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Early pregnancy complications after frozen-thawed embryo transfer in different cycle regimens: A retrospective cohort study

Open AccessPublished:October 21, 2022DOI:https://doi.org/10.1016/j.ejogrb.2022.10.015

      Abstract

      Objective

      Frozen-thawed embryo transfers (FET) are a key component of assisted reproductive technologies (ART) and various cycle regimens are used worldwide because of insufficient evidence to favour particular transfer schedules. In this study, we investigated the associations between different cycle regimens and early pregnancy complications as well as live birth rates (LBR) per pregnancy after FET.
      Study design: We conducted a retrospective cohort study analysing a total of 7342 pregnancies after FET registered in the Swiss IVF Registry from 2014 to 2019. Women were divided into three groups according to the different cycle regimens: Natural Cycles (NC-FET, n = 998), low-dose Stimulation Cycles (SC-FET, n = 984) and Hormone Replacement Cycles (HRC-FET, n = 5360) leading to pregnancy. Outcomes included early pregnancy complications such as bleeding, miscarriages and ectopic pregnancies. Additionally, we evaluated LBR per pregnancy. Incidences were compared using Fisher’s exact or Chi-square tests. Mean values were compared using t-tests. Multivariate mixed model analysis was performed with early pregnancy complications as outcome.

      Results

      The incidence of bleeding in the first trimester (NC: 3.5 %, SC: 4.3 %, HRC: 8.4 %; p < 0.001) and miscarriage < 12 weeks (NC: 19.0 %, SC: 19.7 %, HRC: 29.1 %; p < 0.001) was highest in HRC-FET.
      Multivariate analysis revealed almost doubled adjusted odds ratios of bleeding in the first trimester (aOR 1.92; 95 % CI 1.30–2.81) and miscarriage < 12 weeks (aOR 1.82; 95 % CI 1.51–2.19) in HRC-FET vs NC-FET. There were comparable odds ratios in HRC-FET vs SC-FET. No differences were observed in the outcomes between SC-FET and NC-FET.
      Highest proportion of LBR per pregnancy (NC: 78.0 %, SC: 77.2 %, HRC: 68.2 %%; p < 0.001) was reported in NC-FET.

      Conclusions

      This is the latest large European register study evaluating early pregnancy complications and LBR per pregnancy after FET between all three different cycle regimens. Miscarriage rate was highest in HRC-FET which can be translated into lower LBR. Therefore, HRC-FET should be avoided and replaced by SC-FET or NC-FET to achieve better pregnancy outcomes.

      Abbreviations:

      ART (assisted reproductive technologies), FET (frozen-thawed embryo transfers), HRC (hormone replacement cycle), LBR (live birth rates), NC (natural cycle), PCOS (polycystic ovary syndrome), SC (stimulation cycle)

      Keywords

      Introduction

      Over the past decade, frozen-thawed embryo transfer (FET) cycles have increased progressively due to improvements in cryopreservation techniques leading to higher live birth rates, fertility preservation and new demands of preimplantation testing [

      Wyns C, De Geyter C, Calhaz-Jorge C, Kupka MS, Motrenko T, Smeenk J, et al. ART in Europe, 2017: results generated from European registries by ESHRE. Human Reproduct Open. 2021;2021(3):hoab026.

      ]. So far, the best individual approach for endometrium preparation in FET cycles is controversial: FET can be performed either in natural cycles (NC-FET), in low-dose stimulation cycles (SC-FET) or in hormone replacement cycles (HRC-FET) [

      Mackens S, Santos-Ribeiro S, van de Vijver A, Racca A, Van Landuyt L, Tournaye H, et al. Frozen embryo transfer: a review on the optimal endometrial preparation and timing. Human reproduction (Oxford, England). 2017;32(11):2234-42.

      ]. While NC-FET is only applicable in eumenorrhoeic women, SC-FET and HRC-FET can also be administered in cases of irregular cycles, oligomenorrhea or amenorrhea. HRC-FET is convenient in clinical routine, requiring less monitoring and offering greater flexibility in scheduling blastocyst thawing; however, there is growing evidence that HRC-FET increases the risk of hypertensive disorders [
      • Ginström Ernstad E.
      • Wennerholm U.-B.
      • Khatibi A.
      • Petzold M.
      • Bergh C.
      Neonatal and maternal outcome after frozen embryo transfer: Increased risks in programmed cycles.
      ,

      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. Human Reproduct 2019;34(8):1567-75.

