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Second stimulation in the same ovarian cycle: an option to fully-personalize the treatment in poor prognosis patients undergoing PGT-A



Our primary objective was to assess whether immediately undergoing a second stimulation in the same ovarian cycle (DuoStim) for advanced-maternal-age and/or poor-ovarian-reserve (AMA/POR) patients obtaining ≤ 3 blastocysts for preimplantation-genetic-testing-for-aneuploidies (PGT-A) is more efficient than the conventional-approach.


All AMA/POR patients obtaining ≤ 3 blastocysts after conventional-stimulation between 2017 and 2019 were proposed DuoStim, and 143 couples accepted (DuoStim-group) and were matched for the main confounders to 143 couples who did not accept (conventional-group). GnRH-antagonist protocol with recombinant-gonadotrophins and agonist trigger, intra-cytoplasmatic-sperm-injection (ICSI) with ejaculated sperm, PGT-A and vitrified-warmed euploid single-blastocyst-transfer(s) were performed. The primary outcome was the cumulative-live-birth-delivery-rate per intention-to-treat (CLBdR per ITT) within 1 year. If not delivering, the conventional-group had 1 year to undergo another conventional-stimulation. A cost-effectiveness analysis was also conducted.


The CLBdR was 10.5% in the conventional-group after the first attempt. Only 12 of the 128 non-pregnant patients returned (165 ± 95 days later; drop-out = 116/128,90.6%), and 3 delivered. Thus, the 1-year CLBdR was 12.6% (N = 18/143). In the DuoStim-group, the CLBdR was 24.5% (N = 35/143; p = 0.01), 2 women delivered twice and 13 patients have other euploid blastocysts after a LB (0 and 2 in the conventional-group). DuoStim resulted in an incremental-cost-effectiveness-ratio of 23,303€. DuoStim was costlier and more effective in 98.7% of the 1000 pseudo-replicates generated through bootstrapping, and the cost-effectiveness acceptability curves unveiled that DuoStim would be more cost-effective than the conventional-approach at a willingness-to-pay threshold of 23,100€.


During PGT-A treatments in AMA/POR women, DuoStim can be suggested in progress to rescue poor blastocyst yields after conventional-stimulation. It might indeed prevent drop-out or further aging between attempts.

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The data underlying this article are available in the article and in its online supplementary material.


  1. Alviggi C, Andersen CY, Buehler K, Conforti A, De Placido G, Esteves SC, et al. Poseidon Group. A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Fertil Steril. 2016;105(6):1452–3. PubMed PMID: 26921622.

  2. Esteves SC, Alviggi C, Humaidan P, Fischer R, Andersen CY, Conforti A, et al. The POSEIDON criteria and its measure of success through the eyes of clinicians and embryologists. Front Endocrinol (Lausanne). 2019;10:814.;PubMedCentralPMCID:PMCPMC6880663.

    Article  Google Scholar 

  3. Conforti A, Esteves SC, Cimadomo D, Vaiarelli A, Di Rella F, Ubaldi FM, et al. Management of women with an unexpected low ovarian response to gonadotropin. Front Endocrinol (Lausanne). 2019;10:387.;PubMedCentralPMCID:PMCPMC6610322.

    Article  Google Scholar 

  4. Esteves SC, Yarali H, Ubaldi FM, Carvalho JF, Bento FC, Vaiarelli A, et al. Validation of ART Calculator for Predicting the Number of Metaphase II Oocytes Required for Obtaining at Least One Euploid Blastocyst for Transfer in Couples Undergoing in vitro Fertilization/Intracytoplasmic Sperm Injection. Front Endocrinol (Lausanne). 2019;10:917.;PubMedCentralPMCID:PMCPMC6992582.

    Article  Google Scholar 

  5. Vaiarelli A, Cimadomo D, Ubaldi N, Rienzi L, Ubaldi FM. What is new in the management of poor ovarian response in IVF? Curr Opin Obstet Gynecol. 2018;30(3):155–62. (PubMed PMID: 29664789).

