From the Editor

Is the end of an era here for magnesium sulfate tocolysis?

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It’s time for us to limit or stop this ineffective—and potentially harmful—regimen


 

References

Preterm labor and preterm delivery are major obstetric challenges, with an increasing incidence. Approximately 12% of all births in the United States occur preterm, with significant adverse sequelae for the newborn.

Treatments that have been tested for preterm labor include hydration, magnesium sulfate, atosiban, antibiotics, nitroglycerine, indomethacin, nifedipine, and betamimetics1-6 (TABLE). Of these, Cochrane systematic reviews of the literature resulted in the conclusion that hydration, magnesium sulfate, and atosiban are not more effective than control treatments.1-3 Both nifedipine and betamimetics were reported to be effective, compared with controls, in achieving short-term goals such as preventing delivery before 48 hours after initiation of treatment.7,8

There are no wonder drugs

It is unfortunate that there are no “wonder drugs” to prevent or treat preterm labor. It is likely that, until treatments target the underlying initiating mechanisms of preterm labor, our focus on treating contractions will be only marginally successful. A major problem is that most clinical trials that examine tocolysis have significant flaws, which limits the strength of the findings. Clinicians are left in the unenviable position of choosing among medications that are only marginally effective, such as calcium-channel blockers and betamimetics. However, clinicians can strive to avoid using tocolytics that have no clearly proven efficacy—such as magnesium sulfate.

I confess that I have prescribed magnesium sulfate tocolysis to dozens of women. I also am committed to changing my practice pattern in regard to this agent.

TABLE

Only 2 tocolytics pass muster in Cochrane reviews

AGENT (COCHRANE REFERENCE)TRIALS AND SUBJECTSIS THE AGENT AN EFFECTIVE TOCOLYTIC?COCHRANE REVIEW ADVICE OR CONCLUSION
INEFECTIVE
Hydration12 trials, 228 subjectsNot superior to bed rest aloneNo advantage over bed rest unless the woman is dehydrated
Magnesium223 trials, 2,036 subjectsNot superior to control treatmentsMagnesium is ineffective at delaying birth or preventing preterm birth, compared with control treatments; its use is associated with increased morbidity for the infant
Atosiban311 trials, 1,695 subjectsNot superior to placeboCaution against use
Antibiotics with intact membranes411 trials, 7,428 subjectsReduced maternal infection, but no improvement in newborn outcomes; may increase complexity of neonatal infectionsNot recommended for routine practice
MAY BE INEFFECTIVE
Nitric oxide donors (nitroglycerine)55 trials, 466 subjectsReduced risk of delivery before 37 weeks, but not 32 or 34 weeks; headache is a common side effectInsufficient evidence to support use
Cyclooxygenase inhibitors (indomethacin)613 trials, 713 subjectsReduction in delivery before 37 weeks compared with controlsEstimates are imprecise and should be interpreted with caution
EFFECTIVE COMPARED WITH CONTROLS
Calcium-channel blockers712 trials, 1,029 subjectsReduction in birth within 7 days of treatment and prior to 34 weeks’ gestation; reduced likelihood of termination of therapy because of adverse effects compared with betamimeticsCalcium-channel blockers are preferable to other tocolytic agents; nifedipine* not evaluated against placebo; control groups typically received a betamimetic
Betamimetics817 trials, 1,320 subjectsReduced risk of delivery within 48 hours; many adverse effects reportedBetamimetics delay delivery, allowing for completion of a course of glucocorticoids; multiple adverse effects occur
*Nifedipine is not approved by the FDA for treating preterm labor.

The long story of magnesium tocolysis

In the 1950s and 1960s, magnesium sulfate was not widely used as a tocolytic agent. In his single-author 1962 work, A Textbook of Obstetrics, Duncan E. Reid, MD, does not mention magnesium as a tocolytic agent.9 Magnesium is discussed in the book as an effective agent for seizure prophylaxis and treatment in women with preeclampsia/eclampsia. In the 1985 (17th) edition of Williams Obstetrics, the authors were not enthusiastic about the use of magnesium tocolysis and cited a small trial that concluded that magnesium tocolysis was not superior to placebo.10

  • In the 1970s and 1980s, betamimetics were the most widely used tocolytic. One betamimetic, ritodrine, achieved FDA approval as a tocolytic agent, but is no longer manufactured.
  • Obstetricians were familiar with magnesium because of its marked efficacy in preventing eclamptic seizures. In vitro studies demonstrated that magnesium inhibited myometrial contractility by competing with calcium at the plasma membrane channels and by interfering with calcium activation of myosin light-chain kinase. In addition, there was the theoretical supposition that magnesium might be neuroprotective for the newborn (later proved incorrect). Given obstetricians’ familiarity with magnesium for preeclampsia, it is easy to see how we embraced this treatment for preterm labor.

Safety, efficacy are questionable

Data from trials never clearly demonstrated that magnesium has a clinically significant tocolytic effect compared with “control” treatments. In a Cochrane review of magnesium tocolysis, neither improvement in the risk of delivery before 48 hours nor reduction in risk of birth before 34 or 37 weeks was observed, compared with control treatments. More recent data also suggest that magnesium may increase the risk of adverse neonatal outcomes, including death, especially at the upper end of the magnesium dose range.2

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