The cumulative dose of gonadotropins used for controlled ovarian stimulation does not influence the odds of embryonic aneuploidy in patients with normal ovarian response

Objective: Controlled ovarian hyperstimulation (COH) promotes multifollicular growth, increasing the chance of obtaining euploid embryos that will successfully implant. Whether aneuploidy is increased from COH with exogenous gonadotropins interfering with natural selection of dominant follicles is a concern. This study evaluates the association between gonadotropin exposure and aneuploidy. Methods: This is a retrospective cohort study of 828 patients that underwent 1122 IVF cycles involving controlled ovarian stimulation and trophectoderm biopsy for preimplantation genetic screening (PGS), from 2010 to 2015. Polymerase chain reaction (PCR) was used to assess aneuploidy. Kruskal-Wallis tests and logistic regression with generalized estimating equations (GEEs) were used for data analysis. Results: Overall, after controlling for patient age, ovarian reserve, stimulation protocol, days of stimulation, and diagnoses, there was no significant association between cumulative gonadotropin (GND) dose and the odds of aneuploidy (adjusted OR = 1.049, p = 0.232). Similarly, in cycles where patients did not require COH beyond cycle day 12, there was no significant association between cumulative gonadotropin dose and the odds of aneuploidy (adjusted OR = 0.909, p = 0.148). However, in cases where patients were stimulated past cycle day 12, there was a significant increase in the odds of aneuploidy (adjusted OR = 1.20, 95% CI 1.125–1.282, p < 0.0001) with increasing cumulative gonadotropin dose, with a small effect size (Cohen’s d = 0.10, 95% CI 0.08–0.12). In this cohort, there was a 16.4% increase in the odds of aneuploidy for each 1000-u increase in cumulative GND exposure (adjusted OR = 1.164, p = 0.002). When the analysis was restricted to low responders (peak estradiol <500 pg/mL or <4 mature follicles achieved; there was no significant association between gonadotropin dose and aneuploidy (adjusted OR = 1.12, 95% CI 0.982–1.28, p = 0.09), regardless of the duration of COH required to reach vaginal oocyte retrieval. Conclusion: The degree of exposure to exogenous gonadotropins did not significantly modify the likelihood of aneuploidy in patients with a normal ovarian response to stimulation (not requiring COH beyond cycle day 12). Patients requiring prolonged COH were demonstrated to have elevated odds of aneuploidy with increasing cumulative gonadotropin dose. This finding may reflect an increased tendency towards oocyte and embryonic aneuploidy in patients with a diminished response to gonadotropin stimulation.