Does contemporary ART lead to pre-eclampsia? A cohort study and meta-analysis



Recent publications suggested that the risk for pre-eclampsia (PE) is higher with frozen-thawed embryo transfers (FETs) compared to fresh transfers (IVF-ETs). These studies were based on old data that reflects outdated practices. In this paper, we wanted to assess the incidence of PE in current assisted reproductive technology (ART) practice.


In this cohort study, we present the incidence of PE in all births in the province of Ontario, Canada, for the years 2013–2017 for FET, IVF-ET, and natural conceptions (NC). We also compare our findings to previous studies in a meta-analysis that includes over 4 million births.


The results of our study show that contemporary practice of ART results in comparable risk for PE between FET and IVF-ET; however, the risk is higher than NC.


Current ART practice is associated with a lower risk for PE in frozen embryo transfer; this RR can be further attenuated by using ovulatory endometrial preparation for FETs.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Roque M, Valle M, Guimaraes F, Sampaio M, Geber S. Cost-effectiveness of the freeze-all policy. JBRA Assist Reprod. 2015;19(3):125-30. 10.5935/1518-0557.20150028.

  2. 2.

    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 

  3. 3.

    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 

  4. 4.

    Sabban H, Zakhari A, Patenaude V, Tulandi T, Abenhaim HA. Obstetrical and perinatal morbidity and mortality among in-vitro fertilization pregnancies: a population-based study. Arch Gynecol Obstet. 2017;296(1):107–13.

    Article  PubMed  Google Scholar 

  5. 5.

    O’Gorman N, Wright D, Poon LC, Rolnik DL, Syngelaki A, Wright A, et al. Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks’ gestation. Ultrasound Obstet Gynecol. 2017;49(6):751–5.

    Article  PubMed  Google Scholar 

  6. 6.

    Boulet SL, Mehta A, Kissin DM, Warner L, Kawwass JF, Jamieson DJ. Trends in use of and reproductive outcomes associated with intracytoplasmic sperm injection. JAMA. 2015;313(3):255–63.

    Article  PubMed  Google Scholar 

  7. 7.

    Glujovsky D, Farquhar C. Cleavage-stage or blastocyst transfer: what are the benefits and harms? Fertil Steril. 2016;106(2):244–50.

    Article  PubMed  Google Scholar 

  8. 8.

    Levi-Setti PE, Patrizio P, Scaravelli G. Evolution of human oocyte cryopreservation: slow freezing versus vitrification. Curr Opin Endocrinol Diabetes Obes. 2016;23(6):445–50.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Dunn S, Bottomley J, Ali A, Walker M. 2008 Niday Perinatal Database quality audit: report of a quality assurance project. Chronic Dis Inj Can. 2011;32(1):32–42.

    CAS  PubMed  Google Scholar 

  10. 10.

    Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;350:g7647.

    Article  PubMed  Google Scholar 

  11. 11.

    Huedo-Medina TB, Sanchez-Meca J, Marin-Martinez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods. 2006;11(2):193–206.

    Article  PubMed  Google Scholar 

  12. 12.

    Higgins JPTTJ, Chandler J. Cumpston M, Li T. Welch VA Cochrane Handbook for Systematic Reviews of Interventions. Sixth ed. Cochrane: Page MJ; 2019.

    Google Scholar 

  13. 13.

    Shi W, Xue X, Zhang S, Zhao W, Liu S, Zhou H, et al. Perinatal and neonatal outcomes of 494 babies delivered from 972 vitrified embryo transfers. Fertil Steril. 2012;97(6):1338–42.

    Article  PubMed  Google Scholar 

  14. 14.

    Liu SY, Teng B, Fu J, Li X, Zheng Y, Sun XX. Obstetric and neonatal outcomes after transfer of vitrified early cleavage embryos. Hum Reprod. 2013;28(8):2093–100.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Imudia AN, Awonuga AO, Kaimal AJ, Wright DL, Styer AK, Toth TL. Elective cryopreservation of all embryos with subsequent cryothaw embryo transfer in patients at risk for ovarian hyperstimulation syndrome reduces the risk of adverse obstetric outcomes: a preliminary study. Fertil Steril. 2013;99(1):168–73.

    Article  PubMed  Google Scholar 

  16. 16.

    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 

  17. 17.

