Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study

Abstract

Objective To evaluate the incidence of serious maternal complications after the use of various tocolytic drugs for the treatment of preterm labour in routine clinical situations.Design Prospective cohort study.Setting 28 hospitals in the Netherlands and Belgium.Participants 1920 consecutive women treated with tocolytics for threatened preterm labour.Main outcome measures Maternal adverse events (those suspected of being causally related to treatment were considered adverse drug reactions) leading to cessation of treatment.Results An independent panel evaluated the recorded adverse events, without knowledge of the type of tocolytic used. Of the 1920 women treated with tocolytics, 1327 received a single course of treatment (69.1%), 282 sequential courses (14.7%), and 311 combined courses (16.2%). Adverse drug reactions were categorised as serious or mild in 14 cases each. The overall incidence of serious adverse drug reaction was 0.7%. Compared with atosiban, the relative risk of an adverse drug reaction for single treatment with a β adrenoceptor agonist was 22.0 (95% confidence interval 3.6 to 138.0) and for single treatment with a calcium antagonist was 12 (1.9 to 69). Multiple drug tocolysis led to five serious adverse drug reactions (1.6%). Multiple gestation, preterm rupture of membranes, and comorbidity were not independent risk factors for adverse drug reactions.Conclusions The use of β adrenoceptor agonists or multiple tocolytics for preventing preterm birth is associated with a high incidence of serious adverse drug reactions. Indometacin and atosiban were the only drugs not associated with serious adverse drug reactions. A direct comparison of the effectiveness of nifedipine and atosiban in postponing preterm delivery is needed.

The Prevention, Diagnosis and Treatment of Premature Labor

“…According to a current meta-analysis of nine randomized trials, atosiban is as effective as betamimetics with respect to the prolongation of pregnancy and neonatal development (20), and its side-effect rate is less than 1% (18). No fetal side effects have been reported; the maternal side effects are mild (headache, nausea, vomiting).…”

“…The administration of nifedipine lowers the frequency of neonatal intraventricular hemorrhage (OR 0.53, 95% CI 0.34-0.84), respiratory distress syndrome (OR 0.63, 95% CI 0.46-0.86), and necrotizing enterocolitis (OR 0.21, 95% CI 0.05-0.94) (23). Its side effects, including nausea, flushing, headache, palpitations, and (often) reflex tachycardia, are less severe than those of betamimetics (18).…”

“…Betamimetics have the highest side-effect rates of all tocolytic drugs. Their maternal side effects can be severe, including cardiac arrhythmia and pulmonary edema, and fatalities have been reported (18). Even though fenoterol has been used as a tocolytic for decades in 95% of all German hospitals, often as the sole tocolytic agent in the hospital, the foreign Therapeutic measures: -Inhibition of uterine contraction with drugs -Glucocorticoid administration to promote fetal lung maturation -Antibiotics to treat infections, if present -Avoidance of physical exertion…”

The influence of tocolytic drugs on cardiac function, large arteries, and resistance vessels

“…[1] Tocolytic medication can postpone delivery. [2] Beta-2 adrenoceptor agonistic drugs have been the reference tocolytic drugs in most countries.…”

Investigation of the coordinated interplay among β2-adrenergic receptors, phosphodiesterase 4 and the AKAP-PKA in the cAMP dependent relaxation of the late pregnant uterus

“…A number of agents are used clinically as tocolytics, including magnesium sulphate, indometacin, β 2 -adrenergic receptor (β 2 -AR) agonists, atosiban, progesterone (P4), prostaglandin (PG) synthesis inhibitors, nitric oxide donors and calcium (Ca 2+ ) channel blockers, but the efficacy of the current modes of pharmacological treatment has been questioned [Kim and Shim, 2006]. An ideal tocolytic should postpone delivery at low cost without maternal or fetal side-effects [de Heus et al, 2009] Their preliminary data suggest that the vaginal administration of progesterone -after uterine activity was arrested by atosiban -could prolong pregnancy in subjects with short cervix [Meloni et al, 2009]. Hajagos-Tóth et al investigated the tocolytic effect of β 2 -AR agonists with nifedipine, in vitro and in vivo in rats.…”