      ,
      • 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.
      ].
      There are only few studies which analysed both the associations between cycle regimen and early pregnancy complications as well as live birth rates (LBR) per pregnancy after frozen-thawed embryo transfer (FET). In 2017, a Cochrane analysis did not find sufficient evidence to support the use of a specific cycle regimen in preference to another since there were only four direct comparisons [

      Ghobara T, Gelbaya TA, Ayeleke RO. Cycle regimens for frozen-thawed embryo transfer. Cochrane Database Syst Rev. 2017;7(7):CD003414-CD.

      ]. In 2021, a network meta-analysis including 26 RCTs and 113 cohort studies revealed lowest LBR per transfer in HRC-FET compared with other endometrial preparation protocols [
      • Wu H.
      • Zhou P.
      • Lin X.
      • Wang S.
      • Zhang S.
      Endometrial preparation for frozen-thawed embryo transfer cycles: a systematic review and network meta-analysis.
      ]. Most of the included studies comprised heterogeneous groups of women and differed in the definitions of cycle regimens. Here, the type of ultrasound guidance during transfers was not described despite of clear evidence that ultrasound guidance significantly increases the percentage of ongoing and live birth rates [
      • Cozzolino M.
      • Vitagliano A.
      • Di Giovanni M.V.
      • Laganà A.S.
      • Vitale S.G.
      • Blaganje M.
      • et al.
      Ultrasound-guided embryo transfer: summary of the evidence and new perspectives. A systematic review and meta-analysis.
      ,
      • Larue L.
      • Keromnes G.
      • Massari A.
      • Roche C.
      • Moulin J.
      • Gronier H.
      • et al.
      Transvaginal ultrasound-guided embryo transfer in IVF.
      ]. Furthermore, data on low-dose stimulation cycles is scarce; the majority of comparisons were conducted in NC-FET (with or without ovulation trigger) and HRC-FET [
      • Liu X.
      • Shi W.
      • Shi J.
      Natural cycle frozen-thawed embryo transfer in young women with regular menstrual cycles increases the live-birth rates compared with hormone replacement treatment: a retrospective cohort study.
      ,
      • Pan Y.
      • Li B.
      • Wang Z.
      • Wang Y.
      • Gong X.
      • Zhou W.
      • et al.
      Hormone Replacement Versus Natural Cycle Protocols of Endometrial Preparation for Frozen Embryo Transfer.
      ,
      • Wang A.
      • Murugappan G.
      • Kort J.
      • Westphal L.
      Hormone replacement versus natural frozen embryo transfer for euploid embryos.
      ,
      • Melnick A.P.
      • Setton R.
      • Stone L.D.
      • Pereira N.
      • Xu K.
      • Rosenwaks Z.
      • et al.
      Replacing single frozen-thawed euploid embryos in a natural cycle in ovulatory women may increase live birth rates compared to medicated cycles in anovulatory women.
      ].
      In view of this conflicting data, we aim to evaluate the incidence of early pregnancy complications and LBR in all three different cycle regimens by excluding the confounders of transfer-conditions in a cohort of already pregnant women.

      Materials and methods

      Study population

      We conducted a retrospective cohort study collecting a total of 7342 pregnancies that were registered in the Swiss ART-Registry from 2014 to 2019. Inclusion criteria were all pregnancies declared by the physician as “clinical pregnancy”, i.e. induced abortions were included, and biochemical pregnancies were not included in the analysis. Exclusion criteria were pregnancies without known outcome.
      Women were divided into three groups according to the different cycle regimens for endometrial preparation, which were defined as follows:
      • -
        NC-FET (n = 998): Natural cycle with or without hCG ovulation trigger.
      • -
        SC-FET (n = 984): Women treated with low-dose ovarian stimulation (recombinant and highly purified human menopause gonadotropin with or without gonadotropin-releasing hormone agonist / antagonist) and with or without luteal phase support.
      • -
        HRC-FET (n = 5360): Women who received estradiol and progesterone to stimulate endometrial growth and transformation.

      Study outcomes

      Outcomes included early pregnancy complications, i.e. bleeding in the first trimester, miscarriage < 12 weeks, late miscarriage between 3 and 6 months of pregnancy, ectopic or heterotopic pregnancies. Furthermore, we compared deliveries (including intrauterine deaths) and LBR per pregnancy between the different cycle regimens.

