Ivabradine use in pregnant women-treatment indications and pregnancy outcome: an evaluation of the German Embryotox database

Abstract

Purpose: Ivabradine has been approved for the treatment of chronic heart failure and chronic stable angina pectoris in Europe. Based on adverse outcomes of reproductive animal studies and the lack of human data, ivabradine is considered contraindicated during pregnancy. The aim of this observational study is to analyse ivabradine use before and during pregnancy.

Methods: We evaluated all ivabradine-related requests to the German Embryotox Institute from 2007 to 2019. Exposed pregnancies were analysed as to their outcome.

Results: Off-label use for supraventricular tachycardia was frequent in women of childbearing age. Of 38 prospectively ascertained pregnancies with ivabradine exposure and completed follow-up, 32 resulted in live births, 3 in spontaneous abortions, and 3 were electively terminated. One neonate presented with major birth defects (atrial septal defect and cleft palate). In 33/38 patients, ivabradine was discontinued after confirmation of pregnancy without cardiac deterioration and 5/38 women continued ivabradine throughout pregnancy. In addition, there were 3 retrospectively reported pregnancies including one major birth defect (tracheal atresia).

Conclusion: This case series represents the largest cohort of ivabradine-exposed pregnancies, published so far. According to our findings, ivabradine appears not to be a major teratogen. However, established drugs of choice with strong evidence of low risk for the unborn should be preferred in women planning pregnancy. After inadvertent exposure during pregnancy or lack of treatment alternatives, fetal ultrasound for structural anomalies and growth restriction is recommended. In addition, close monitoring is necessary in pregnant women with supraventricular arrhythmias or cardiac disease.

Keywords: Drug safety; Ivabradine; Pregnancy; Reproductive age; Tachycardia.

Fig. 1

Overview on information requests to the German Embryotox institute on ivabradine

Fig. 2

Treatment indication for ivabradine in 97 Embryotox requests over time in relation to pregnancy labelling and approval status by EMA/FDA. Recommendations for use of ivabradine in supraventricular tachycardias, i.e. inappropriate sinus tachycardia and postural orthostatic tachycardia syndrome: HRS/ESC 2015 [13], ACC/AHA/HFSA 2016 [14], ESC 2019 [15]. ACC, American College of Cardiology; EMA, European Medicines Agency; ESC, European Society of Cardiology; FDA, US Food and Drug Administration; HRS, Heart Rhythm Society

Fig. 3

Ivabradine exposure and pregnancy outcome of prospectively (n = 38) and retrospectively (n = 3) ascertained pregnancies