OBJECTIVE: To determine the factors influencing the likelihood of biochemical pregnancy loss (BPL) after transfer of a euploid embryo from preimplantation genetic testing for aneuploidy (PGT-A) cycles.
METHODS: The study employed an observational, retrospective cohort design, encompassing 6020 embryos from 2879 PGT-A cycles conducted between February 2013 and September 2021. Trophectoderm biopsies in day 5 (D5) or day 6 (D6) blastocysts were analyzed by next generation sequencing (NGS). Only single embryo transfers (SET) were considered, totaling 1161 transfers. Of these, 49.9% resulted in positive pregnancy tests, with 18.3% experiencing BPL. To establish a predictive model for BPL, both classical statistical methods and five different supervised classification machine learning algorithms were used. A total of forty-seven factors were incorporated as predictor variables in the machine learning models.
RESULTS: Throughout the optimization process for each model, various performance metrics were computed. Random Forest model emerged as the best model, boasting the highest area under the ROC curve (AUC) value of 0.913, alongside an accuracy of 0.830, positive predictive value of 0.857, and negative predictive value of 0.807. For the selected model, SHAP (SHapley Additive exPlanations) values were determined for each of the variables to establish which had the best predictive ability. Notably, variables pertaining to embryo biopsy demonstrated the greatest predictive capacity, followed by factors associated with ovarian stimulation (COS), maternal age, and paternal age.
CONCLUSIONS: The Random Forest model had a higher predictive power for identifying BPL occurrences in PGT-A cycles. Specifically, variables associated with the embryo biopsy procedure (biopsy day, number of biopsied embryos, and number of biopsied cells) and ovarian stimulation (number of oocytes retrieved and duration of stimulation), exhibited the strongest predictive power.

OBJECTIVE: To evaluate the positive predictive value (PPV) of prenatal cell-free DNA screening for chromosomal aneuploidies in pregnancies achieved either after single euploid transfer in IVF/PGT cycles or transfer of single untested embryo, and to assess the concordance of prenatal-cfDNA-screening and PGT-A results.
METHODS: Single centre retrospective cohort study SUBJECTS: 2973 prenatal-cfDNA-screening results for the most common trisomies(T)(T13,T18,T21,X,Y) and microdeletions(1p36;4p16.3;5p15.2;15q11.2;22q11.2) from singleton pregnancies allocated into 2 groups: PGT-A group (n=1204) pregnancy after single euploid transfer and non-PGT-A group (n=1769) pregnancy after transfer of single untested embryo, between 2016 and 2023.
METHODS: Primary outcome measure was accuracy of prenatal-cell-free-DNA-screening. Positive and negative prenatal-cell-free-DNA-screening results, and subsequent prenatal or postnatal diagnostic testing were used to classify each positive prenatal-cell-free-DNA-screening result as a true or a false positive. Secondary endpoints were to evaluate the concordance of PGT-A and prenatal-cell-free-DNA-screening results and to assess the differences of the fetal fraction of cell-free-DNA used for prenatal-cell-free-DNA-screening report between the study groups.
RESULTS: Prenatal-cell-free-DNA-screening was performed at mean 11.3±1.8weeks gestational age (GA) and yielded results in 99.9% of the patients (0.1% cancellation rate). There was no difference in the fetal fraction between PGT-A tested and not tested pregnancies (9.5%±4% vs 10.3%±4%). 13 positive prenatal-cell-free-DNA-screening results (2-T21,2-X0,4-XXX,1-XYY, 1-indeterminate sex, 2-22q11 del/dup, 1-15q11.2) were received for PGT-A group. Only one (22q11 dup) was confirmed with amniocentesis and fetal autopsy, giving a PPV for an abnormal prenatal-cfDNA-screening of 7.7%, the rest had results concordant with PGT-A. Sex chromosomes were 100% concordant between prenatal-cell-free-DNA-screening and PGT-A results, giving a 100% PPV for PGT-A for sex chromosomes and 100% NPV for aneuploidies. Positive prenatal-cell-free-DNA-screening results were received for 27 pregnancies from untested embryos (1.5%), follow up testing was electively performed for 21, and 8 had confirmed the prenatal-cell-free-DNA-screening result, giving a PPV for the non-PGT-A group of 38%.
CONCLUSIONS: This study demonstrates that patients undergoing IVF/PGT and single euploid embryo transfer can reliably do prenatal-cell-free-DNA-screening during their first trimester. Fetal fraction in singleton pregnancies after PGT-A tested embryos is not different from pregnancies with untested embryos. PPV for an abnormal prenatal-cell-free-DNA-screening result after euploid embryo transfer was reassuringly low (7.7%). PGT-A reliably selects against aneuploidy with 100% concordance with fetal sex.