    Article  PubMed  Google Scholar 

  6. Ubaldi FM, Cimadomo D, Vaiarelli A, Fabozzi G, Venturella R, Maggiulli R, et al. Advanced Maternal Age in IVF: Still a Challenge? The Present and the Future of Its Treatment. Front Endocrinol (Lausanne). 2019;10:94.;PubMedCentralPMCID:PMCPMC6391863.

    Article  Google Scholar 

  7. Cimadomo D, Fabozzi G, Vaiarelli A, Ubaldi N, Ubaldi FM, Rienzi L. Impact of Maternal Age on Oocyte and Embryo Competence. Front Endocrinol (Lausanne). 2018;9:327.;PubMedCentralPMCID:PMCPMC6033961.

    Article  Google Scholar 

  8. Venturella R, Vaiarelli A, Lico D, Ubaldi FM, Zullo F, C DIC. A modern approach to the management of candidates for assisted reproductive technology procedures. Minerva Ginecol. 2018;70(1):69–83. doi: PubMed PMID: 28895679.

  9. Vaiarelli A, Cimadomo D, Petriglia C, Conforti A, Alviggi C, Ubaldi N, et al. DuoStim - a reproducible strategy to obtain more oocytes and competent embryos in a short time-frame aimed at fertility preservation and IVF purposes. A systematic review. Ups J Med Sci. 2020:1–10. PubMed PMID: 32338123.

  10. Sfakianoudis K, Pantos K, Grigoriadis S, Rapani A, Maziotis E, Tsioulou P, et al. What is the true place of a double stimulation and double oocyte retrieval in the same cycle for patients diagnosed with poor ovarian reserve? A systematic review including a meta-analytical approach. J Assist Reprod Genet. 2020;37(1):181–204.;PubMedCentralPMCID:PMCPMC7000611.

    Article  PubMed  Google Scholar 

  11. Kuang Y, Chen Q, Hong Q, Lyu Q, Ai A, Fu Y, et al. Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). Reprod Biomed Online. 2014;29(6):684–91. (PubMed PMID: 25444501).

    Article  PubMed  Google Scholar 

  12. Ubaldi FM, Capalbo A, Vaiarelli A, Cimadomo D, Colamaria S, Alviggi C, et al. Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation. Fertil Steril. 2016;105(6):1488–95 e1. doi: PubMed PMID: 27020168.

  13. Cimadomo D, Vaiarelli A, Colamaria S, Trabucco E, Alviggi C, Venturella R, et al. Luteal phase anovulatory follicles result in the production of competent oocytes: intra-patient paired case-control study comparing follicular versus luteal phase stimulations in the same ovarian cycle. Hum Reprod. 2018. (PubMed PMID: 29912374).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Vaiarelli A, Cimadomo D, Alviggi E, Sansone A, Trabucco E, Dusi L, et al. The euploid blastocysts obtained after luteal phase stimulation show the same clinical, obstetric and perinatal outcomes as follicular phase stimulation-derived ones: a multicenter study. Hum Reprod. 2020;35(11):2598–608. (PubMed PMID: 32951051).

    Article  PubMed  Google Scholar 

  15. Vaiarelli A, Cimadomo D, Conforti A, Schimberni M, Giuliani M, D’Alessandro P, et al. Luteal phase after conventional stimulation in the same ovarian cycle might improve the management of poor responder patients fulfilling the Bologna criteria: a case series. Fertil Steril. 2020;113(1):121–30. (PubMed PMID: 31837743).

    CAS  Article  PubMed  Google Scholar 

  16. Rienzi L, Cimadomo D, Vaiarelli A, Gennarelli G, Holte J, Livi C, et al. Measuring success in IVF is a complex multidisciplinary task: time for a consensus? Reprod Biomed Online. 2021. Epub 2021/09/09. doi: PubMed PMID: 34493463.

  17. Mazzilli R, Cimadomo D, Vaiarelli A, Capalbo A, Dovere L, Alviggi E, et al. Effect of the male factor on the clinical outcome of intracytoplasmic sperm injection combined with preimplantation aneuploidy testing: observational longitudinal cohort study of 1,219 consecutive cycles. Fertil Steril. 2017. (PubMed PMID: 28985908).

    Article  PubMed  Google Scholar 

  18. Maggiulli R, Cimadomo D, Fabozzi G, Papini L, Dovere L, Ubaldi FM, et al. The effect of ICSI-related procedural timings and operators on the outcome. Hum Reprod. 2020;35(1):32–43. (PubMed PMID: 31916573).

