Ivabradine Safety In Pregnancy: What's The Verdict?

Ivabradine, a heart rate-lowering agent, is considered unsafe for use during pregnancy. It is contraindicated in the US, UK, and Australia due to the risk of fetal harm, including embryofetal toxicity, teratogenicity, and increased post-implantation loss. Animal studies have shown increased intrauterine and postnatal mortality, as well as cardiac defects. While human data is limited, one observational study found that ivabradine exposure during pregnancy did not result in a high number of major birth defects. However, established drugs with a stronger evidence base of low risk to the fetus should be prioritized for pregnant women or those planning pregnancy.

Ivabradine is contraindicated in the UK, US, and Australia

Ivabradine is a medication used for the treatment of chronic heart failure and the symptoms of chronic angina in adults who are unsuited to or unable to take beta-blockers. It is also used in combination with beta-blockers when an optimal beta-blocker dose is insufficient.

In the UK, US, and Australia, Ivabradine is contraindicated for use during pregnancy. This is due to evidence from animal studies that suggest fetotoxicity and teratogenic effects. In pregnant rats, for example, Ivabradine exposure was associated with increased intrauterine and postnatal mortality, as well as ventricular septal defects and complex anomalies of the great arteries. In pregnant rabbits, reduced fetal and placental weight, as well as ectrodactyly, were observed.

Additionally, there is a lack of human data on the effects of Ivabradine during pregnancy. Therefore, it is recommended that other established drugs with a strong evidence base of low risk to the unborn child are preferred for women who are pregnant or planning to become pregnant.

Embryo-fetal toxicity and teratogenic effects observed in animal studies

Ivabradine is a drug used to treat chronic heart failure and chronic stable angina pectoris in Europe. It has been found to cause embryo-fetal toxicity and teratogenic effects in animal studies.

In pregnant rats, exposure to ivabradine at therapeutic human levels was associated with increased mortality during the intrauterine and postnatal stages. Ventricular septal defects and complex anomalies of the great arteries were observed at doses three times the therapeutic human exposure. In pregnant rabbits, a dose 15 times higher than the therapeutic human exposure led to reduced fetal and placental weight, as well as ectrodactyly. In chicken and mice embryos, dose-dependent mortality was observed.

Due to these adverse outcomes in animal studies, ivabradine is considered contraindicated during pregnancy. The limited human data available makes it challenging to provide accurate counselling to pregnant women who have been exposed to ivabradine and their healthcare providers.

The German Embryotox Institute, which offers risk assessments on drug exposure during pregnancy, recorded 97 requests related to ivabradine between 2007 and 2019. Of these, 56 were from healthcare providers and 41 were from patients. The institute documented 38 prospectively ascertained pregnancies with ivabradine exposure, resulting in 32 live births, three spontaneous abortions, and three elective terminations. One neonate presented with major birth defects, including an atrial septal defect and a cleft palate.

While this case series suggests that ivabradine may not be a major teratogen, the limited sample size prevents conclusive evidence. Therefore, it is recommended to prefer established drugs with strong evidence of low risk to the fetus for women planning pregnancies. If inadvertent exposure occurs during pregnancy or there are no alternative treatment options, fetal ultrasound for structural anomalies and growth restriction is advised. Close monitoring is also necessary for pregnant women with supraventricular arrhythmias or cardiac disease.

Ivabradine is not assigned a US FDA pregnancy category

Due to these adverse effects, ivabradine is contraindicated during pregnancy. The German Embryotox Institute, which offers risk assessments on drug exposure during pregnancy, received 97 requests related to ivabradine between 2007 and 2019, with 56 of those related to maternal exposure during pregnancy. Of the 41 cases with completed follow-up, 32 resulted in live births, 3 in spontaneous abortions, and 3 were elective terminations. One neonate had major birth defects, including an atrial septal defect and cleft palate.

While this case series suggests that ivabradine may not be a major teratogen, the limited human data and adverse outcomes in animal studies indicate that it should be avoided during pregnancy. Established drugs with strong evidence of low risk to the fetus should be prioritized for women planning a pregnancy. If a woman is inadvertently exposed to ivabradine during pregnancy or has no alternative treatment options, fetal ultrasound for structural anomalies and growth restriction is recommended, along with close monitoring for any potential complications.

Ivabradine may cause fetal toxicity in pregnant women

Ivabradine, a heart rate-lowering agent, is considered unsafe for use during pregnancy. It is contraindicated in the US, UK, and Australia, and is categorised as a drug that may cause fetal harm.

Animal studies have shown evidence of embryofetal toxicity, teratogenicity, and increased post-implantation loss, as well as increased intrauterine and postnatal mortality. In pregnant rats, ivabradine exposure at therapeutic human levels resulted in increased mortality, ventricular septal defects, and complex anomalies of the great arteries. In pregnant rabbits, reduced fetal and placental weight, as well as ectrodactyly, were observed at doses 15 times higher than human therapeutic exposure. Embryotoxic effects were also seen in chicken and mice embryos.

While there is limited data on ivabradine-exposed pregnancies, the largest cohort study to date found that of 38 prospectively ascertained pregnancies with ivabradine exposure, 32 resulted in live births, 3 in spontaneous abortions, and 3 were elective terminations. One neonate had major birth defects (atrial septal defect and cleft palate), and another retrospectively reported pregnancy resulted in a neonate with tracheal atresia.

Although this study suggests that ivabradine may not be a major teratogen, the sample size is too small to rule out embryotoxic effects. As a result, it is recommended that established drugs with strong evidence of low risk to the fetus be preferred for women planning pregnancies. For women who are inadvertently exposed to ivabradine during pregnancy or who lack treatment alternatives, fetal ultrasound for structural anomalies and growth restriction is advised. Close monitoring is necessary for pregnant women with supraventricular arrhythmias or cardiac disease.

Ivabradine is excreted into animal milk

Ivabradine is a heart rate-lowering agent that acts through selective inhibition of the If (I-funny) channel without additional hemodynamic effects on cardiac function. The drug is approved for the treatment of chronic heart failure and symptomatic treatment of chronic stable angina pectoris after failing or intolerance of beta-blockers.

While the effects of ivabradine on nursing infants are unknown, it has been established that the drug is excreted into animal milk. Ivabradine has been identified as a teratogen in animal studies, although it is unclear what effect, if any, the potentially low levels in breast milk could have on the developing infant.

Due to the lack of human data, ivabradine is considered contraindicated during pregnancy. According to the Australian Therapeutic Goods Administration (TGA), it falls under pregnancy category D, meaning it has "caused, is suspected to have caused, or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage." The US Food and Drug Administration (FDA) has not assigned a pregnancy category for ivabradine.

In cases of inadvertent exposure during pregnancy or lack of treatment alternatives, fetal ultrasound for structural anomalies and growth restriction is recommended. Close monitoring is necessary for pregnant women with supraventricular arrhythmias or cardiac disease.

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