      Statistical analysis

      Data was analysed by cycle regimens (NC-FET, SC-FET, HRC-FET) for the entire population. Descriptive statistics were used to present patient and cycle characteristics and early pregnancy outcomes. Occurrences in parameters with two categories were compared using a Fisher’s exact test, occurrences in parameters with more than two categories were compared using a Chi-square test. Mean values were compared using a t-test. Odds ratios for the pregnancy complications given the cycle regimen were calculated. Adjusted odds ratios with pregnancy complications as outcome and cycle regimen, fertilization technique, number of embryos/zygotes transferred, age of mother, polycystic ovary syndrome (PCOS) and chronic anovulation as fixed effects and centre ID as random effect were also calculated.
      None of the p-values generated for the analysis was corrected for multiple testing; p-values are therefore nominal and need to be interpreted accordingly. A p-value < 0.05 was considered to be statistically significant. All analyses were performed with SAS 9.4.

      Ethical considerations

      Each of the 29 Swiss ART centres was informed about the use of the health-related personal data collected in the registry and gave consent for this research project. The local ethics board approved the protocol (Project-ID: 2021–01671).

      Results

      Patient characteristics

      The mean maternal age was 35.5, 35.6 and 35.3 years in the NC-FET, SC-FET and HRC-FET group respectively. The proportion of previous recurrent miscarriages was overall low (NC: 0.3 %, SC: 0.3 %, HRC: 0.8 %; p = 0.062). The FET groups differed significantly in the proportion of chronic anovulation / PCOS and endometriosis: Lowest rate of chronic anovulation / PCOS (5.7 %) and highest rate of mild endometriosis (8.1 %) were observed in NC-FET. By contrast, chronic anovulation / PCOS (17.6 %) and severe endometriosis (5.7 %) were more present in HRC-FET. Except for thyroid disease (NC: 3.4 %, SC: 3.2 %, HRC: 6.2 %; p < 0.001), there were no significant differences in other clinically relevant comorbidities (Table 1).
      Table 1Maternal characteristics in pregnancies after FET by cycle regimen.
      CharacteristicsNC-FET

      (n = 998)
      SC-FET

      (n = 984)
      HRC-FET

      (n = 5360)
      p-value
      Maternal age (years), mean (SD)35.5 (3.9)35.6 (4.0)35.3 (4.1)0.007
      Recurrent miscarriage > 2 (%)3 (0.3)3 (0.3)44 (0.8)0.062
      Cause of infertility, n (%)
      Chronic anovulation / PCOS57 (5.7)96 (9.8)945 (17.6)<0.001
      Tubal factor125 (12.5)145 (14.7)730 (13.6)0.356
      Uterine malformation5 (0.5)13 (1.3)59 (1.1)0.126
      Uterine fibroids8 (0.8)17 (1.7)73 (1.4)0.184
      Endometriosis (I/II)81 (8.1)53 (5.4)399 (7.4)0.034
      Endometriosis (III/IV)37 (3.7)

      34 (3.5)

      306 (5.7)

      0.001
      Hypergonadotropic ovarian insufficiency (WHO III)12 (1.2)

      7 (0.7)99 (1.9)0.015
      Hypogonadotropic ovarian insufficiency (WHO I)1 (0.1)3 (0.3)58 (1.1)<0.001
      Other female pathologies, n (%)57 (5.7)140 (14.2)603 (11.3)<0.001
      Co-morbidities, n (%)
      Diabetes mellitus I/II1 (0.1)2 (0.2)7 (0.1)0.769
      Thyroid disease34 (3.4)31 (3.2)330 (6.2)<0.001
      Breast cancer

      Malignancy of the genital tract
      3 (0.3)

      0 (0)
      1 (0.1)

      0 (0)
      7 (0.1)

      9 (0.2)
      0.367

      0.326
      Treatment type, n (%)
      IVF170 (17.0)202 (20.5)892 (16.6)<0.001
      ICSI773 (77.5)411 (41.8)4247 (79.2)
      Mixed55 (5.5)371 (37.7)221 (4.1)
      Number of embryos / zygotes transferred, n (%)
      1487 (48.8)380 (38.6)2992 (55.8)<0.001
      2483 (48.4)536 (54.5)2249 (42.0)
      328 (2.8)68 (6.9)119 (2.2)
      Number of gestational sacs at beginning of pregnancy, n (%)
      037 (3.7)23 (2.3)254 (4.7)<0.001
      1857 (85.9)812 (82.5)4511 (84.2)
      2101 (10.1)143 (14.5)515 (9.6)
      31 (0.1)4 (0.4)12 (0.2)
      >3

