STUDY QUESTION After controlled ovarian stimulation (COS) and IUI, is it clinically feasible to recover in vivo conceived and matured human blastocysts by uterine lavage from fertile women for preimplantation genetic testing for aneuploidy (PGT-A) and compare their PGT-A and Gardner scale morphology scores with paired blastocysts from IVF control cycles? SUMMARY ANSWER In a consecutive series of 134 COS cycles using gonadotrophin stimulation followed by IUI, uterine lavage recovered 136 embryos in 42% (56/134) of study cycles, with comparable in vivo and in vitro euploidy rates but better morphology in in vivo embryos. WHAT IS KNOWN ALREADY In vivo developed embryos studied in animal models possess different characteristics compared to in vitro developed embryos of similar species. Such comparative studies between in vivo and in vitro human embryos have not been reported owing to lack of a reliable method to recover human embryos. STUDY DESIGN, SIZE, DURATION We performed a single-site, prospective controlled trial in women (n = 81) to evaluate the safety, efficacy and feasibility of a novel uterine lavage catheter and fluid recovery device. All lavages were performed in a private facility with a specialized fertility unit, from August 2017 to June 2018. Subjects were followed for 30 days post-lavage to monitor for clinical outcomes and delayed complications. In 20 lavage subjects, a single IVF cycle (control group) with the same ovarian stimulation protocol was performed for a comparison of in vivo to in vitro blastocysts. PARTICIPANTS/MATERIALS, SETTINGS, METHODS Women were stimulated with gonadotrophins for COS. The ovulation trigger was given when there were at least two dominant follicles ≥18 mm, followed by IUI of sperm. Uterine lavage occurred 4–6 days after the IUI. A subset of 20 women had a lavage cycle procedure followed by an IVF cycle (control IVF group). Recovered embryos were characterized morphologically, underwent trophectoderm (TE) biopsy, vitrified and stored in liquid nitrogen. Biopsies were analyzed using the next-generation sequencing technique. After lavage, GnRH antagonist injections were administered to induce menstruation. MAIN RESULTS AND THE ROLE OF CHANCE A total of 134 lavage cycles were performed in 81 women. Uterine lavage recovered 136 embryos in 56 (42%) cycles. At the time of cryopreservation, there were 40 (30%) multi-cell embryos and 96 (70%) blastocysts. Blastocysts were of good quality, with 74% (70/95) being Gardener grade 3BB or higher grade. Lavage blastocysts had significantly higher morphology scores than the control IVF embryos as determined by chi-square analysis (P < 0.05). This is the first study to recover in vivo derived human blastocysts following ovarian stimulation for embryo genetic characterization. Recovered blastocysts showed rates of chromosome euploidy similar to the rates found in the control IVF embryos. In 11 cycles (8.2%), detectable levels of hCG were present 13 days after IUI, which regressed spontaneously in two cases and declined after an endometrial curettage in two cases. Persistent hCG levels were resolved after methotrexate in three cases and four cases received both curettage and methotrexate. LIMITATIONS, REASON FOR CAUTION The first objective was to evaluate the feasibility of uterine lavage following ovarian stimulation to recover blastocysts for analysis, and that goal was achieved. However, the uterine lavage system was not completely optimized in our earlier experience to levels that were achieved late in the clinical study and will be expected in clinical service. The frequency of chromosome abnormalities of in vivo and IVF control embryos was similar, but this was a small-size study. However, compared to larger historical datasets of in vitro embryos, the in vivo genetic results are within the range of high-quality in vitro embryos. WIDER IMPLICATIONS OF THE FINDINGS Uterine lavage offers a nonsurgical, minimally invasive strategy for recovery of embryos from fertile women who do not want or need IVF and who desire PGT, fertility preservation of embryos or reciprocal IVF for lesbian couples. From a research and potential clinical perspective, this technique provides a novel platform for the use of in vivo conceived human embryos as the ultimate benchmark standard for future and current ART methods. STUDY FUNDING/COMPETING INTEREST(S) Previvo Genetics, Inc., is the sole sponsor for the Punta Mita, Mexico, clinical study. S.M. performs consulting for CooperGenomics. J.E.B. and S.A.C. are co-inventors on issued patents and patents owned by Previvo and ownshares of Previvo. S.N. is a co-author on a non-provisional patent application owned by Previvo and holds stock options in Previvo. S.T.N. and M.J.A. report consulting fees from Previvo. S.T.N., S.M., M.V.S., M.J.A., C.N. and J.E.B. are members of the Previvo Scientific Advisory Board (SAB) and hold stock options in Previvo. J.E.B and S. M are members of the Previvo Board of Directors. A.N. and K.C. are employees of Previvo Genetics. L.V.M, T.M.M, J.L.R and S. S have no conflicts to disclose. TRIAL REGISTRATION NUMBER Protocol Registration and Results System (PRS) Trial Registration Number and Name: Punta Mita Study TD-2104: Clinical Trials NCT03426007.

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OBJECTIVE: This increase on the aneuploidy rate could with the advance of the maternal age could be cause by either an increase of aneuploid embryos per cycle or by a reduction on the absolute number of euploid embryos per cycle. The objective of this study is to ascertain if the source of increase in the rate of aneuploid embryos with advancing maternal age is due to one or the other DESIGN: Retrospective study MATERIALS AND METHODS: Retrospective study of 55,403 embryos from 10,497 cycles from 2013 to 2017, from 126 IVF centers analyzed by Next Generation Sequencing (NGS). Embryos were classified by their diagnosis into: euploid, mosaic, complex mosaic, aneuploid, complex aneuploid, ''mosaic and aneuploid'', and mixed complex. Cycles were distributed in age groups (<35, 35-37, 38-40, 41-42, >42) plus an egg donor group. For each age group, the average and standard deviation of each type of embryo per cycle were obtained.ANOVA analysis was applied to compare the difference ''between'' age groups and ''inside'' age groups for the different types of embryos. Pearson C values were obtained to study the degree of correlation of average number of the different types of embryos with age. RESULTS: The results are summarized in table 1. Euploid and ''mosaics with a euploid'' line showed strong negative correlations with maternal age but aneuploid and ''aneuploid and mosaic'' only showed a mild increase with the bulk of the increase in aneuploidy rates being caused by a decrease in euploid embryos, not an increase in aneuploid ones. CONCLUSIONS: The dramatic decrease in aneuploidy rates is mostly cause by a decrease in euploid embryos, not an increase in aneuploid ones. That is, there are no more aneuploid eggs made or recruited with age but fewer euploid ones, with euploid ones almost exhausted after age 42. The observation that aneuploid embryos are almost constant with age suggest a different causative mechanism than one in which aneuploid embryos would increase with age and euploid ones remain constant or decrease. Mosaics, being post-meiotic are just a fraction of euploid or aneuploid ones, and thus increase or decrease with them.