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Impact of Embryo Cryopreservation on Large for Gestational Age Babies Born by Embryo Transfer: Cohort Retrospective Study

  • Reproductive Biology: Original Article
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Abstract

The transfer of frozen-thawed embryos has been associated with an increased risk of large for gestational age at birth. Our objective is to assess its impact on the risk of large for gestational age (LGA) in order to improve the bias control in relation with the available studies. Retrospective cohort study on cumulative sample of 801 single live births of 32 weeks or longer of gestation, resulting from pregnancies obtained by cryopreserved or fresh embryo transfer which are not affected by disorders that could impair fetal growth and carried out at Hospital General Universitario Gregorio Marañón, in Madrid, during the period 2005–2017. The relative risk (RR) of LGA has been estimated with its confidence interval (CI) at 95%. Multivariate analysis using logistic regression was applied to adjust the crude effect. LGA was more frequent in babies born after cryotransfer in comparison with the reference group (20.9% vs. 6.0%; p < 0.001), as well as macrosomia (8.2% vs. 0.9%; p < 0.001). Frequencies of weight > 4500 g were similar (0.7% vs. 0.1%; p > 0.05). Nulliparity was associated to a higher risk of LGA (RR: 3.8; CI95%: 2.0–7.0; p < 0.005), as well as cleaving embryo transfer (RR: 2; CI95%: 1.07–3.8; p < 0.05). According to the multivariate analysis, the exposure variable was the only one independently associated with LGA (OR: 3.5; CI95%: 2.0–6.1; p < 0.001). Frozen-thawed embryo transfer significantly increases the risk of LGA, regardless of the influence of factors relating to the patient’s condition, the embryos transferred, or the fetal sex.

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Availability of Data and Materials

The information about variables included in the study was essentially obtained from primary sources (clinical records, embryo laboratory registries from the embryo bank of the Assisted Reproduction Unit of the Hospital General Universitario Gregorio Marañón) and, exceptionally, from secondary sources (progress or discharge reports).

Code Availability

Version 26 of the SPSS (Statistical Package for Social Sciences, IBM Spain) computer program for Windows.

References

  1. Pfeifer S, Butts S, Fossum G, Gracia C, La Barbera A, Mersereau J, et al. Optimizing natural fertility: a committee opinion. Fertil Steril. 2017;107(1):52–8.

    Article  Google Scholar 

  2. Bosch E, De Vos M, Humaidan P. 2020 The future of cryopreservation in assisted reproductive technologies. Front Endocrinol [Internet]. Feb 20 [cited 2020 Nov 21];11. Available from: https://www.frontiersin.org/article/https://doi.org/10.3389/fendo.2020.00067/full

  3. Comité de Registro de la Sociedad Española de Fertilidad. Registro Nacional de Actividad de Centros de Reproducción Asistida-Registro SEF: Informe estadístico sobre técnicas de reproducción asistida 2017. [Internet]. 2017. Available from: https://www.registrosef.com/public/docs/sef2017_IAFIVm.pdf.

  4. Roque M. Freeze-all policy: is it time for that? J Assist Reprod Genet. 2015;32(2):171–6.

    Article  PubMed  Google Scholar 

  5. Orvieto R, Kirshenbaum M, Gleicher N. 2020 Is Embryo cryopreservation causing macrosomia—and what else? Front Endocrinol [Internet]. Jan 28 [cited 2020 Nov 21];11. Available from: https://www.frontiersin.org/article/https://doi.org/10.3389/fendo.2020.00019/full

  6. Maheshwari A, Pandey S, Shetty A, Hamilton M, Bhattacharya S. Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of frozen thawed versus fresh embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis. Fertil Steril. 2012;98(2):368-377.e9.

    Article  PubMed  Google Scholar 

  7. Maheshwari A, Pandey S, Amalraj Raja E, Shetty A, Hamilton M, Bhattacharya S. Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer? Hum Reprod Update. 2018;24(1):35–58.

    Article  PubMed  Google Scholar 

  8. Somigliana E, Vanni VS, Busnelli A, Reschini M, Papaleo E, Viganò P. 2018 Excessive fetal growth in frozen embryo transfer: false alarm or clinical concern? Hum Reprod Update [Internet]. Apr 18 [cited 2020 Nov 21]; Available from: https://academic.oup.com/humupd/advance-article/doi/https://doi.org/10.1093/humupd/dmy010/4975748

  9. Sha T, Yin X, Cheng W, Massey IY. Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis. Fertil Steril. 2018;109(2):330-342.e9.

