal mortality at the Chicago Ly-ing-In Hospital from 1986 to 1999found a statistically significant in-

crease in risk of death with cumu-lative magnesium doses greaterthan 48 g.9 The odds ratio of deathwith this dose was 4.7 (95% CI1.120.0) compared with lowerdoses. Doses greater than 48 g oc-cur with regimens such as a 4 6 gbolus followed by 24 g/h for 24hours, used commonly for tocoly-

sis. Not all studies reveal that mag-nesium sulfate causes harm to thefetus or infant, and one study sug-gests a possible benefit.10 However,the doses of magnesium used inthis trial were lower than thosecommonly used for tocolysis (oftengreater than 50 g over 24 hours),

and a narrow therapeutic windowmay exist between benefit andharm (Mittendorf R, Lee KS, Roi-zen NJ, Pryde PG. Magnesium sul-fate for preterm neuroprotection[letter]. JAMA 2004;291:9401).

One inventory lists 23 mater-nal complications of magnesiumtocolysis. Respiratory arrest canresult from accidental overdosesof magnesium. Pulmonary edemaalso can be life-threatening. In

one study of pulmonary edema inpregnant women, the most com-mon cause was the use of toco-lytic agents, primarily intrave-nous magnesium sulfate. Othermore common side effects in-clude flushing, nausea, lethargy,chest tightness, and blurred vi-sion.

ALTERNATIVE TOCOLYTIC

AGENTS

If tocolytics are desired, otheragents are preferable to magne-sium sulfate. The strongest evi-dence exists for calcium channelblockers, usually nifedipine. In aCochrane systematic review ofrandomized trials, these drugs re-duced the number of women giv-ing birth within seven days (RR0.76; 95% CI 0.600.97) and be-fore 34 weeks of gestation (RR0.83; 95% CI 0.690.99). Fewer

women discontinued tocolytictherapy because of adverse drugreactions than with alternativeagents (RR 0.14; 95% CI 0.050.36). In addition, statistically sig-nificant benefit has been seen forinfants in terms of respiratory dis-tress syndrome, necrotizing en-terocolitis, intraventricular hem-

orrhage, and jaundice. In contrast,betamimetic drugs, such as ter-butaline, have little benefit. Theseagents decrease the number ofwomen giving birth within 48hours (RR 0.63; 95% CI 0.530.75)but do not reduce births withinseven days; they are often discontin-ued because of noxious side effects.Data are insufficient to assess the roleof cyclooxygenase inhibitors, such asindomethacin. Randomized con-trolled trials have not confirmed thesuperiority of oxytocin receptor an-tagonists (atosiban) over betami-metic drugs or placebo.

CONCLUSION

Magnesium sulfate is ineffectiveas a tocolytic (even in delayinglabor for the short time needed toadminister corticosteroids), po-tentially harmful to infants, andunpleasant for women. Hence,further use of this agent is inap-propriate unless in the context ofa formal clinical trial with institu-tional review board approval andinformed consent for participants.Although inconsistent, evidence

suggests that magnesium sulfatetocolysis may be associated withan excess of 1,900 to 4,800 fetaland neonatal deaths annually inthe U.S., depending on the extentof its use and attributable mortal-ity.1 If so, 7% of infant mortalitymight be caused by this agent.1

Should magnesium ultimately befound to be protective of the cen-tral nervous system of infants,that still would not justify its use

for tocolysis, for which it has beenfound worthless.5

Overgrazing of ineffective andharmful practices on the medicalcommons is a stubborn problem inobstetrics. When we recount the in-appropriate and unethical use of in-travenous ethanol as a tocolyticagent three decades ago, resident

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physicians today find it laughable.Few realize, however, that contem-porary tocolysis with intravenousEpsom salt (magnesium sulfate) mayseem equally ludicrous three de-cades from now. Tocolysis with mag-nesium sulfate is ineffective, and thepractice should stop.

REFERENCES1. Mittendorf R, Pryde P, Khoshnood B,

Lee KS. If tocolytic magnesium sulfateis associated with excess total pediatricmortality, what is its impact? ObstetGynecol 1998;92:30811.

2. Mittendorf R, Pryde PG. A review ofthe role for magnesium sulphate in pre-

term labour. BJOG 2005;112 suppl:848.

3. Elliott JP. Magnesium sulfate as a toco-lytic agent. Am J Obstet Gynecol 1983;147:27784.

4. Norwitz ER, Robinson JN, Challis JR.The control of labor. N Engl J Med1999;341:6606.

5. Crowther CA, Hiller JE, Doyle LW.

Magnesium sulphate for preventingpreterm birth in threatened pretermlabour. Cochrane Database Syst Rev2002;CD001060.

6. Gyetvai K, Hannah ME, Hodnett ED,Ohlsson A. Tocolytics for pretermlabor: a systematic review. ObstetGynecol 1999;94:86977.

7. Mittendorf R, Covert R, Boman J,Khoshnood B, Lee KS, Siegler M. Istocolytic magnesium sulphate associ-

ated with increased total paediatricmortality? Lancet 1997;350:15178.

8. Cox SM, Sherman ML, Leveno KJ.Randomized investigation of magne-sium sulfate for prevention of pretermbirth. Am J Obstet Gynecol 1990;163:76772.

9. Scudiero R, Khoshnood B, Pryde PG,Lee KS, Wall S, Mittendorf R. Perina-

tal death and tocolytic magnesiumsulfate. Obstet Gynecol 2000;96:17882.

10. Crowther CA, Hiller JE, Doyle LW,Haslam RR, Australasian CollaborativeTrial of Magnesium Sulphate(ACTOMg SO4) Collaborative Group.Effect of magnesium sulfate given forneuroprotection before preterm birth: arandomized controlled trial. JAMA2003;290:266976.

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