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.


CONCLUSIONS
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.
Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, Klingenstein Pavilion 1176 Fifth Avenue 9th Floor, New York, NY, 10029, USA.|Reproductive Medicine Associates of New York, 635 Madison Ave 10th Floor, New York, NY, 10022, USA.
Lucky
L
Sekhon
Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, Klingenstein Pavilion 1176 Fifth Avenue 9th Floor, New York, NY, 10029, USA.
Kathryn
K
Shaia
Celmatix Inc., 14 Wall St, Suite 16D, New York, NY, 10005, USA.
Anthony
A
Santistevan
Celmatix Inc., 14 Wall St, Suite 16D, New York, NY, 10005, USA.
Karen Hunter
KH
Cohn
Reproductive Medicine Associates of New York, 635 Madison Ave 10th Floor, New York, NY, 10022, USA. jlee@rmany.com.
Joseph A
JA
Lee
Celmatix Inc., 14 Wall St, Suite 16D, New York, NY, 10005, USA.
Piraye Yurttas
PY
Beim
Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, Klingenstein Pavilion 1176 Fifth Avenue 9th Floor, New York, NY, 10029, USA.|Reproductive Medicine Associates of New York, 635 Madison Ave 10th Floor, New York, NY, 10022, USA.
Alan B
AB
Copperman
D000328:Adult; D000782:Aneuploidy; D004624:Embryo Transfer / Q000379:methods; D005260:Female; D006062:Gonadotropins / Q000008:administration & dosage*; D006801:Humans; D054315:Oocyte Retrieval / Q000379:methods; D009865:Oocytes / Q000187:drug effects / Q000254:growth & development; D006080:Ovarian Follicle / Q000187:drug effects* / Q000254:growth & development; D016471:Ovarian Hyperstimulation Syndrome / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D010062:Ovulation Induction; D011247:Pregnancy; D019836:Preimplantation Diagnosis
D006062:Gonadotropins
Aneuploidy; Controlled ovarian stimulation; Exogenous gonadotropins; Human embryos; In vitro fertilization; Preimplantation genetic screening