Abstract
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.
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References
Hassold TJ, Jacobs PA. Trisomy in man. Annu Rev Genet. 1984;18:69–97.
Boue A, Boue J, Gropp A. Cytogenetics of pregnancy wastage. Adv Hum Genet. 1985;14:1–57.
Check JH. Mild ovarian stimulation. J Assist Reprod Genet. 2007;24(12):621–7.
Flisser E, Scott Jr RT, Copperman AB. Patient-friendly IVF: how should it be defined? Fertil Steril. 2007;88(3):547–9.
Forman EJ, et al. IVF with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril. 2013;100(1):100–7.
Chao HT, Lee SY, Lee HM, Liao TL, Wei YH, Kao SH. Repeated ovarian stimulations induce oxidative damage and mitochondrial DNA mutations in mouse ovaries. Ann N Y Acad Sci. 2005;1042:148–56.
Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NGM, Verhoeff A, Macklon NS, Fauser BCJM. Milder ovarian stimulation for in vitro fertilization reduced aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod. 2007;22:980–8.
Nargund G, Waterstone J, Bland J, Philips Z, Parsons J, Campbell S. Cumulative conception and live birth rates in natural (unstimulated) IVF cycles. Hum Reprod. 2001;16:259–62.
Pelinck MJ, Vogel NE, Hoek A, Arts EG, Simons AH, Heineman MJ. Minimal stimulation IVF with late follicular phase administration of the GnRH antagonist cetrorelix and concomitant substitution with recombinant FSH: a pilot study. Hum Reprod. 2005;20:642–8.
Verpoest W, Fauser BC, Papanikolaou E, Staessen C, Van Landuyt L, Donoso P, Tournaye H, Liebaers I, Devroey P. Chromosomal aneuploidy in embryos conceived with unstimulated cycle IVF. Hum Reprod. 2008a;23:2369–71.
Mastenbroek S, Twisk M, van der Veen F, Repping S. Preimplantation genetic screening: a systematic review and meta-analysis of RCTs. Hum Reprod Update. 2011;17:454–66.
The Ganirelix Dose-Finding Study Group. A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon). Hum Reprod. 1998;13:3023–31.
MeldrumRol-El R, Herman A, Golan A, Nachun H, Soffer Y, Caspi E. Gonadotropins and combined gonadotropin-releasing hormone agonist—gonadotropin protocols in a randomized prospective study. Fertil Steril. 1991;55:574.
Engel JB, Ludwig M, Felderbaum R, Albano C, Devroey P, Diedrich K. Use of cetrorelix in combination with clomiphene citrate and gonadotropins: a suitable approach to “friendly IVF”? Hum Reprod. 2002;17:2022.
Shastri SM, Barbieri E, Kligman I, Schoyer KD, Davis OK, Rosenwaks Z. Stimulation of the young poor responder: comparison of the luteal estradiol/gonadotropin-releasing hormone antagonist priming protocol versus oral contraceptive microdose leuprolide. Fertil Steril. 2011;95(2):592–5.
Scott RT, Navot D. Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonist during ovulation induction for in vitro fertilization. Fertil Steril. 1994;61:880–5.
Højsgaard S, Halekoh U, Yan J. The R Package geepack for generalized estimating equations. J Stat Softw. 2006;15(2):1–11.
Chuang M, Zapantis A, Taylor M, Jindal SK, Neal-Perry GS, Lieman HJ, et al. Prolonged gonadotropin stimulation is associated with decreased ART success. J Assist Reprod Genet. 2010;27:711–7.
Reis Soares S, Rubio C, Rodrigo L, Simon C, Remohi J, Pellicer A. High frequency of chromosomal abnormalities in embryos obtained from oocyte donation cyces. Fertil Steril. 2003;80(3):656–7.
Munné S, Ary J, Zouves C, Escudero T, Barnes F, Cinioglu C, Ary B, Cohen J. Wide range of chromosome abnormalities in the embryos of young egg donors. Reprod BioMed Online. 2006;12:340–6.
Jackson KV, Ginsburg ES, Hornstein MD, Rein MS, Clarke RN. Multinucleation in normally fertilized embryos is associated with an accelerated ovulation induction response and lower implantation and pregnancy rates in in vitro fertilization-embryo transfer cycles. Fertil Steril. 1998;70:60–6.