    Article  PubMed  Google Scholar 

  19. Cimadomo D, Vaiarelli A, Petriglia C, Fabozzi G, Ferrero S, Schimberni M, et al. Oocyte competence is independent of the ovulation trigger adopted: a large observational study in a setting that entails vitrified-warmed single euploid blastocyst transfer. J Assist Reprod Genet. 2021. (PubMed PMID: 33661465).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cimadomo D, Capalbo A, Dovere L, Tacconi L, Soscia D, Giancani A, et al. Leave the past behind: women’s reproductive history shows no association with blastocysts’ euploidy and limited association with live birth rates after euploid embryo transfers. Hum Reprod. 2021. (PubMed PMID: 33608730).

    Article  PubMed  Google Scholar 

  21. Drakopoulos P, Blockeel C, Stoop D, Camus M, de Vos M, Tournaye H, et al. Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod. 2016;31(2):370–6. doi: PubMed PMID: 26724797.

  22. Polyzos NP, Drakopoulos P, Parra J, Pellicer A, Santos-Ribeiro S, Tournaye H, et al. Cumulative live birth rates according to the number of oocytes retrieved after the first ovarian stimulation for in vitro fertilization/intracytoplasmic sperm injection: a multicenter multinational analysis including approximately 15,000 women. Fertil Steril. 2018;110(4):661–70 e1. doi: PubMed PMID: 30196963.

  23. Magnusson A, Kallen K, Thurin-Kjellberg A, Bergh C. The number of oocytes retrieved during IVF: a balance between efficacy and safety. Hum Reprod. 2017:1–7. doi: PubMed PMID: 29136154.

  24. Nelson SM, Lawlor DA. Predicting live birth, preterm delivery, and low birth weight in infants born from in vitro fertilisation: a prospective study of 144,018 treatment cycles. PLoS Med. 2011;8(1): e1000386.;PubMedCentralPMCID:PMCPMC3014925.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, et al. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril. 2017;108(3):393–406. (PubMed PMID: 28760517).

    Article  PubMed  Google Scholar 

  26. Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, et al. The International Glossary on Infertility and Fertility Care, 2017. Hum Reprod. 2017;32(9):1786–801.;PubMedCentralPMCID:PMCPMC5850297.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Reynolds KA, Omurtag KR, Jimenez PT, Rhee JS, Tuuli MG, Jungheim ES. Cycle cancellation and pregnancy after luteal estradiol priming in women defined as poor responders: a systematic review and meta-analysis. Hum Reprod. 2013;28(11):2981–9.;PubMedCentralPMCID:PMCPMC3795468.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Chang X, Wu J. Effects of luteal estradiol pre-treatment on the outcome of IVF in poor ovarian responders. Gynecol Endocrinol. 2013;29(3):196–200. (PubMed PMID: 23194136).

    CAS  Article  PubMed  Google Scholar 

  29. Lawrenz B, Ruiz F, Engelmann N, Fatemi HM. Individual luteolysis post GnRH-agonist-trigger in GnRH-antagonist protocols. Gynecol Endocrinol. 2017;33(4):261–4. (PubMed PMID: 28019139).

    CAS  Article  PubMed  Google Scholar 

  30. Rienzi L, Ubaldi F, Anniballo R, Cerulo G, Greco E. Preincubation of human oocytes may improve fertilization and embryo quality after intracytoplasmic sperm injection. Hum Reprod. 1998;13(4):1014–9 (PubMed PMID: 9619563).

    CAS  Article  Google Scholar 

  31. Capalbo A, Rienzi L, Cimadomo D, Maggiulli R, Elliott T, Wright G, et al. Correlation between standard blastocyst morphology, euploidy and implantation: an observational study in two centers involving 956 screened blastocysts. Hum Reprod. 2014;29(6):1173–81. (PubMed PMID: 24578475).

    Article  PubMed  Google Scholar 

  32. Maggiulli R, Giancani A, Cimadomo D, Ubaldi FM, Rienzi L. Human Blastocyst Biopsy and Vitrification. J Vis Exp. 2019;(149). PubMed PMID: 31403619.

