TRANSLATIONAL AND CLINICAL MEDICINE - Georgian Medical Journal

Abstract

Background

Hypertensive disorders are one of the leading causes of maternal and perinatal morbidity and mortality worldwide. ⁽¹⁾ It is responsible for around 16% of maternal deaths globally, in 2023 this was the equivalent to around 42 000 deaths ^{(2, 3).}

Aim

To define the impact of conception method on the risk of preeclampsia.

Methods

A prospective observational study was conducted at the Zurab Sabakhtarashvili Reproductive Clinic on the pregnant women from 2021 (january)-2025 (november). All of the participants of the study underwent preeclampsia first-semester screening test. 537 pregnant women, who were conceived with artificial reproductive technology (In vitro fertilization and Ovarian stimulation) were selected as group l. In addition to that, 407 woman who had a spontaneous pregnancy were chosen as a control group (group II). Logistic regression was used to exclude confounding factors.

Results:

In 01.01.2021 – 31.11.2025, 988 preeclampsia screening tests were performed at Zurab Sabakhtarashvili Reproductive Clinic. In 520 cases were confirmed a high risk (52.63%). Group 1 was seperated into three subgroups. Subgroup 1 – method of conception in vitro fertilization and frozen embryo transfer (240 women). Subgroup 2 - method of conception in vitro fertilization and fresh embryo transfer (149 women). Subgroup 3 - method of conception – ovulation drugs (148 women). For control group were selected women with spontaneous pregnancy (407 women). The difference in subgroup 1 and subgroup 2 was not significant (p value = 0.47). The difference between group 1 and group 2 (Assisted reproductive technology vs spontaneous pregnancy) was significant (p value = 0.002).

Conclusion:

Absence of corpus luteum in frozen embryo transfer regimen is considered to be a key point of increasing risks of Preeclampsia during pregnancy. The mechanism, however is unknown and the results from different studies are controversial. In our study no statistical difference was found between frozen embryo transfer and embryo transfer (p = 0.47). In contrast, statistical difference was found between spontaneous and assisted reproductive technology pregnancy groups (p value = 0.002). According to the results of our study we conclude that, frozen embryo transfer regimen does not make a difference for risk of preeclampsia, but assisted reproductive technology does make a difference.

Keywords:

Preeclampsia risk factors; Infertility; ART; spontaneous pregnancy

References

Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P, Audibert F, Bujold E, Côté AM, Douglas MJ, Eastabrook G, Firoz T. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary. Journal of Obstetrics and Gynaecology Canada. 2014;36(5):416.

Cresswell JA, et al. Global and regional causes of maternal deaths 2009–20: a WHO systematic analysis. Lancet Glob Health. 2025;13(4):e626–e634. doi:10.1016/S2214-109X(24)00560-6.

Trends in maternal mortality estimates 2000 to 2023: estimates by WHO, UNICEF, UNFPA, World Bank Group and UNDESA/Population Division. Geneva: World Health Organization; 2025.

Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. The lancet. 2006 Apr 1;367(9516):1066-74.

Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure during pregnancy. Cochrane Database of Systematic Reviews. 2013(7).

Magee LA, Nicolaides KH, Von Dadelszen P. Preeclampsia. New England Journal of Medicine. 2022 May 12;386(19):1817-32.

Moore GS, Allshouse AA, Post AL, Galan HL, Heyborne KD. Early initiation of low-dose aspirin for reduction in preeclampsia risk in high-risk women: a secondary analysis of the MFMU High-Risk Aspirin Study. Journal of Perinatology. 2015 May;35(5):328-31.

Kassebaum NJ, Barber RM, Bhutta ZA, Dandona L, Gething PW, Hay SI, Kinfu Y, Larson HJ, Liang X, Lim SS, Lopez AD. Global, regional, and national levels of maternal mortality, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. The lancet. 2016 Oct 8;388(10053):1775-812.

Raymond D, Peterson E. A critical review of early-onset and late-onset preeclampsia. Obstet Gynecol Surv. 2011;66(8):497–506

Pereira MM, Mainigi M, Strauss JF. Secretory products of the corpus luteum and preeclampsia. Hum Reprod Update. 2021;27(4):651–672.

hapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C. Clinical rationale for cryopreservation of entire embryo cohorts in lieu of fresh transfer. Fertil Steril. 2014;102(1)

Wei D, Liu JY, Sun Y, Shi Y, Zhang B, Liu JQ, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet. 2019;393(10178):1310–1318.

Chen ZJ, Shi Y, Sun Y, Zhang B, Liang X, Cao Y, et al. Fresh versus frozen embryos for infertility in the polycystic ovary syndrome. N Engl J Med. 2016;375(6):523–533

Niu Y, Suo L, Zhao D, et al. Is artificial endometrial preparation more associated with early-onset or late-onset preeclampsia after frozen embryo transfer?. J Assist Reprod Genet. 2023;40(5):1045-1054.

Zaat TR, Brink AJ, de Bruin JP, Goddijn M, Broekmans FJM, Cohlen BJ, et al. Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers? Reprod Biomed Online. 2021;42(5):919–929.

methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus. Hum Reprod. 2019;34(8):1567–1575.

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

Zong L, Liu P, Zhou L, Wei D, Ding L, Qin Y. Increased risk of maternal and neonatal complications in hormone replacement therapy cycles in frozen embryo transfer. Reprod Biol Endocrinol. 2020;18(1):36.

Makhijani R, Bartels C, Godiwala P, Bartolucci A, Nulsen J, Grow D, et al. Maternal and perinatal outcomes in programmed versus natural vitrified-warmed blastocyst transfer cycles. Reprod Biomed Online. 2020;41(2):300–308.