      Unknown
      0 (0)

      2 (0.2)
      0 (0)

      2 (0.2)
      1 (0)

      67 (1.3)
      FET = frozen-thawed embryo transfers; NC = natural cycle, SC = low-dose stimulation cycle, HRC = hormone replacement cycle.
      Occurrences for parameters with two categories were compared using a Fisher’s exact test. Occurrences for parameters with more than two categories were compared using a Chi-square test. Mean values were compared using a t-test. None of the p-values was corrected for multiple testing.

      Outcomes

      Pregnancy outcomes revealed highest incidence of early pregnancy bleeding in HRC-FET (8.4 %) compared to NC-FET (3.5 %) and SC-FET (4.3 %). There were comparable results in the incidence of miscarriage < 12 weeks (NC: 19.0 %, SC: 19.7 %, HRC: 29.1 %; p < 0.001) and no differences in late miscarriages or ectopic pregnancies between the cycle regimens. Highest LBR per pregnancy (78 %) and proportion of singleton deliveries (70.5 %) were achieved in NC-FET (Table 2).
      Table 2Early pregnancy outcome and delivery rates after FET by cycle regimen.
      Pregnancy Outcome (%)NC-FET

      (n = 998)
      SC-FET

      (n = 984)
      HRC-FET

      (n = 5360)
      p-value
      Bleeding 1. trimester35 (3.5)42 (4.3)452 (8.4)<0.001
      Early miscarriage (<12 weeks)190 (19.0)194 (19.7)1557 (29.1)<0.001
      Late miscarriage (3–6 months)8 (0.8)6 (0.6)37 (0.7)0.897
      Ectopic pregnancy16 (1.6)8 (0.8)56 (1.0)0.203
      Heterotopic pregnancy0 (0)1 (0.1)0 (0)0.134
      Induced abortions5 (0.5)16 (1.6)48 (0.9)0.037
      Delivery (incl. intrauterine death) (%)
      No birth219 (21.9)224 (22.8)1699 (31.7)<0.001
      Singletons704 (70.5)663 (67.4)3278 (61.2)
      Twins73 (7.3)96 (9.8)375 (7.0)
      Triplets2 (0.2)1 (0.1)8 (0.2)
      Live birth / pregnancy (%)778 (78.0)760 (77.2)3655 (68.2)<0.001
      FET = frozen-thawed embryo transfers; NC = natural cycle, SC = low-dose stimulation cycle, HRC = hormone replacement cycle.
      Occurrences for parameters with two categories were compared using a Fisher’s exact test. Occurrences for parameters with more than two categories were compared using a Chi-square test. None of the p-values was corrected for multiple testing.
      Multivariate analysis revealed>2-fold adjusted odds ratios of bleeding in the first trimester in HRC-FET compared to NC-FET (aOR 1.92; 95 % CI 1.30–2.81) and SC-FET (aOR 2.09; 95 % CI 1.34–3.24). The odds ratios of miscarriage < 12 weeks were approximately doubled in HRC-FET compared to NC-FET (aOR 1.82; 95 % CI 1.51–2.19) and SC-FET (aOR 2.06; 95 % CI 1.67–2.54). NC-FET and SC-FET revealed comparable odds (Table 3).
      Table 3Early pregnancy complications after FET by cycle regimen.
      HRC-FET vs NC-FETHRC-FET vs SC-FETSC-FET vs NC-FET
      OutcomeCrude OR

      (95 % CI)
      Adjusted OR (95 % CI) p-valueCrude OR (95 % CI)Adjusted OR (95 % CI) p-valueCrude OR (95 % CI)Adjusted OR (95 % CI) p-value
      Bleeding 1st trimester2.53 (1.78–3.60)1.92 (1.30–2.81)<0.0012.07

      (1.49–2.86)
      2.09 (1.34–3.24)<0.0011.23 (0.78–1.94)0.92 (0.53–1.59)0.761
      Early miscarriage