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OBJECTIVE: To assess the impact of maternal age on the association between maternal basal FSH and aneuploidy.
METHODS: A retrospective study including data from 1749 blastocysts diagnosed as euploid or aneuploid by PGT-A (preimplantation genetic testing for aneuploidy). Aneuploidy incidence was compared between embryos from mothers with high vs. low basal FSH levels (above and below the group median, respectively) in total, pre-AMA (advanced maternal age; < 35 years, 198 embryos) and AMA (≥ 35 years, 1551 embryos) patient groups, separately. To control for the interference of potentially confounding variables, the association between aneuploidy and high basal FSH levels was assessed by multivariate logistic analysis in overall, pre-AMA and AMA patient groups.
RESULTS: Overall, aneuploidy rate was 9% higher (p = 0.02) in embryos from patients with high basal FSH (63.7%) compared to those with low basal FSH (58.4%). In the pre-AMA subgroup, aneuploidy incidence was 35% higher (p = 0.04) in embryos from patients with high basal FSH (53.5%) compared to those with low basal FSH (39.4%). Differently, aneuploidy occurrence did not vary between embryos from AMA patients with low (61.0%) and high (64.8%) basal FSH (p = 0.12). The multivariate analysis revealed that, in pre-AMA embryos, the association between aneuploidy occurrence and high basal FSH is independent of potential confounding variables (p = 0.04).
CONCLUSIONS: Maternal basal FSH values are associated with embryo aneuploidy in pre-AMA but not in AMA patients. The present findings suggest that basal FSH is a useful parameter to assess aneuploidy risk in pre-AMA patients and reinforce the hypothesis that excessive FSH signalling can predispose to oocyte meiotic errors.

Preimplantation genetic testing (PGT) is a diagnostic procedure that has become a powerful complement to assisted reproduction techniques. PGT has numerous indications, and there is a wide range of techniques that can be used, each with advantages and limitations that should be considered before choosing the more adequate one. In this article, it is reviewed the indications for PGT, biopsy and diagnostic technologies, along with their evolution, while also broaching new emerging methods.

OBJECTIVE: Investigate patient preferences in embryo selection for transfer regarding quality versus sex in IVF/ICSI cycles with PGT-A and assess associated clinical implications.
METHODS: Retrospective cohort study at a university fertility practice from January 2012 to December 2021. Included were patients undergoing single frozen euploid transfers with at least one embryo of each sex available. Primary outcomes were preference for embryo selection (quality vs. sex) and sex preference (male vs. female). Trends over 10 years were evaluated and clinical outcomes, including clinical pregnancy rate (CPR), sustained implantation rate (SIR), and live birth rate (LBR), were compared.
RESULTS: A total of 5,145 embryo transfer cycles were included; 54.5% chose the best-quality embryo, while 45.5% selected based on sex. Among those choosing based on sex, 56.5% chose male embryos and 43.5% chose female. Preference for quality remained consistent over the decade (p = 0.30), while male embryos were consistently favored (p = 0.64). Best-quality embryos had higher grades (p < 0.001). Clinical outcomes were similar between groups (CPR: 74.4% vs. 71.9%, p = 0.05; SIR: 64.9% vs. 63.4%, p = 0.26; LBR: 58.8% vs. 56.7%, p = 0.13), and between male and female embryo selections.
CONCLUSIONS: Sex selection remains common, with 45.5% selecting embryos based on sex, predominantly favoring males. This trend persisted over 10 years, with comparable clinical outcomes regardless of selection criteria.

