Impact of antenatal exposure of mice to fenfluramine on cardiac development and long-term growth of the offspring

The objective of this investigation was to determine, in a placebo-controll ed manner, whether antenatal exposure to formulations of fenfluramine and d exfenfluramine impacted cardiac development and long-term growth of exposed mice offspring. One hundred forty-four CD-I mice were randomized to six tr eatment groups (n = 23 or 25) to obtain, per group, 5 gravids for killing o n gestational day (GD) 15 and less than or equal to 10 deliveries for asses sing growth of the offspring. Either fenfluramine preparation was administe red in feed bars in two doses: 1 and 3.2 times the equivalent human daily d osage according to body surface area. The drugs were given from 2 weeks bef ore mating until GD 15. The mice ingested each drug at target values, avera ging 10.5 +/- 0.3 and 31.8 +/- 1.9 mg/kg/d for fenfluramine and 5.0 +/- 0.2 and 16.2 +/- 0.4 mg/kg/d for dexfenfluramine. The drug concentration was a bout 36% in the fetal brain compared with the adult brain. The maternal and the offspring hearts, including mitral and aortic valves, of fenfluramine- exposed mice were indistinguishable from the placebo-exposed mice. The dura tion of gestation and the litter size were the same between the treatment g roups. The mean body weights, body lengths, and head circumferences and ear ly functional testing did not differ significantly between the fenfluramine or dexfenfluramine-exposed offspring and the placebo-exposed offspring. Th ere were no significant treatment differences in growth measured as body we ights to PND 120. Neither fenfluramine formulation, given before conception and during gestation, impacted cardiac development and long-term growth of the mice offspring.