      (<12 weeks)
      1.74 (1.47–2.06)1.82 (1.51–2.19)<0.0011.67 (1.41–1.97)2.06 (1.67–2.54)<0.0011.04 (0.84–1.30)0.88 (0.68–1.15)0.355
      Late miscarriage

      (3–6 months)
      0.86 (0.40–1.85)0.88 (0.40–1.94)0.7531.13 (0.48–2.69)1.41 (0.53–3.78)0.4920.76 (0.26–2.20)0.62 (0.20–1.98)0.424
      Ectopic pregnancy0.65 (0.37–1.13)N/A1.29

      (0.61–2.71)
      N/A0.50 (0.21–1.18)N/A
      Heterotopic pregnancyN/AN/AN/AN/AN/AN/A
      FET = frozen-thawed embryo transfers; N/A = not applicable, NC = natural cycle, SC = low-dose stimulation cycle, HRC = hormone replacement cycle.
      Adjusted OR were corrected for cycle regimen, fertilization technique, number of embryos/zygotes transferred, age of mother, chronic anovulation or polycystic ovary syndrome and centre ID. None of the p-values was corrected for multiple testing.

      Discussion

      Main findings

      This study supports adverse early pregnancy outcomes in cycles in which the corpus luteum is suppressed. We found the highest incidence of early pregnancy bleeding, revealed the highest miscarriage rate < 12 weeks and added the lowest LBR per pregnancy in HRC-FET compared to NC-FET or SC-FET as further important findings (Table 2, Table 3).

      Strengths and limitations

      The great strength of our study is the large cohort of pregnancies (n = 7342) after FET in three different cycle regimens, representing the total Swiss ART data during 2014 – 2019. We only included pregnant women in our cohort, thereby excluding potential confounding factors for higher pregnancy rates such as endometrium thickness, its receptivity and synchronization to the embryo [
      • Sahin G.
      • Acet F.
      • Calimlioglu N.
      • Meseri R.
      • Tavmergen Goker E.N.
      • Tavmergen E.
      Live birth after frozen-thawed embryo transfer: which endometrial preparation protocol is better?.
      ] as well as hormonal conditions [
      • Beck-Fruchter R.
      • Nothman S.
      • Baram S.
      • Geslevich Y.
      • Weiss A.
      Progesterone and estrogen levels are associated with live birth rates following artificial cycle frozen embryo transfers.
      ,
      • Alsbjerg B.
      • Labarta E.
      • Humaidan P.
      Serum progesterone levels on day of embryo transfer in frozen embryo transfer cycles-the truth lies in the detail.
      ].
      The use of the Swiss ART data registry is both one strength as well as the main limitation of our analysis: studies based on registry data are often accompanied by selection bias (nonrandomized) and missing data (lack of documentation). Potential confounders such as BMI, history of hypertension or preeclampsia [
      • Mol B.W.J.
      • Roberts C.T.
      • Thangaratinam S.
      • Magee L.A.
      • de Groot C.J.M.
      • Hofmeyr G.J.
      Pre-eclampsia.
      ,
      • Palomba S.
      • Falbo A.
      • Daolio J.
      • Battaglia F.A.
      • La Sala G.B.
      Pregnancy complications in infertile patients with polycystic ovary syndrome: updated evidence.
      ] and laboratory parameters including vitamin D status [
      • Laganà A.S.
      • Vitale S.G.
      • Ban Frangež H.
      • Vrtačnik-Bokal E.
      • D'Anna R.
      Vitamin D in human reproduction: the more, the better? An evidence-based critical appraisal.
      ,
      • Colonese F.
      • La Rosa V.L.
      • Laganà A.S.
      • Vitale S.G.
      • Cortinovis D.
      • Bidoli P.
      Comment on: “Is there a role for vitamin D in human reproduction?”.
      ] were not documented and could not be considered while analysing the data. Additionally, different endometrial preparation protocols within specific protocols were not registered and may affect outcomes. Furthermore, PGT data was not available for the analysis period, as PGT was not legally permitted in Switzerland before the end of 2017 and was subsequently slowly introduced over the following years. Selection bias was observed in the form of unequally distributed maternal characteristics and in treatment type (Table 1). The proportion of chronic anovulation / PCOS (17.6 %), severe endometriosis (5.7 %) and thyroid disease (6.2 %) were highest in the HRC-FET group. It has been shown that PCOS is a risk factor for miscarriage in both obese and non-obese women [
      • Liu L.
      • Tong X.
      • Jiang L.
      • Li T.C.
      • Zhou F.
      • Zhang S.
      A comparison of the miscarriage rate between women with and without polycystic ovarian syndrome undergoing IVF treatment.
      ], whereas only adenomyosis seems to be associated with miscarriage [

      Younes G, Tulandi T. Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta-analysis. Fertil Steril 2017;108(3):483-90.e3.