OBJECTIVE: To find a useful tool for estimating the minimum number of metaphase II (MII) oocytes needed to obtain at least one euploid blastocyst according to female age.
METHODS: Retrospective analysis of in vitro fertilization (IVF) treatment cycles with preimplantational genetic testing for aneuploidies (PGT-A) performed over 5 years in IVIRMA Valencia (Spain), January 2017-March 2022. Approval from the Institutional Review Board of IVI Valencia (2204-VLC-040-CR).
METHODS: Private infertility clinic in Spain.
METHODS: Eligible patients were undergoing their first IVF-PGT-A treatment cycle, in which at least one MII oocyte was obtained, regardless of oocyte and semen origin. Oocyte donation cycles were included in the donor group (≤34 years old). Treatment cycles from women with their own oocytes were selected only when the oocytes were aged ≥35 years (patient group). Only trophoectoderm biopsies performed on days 5 or 6 of development and analyzed using next-generation sequencing were included. Preimplantational genetic testing for aneuploidy cycles because of a known abnormal karyotype were excluded.
METHODS: Not applicable.
METHODS: Number of MII oocytes needed to obtain one euploid blastocyst according to female age.
RESULTS: A total of 2,660 IVF-PGT-A treatment cycles were performed in the study period in the eligible population (patients group = 2,462; donors group =198). The mean number of MII oocytes needed to obtain one euploid blastocyst increased with age, as did the number of treatment cycles that did not get at least one euploid blastocyst. An adjusted multivariate binary regression model was designed using 80% of the patient group sample (n = 2,462; training set). A calculator for the probability of obtaining at least one euploid blastocyst was created using this model. The validation of this model in the remaining 20% of the patient group sample (n = 493; validation set) showed that it could estimate the event of having at least one euploid blastocyst with an accuracy of 72.0%.
CONCLUSIONS: Our results show a preliminary model capable of predicting the number of MII oocytes needed to obtain at least one euploid blastocyst according to female age, calculated with the largest database of IVF-PGT-A treatment cycles ever used for this purpose, including only treatment cycles using next-generation sequencing on trophoectoderm biopsies. Once this model has been properly validated, it could help with decision-making for both clinicians and patients coming to an infertility clinic.

OBJECTIVE: The presence of embryonic cell-free DNA (cfDNA) in spent embryo culture media (SECM) may offer valuable advantages for non-invasive testing of embryo ploidy or genetic characteristics compared to trophectoderm (TE) biopsy. This study aimed to assess the diagnostic potential of SECM cfDNA as a non-invasive sample for chromosomal copy number testing in blastocysts within the clinical setting of in-vitro fertilization.
METHODS: This prospective observational study collected 28 SECM cfDNA samples matched with TE biopsy samples from 21 infertile couples who underwent IVF-PGT-A cycles. SECM samples were obtained from blastocysts that were cultured for approximately 5/6 days in an uninterrupted time-lapse incubator. Both sets of samples were collected during the biopsy procedure. The Variseq Illumina platform was utilized for ploidy measurement. The study evaluated the informativity and interpretability of SECM cfDNA, concordance of general ploidy status, and sex chromosome agreement between the two sample types.
RESULTS: SECM cfDNA had a high informativity rate (100 %) after double amplification procedure, with a result interpretability of 93 %. Two out of the 28 SECM cfDNA samples were uninterpretable and regarded as overall noise samples. The diagnostic potential of SECM cfDNA, when compared to TE biopsy the standard reference, was relatively low at 50 %. Maternal DNA contamination remains the major obstacle that hinders the widespread clinical adoption of SECM cfDNA in the routine practice of pre-implantation genetic testing for aneuploidy within IVF settings.
CONCLUSIONS: A significant modification must be implemented in the IVF laboratory to minimize DNA contamination and this necessitates suggesting adjustments to oocyte denudation, embryo culture media preparation, and sample collection procedures.

The use of preimplantation genetic testing for aneuploidy (PGT-A) in the United States has been increasing steadily. Moreover, the underlying technology used for 24-chromosome analysis continues to evolve rapidly. The value of PGT-A as a routine screening test for all patients undergoing in vitro fertilization has not been demonstrated. Although some earlier single-center studies reported higher live-birth rates after PGT-A in favorable-prognosis patients, recent multicenter, randomized control trials in women with available blastocysts concluded that the overall pregnancy outcomes via frozen embryo transfer were similar between PGT-A and conventional in vitro fertilization. The value of PGT-A to lower the risk of clinical miscarriage is also unclear, although these studies have important limitations. This document replaces the document of the same name, last published in 2018.

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