    Sazonova A, Kallen K, Thurin-Kjellberg A, Wennerholm UB, Bergh C. Obstetric outcome in singletons after in vitro fertilization with cryopreserved/thawed embryos. Hum Reprod. 2012;27(5):1343–50.

    Article  PubMed  Google Scholar 

  18. 18.

    Opdahl S, Henningsen AA, Tiitinen A, Bergh C, Pinborg A, Romundstad PR, et al. Risk of hypertensive disorders in pregnancies following assisted reproductive technology: a cohort study from the CoNARTaS group. Hum Reprod. 2015;30(7):1724–31.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Ginstrom 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- e18. 10.1016/j.ajog.2019.03.010.

  20. 20.

    Xiong F, Hu L, Zhang Y, Xiao X. Correlation of hypertensive disorders in pregnancy with procedures of in vitro fertilization and pregnancy outcomes. Exp Ther Med. 2017;14(6):5405–10.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Shavit T, Oron G, Weon-Young S, Holzer H, Tulandi T. Vitrified-warmed single-embryo transfers may be associated with increased maternal complications compared with fresh single-embryo transfers. Reprod Biomed Online. 2017;35(1):94–102.

    Article  PubMed  Google Scholar 

  22. 22.

    Sites CK, Wilson D, Barsky M, Bernson D, Bernstein IM, Boulet S, et al. Embryo cryopreservation and preeclampsia risk. Fertil Steril. 2017;108(5):784–90.

    Article  PubMed  Google Scholar 

  23. 23.

    Johnson KM, Hacker MR, Resetkova N, O’Brien B, Modest AM. Risk of ischemic placental disease in fresh and frozen embryo transfer cycles. Fertil Steril. 2019;111(4):714–21.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Luke B, Brown MB, Eisenberg ML, Callan C, Botting BJ, Pacey A et al. In vitro fertilization and risk for hypertensive disorders of pregnancy: associations with treatment parameters. Am J Obstet Gynecol. 2020;222(4):350 e1- e13. 10.1016/j.ajog.2019.10.003.

  25. 25.

    Moore RA, Gavaghan DJ, Edwards JE, Wiffen P, McQuay HJ. Pooling data for number needed to treat: no problems for apples. BMC Med Res Methodol. 2002;2:2.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    von Versen-Hoynck F, Schaub AM, Chi YY, Chiu KH, Liu J, Lingis M, et al. Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum. Hypertension. 2019;73(3):640–9.

    CAS  Article  Google Scholar 

  27. 27.

    Wang Z, Liu H, Song H, Li X, Jiang J, Sheng Y et al. Increased risk of pre-eclampsia after frozen-thawed embryo transfer in programming cycles. Front Med (Lausanne). 2020;7:104. 10.3389/fmed.2020.00104.

  28. 28.

    Liu KE, Hartman M, Hartman A, Luo ZC, Mahutte N. The impact of a thin endometrial lining on fresh and frozen-thaw IVF outcomes: an analysis of over 40 000 embryo transfers. Hum Reprod. 2018;33(10):1883–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Dayan N, Lanes A, Walker MC, Spitzer KA, Laskin CA. Effect of chronic hypertension on assisted pregnancy outcomes: a population-based study in Ontario. Canada. Fertil Steril. 2016;105(4):1003–9.

    Article  PubMed  Google Scholar 

  30. 30.

    Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, de Paco MC, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017;377(7):613–22.

    CAS  Article  PubMed  Google Scholar 

Download references


We wish to acknowledge the Better Outcomes Registry and Network (BORN) Ontario as the source of the data and CARTR Plus for providing Extract ART and birth data (Years provided: 2013 to 2017). The data was provided in 2020.


The study was funded internally.

Author information




SK and YB reviewed previous publications, analyzed current data & wrote the manuscript.

Corresponding author

Correspondence to Yaakov Bentov.

Ethics declarations


All inferences, opinions, and conclusions drawn in this publication are those of the authors, and do not necessarily reflect the options or policies of BORN Ontario.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information


(PNG 441 kb)

High Resolution Image (TIF 600 kb)


(XLSX 44.3 kb)


(CSV 17.1 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kenigsberg, S., Bentov, Y. Does contemporary ART lead to pre-eclampsia? A cohort study and meta-analysis. J Assist Reprod Genet (2021).

Download citation


  • Pre-eclampsia
  • Hypertensive disorders of pregnancy
  • Frozen embryo transfer
  • Fresh embryo transfer
  • Natural conception
  • Assisted reproductive technology