Elective Single Cleavage‑Stage Embryo Transfer in IVF Patients with Suboptimal Ovarian Response is Not Detrimental to Cumulative Pregnancy and Reduces Multiple Pregnancy Rates.

Alessio Paffoni¹ · Sabrina Cesana¹ · Laura Corti¹ · Hilda Wyssling¹ · Alessandro Kunderfranco¹ · Marco Claudio Bianchi¹

Alessio Paffoni alessio.paffoni@alice.it

1 UOSD Infertility Unit, ASST Lariana, via Domea, 22063 Cantù, Como, Italy

Purpose To evaluate whether elective single embryo transfer in patients with suboptimal response to ovarian stimulation is
detrimental to pregnancy rates compared to double embryo transfer.
Methods A case–control retrospective study was performed in a cohort of couples undergoing IVF at the Infertility Unit of
the ASST Lariana with ≤ 9 oocytes and at least 2 viable embryos. A total of 424 women were analyzed in the “double embryo
transfer” group (n = 212) and elective “single embryo transfer” group (n = 212); they were matched 1:1 for female age, ovarian
reserve and number of previous cycles. Cumulative clinical pregnancy rate per oocyte retrieval was the main outcome.
Results The cumulative pregnancy rate per cycle, including the fresh embryo and subsequent frozen embryo transfers, was
26% and 26%, respectively. Considering the main confounding factors, a binomial logistic model indicated that the cumulative
clinical pregnancy rate was not significantly affected when a single embryo transfer was performed in women recovering
up to nine oocytes.
Conclusion Live birth rate was similar between the two groups, while twin pregnancies were significantly reduced in women
receiving single embryo transfer suggesting that elective single embryo transfer in patients with a limited number of embryos
is not detrimental to pregnancy rates.

Keywords : Poor ovarian response · Single embryo transfer · In vitro fertilization · Twin pregnancy

In recent years, multiple higher-order pregnancies in in vitro fertilization (IVF) programs have dropped significantly due to the evolution of embryo culture and selection techniques as well as specific legal constraints in some countries trending toward the transfer of fewer embryos; however, the incidence of twin pregnancies is currently 5–15% with well described life-threatening maternal morbidities, neonatal risks, and financial burden associated with this on the health system [1–4]. The likelihood of having multiple babies is strongly influenced by the number of embryos that are transferred during IVF treatment. Therefore, it's important to set limits on the number of embryos transferred while still maintaining the chances of success. Some analyses have suggested that replacing the transfer of two embryos with elective single embryo transfer (eSET) could be a cost-effective option allowing to reduce twin pregnancies without compromising pregnancy rates in good prognosis patients [5, 6] and also in women of advanced maternal age or those with reduced response to ovarian stimulation [7, 8].

Prolonged culture up to the blastocyst stage and the application of preimplantation genetic testing has been proposed as a “high-tech” choice to reduce the number of embryos to be transferred [9], but many routines do not involve blastocyst culture in the case of small number of embryos to limit the risk of cancelation of the cycle. In this regard, a strategy that deserves consideration may involve the transfer of a single embryo in the cleavage stage, thus reducing the risk of cancelation of the cycle, and the freezing of supernumerary embryos after extended culture at the blastocyst stage, thus limiting the use of cryopreservation to the embryos with an appropriate developmental potential. This practice, which employs the classic morphological criteria as a key element for choosing the best embryo to be transferred in the fresh cycle, has been implemented in our center since 2018 for all couples with the aim of reducing the rate of twin births. The retrospective analysis proposed here represents a pre- and post-intervention study to contribute to the lack of specific data on the efficacy of eSET in couples with small numbers of embryos. In particular, we identified double embryo transfer (DET) controls and eSET cases using a matched case–control study design within couples with a poor or suboptimal response to ovarian stimulation (≤ 9 oocytes) with the main aim to compare cumulative pregnancy rates.

