Design
We conducted a retrospective cohort study of all patients who underwent embryo transfer after FST for EMCA or EH between January 1st, 2003 and December 31st, 2018 at the New York University (NYU) Langone Fertility Center. The study was performed with NYU IRB approval (#s13-00389). All procedures performed in this study were in accordance with the consent process of the institution and in accordance with relevant guidelines/regulations. In accordance with the consent process of the institution, and the retrospective nature of the study, informed consent was waived.
Subjects
Patients were identified through a query that searched all patient records for the terms “endometrial cancer,” “hyperplasia,” “endometrial intraepithelial neoplasm,” “EMCA,” “cancer,” and “carcinoma.” All patient charts identified through the query were reviewed for inclusion, for a complete sampling method. Patients were included if they had: 1) a documented diagnosis of either EMCA or EH, 2) received any duration of FST and 3) had undergone at least one embryo transfer. We excluded patients who: 1) utilized ART but did not yet return for embryo transfer 2) utilized ART but elected for intrauterine insemination (IUI) or 3) had an embryo transfer that occurred prior to EMCA/EH diagnosis or prior to FST.
Variables and statistical analysis
All variables were collected from the electronic medical record of included patients. Demographic variables collected included age at diagnosis (years), age at egg retrieval (years), body mass index (BMI), gravidity, parity, endometrial diagnosis, type of fertility-sparing treatment, number of oocytes retrieved, number of total resulting embryos, embryo transfer type (fresh or frozen), use of preimplantation genetic testing for aneuploidy (PGT-A), embryo transfer date, time to transfer from diagnosis (years), endometrial thickness at time of transfer (mm), and risk factors for endometrial disease. Any missing data were excluded.
The primary outcome was live birth rate (defined as number of live births per number of transfers performed). Secondary outcomes included the number of live births, spontaneous abortions, or negative pregnancy tests. Continuous variables were first assessed for normality using the Kolmogorov–Smirnov test. Descriptive data are presented as a median with an interquartile range unless otherwise specified. Observed outcomes were compared to expected outcomes at our center based on outcomes from 2016–2018. These expected outcomes, derived from 484 untested autologous frozen embryo transfers (FET) and 2,062 tested autologous FETs from patients without EMCA/EH, included age of egg at embryo creation, and type of transfer (fresh or frozen, number of embryos transferred, and with or without PGT-A). A subgroup analysis of euploid embryos comparing observed and expected outcomes was also performed. Statistical analysis included the Wilcoxon Signed-Rank Test. P < 0.05 was considered statistically significant.
Embryo cryopreservation and warming
Controlled ovarian hyperstimulation (COH) utilizing a GnRH antagonist protocol with administration of gonadotropins (recombinant Follicle Stimulating Hormone [FSH], Human Menopausal Gonadotropins [HMG], or both) were prescribed for each patient based on their antral follicle count, age, FSH level and AMH level (if available) as determined by their physician. Follicular growth and maturation were monitored by transvaginal ultrasound and serum estradiol (E2) level. The GnRH antagonist was added when a lead follicle was identified as 13mm or greater or the E2 was greater than 1000 pg/mL. Either human chorionic gonadotropin (hCG) alone or hCG with leuprolide acetate was used for trigger of final follicular maturation with oocyte aspiration scheduled for 35 hours after administration. Oocyte retrieval was performed via ultrasound guided transvaginal aspiration. Both insemination and ICSI were used for fertilization of oocytes. ICSI was utilized if indicated by semen parameters, but in our center PGT-A alone is not an indication for the use of ICSI.
Standard laboratory techniques were employed and embryos cultured to the blastocyst stage. If PGT-A was desired, trophectoderm biopsy was performed on day 5 or 6 at the blastocyst stage prior to embryo cryopreservation via vitrification. Biopsy analysis was performed by array comparative genomic hybridization (aCGH) or next generation sequencing (NGS) based on platform utilization at the time of biopsy. Blastocysts of patients who returned for FET underwent standard embryo warming in our laboratory.
Embryo transfer
Patients who pursued a fresh embryo transfer during an IVF cycle after FST had an embryo transfer on either day 3, day 5 or day 6 after oocyte retrieval. Progesterone suppositories were initiated on post-operative day 1 after retrieval and continued until at least the first pregnancy test. A programmed or hormone-replaced embryo transfer protocol was utilized for patients undergoing FET, all of which were blastocyst embryo transfers. As part of that protocol, patients were administered oral estradiol up-titrated from 2mg/day to 6mg/day for at least 10 days or until the endometrium measured ≥ 7mm in diameter. Progesterone in oil was initiated and embryo transfer planned for the 6th day of progesterone administration. Patients were counseled based on their age, blastocyst formation, embryo quality and ploidy (if applicable) and a shared decision was made as to proceed with fresh, frozen as well as multiple embryo transfers. All embryo transfers were direct transfers utilizing ultrasound guidance.