Tocolysis for Preterm Labor

Preterm labor is the most common complication of pregnancy and one of the most catastrophic occurring in 10-12% of all pregnancies and accounting for up to 80% of the neonatal morbidity1. In addition, the delivery of a very low birth weight baby often leads to a reduction in cognitive and academic skills as well an increased in mental retardation by age five2,3. While there are many strategies to treat women in preterm labor all of the agents which have been used have side effects, acutely prolong the pregnancy only for a few days, and there have been no universally accepted treatment for long term prolongation using oral tocolytics in the home4,5,6. While beta-agonists have been used for several decades as primary agents for acute tocolysis, side effects have led to these agents being relegated to adjunctive therapy or in home care program with the programmable subcutaneous pump7. Consequently there are no tocolytic agents approved by the FDA for use during pregnancy.

The most common drug used for acute tocolysis is magnesium sulfate, which is administered intravenously to stop contractions8. While it appears to be effective for short-term tocolysis it is thought to be not as effective as anti-prostaglandins or calcium channel antagonists in quickly suppressing uterine activity. In addition, there has been controversy as to adverse effects on the neonate when this drug is used to impede uterine contractions9. Some authors feel that it causes adverse neurologic function in the baby where as others feel that it is not associated with any increase neonatal morbidity/mortality in premature infants9.10. Regardless, for clinicians treating women in preterm labor magnesium remains the main stay of therapy.

Newer developments, however, point to the improved effectiveness of anti-prostaglandin agents and calcium channel antagonists as it concerns treating such patients7,11. Calcium channel antagonists are just as effective and appear to be safer than magnesium for primary tocolytic treatment of women in preterm labor12-14. Tocolytic treatment with anti-prostaglandin drugs such as indomethacin, a Cox-1 inhibitor, has demonstrated them to be the most effective and most rapid tocolytic agent available15. Initially there were reports of increasing complications with the use of this drug16,17. However, it has been shown that these concerns are unwarranted if indomethacin use is limited to 48 hours per treatment cycle and the amniotic fluid assessed for oligohydramnios; therefore, in pregnancies <32 weeks there ample evidence to justify its use as a primary tocolytic18,19,20. This is particularly true with the newer agents of this class (Cox-2 inhibitors) which have fewer fetal side effects7,11. In sum, however, there are no randomized trials which demonstrate the effectiveness of these three types of agents.

B. Specific Aim

The purpose of this study is to compare the three categories of clinically used tocolytic agents in a prospective study that will allow direct comparison of outcomes in women with confirmed preterm labor. While magnesium sulfate tocolysis for acute treatment of preterm labor is the standard of care, there appear to be better tocolytic agents with less maternal and fetal side effects which could be used as primary agents.