Taŕın JJ, Pellicer A. Consequences of high ovarian response to gonadotropins: a cytogenetic analysis of unfertilized human oocytes. Fertil Steril. 1990;54:665–70.
Vogel R, Spielmann H. Genotoxic and embryotoxic effects of gonadotropin-hyperstimulated ovulation of murine oocytes, preimplantation embryos, and term fetuses. Reprod Toxicol. 1992;6:329–33.
Golbus MS. The influence of strain, maternal age, and method of maturation on mouse oocyte aneuploidy. Cytogenet Cell Genet. 1981;31:84–90.
Kaleli S, Yanikkaya-Demirel G, Erel CT, Senturk LM, Topcuoglu A, Irez T. High rate of aneuploidy in luteinized granulosa cells obtained from follicular fluid in women who underwent controlled ovarian hyperstimulation. Fertil Steril. 2005;84(3):802–4.
Melsheimer P, Grunwald K, Feldmann K, Rabe T, Runnebaum B, Rummel HH. Aneuploidy of human granulosa cells in follicular fluids from in vitro fertilization patients. Anal Quant Cytol Histol. 1997;19:75–9.
Katz-Jaffe MG, Trounson AO, Cram DS. Chromosome 21 mosaic human preimplantation embryos predominantly arise from diploid conceptions. Fertil Steril. 2005;84:634–43.
Rubio C, Mercader A, Alama P, Lizan C, Rodrigo L, Labarta E, Melo M, Pellicer A, Remohi J. Prospective cohort study in high responder oocyte donors using two hormonal stimulation protocols: impact on embryo aneuploidy and development. Hum Reprod. 2010;25(9):2290–7.
Verpoest W, Fauser BC, Papanikolaou E, Staessen C, Van Landuyt L, Donoso P, Tournaye H, Liebaers I, Devroey P. Chromosomal aneuploidy in embryos conceived with unstimulated cycle IVF. Hum Reprod. 2008b;23:2369–71.
Labarta E, Bosch E, Alama P, Rubio C, Rodrigo L, Pellicer A. Moderate ovarian stimulation does not increase the incidence of human embryo chromosomal abnormalities in in vitro fertilization cycles. J Clin Endoctinol Metab. 2012;97(10):1987–94.
Braga D, Setti A, Figueira R, Iaconelli A, Borges E. Contributing factors for the incidence of aneuploidy in older patients undergoing intracytoplasmic sperm injection cycles. J Assist Reprod Genet. 2012;29:911–6.
Papanikolaou EG, Camus M, Kolibianakis EM, Van Landuyt L, Van Steirteghem A, Devroey P. In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos. N Engl J Med. 2006;354:1139–46.
Corbett S, Shmorgun D, Claman P, Reproductive Endocrinology Infertility Committee, Healey S, Gysler M. The prevention of ovarian hyperstimulation syndrome. J Obstet Gynaecol Can. 2014;36(11):1024–36.
Mastenbroek S, Twist M, van Echten-Arends J, Sikkema-Raddatz B, Korevaar JC, Verhoeve HR, Vogel NE, Arts EG, de Vris JW, Bossuyt PM, Buys CH, Heineman MJ, Repping S, van der Veen F. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357:9–17.
Scott Jr RT, Upham KM, Forman EJ, Hong KH, Scott KL, Taylor D, Tao X, Treff NR. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil Steril. 2013;100(3):697–703.
Edgar DH, Whalley KM, Mills JA. Effects of high-dose and multiple-dose gonadotropin stimulation on mouse oocyte quality as assessed by preimplantation development following in vitro fertlization. J In Vitro Fert Embryo Transf. 1987;4:273–6.
Weghofer A, Munne S, Brannath W, Chen S, Barad D, Cohen J, Gleicher N. The impact of LH-containing gonadotropin stimulation on euploidy rates in preimplantation embryos: antagonist cycles. Fertil Steril. 2009;92(3):937–42.
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Research approval was obtained from Western Institutional Review Board, and all subjects provided informed consent.
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Sekhon, L., Shaia, K., Santistevan, A. et al. The cumulative dose of gonadotropins used for controlled ovarian stimulation does not influence the odds of embryonic aneuploidy in patients with normal ovarian response. J Assist Reprod Genet 34, 749–758 (2017). https://doi.org/10.1007/s10815-017-0909-3
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DOI: https://doi.org/10.1007/s10815-017-0909-3