No effect of ovarian stimulation and oocyte yield on euploidy and live birth rates: an analysis of 12 298 trophectoderm biopsies

Abstract

STUDY QUESTION Does ovarian stimulation affect embryo euploidy rates or live birth rates (LBRs) after transfer of euploid embryos? SUMMARY ANSWER Euploidy rates and LBRs after transfer of euploid embryos are not significantly influenced by gonadotropin dosage, duration of ovarian stimulation, estradiol level, follicle size at ovulation trigger or number of oocytes retrieved, regardless of a woman’s age. WHAT IS KNOWN ALREADY Aneuploidy rates increase steadily with age, reaching >80% in women >42 years old. The goal of ovarian stimulation is to overcome this high aneuploidy rate through the recruitment of several follicles, which increases the likelihood of obtaining a euploid embryo that results in a healthy conceptus. However, several studies have suggested that a high response to stimulation might be embryotoxic and/or increase aneuploidy rates by enhancing abnormal segregation of chromosomes during meiosis. Furthermore, a recent study demonstrated a remarkable difference in euploidy rates, ranging from 39.5 to 82.5%, among young oocyte donors in 42 fertility centres, potentially suggesting an iatrogenic etiology resulting from different stimulation methods. STUDY DESIGN, SIZE, DURATION This is a retrospective cohort study that included 2230 in vitro fertilisation (IVF) with preimplantation genetic testing for aneuploidy (PGT-A) cycles and 930 frozen-thawed single euploid embryo transfer (FET) cycles, performed in our centre between 2013 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 12 298 embryos were analysed for ploidy status. Women were divided into five age groups (<35, 35–37, 38–40, 41–42 and >42 years old). Outcomes were compared between different durations of stimulation (<10, 10–12 and ≥13 days), total gonadotropin dosages (<4000, 4000–6000 and >6000 IU), numbers of oocytes retrieved (<10, 10–19 and ≥20 oocytes), peak estradiol levels (<2000, 2000–3000 and >3000 pg/mL), and sizes of the largest follicle on the day of trigger (<20 and ≥20 mm). MAIN RESULTS AND THE ROLE OF CHANCE Within the same age group, both euploidy rates and LBRs were comparable between cycles regardless of their differences in total gonadotropin dosage, duration of stimulation, number of oocytes harvested, size of the largest follicles or peak estradiol levels. In the youngest group, (<35 years, n = 3469 embryos), euploidy rates were comparable between cycles with various total gonadotropin dosages (55.6% for <4000 IU, 52.9% for 4000–6000 IU and 62.3% for >6000 IU; P = 0.3), durations of stimulation (54.4% for <10 days, 55.2% for 10–12 days and 60.9% for >12 days; P = 0.2), number of oocytes harvested (59.4% for <10 oocytes, 55.2% for 10–19 oocytes and 53.4% for ≥20 oocytes; P = 0.2), peak estradiol levels (55.7% for E2 < 2000 pg/mL, 55.4% for E2 2000–3000 pg/mL and 54.8% for E2 > 3000 pg/mL; P = 0.9) and sizes of the largest follicle (55.6% for follicles <20 mm and 55.1% for follicles ≥20 mm; P = 0.8). Similarly, in the oldest group (>42 years, n = 1157 embryos), euploidy rates ranged from 8.7% for gonadotropins <4000 IU to 5.1% for gonadotropins >6000 IU (P = 0.3), from 10.8% for <10 days of stimulation to 8.5% for >12 days of stimulation (P = 0.3), from 7.3% for <10 oocytes to 7.4% for ≥20 oocytes (P = 0.4), from 8.8% for E2 < 2000 pg/mL to 7.5% for E2 > 3000 pg/mL (P = 0.8) and from 8.2% for the largest follicle <20 mm to 8.9% for ≥20 mm (P = 0.7). LBRs after single FET were also comparable between these groups. LIMITATIONS, REASONS FOR CAUTION Although this large study (2230 IVF/PGT-A cycles, 12 298 embryos and 930 single FET cycles) demonstrates the safety of ovarian stimulation in terms of aneuploidy and implantation potential of euploid embryos, a multi-centre study may help to prove the generalisability of our single-centre data. WIDER IMPLICATIONS OF THE FINDINGS These findings reassure providers and patients that gonadotropin dosage, duration of ovarian stimulation, estradiol level, follicle size at ovulation trigger and number of oocytes retrieved, within certain ranges, do not appear to significantly influence euploidy rates or LBRs, regardless of the woman’s age. STUDY FUNDING/COMPETING INTEREST(S) No external funding was received and there are no competing interests to declare. TRIAL REGISTRATION NUMBER N/A

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“…In addition, supraphysiological estradiol level after higher dose of Gn used, may increase the growth hormone-binding protein in bio-neutralizing GH and diminishing the level of insulin-like growth factor, which played a role in synergism with FSH and the follicular metabolism in stimulated cycles (46). Although no difference in euploidy rates and live birth rates following the transfer of euploid embryos between cycles with higher and lower stimulation dosages were noted in a recent retrospective cohort study (47), it has been suspected that high dose of the FSH might lead to adverse effects on the oocyte through some sort of epigenetic impacts or the FSH dosing was a surrogate marker for some intrinsic de ciency in the oocyte quality (48). Our present result mirrors those publications in that lower total dose of Gn used has better pregnancy and live birth rates.…”

Safety of Ovaleap® (Follitropin Alfa) in Infertile Women Undergoing Superovulation for Assisted Reproductive Technologies: A Multinational Comparative, Prospective Cohort Study

“…It is widely accepted that the ART treatment process is highly complex and subject to multiple factors that can impact clinical outcomes, such as the number of oocytes retrieved, specific laboratory procedures, embryo transfer procedure and degree of endometrial priming (24)(25)(26). Additionally, the number of ovarian follicles recruited and the endocrine environment do not affect embryo quality and ploidy status (27).…”

Preimplantation Genetic Testing for Chromosomal Abnormalities: Aneuploidy, Mosaicism, and Structural Rearrangements

“…Overall, about half of ART-generated preimplantation embryos contain uniform aneuploidy when assessed by PGT-A [ 11 , 12 , 25 ], but there is a distinctive maternal age-related effect. Three studies, each analyzing over 12,000 human blastocysts from ART patients using different genetic testing platforms, came to comparable conclusions: average percent euploid embryos increased from ~60% to ~75% between maternal ages 22 and 28, dipping to ~60% by age 35, followed by a steady decline to ~40% by age 40 until reaching ~10% by age 45 [ 26 , 27 , 28 ]. Logically, the incidence of aneuploidy followed the inverse trend, exhibiting its lowest incidence of ~25% at ages 28–29, and a steep rise after age 35, reaching its peak of 90% at age 45 [ 27 ].…”