Unexplained infertility in assisted reproductive technology cycles: clinical significance of PGT-A and whole-exome sequencing in early embryonic developmental arrest
Ishchuk M.P., Tsabai P.N., Perminova S.G., Ekimov A.N., Ritcher O.V., Mukosey I.S.
Objective. To evaluate the embryological and clinical outcomes of assisted reproductive technology cycles in couples with unexplained infertility based on the use of preimplantation genetic testing for aneuploidy
(PGT-A) and to assess the diagnostic value of whole-exome sequencing in couples with recurrent early embryonic developmental arrest.
Materials and methods. A retrospective analysis of 226 assisted reproductive technology cycles in couples with unexplained infertility treated at a single center was performed: 122 cycles without PGT-A and 104 cycles with PGT-A. The groups were defined based on the actual use of PGT-A in the index cycle. The primary analysis of clinical outcomes was performed per each oocyte retrieval. The cumulative live birth rate was calculated considering all embryo transfers derived from a single oocyte retrieval, including subsequent frozen-thawed embryo transfers. For binary clinical outcomes, relative risks (RRs) with 95% confidence intervals (CIs) were calculated. To assess the association between PGT-A use and binary live birth outcomes after index oocyte retrieval, accounting for baseline between-group differences, a multivariate logistic regression model was constructed, adjusting for patient age, number of previous IVF attempts, and anti-Mullerian hormone levels. Whole-exome DNA sequencing was performed in a subgroup of 25 couples with recurrent early embryonic developmental arrest.
Results. Patients in the PGT-A group were older and had a higher number of previous IVF attempts. The main quantitative embryological parameters did not differ significantly between the groups. In the PGT-A group, 365 embryos were biopsied, and the proportion of euploid embryos decreased with increasing female age (p=0.006). Embryo transfer from the analyzed oocyte retrieval was performed less frequently in the PGT-A group, reflecting the stage of embryological and genetic selection process. Among performed embryo transfers, the clinical pregnancy rate was lower in the PGT-A group: 51/85 (60.0%) versus 91/121 (75.2%); RR 0.80; 95% CI 0.65–0.98; p=0.020. The cumulative live birth rate per oocyte retrieval was also lower in the PGT-A group (38/104 (36.5 %) vs. 68/122 (55.7 %); RR 0.66; 95% CI 0.49–0.88; p=0.004). In the multivariable logistic regression model, PGT-A use remained associated with lower odds of the binary live birth outcome after index oocyte retrieval, after adjustment for female age, number of previous IVF attempts, and anti-Müllerian hormone level: adjusted OR 0.50; 95% CI 0.28–0.89; p=0.020. Increasing female age was also associated with lower odds of the same binary live birth outcome (adjusted OR 0.91; 95% CI 0.84–0.99; p=0.025). In the subgroup of couples with early embryonic developmental arrest, whole-exome sequencing identified rare genetic variants potentially associated with the reproductive phenotype in 7/25 (28 %) couples, including variants in TLE6, PADI6, and TBPL2 in women, as well as variants in DNAH7, DNHD1, and STK33 and an Xp22.13–p22.12 duplication involving ADGRG2 in men.
Conclusion. In this sample of patients with unexplained infertility, PGT-A use was not associated with an increased cumulative live birth rate per oocyte retrieval and was accompanied by a higher frequency of embryo transfer cancellation after embryological and genetic selection. These findings highlight the need for cautious interpretation of PGT-A effectiveness in studies with baseline differences between the comparison groups. Whole-exome sequencing in couples with recurrent early embryonic developmental arrest may be informative for identifying rare genetic variants potentially associated with impaired early embryogenesis.
Authors' contributions. Perminova S.G. – conception and design of the study; Ishchuk M.P. – data collection, drafting of the manuscript, statistical analysis; Tsabai P.N. – organization and implementation of molecular genetic studies, scientific editing of the manuscript; Ekimov A.N., Ritcher O.V. – performance of PGT-A and evaluation of embryological material; Mukosey I.S. – bioinformatics processing of whole-exome sequencing data and interpretation of the identified genetic variants.
Conflicts of interest. The authors have no conflicts of interest to declare.
Funding. The study was supported by the grant of the Russian Science Foundation No. 25-65-00040.
Ethical Approval. The study was reviewed and approved by the Research Ethics Committee of the V.I. Kulakov NMRC for OG&P (protocol No. 5 dated November 12, 2023).
Generative Artificial Intelligence. During manuscript preparation, the DoTrace service was utilized for technical formatting and to ensure structural compliance with the journal's guidelines.
Patient Consent for Publication. All patients provided informed consent for the publication of their data.
Authors' Data Sharing Statement. The data supporting the findings of this study are available upon request from the corresponding author after approval from the principal investigator.
For citation Ishchuk M.P., Tsabai P.N., Perminova S.G., Ekimov A.N., Ritcher O.V., Mukosey I.S.
Unexplained infertility in assisted reproductive technology cycles: clinical significance of PGT-A
and whole-exome sequencing in early embryonic developmental arrest.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2026; (9): 95-108 (in Russian)
https://dx.doi.org/10.18565/aig.2026.189
Keywords
unexplained infertility
PGT-A
aneuploidy
euploid embryo
trophectoderm biopsy
whole-exome sequencing
live birth
assisted reproductive technology
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Received 19.06.2026
Accepted 10.07.2026
About the Authors
Maria P. Ishchuk, PhD Student, F. Paulsen Research and Educational Center for ART with the Clinical Department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparina str., 4, marumariyaish@gmail.com,https://orcid.org/0000-0002-9577-1777
Polina N. Tsabai, geneticist, M.D., Department of Clinical Genetics, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, 117997, Russia, Moscow, Ac. Oparina str., 44, Ac. Oparina str., Moscow, Russia, 117997, p_tsabai@oparina4.ru, https://orcid.org/0000-0001-5110-0827
Svetlana G. Perminova, Dr. Med. Sci., Professor, Leading Researcher, F. Paulsen Research and Educational Center for ART with the Clinical Department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4,
s_perminova@oparina4.ru, https://orcid.org/0000-0003-4438-1354
Аlexey N. Ekimov, PhD, Head of the Laboratory of Preimplantation Genetic Testing and Genetic Diagnostics, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, a_ekimov@oparina4.ru,
https://orcid.org/0000-0001-5029-0462
Olga V. Ritcher, doctor of clinical laboratory diagnostics at the Laboratory of Preimplantation Genetic Testing and Genetic Diagnostics, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, o_ritcher@oparina4.ru
Irina S. Mukosey, Researcher at the Laboratory of Genomic Data Analysis, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, i_mukosei@oparina4.ru, https://orcid.org/0000-0002-2225-8366
Corresponding author: Maria P. Ishchuk, marumariyaish@gmail.com
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