Preterm delivery is the major cause of perinatal morbidity and mortality in the United States and Europe. Although many factors have been linked to preterm delivery, including infection, fetal abnormality and antepartum hemorrhage, no specific cause can be identified in more than one half of all cases. The use of ritodrine and other tocolytic drugs has not significantly reduced the overall incidence of preterm deliveries, but these agents may reduce the proportion of deliveries within 48 hours of onset of preterm labor. This delay allows for administration of steroids, which induce fetal lung maturation, thereby reducing neonatal respiratory distress. Recently, evidence that glyceryl trinitrate's relaxant effect on uterine smooth muscle may be enhanced during pregnancy has raised interest in its use. Glyceryl trinitrate could also have fewer adverse effects on the mother and fetus than ritodrine. Lees and colleagues compared the tocolytic effect of glyceryl trinitrate with ritodrine.
Women in preterm labor were recruited at 20 international medical centers. Preterm labor was defined as regular painful, palpable contractions occurring more than twice every 10 minutes for more than one hour in women between 24 and 36 weeks of gestation. Exclusion criteria were hypotension, major fetal abnormality, unexplained bleeding, evidence of infection, abnormal results on fetal heart monitoring, evidence of ruptured membranes or contraindications to therapy. Patients were randomized to treatment with transdermal glyceryl trinitrate or intravenous ritodrine. Initial assessments were conducted every 15 minutes and then hourly once the patient's condition was stable. The study could not be blinded because of the different routes of administration. Glyceryl trinitrate treatment consisted of an initial 10-mg patch, followed by a second 10-mg patch one hour later if there was no reduction in the frequency or strength of contractions. Patches remained in place for 24 hours, after which time they were removed, and the patient was reassessed.
The initial dose of ritodrine was 50 mg per minute, and then the dosage was titrated to contractions. Both treatments were discontinued if contractions ceased for 24 hours or delivery occurred. The primary outcome measure was the time from randomization to delivery.
Data from 233 women were analyzed. Baseline characteristics at randomization were comparable between groups, as were the number of patients who discontinued therapy and those who required emergency cesarean delivery. There was no significant difference between groups in the primary outcome measure, percentage of prolongation of gestation to 37 weeks. Of the 113 women in the glyceryl trinitrate group, 42 (37 percent) delivered before 37 weeks' gestation. Of the 120 women in the ritodrine group, 58 (48 percent) had a preterm delivery. This difference was close to statistical significance. The proportion of women who delivered at randomization or at some time up to 37 weeks was also similar between groups. Adverse effects were common, but differed between groups. Headache occurred in 30 percent of women in the glyceryl trinitrate group, while tachycardia (58 percent), palpitations (13 percent) and nausea (10 percent) were common in the ritodrine group. Pulmonary edema developed in one woman in the ritodrine group.
The authors conclude that although no statistically significant improvement was demonstrated, glyceryl trinitrate therapy appears to be superior to ritodrine in reducing the rate of preterm deliveries. Glyceryl trinitrate was also easier to administer and had a more benign side effect profile than ritodrine. Transdermal glyceryl trinitrate could become standard therapy to treat or prevent preterm labor, when used at low dosages to prevent headaches and other side effects.