  33. Cimadomo D, Capalbo A, Levi-Setti PE, Soscia D, Orlando G, Albani E, et al. Associations of blastocyst features, trophectoderm biopsy and other laboratory practice with post-warming behavior and implantation. Hum Reprod. 2018;33(11):1992–2001. (PubMed PMID: 30265329).

    Article  PubMed  Google Scholar 

  34. Treff NR, Tao X, Ferry KM, Su J, Taylor D, Scott RT Jr. Development and validation of an accurate quantitative real-time polymerase chain reaction-based assay for human blastocyst comprehensive chromosomal aneuploidy screening. Fertil Steril. 2012;97(4):819–24. (PubMed PMID: 22342859).

    CAS  Article  PubMed  Google Scholar 

  35. Capalbo A, Treff NR, Cimadomo D, Tao X, Upham K, Ubaldi FM, et al. Comparison of array comparative genomic hybridization and quantitative real-time PCR-based aneuploidy screening of blastocyst biopsies. Eur J Hum Genet. 2015;23(7):901–6.;PubMedCentralPMCID:PMCPMC4463508.

    CAS  Article  PubMed  Google Scholar 

  36. Garcia-Pascual CM, Navarro-Sanchez L, Navarro R, Martinez L, Jimenez J, Rodrigo L, et al. Optimized NGS Approach for Detection of Aneuploidies and Mosaicism in PGT-A and Imbalances in PGT-SR. Genes (Basel). 2020;11(7). doi: PubMed PMID: 32610655; PubMed Central PMCID: PMCPMC7397276.

  37. Forman EJ. Demystifying “mosaic” outcomes. Fertil Steril. 2019;111(2):253. (PubMed PMID: 30691625).

    Article  PubMed  Google Scholar 

  38. Goodrich D, Tao X, Bohrer C, Lonczak A, Xing T, Zimmerman R, et al. A randomized and blinded comparison of qPCR and NGS-based detection of aneuploidy in a cell line mixture model of blastocyst biopsy mosaicism. J Assist Reprod Genet. 2016;33(11):1473–80.;PubMedCentralPMCID:PMCPMC5125146.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Girardi L, Patassini C, Fabiani M, Caroselli S, Serdarogullari M, Coban O, et al. The application of more stringent parameters for mosaic classification in blastocyst-stage preimplantation genetic testing for aneuploidies reduces false positive mosaic rates without comprising true detection. Human Reproduction. 2020;35(Suppl July 2020):i35-i6.

  40. Girardi L, Serdarogullari M, Patassini C, Poli M, Fabiani M, Caroselli S, et al. Incidence, Origin, and Predictive Model for the Detection and Clinical Management of Segmental Aneuploidies in Human Embryos. Am J Hum Genet. 2020. (PubMed PMID: 32220293).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Popovic M, Dhaenens L, Taelman J, Dheedene A, Bialecka M, De Sutter P, et al. Extended in vitro culture of human embryos demonstrates the complex nature of diagnosing chromosomal mosaicism from a single trophectoderm biopsy. Hum Reprod. 2019;34(4):758–69. (PubMed PMID: 30838420).

    CAS  Article  PubMed  Google Scholar 

  42. Popovic M, Dhaenens L, Boel A, Menten B, Heindryckx B. Chromosomal mosaicism in human blastocysts: the ultimate diagnostic dilemma. Hum Reprod Update. 2020. (PubMed PMID: 32141501).

    Article  PubMed  Google Scholar 

  43. Capalbo A, Poli M, Cimadomo D, Benini F, Patassini C, Rubio C, et al. Low-degree mosaicism profiles do not provide clinically useful predictive values: interim results from the first multicenter prospective non-selection study on the transfer of mosaic embryos. Human Reproduction. 2020;35(Suppl July 2020):i368.

  44. Vaiarelli A, Cimadomo D, Patrizio P, Venturella R, Orlando G, Soscia D, et al. Biochemical pregnancy loss after frozen embryo transfer seems independent of embryo developmental stage and chromosomal status. Reprod Biomed Online. 2018;37(3):349–57. (PubMed PMID: 30314887).

