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Editorial


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

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

January 2007 · Vol. 19, No. 01

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 SUBJECTS

IS THE AGENT AN EFFECTIVE TOCOLYTIC?

COCHRANE REVIEW ADVICE OR CONCLUSION

INEFECTIVE

Hydration1

2 trials, 228 subjects

Not superior to bed rest alone

No advantage over bed rest unless the woman is dehydrated

Magnesium2

23 trials, 2,036 subjects

Not superior to control treatments

Magnesium is ineffective at delaying birth or preventing preterm birth, compared with control treatments; its use is associated with increased morbidity for the infant

Atosiban3

11 trials, 1,695 subjects

Not superior to placebo

Caution against use

Antibiotics with intact membranes4

11 trials, 7,428 subjects

Reduced maternal infection, but no improvement in newborn outcomes; may increase complexity of neonatal infections

Not recommended for routine practice

MAY BE INEFFECTIVE

Nitric oxide donors (nitroglycerine)5

5 trials, 466 subjects

Reduced risk of delivery before 37 weeks, but not 32 or 34 weeks; headache is a common side effect

Insufficient evidence to support use

Cyclooxygenase inhibitors (indomethacin)6

13 trials, 713 subjects

Reduction in delivery before 37 weeks compared with controls

Estimates are imprecise and should be interpreted with caution

EFFECTIVE COMPARED WITH CONTROLS

Calcium-channel blockers7

12 trials, 1,029 subjects

Reduction 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 betamimetics

Calcium-channel blockers are preferable to other tocolytic agents; nifedipine* not evaluated against placebo; control groups typically received a betamimetic

Betamimetics8

17 trials, 1,320 subjects

Reduced risk of delivery within 48 hours; many adverse effects reported

Betamimetics 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

In the absence of demonstrated clinical efficacy and a concern over potentially negative neonatal effects, obstetricians should consider strictly limiting their use of magnesium for tocolysis.11

If not magnesium, what?

Cochrane analyses indicate that data reliably support the superiority of two tocolytics over controls: calcium-channel blockers and betamimetics (TABLE). The calcium-channel blocker nifedipine has been demonstrated to reduce the risk of birth within 7 days of initiating treatment and of birth prior to 34 weeks’ gestation, compared with betamimetics. Women in preterm labor who are receiving a calcium-channel blocker are less likely to require discontinuation of the treatment due to adverse effects compared with women treated with a betamimetic. Given the demonstrated clinical efficacy of calcium-channel blockers and their few adverse side effects, these agents should be more widely used as tocolytics.

Nifedipine. This calcium-channel blocker has the longest and widest use as a tocolytic. A typical regimen is to administer nifedipine, 10 mg orally, every 20 minutes up to 4 doses as needed to reduce contractions and avoid hypotension. Maintenance treatment is nifedipine, 20 mg orally, every 4 to 8 hours. The maximum daily dosage is in the range of 120 to 180 mg. Nifedipine inhibits voltage-dependent L-type calcium channels, which leads to vascular and other smooth-muscle relaxation and negative inotropic and chronotropic effects on the heart.

Not surprisingly, nifedipine has been reported to be associated with many adverse cardiovascular side effects, including acute pulmonary edema,12 arrhythmias,13 and hypotension. Caution is advised when using nifedipine in multiple-gestation pregnancy and maternal cardiac disease.14,15 Many authorities strongly caution against the use of nifedipine with magnesium or betamimetics because of additive adverse effects on the cardiovascular system.

If the goal of therapy is to complete a course of betamethasone, then nifedipine may be discontinued after 48 hours. Alternatively, the medication can be continued to achieve another endpoint, such as prolonging pregnancy up to 34 weeks when a condition such as polyhydramnios is present.

We need research

Preterm delivery is a major public health problem, and more research is required to identify the fundamental biologic causes of preterm labor. In the near future, basic science discoveries will be translated from the bench to the bedside, resulting in new treatments for the real causes of preterm labor that will be far superior to available tocolytics.

For more on magnesium sulfate tocolysis, please see Medical Verdicts.

REFERENCES

1. Stan C, Boulvain M, Hirsbrunner-Amagbaly P, Pfister R. Hydration for treatment of preterm labour. Cochrane Database Syst Rev. 2002;(2):CD003096.-

2. Crowther CA, Hiller JE, Doyle LW. Magnesium sulfate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev.

3. Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev. 2005;(3):CD004452.-

4. King J, Flenady V. Prophylactic antibiotics for inhibiting preterm labour with intact membranes. Cochrane Database Syst Rev. 2002;(4):CD000246.-

5. Duckitt K, Thornton S. Nitric oxide donors for the treatment of preterm labour. Cochrane Database Syst Rev. 2002;(3):CD002860.-

6. King J, Flenady V, Cole S, Thornton S. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev. 2005;(2):CD001992.-

7. King JF, Flenady VJ, Papatsonis DNM, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev. 2003;(1):CD002255.-

8. Anotayanonth S, Subhedar NV, Neilson JP, Harigopal S. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev. 2004;(4):CD004352.-

9. Reid DE. A Textbook of Obstetrics. Philadelphia: WB Saunders; 1962.

10. Pritchard JA, MacDonald PC, Gant NF.Williams Obstetrics, 17th ed. Norwalk, Conn: Appleton-Century Crofts; 1985.

11. Grimes DA, Nanda K. Magnesium sulfate tocolysis. Time to quit. Obstet Gynecol. 2006;108:986-989

12. Abbas OM, Nassar AH, Lanj NA, Usta IM. Acute pulmonary edema during tocolytic therapy with nifedipine. Am J Obstet Gynecol. 2006;195:e3-e4

13. Parasuraman R, Gandhi MM, Liversedge NH. Nifedipine tocolysis associated atrial fibrillation responds to DC cardioversion. BJOG. 2006;113:844-845

14. van Geijn HP, Lenglet JE, Bolte AC. Nifedipine trials: effectiveness and safety aspects. BJOG. 2005;112(Suppl1):79-83

15. Oei SG. Calcium channel blockers for tocolysis: a review of their role and safety following reports of serious adverse events. Eur J Obstet Gynecol Reprod Biol. 2006;126:137-145

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