    Article  PubMed  Google Scholar 

  10. Mani S, Ghosh J, Coutifaris C, Sapienza C, Mainigi M. Epigenetic changes and assisted reproductive technologies. Epigenetics. 2020;15(1–2):12–25.

    Article  PubMed  Google Scholar 

  11. Pelkonen S, Koivunen R, Gissler M, Nuojua-Huttunen S, Suikkari AM, Hydén-Granskog C, et al. Perinatal outcome of children born after frozen and fresh embryo transfer: the Finnish cohort study 1995–2006. Hum Reprod. 2010;25(4):914–23.

    Article  CAS  PubMed  Google Scholar 

  12. Wikland M, Hardarson T, Hillensjo T, Westin C, Westlander G, Wood M, et al. Obstetric outcomes after transfer of vitrified blastocysts. Hum Reprod. 2010;25(7):1699–707.

    Article  CAS  PubMed  Google Scholar 

  13. Kato O, Kawasaki N, Bodri D, Kuroda T, Kawachiya S, Kato K, et al. Neonatal outcome and birth defects in 6623 singletons born following minimal ovarian stimulation and vitrified versus fresh single embryo transfer. Eur J Obstet Gynecol Reprod Biol. 2012;161(1):46–50.

    Article  PubMed  Google Scholar 

  14. Wennerholm UB, Henningsen AKA, Romundstad LB, Bergh C, Pinborg A, Skjaerven R, et al. Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group. Hum Reprod. 2013;28(9):2545–53.

    Article  PubMed  Google Scholar 

  15. Ishihara O, Araki R, Kuwahara A, Itakura A, Saito H, Adamson GD. Impact of frozen-thawed single-blastocyst transfer on maternal and neonatal outcome: an analysis of 277,042 single-embryo transfer cycles from 2008 to 2010 in Japan. Fertil Steril. 2014;101(1):128–33.

    Article  PubMed  Google Scholar 

  16. Li Z, Wang YA, Ledger W, Edgar DH, Sullivan EA. Clinical outcomes following cryopreservation of blastocysts by vitrification or slow freezing: a population-based cohort study. Hum Reprod. 2014;29(12):2794–801.

    Article  CAS  PubMed  Google Scholar 

  17. Pinborg A, Henningsen AA, Loft A, Malchau SS, Forman J, Andersen AN. Large baby syndrome in singletons born after frozen embryo transfer (FET): is it due to maternal factors or the cryotechnique? Hum Reprod. 2014;29(3):618–27.

    Article  CAS  PubMed  Google Scholar 

  18. Maheshwari A, Raja EA, Bhattacharya S. Obstetric and perinatal outcomes after either fresh or thawed frozen embryo transfer: an analysis of 112,432 singleton pregnancies recorded in the Human Fertilisation and Embryology Authority anonymized dataset. Fertil Steril. 2016;106(7):1703–8.

    Article  PubMed  Google Scholar 

  19. Van Heertum K, Weinerman R. Neonatal outcomes following fresh as compared to frozen/thawed embryo transfer in in vitro fertilization. Birth Defects Res. 2018;110(8):625–9.

    Article  PubMed  Google Scholar 

  20. Xu H, Simonet F, Luo ZC. Optimal birth weight percentile cut-offs in defining small- or large-for-gestational-age. Acta Paediatr. 2010;99(4):550–5.

    Article  CAS  PubMed  Google Scholar 

  21. Sharifzadeh F, Kashanian M, Jouhari S, Sheikhansari N. Relationship between pre-pregnancy maternal BMI with spontaneous preterm delivery and birth weight. J Obstet Gynaecol J Inst Obstet Gynaecol. 2015;35(4):354–7.

    Article  CAS  Google Scholar 

  22. Pongcharoen T, Gowachirapant S, Wecharak P, Sangket N, Winichagoon P. Pre-pregnancy body mass index and gestational weight gain in Thai pregnant women as risks for low birth weight and macrosomia. Asia Pac J Clin Nutr. 2016;25(4):810–7.