    CAS  Article  PubMed  Google Scholar 

  45. Malizia BA, Hacker MR, Penzias AS. Cumulative live-birth rates after in vitro fertilization. N Engl J Med. 2009;360(3):236–43. (PubMed PMID: 19144939).

    CAS  Article  PubMed  Google Scholar 

  46. Ubaldi FM, Cimadomo D, Capalbo A, Vaiarelli A, Buffo L, Trabucco E, et al. Preimplantation genetic diagnosis for aneuploidy testing in women older than 44 years: a multicenter experience. Fertil Steril. 2017;107(5):1173–80. (PubMed PMID: 28433373).

    Article  PubMed  Google Scholar 

  47. Modest AM, Wise LA, Fox MP, Weuve J, Penzias AS, Hacker MR. IVF success corrected for drop-out: use of inverse probability weighting. Hum Reprod. 2018;33(12):2295–301.;PubMedCentralPMCID:PMCPMC6238364.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Gameiro S, Boivin J, Peronace L, Verhaak CM. Why do patients discontinue fertility treatment? A systematic review of reasons and predictors of discontinuation in fertility treatment. Hum Reprod Update. 2012;18(6):652–69.;PubMedCentralPMCID:PMCPMC3461967.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Vaughan DA, Leung A, Resetkova N, Ruthazer R, Penzias AS, Sakkas D, et al. How many oocytes are optimal to achieve multiple live births with one stimulation cycle? The one-and-done approach. Fertil Steril. 2017;107(2):397–404 e3. doi: PubMed PMID: 27916206.

  50. Cobo A, Garrido N, Crespo J, Jose R, Pellicer A. Accumulation of oocytes: a new strategy for managing low-responder patients. Reprod Biomed Online. 2012;24(4):424–32. (PubMed PMID: 22386762).

    CAS  Article  PubMed  Google Scholar 

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Authors and Affiliations



AV, DC, LR and FMU designed the study. AV, SC, CA, MG, and FMU recruited the patients. AV and DC analyzed the data and drafted the manuscript. DC, VC and ADA designed and performed the cost-effectiveness analyses. All authors contributed to the discussion of the results.

Corresponding author

Correspondence to Alberto Vaiarelli.

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Institutional Review Board approval for this study was obtained from Clinica Valle Giulia.

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Supplementary Information

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Supplementary Figure 1. Results from the couples in the conventional approach (COS 1 + COS 2) group and their matched* couples in the DuoStim (Stim I + Stim II in the same ovarian cycle) group. Each circle represents a cumulus oocyte complex (COC) retrieved. If green, it developed as an euploid blastocyst and resulted in a live birth after transfer; if purple, it developed as an euploid blastocyst but did NOT result in a live birth after transfer; if orange, it developed as an euploid blastocyst which is still available for transfer; if red, it developed as an aneuploid blastocyst; if grey, it did not reach the blastocyst stage. In the conventional approach group, we highlighted the couples who dropped-out from the treatment after a failed first attempt. In the DuoStim group, we highlighted the patients who did not respond to the second stimulation in the same ovarian cycle. *The couples were matched for maternal age, sperm factor, number of cumulus oocytes complexes (COCs) and blastocysts obtained after the first COS.

Supplementary file1 (PDF 264 kb)


Supplementary Figure 2. Sub-analysis of the cumulative live birth delivery rates (CLBdR) in the conventional approach and the matched* DuoStim groups according to the number of blastocysts obtained after the first controlled ovarian stimulation (COS). The treatment drop-out rate among couples who failed the first attempt has been reported also for the former group. Below each cluster we reported also the mean maternal age. *Besides maternal age and number of blastocysts obtained after the first COS, the couples were matched also for sperm factor and number of cumulus oocyte complexes retrieved after first COS.

Supplementary file2 (PDF 77 kb)

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Vaiarelli, A., Cimadomo, D., Gennarelli, G. et al. Second stimulation in the same ovarian cycle: an option to fully-personalize the treatment in poor prognosis patients undergoing PGT-A. J Assist Reprod Genet 39, 663–673 (2022).

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  • DuoStim
  • Double stimulation
  • Treatment personalization
  • Poor prognosis
  • Advanced maternal age