Has ritodrine any advantage compared to terbutaline in the treatment of preterm labor?

Fråga: Has ritodrine any advantage compared to terbutaline in the treatment of preterm labor?

Sammanfattning: In view of the methodological drawbacks in the referenced studies and the small number of patients involved, there is no strong evidence to suggest that there is any advantage of one drug over the other. However, both drugs have the potential to cause serious complications including maternal death. Hence there is a need for careful selection of patients and judicious use of these drugs.

Svar: Ritodrine and terbutaline are both beta-2-adrenergic agonists. Ritodrine was developed specifically for the treatment of premature labor and was approved for this use in 1980 in the USA. Terbutaline is used both for bronchodilatation and inhibition of preterm labor. Adverse side effects for both these drugs are those that are expected from sympathomimetic stimulation including cardiovascular and metabolic disturbances.

A Medline search from 1966 to 1990 revealed only 4 prospective studies (1-4) and one retrospective study (5) comparing ritodrine and terbutaline in the management of preterm labor.

In 3 of the prospective studies the investigators compared the use of intravenous infusion followed by oral therapy of ritodrine to terbutaline. Caritis et al in a double blind randomised study reported that in patients with intact membrane, ritodrine (31 patients) and terbutaline (27 patients) were comparably effective during intravenous therapy. But with the 5 days oral therapy terbutaline was significantly more effective than ritodrine in preventing recurrent labor. Pregnancy was prolonged 40 +/- 25 days in the terbutaline treated women compared to 22 +/- 24 days in the ritodrine group. Kosasa et al in a non-blinded study treated alternate patients with ritodrine (49 patients) or terbutaline (50 patients. A different dosage regimen and a much higher dose of terbutaline (bolus 0.25 mg followed by 10 ug/min and increased by 5 ug/min every 10 min to a maximum of 80 ug/min) was used compared to that administered by Caritis et al (2.5 ug/min followed by an increase of 2.5 ug/min every 20 minutes to a maximum of 17.5 ug/min). They found that delivery was delayed for 25.8 days in the terbutaline treated patients and 13 days in the patients treated with ritodrine and concluded that terbutaline was more effective than ritodrine in the management of pre-term labor. Contrary to the findings of Caritis et al and Kosasa et al, Beall et al in a prospective randomised study comparing ritodrine, terbutaline and magnesium sulfate for the management of preterm labor had 45 patients in the ritodrine treatment group and 40 patients in the terbutaline group. Again a much higher dose of terbutaline infusion (20 ug/min followed by an increase of 10 ug/min every 10 minutes to a maximum of 70 ug/min) was used compared to that administered by Caritis et al to their patients. They concluded that there was no significant difference in efficacy between the drugs as the days gained in delaying delivery was 43 +/- 25 in the ritodrine group compared to 55 +/- 17 in the terbutaline group. The fourth study by Kopelman et al compared only oral ritodrine and terbutaline for the prevention of recurrent preterm labor. Following intravenous ritodrine tocolysis 102 women were randomised to receive either oral ritodrine or terbutaline. They found that though initial failure appears more frequently in the oral ritodrine treated than terbutaline treated groups (9 vs 2) both drugs were comparable in efficacy and safety in the management of preterm labor (4) when used on a long term basis.

The one retrospective study by Weiss (5) had only 14 patients (7 ritodrine and 7 terbutaline). Due to the small number of patients and the nature of the study, no comments can be made on the results.

In terms of adverse effects Caritis et al reported that women on terbutaline were significantly more likely to develop increased serum glucose. But a higher percentage of ritodrine treated patients have heart rates > 130 bpm during intravenous infusion. There were no serious complications such as pulmonary edema in this study. Therapy was discontinued in 13 per cent of the ritodrine treated patients and 11 per cent of the terbutaline treated patients because of adverse effects. As expected with the higher dosages administered by Kosasa et al and Beall et al, there were more problems with adverse drug effects. In the study by Kosasa et al 2 patients treated with terbutaline and one patient treated with ritodrine developed pulmonary edema. Other parameters of cardiovascular and biochemical monitoring were not presented. The percentage of patients in whom drug therapy was stopped because of adverse effects were not stated in this study. In the study by Beall et al 60 per cent of the patients on terbutaline and 38 per cent of the patients on ritodrine had drug therapy discontinued because of adverse effects. The common adverse effects in both treatment groups were hypotension (< 40 mmHg), tachycardia (> 140 bpm) and chest pain.

In summary, 2 studies found terbutaline to be more effective in prolonging pregnancy than ritodrine and in 2 studies the drugs were comparable. Adverse reactions to terbutaline were significant in 2 studies probably due to the higher dosages administered. However, in evaluating the studies the following points should be considered:

1) The criteria for diagnosis of preterm labor was either not stated (1) or unclear (2,3). In a national survey on preterm labor in US, there was a wide variation of the American obstetricians´ criteria for the diagnosis of preterm labor (6).

2) Different dosages and treatment schedules for both drugs were used in all the studies. It is possible that failure or success of a drug may be due to dosage or the schedule. Therefore, one may not be comparing the efficacy of the 2 drugs if optimum dosage is not used for both the drugs. 1 Caritis SN, Toig G, Heddinger LA, Ashmead G: A double-blind study comparing ritodrine and terbutaline in the treatment of preterm labor. Am J Obstet Gynecol 1984; 150: 7-14 2 Kosasa TS, Nakayama RT, Hale RW, Rinzler GS, Freitas CA: Ritodrine and terbutaline compared for the treatment of preterm labor. Acta Obstet Gynecol Scand 1985; 64: 421-426 3 Beall MH, Edgar BW, Paul RH, Smith-Wallace T: A comparison of ritodrine, terbutaline, and magnesium sulfate for the suppression of preterm labor. Am J Obstet Gynecol 1985; 153: 854-859 4 Kopelman JN, Duff P, Read JA: Randomized comparison of oral terbutaline and ritodrine for preventing recurrent preterm labor. J Reprod Med 1989; 34: 225-230 5 Weiss MA: Retrospective analysis of the effects of ritodrine and terbutaline in the management of preterm labor. Clin Pharm 1982; 1: 453-456 6 Taslimi MM, Sibai BM, Amon E, Taslimi CK, Herrick CN: A national survey on preterm labor. Am J Obstet Gynecol 1989; 160: 1352-1360