    CAS  PubMed  Google Scholar 

  23. Du MK, Ge LY, Zhou ML, Ying J, Qu F, Dong MY, et al. Effects of pre-pregnancy body mass index and gestational weight gain on neonatal birth weight. J Zhejiang Univ Sci B. 2017;18(3):263–71.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Goldstein RF, Abell SK, Ranasinha S, Misso ML, Boyle JA, Harrison CL, et al. 2018 Gestational weight gain across continents and ethnicity: systematic review and meta-analysis of maternal and infant outcomes in more than one million women. BMC Med [Internet]. Dec [cited 2022 Jul 27];16(1). Available from:https://bmcmedicine.biomedcentral.com/articles/https://doi.org/10.1186/s12916-018-1128-1

  25. Santos S, Voerman E, Amiano P, Barros H, Beilin L, Bergström A, et al. 2019 Impact of maternal body mass index and gestational weight gain on pregnancy complications: an individual participant data meta‐analysis of European, North American, and Australian cohorts. BJOG Int J Obstet Gynaecol [Internet]. Mar 20 [cited 2022 Jul 27]; Available from: https://onlinelibrary.wiley.com/doi/https://doi.org/10.1111/1471-0528.15661

  26. Roque M, Haahr T, Geber S, Esteves SC, Humaidan P. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update. 2019;25(1):2–14.

    Article  PubMed  Google Scholar 

  27. Anav M, Phillips S, Ferrieres-Hoa A, Gala A, Fournier A, Vincens C, et al. Cryopreserved embryo replacement is associated with higher birthweight compared with fresh embryo: multicentric sibling embryo cohort study. Sci Rep [Internet]. 2019 Dec [cited 2020 Nov 21];9(1). Available from: http://www.nature.com/articles/s41598-019-49708-7

  28. Gu F, Li S, Zheng L, Gu J, Li T, Du H, et al. Perinatal outcomes of singletons following vitrification versus slow-freezing of embryos: a multicenter cohort study using propensity score analysis. Hum Reprod. 2019;34(9):1788–98.

    Article  PubMed  Google Scholar 

  29. Ginström Ernstad E, Wennerholm UB, Khatibi A, Petzold M, Bergh C. Neonatal and maternal outcome after frozen embryo transfer: increased risks in programmed cycles. Am J Obstet Gynecol. 2019;221(2):126.e1-126.e18.

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors want to thank “Agencia de traducción medico-científica V de A” for providing language help.

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Authors and Affiliations

  1. Department of Obstetrics and Gynaecology and Reproductive Medicine, Hospital General Universitario Gregorio Marañón, c/ O’Donnell 48, 28009, Madrid, Spain

    Duna Trobo, Cecilia García, Marta Martínez, Inés Rodríguez, María Rojo, Sonsoles Moreno, Gonzalo Nozaleda, Laura Pérez, Miguel Caballero, Elena Ceballos, María T. Navarro & Federico Mariano Pérez-Milán

  2. Department of Obstetrics and Gynaecology, Hospital Fundación Jove, Avenida Eduardo de Castro 161, 33290, Gijon, Asturias, Spain

    Ana Solís

Authors
  1. Duna Trobo
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  2. Cecilia García
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  3. Marta Martínez
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  4. Inés Rodríguez
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  5. María Rojo
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  6. Sonsoles Moreno
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  7. Gonzalo Nozaleda
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  9. Laura Pérez
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  10. Miguel Caballero
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  13. Federico Mariano Pérez-Milán
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Contributions

All the authors contributed to the study conception and design. Material preparation and data collection were performed by Duna Trobo, Cecilia García, Marta Martínez, Inés Rodríguez, María Rojo, Sonsoles Moreno, Gonzalo Nozaleda, and Ana Solís. Analysis was performed by Duna Trobo, Marta Martínez, Inés Rodríguez, María Rojo, and Federico M.Pérez Milán. The first draft of the manuscript was written by Duna Trobo, and all the authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Duna Trobo.

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Ethics Approval

This study was authorized by the Hospital Universitario Gregorio Marañón Clinical Research Ethics Committee in view of the retrospective nature of the study, and all the procedures being performed were part of routine care.

Consent to Participate and Publish

The retrospective nature of the study, together with the long-term observation period, was the reason for the waiver request for obtaining informed consent, which was granted.

Conflict of Interest

The authors declare no competing interests.

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Trobo, D., García, C., Martínez, M. et al. Impact of Embryo Cryopreservation on Large for Gestational Age Babies Born by Embryo Transfer: Cohort Retrospective Study. Reprod. Sci. 30, 1257–1265 (2023). https://doi.org/10.1007/s43032-022-01075-x

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  • DOI: https://doi.org/10.1007/s43032-022-01075-x

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