Callahan TL, Hall JE, Ettner SL, Christiansen CL, Greene MF, Crowley WF Jr. The economic impact of multiple-gestation pregnancies and the contribution of assisted- reproduction techniques to their incidence. N Engl J Med. 1994;33:244–9.
European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE). ART in Europe. results generated from European registries by ESHRE. Hum Reprod Open. 2016;2020(3):hoaa032.
National Center for Chronic Disease Prevention and Health Promotion, Division of Reproductive Health. https:// www. cdc. gov/ art/ repor ts/ 2018/ ferti lity- clinic. html. Accessed July 23, 2021.
Human Fertilisation and Embryology Authority.[cited 2021 July 23]. Available from https://www.hfea.gov.uk/about-us/publications/ resea rch- and- data/ ferti lity- treat ment- 2019- trends- and- figur es/# Secti on1.
van Heesch MM, van Asselt AD, Evers JL, et al. Cost-effectiveness of embryo transfer strategies: a decision analytic model using long-term costs and consequences of singletons and multiples born as a consequence of IVF. Hum Reprod. 2016;31:2527–40.
Bergh C, Kamath MS, Wang R, Lensen S. Strategies to reduce multiple pregnancies during medically assisted reproduction. Fertil Steril. 2020;114:673–9.
Leijdekkers JA, Eijkemans MJC, van Tilborg TC, et al. Cumulative live birth rates in low- prognosis women. Hum Reprod. 2019;34:1030–41.
Niinimäki M, Suikkari AM, Mäkinen S, Söderström-Anttila V, Martikainen H. Elective single-embryo transfer in women aged 40–44 years. Hum Reprod. 2013;28:331–5.
Ubaldi FM, Capalbo A, Colamaria S, et al. Reduction of multiple pregnancies in the advanced maternal age population after implementation of an elective single embryo transfer policy coupled with enhanced embryo selection: pre- and post-intervention study. Hum Reprod. 2015;30:2097–106.
de Graaf MA, Jager KJ, Zoccali C, Dekker FW. Matching, an appealing method to avoid confounding? Nephron Clin Pract. 2011;118:c315-318.
Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011;26:1270–83.
Kamath MS, Mascarenhas M, Kirubakaran R, Bhattacharya S. Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database Syst Rev. 2020;8:CDS003416.
Van der Auwera I, Debrock S, Spiessens C, et al. A prospective randomized study: day 2 versus day 5 embryo transfer. Hum Reprod. 2002;17:1507–12.
Grifo J, Kofinas J, Schoolcraft WB. The practice of in vitro fertilization according to the published literature. Fertil Steril. 2014;102:658–9.
Adler A, Lee HL, McCulloh DH, et al. Blastocyst culture selects for euploid embryos: comparison of blastomere and trophectoderm biopsies. Reprod Biomed Online. 2014;28:485–91.
Glujovsky D, Farquhar C, Quinteiro Retamar AM, Alvarez Sedo CR, Blake D. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev. 2016;2016:CDS002118.
Papanikolaou EG, Camus M, Kolibianakis EM, Van Landuyt L, Van Steirteghem A, Devroey P. In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos. N Engl J Med. 2006;354:1139–46.
Frattarelli JL, Leondires MP, McKeeby JL, Miller BT, Segars JH. Blastocyst transfer decreases multiple pregnancy rates in in vitro fertilization cycles: a randomized controlled trial. Fertil Steril. 2003;79:228–30.
Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Blastocyst culture and transfer in clinical-assisted reproduction: a committee opinion. Fertil Steril. 2013;99:667–72.
Alviggi C, Andersen CY, Buehler K, Conforti A, De Placido G, Esteves SC, et al. A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Fertil Steril. 2016;105:1452–3.
Somigliana E, Busnelli A, Paffoni A, et al. Cost-effectiveness of preimplantation genetic testing for aneuploidies. Fertil Steril. 2019;111:1169–76.
Esteves SC, Yarali H, Vuong LN, et al. Cumulative delivery rate per aspiration IVF/ICSI cycle in POSEIDON patients: a real-world evidence study of 9073 patients. Hum Reprod. 2021;36:2157–69.
Li Y, Li X, Yang X, et al. Cumulative live birth rates in low prognosis patients according to the POSEIDON criteria: an analysis of 26,697 cycles of in vitro fertilization/intracytoplasmic sperm injection. Front Endocrinol (Lausanne). 2019;10:642.
Jonsdottir I, Lundin K, Bergh C. Double embryo transfer gives good pregnancy and live birth rates in poor responders with a modest increase in multiple birth rates: results from an observational study. Acta Obstet Gynecol Scand. 2011;90:761–6.
Gleicher N, Vega MV, Darmon SK, et al. Live-birth rates in very poor prognosis patients, who are defined as poor responders under the Bologna criteria, with nonelective single embryo, two-embryo, and three or more embryos transferred. Fertil Steril. 2015;104:1435–41.
Wong KM, Repping S, Mastenbroek S. Limitations of embryo selection methods. Semin Reprod Med. 2014;32:127–33.