Introduction
Clomiphene citrate (CC) is a widely used first-line treatment for ovulation induction in subfertile women. Concerns over adverse impact of unintentional post-ovulatory exposure in early pregnancy have been raised. This study aimed to investigate the consequences of pre-implantation exposure to CC on pregnancy outcome in mice.
Materials and Methods
CBA x C57Bl/6 F1 female mice mated with Balb/c males were administered 5 µg, 15 µg or 50 µg of CC, or saline, s.c. on gestational day (GD) 0.5 and 1.5. Fetuses were assessed for size and developmental stage on GD 14.5. A second cohort of females treated with either 15 µg CC or saline progressed to birth and perinatal parameters were analysed.
Results and Discussion
CC-treated mice exhibited a dose-dependent adverse effect of CC on pregnancy rate with 87.5% (7/8; 5 µg), 62.5% (6/8; 15 µg) and 12.5% (1/8; 50 µg) of mated females pregnant at GD 14.5 compared to 100% (8/8) in the control group. In surviving fetuses, fetal weight was progressively reduced with increasing dose of CC. A higher degree of fetal developmental retardation was evident with 15 µg and 50 µg CC doses. Females given 15 µg CC delivered later with smaller litters compared to control females, with higher rates of postnatal loss. These results indicate that in utero exposure to clomiphene citrate during the pre-implantation period can inhibit implantation and impact fetal growth and development, and perinatal outcomes. These findings reinforce the necessity for close supervision of clomiphene citrate use in infertility treatment in women.