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.
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|
|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