HEART RATE CHANGES MEDIATE THE EMBRYOTOXIC EFFECTS OF ANTIARRHYTHMIC DRUGS IN THE CHICK EMBRYO

Background
We face the need of drug treatment during pregnancy more frequently during last decades. The heart rate is the most important determinant of cardiac output in the embryonic heart, and we hypothesized that drug-induced bradycardia is the leading mechanism of heart failure.
Methods
ED4 and ED8 chick embryos were studied by video microscopy and ultrasound biomicroscopy ex ovo after intraamniotic injection of metoprolol, ivabradine, carvedilol for 30 minutes. Stroke volume was calculated by Simpson method (ED8) and prolate ellipsoid formula (ED4). Cardiac output was calculated from equation CO(µl/min)=SV(µl)*HR(BPM). Embryotoxicity was tested in ovo after administration of various doses of studied drugs between ED3-ED8.
Results
We describe a significant decrease of heart rate in ED4 embryos after administration of metoprolol (33%), carvedilol (27%) and ivabradine (55%) compare to controls (6%). In ED8 embryos this effect was more pronounced (metoprolol 71%, carvedilol 54%, ivabradine 53%, controls 36%). Decreasing trend in CO was not statistically significant in ED4. This trend was statistically significant in ED8 embryos injected with metoprolol (61% metoprolol, 36% controls).
No significant mortality was observed in ED4 embryos injected by metoprolol but 39% mortality in ED8 embryos injected by 200 µl of metoprolol. A significant mortality was achieved in ED4 embryos injected by 200 µl of carvedilol (86%) and by 200 µl of ivabradine (80%). 
Conclusion
Sensitivity to negative chronotropic effect of metoprolol, carvedilol and ivabradine increases with development. The embryonic heart has limited potential to vary stroke volume and significant bradycardia is followed by a significant decrease in cardiac output. Metoprolol in usual doses appears to be relatively safe in pregnancy whereas carvedilol and ivabradine might cause not.