Roelens C, Blockeel C. Impact of different endometrial preparation protocols before frozen embryo transfer on pregnancy outcomes: a review. Fertil Steril. 2022;118(5):820–827.

Bortoletto P, Prabhu M, Baker VL. Association between programmed frozen embryo transfer and hypertensive disorders of pregnancy. Fertil Steril. 2022;118(5):839–848.

Atallah A, Lecarpentier E, Goffinet F, Doret-Dion M, Gaucherand P, Tsatsaris V. Aspirin for prevention of preeclampsia. Drugs. 2017 Nov;77(17):1819-31.

Gardner DK, Lane M, Schoolcraft WB. Physiology and culture of the human blastocyst. J Reprod Immunol. 2002;55(1–2):85–100.

Ciobanu A, Wright A, Panaitescu A, et al. Prediction of imminent preeclampsia at 35–37 weeks gestation. Am J Obstet Gynecol 2019;220:584.e1-11.

Poon LC, Wright D, Rolnik DL, et al. Aspirin for Evidence-Based Preeclampsia Prevention trial: effect of aspirin in prevention of preterm preeclampsia in subgroups of women according to their characteristics and medical and obstetrical history. Am J Obstet Gynecol 2017;217:585.e1-5

Costa FD, Murthi P, Keogh R, Woodrow N. Early screening for preeclampsia. Revista Brasileira de Ginecologia e Obstetrícia. 2011;33:367-75.

Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-trimester prediction of hypertensive disorders in pregnancy. Hypertension. 2009;53(5):812-8.

McDuffie RS Jr, Beck A, Bischoff K, Cross J, Orleans M. Effect of frequency of prenatal care visits on perinatal outcome among low-risk women: a randomized controlled trial. JAMA. 1996;275(11):847-851.

Niu Y, Suo L, Zhao D, et al. Is artificial endometrial preparation more associated with early-onset or late-onset preeclampsia after frozen embryo transfer?. J Assist Reprod Genet. 2023;40(5):1045-1054.

Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C. Clinical rationale for cryopreservation of entire embryo cohorts in lieu of fresh transfer. Fertil Steril. 2014;102(1):3

Chen ZJ, Shi Y, Sun Y, Zhang B, Liang X, Cao Y, et al. Fresh versus frozen embryos for infertility in the polycystic ovary syndrome. N Engl J Med. 2016;375(6):523–533.

Wei D, Liu JY, Sun Y, Shi Y, Zhang B, Liu JQ, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet. 2019;393(10178):1310–1318.

Sites CK, Wilson D, Barsky M, Bernson D, Bernstein IM, Boulet S, et al. Embryo cryopreservation and preeclampsia risk. Fertil Steril. 2017;108(5):784–790.

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.

Jing S, Li XF, Zhang S, Gong F, Lu G, Lin G. Increased pregnancy complications following frozen-thawed embryo transfer during an artificial cycle. J Assist Reprod Genet. 2019;36(5):925–933. 32

Saito K, Kuwahara A, Ishikawa T, Morisaki N, Miyado M, Miyado K, et al. Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus. Hum Reprod. 2019;34(8):1567–1575.

Hu KL, Zhang D, Li R. Endometrium preparation and perinatal outcomes in women undergoing single-blastocyst transfer in frozen cycles. Fertil Steril. 2021;115(6):1487–1494.

Zaat TR, Brink AJ, de Bruin JP, Goddijn M, Broekmans FJM, Cohlen BJ, et al. Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers? Reprod Biomed Online. 2021;42(5):919–929.

Zaat TR, Brink AJ, de Bruin JP, Goddijn M, Broekmans FJM, Cohlen BJ, et al. Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers? Reprod Biomed Online. 2021;42(5):919–929.

Zong L, Liu P, Zhou L, Wei D, Ding L, Qin Y. Increased risk of maternal and neonatal complications in hormone replacement therapy cycles in frozen embryo transfer. Reprod Biol Endocrinol. 2020;18(1):36.

Asserhoj LL, Spangmose AL, Aaris Henningsen AK, Clausen TD, Ziebe S, Jensen RB, et al. Adverse obstetric and perinatal outcomes in 1,136 singleton pregnancies conceived after programmed frozen embryo transfer (FET) compared with natural cycle FET. Fertil Steril. 2021;115(4):947–956.

Busnelli A, Schirripa I, Fedele F, Bulfoni A, Levi-Setti PE. Obstetric and perinatal outcomes following programmed compared to natural frozen-thawed embryo transfer cycles: a systematic review and meta-analysis. Hum Reprod. 2022

Roelens C, Blockeel C. Impact of different endometrial preparation protocols before frozen embryo transfer on pregnancy outcomes: a review. Fertil Steril. 2022;118(5):820–827

Li C, He YC, Xu JJ, Wang Y, Liu H, Duan CC, et al. Perinatal outcomes of neonates born from different endometrial preparation protocols after frozen embryo transfer: a retrospective cohort study. BMC Pregnancy Childbirth. 2021;21(1):341.

Bortoletto P, Prabhu M, Baker VL. Association between programmed frozen embryo transfer and hypertensive disorders of pregnancy. Fertil Steril. 2022;118(5):839–848.

Pereira MM, Mainigi M, Strauss JF. Secretory products of the corpus luteum and preeclampsia. Hum Reprod Update. 2021;27(4):651–672

Garovic VD, White WM, Vaughan L, Saiki M, Parashuram S, Garcia-Valencia O, et al. Incidence and long-term outcomes of hypertensive disorders of pregnancy. J Am Coll Cardiol. 2020;75(18):2323–2334.