      ,
      • Huang Y.
      • Zhao X.
      • Chen Y.
      • Wang J.
      • Zheng W.
      • Cao L.
      • et al.
      Miscarriage on Endometriosis and Adenomyosis in Women by Assisted Reproductive Technology or with Spontaneous Conception: A Systematic Review and Meta-Analysis.
      ,
      • Horton J.
      • Sterrenburg M.
      • Lane S.
      • Maheshwari A.
      • Li T.C.
      • Cheong Y.
      Reproductive, obstetric, and perinatal outcomes of women with adenomyosis and endometriosis: a systematic review and meta-analysis.
      ]. Thyroid disease might also negatively influence early pregnancy outcomes [
      • Nazarpour S.
      • Ramezani Tehrani F.
      • Simbar M.
      • Azizi F.
      Thyroid dysfunction and pregnancy outcomes.
      ]. However, HRC-FET was applied in a far higher proportion (73 %), implying that most normoovulatory, healthy women also received HRC-FET for practical reasons.

      Interpretation

      The reasons for better early pregnancy outcomes and higher LBR per pregnancy may lie in the physiological preparation of the endometrium in cycles in which the corpus luteum is not suppressed. So far, it remains unclear whether hormonal substitution in HRC-FET harms embryo development. Supraphysiological hormone levels during early trophoblast invasion might lead to abnormal pregnancy. Excess estradiol levels in the early stage of pregnancy can have adverse effects on placentation, causing cell death and inhibiting trophoblast invasion in cytotrophoblast and placental cell lines [
      • Patel S.
      • Kilburn B.
      • Imudia A.
      • Armant D.R.
      • Skafar D.F.
      Estradiol Elicits Proapoptotic and Antiproliferative Effects in Human Trophoblast Cells.
      ]. Furthermore, exogenous hormones may lead to thromboembolic events which could impede implantation and cause miscarriage [
      • Patel S.
      • Kilburn B.
      • Imudia A.
      • Armant D.R.
      • Skafar D.F.
      Estradiol Elicits Proapoptotic and Antiproliferative Effects in Human Trophoblast Cells.
      ,
      • Hancke K.
      • More S.
      • Kreienberg R.
      • Weiss J.M.
      Patients undergoing frozen-thawed embryo transfer have similar live birth rates in spontaneous and artificial cycles.
      ]. It is presumed that the corpus luteum in NC-FET and SC-FET produces circulating vasoactive hormones such as relaxin and vascular endothelial growth factor [

      Versen-Höynck Fv, Schaub AM, Chi Y-Y, Chiu K-H, 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. 2019;73(3):640-9.

      ,
      • von Versen-Höynck F.
      • Narasimhan P.
      • Selamet Tierney E.S.
      • Martinez N.
      • Conrad K.P.
      • Baker V.L.
      • et al.
      Absent or Excessive Corpus Luteum Number Is Associated With Altered Maternal Vascular Health in Early Pregnancy.
      ,
      • Singh B.
      • Reschke L.
      • Segars J.
      • Baker V.L.
      Frozen-thawed embryo transfer: the potential importance of the corpus luteum in preventing obstetrical complications.
      ] which reduces the risk of hypertensive disorders in later stages of pregnancy [
      • Ginström Ernstad E.
      • Wennerholm U.-B.
      • Khatibi A.
      • Petzold M.
      • Bergh C.
      Neonatal and maternal outcome after frozen embryo transfer: Increased risks in programmed cycles.
      ,

      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. Human Reproduct 2019;34(8):1567-75.

      ,
      • 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.
      ].
      Previous studies have found conflicting results in pregnancy outcomes between the different cycle regimens. In terms of pregnancy rates, they seem to be equally effective [

      Ghobara T, Gelbaya TA, Ayeleke RO. Cycle regimens for frozen-thawed embryo transfer. Cochrane Database Syst Rev. 2017;7(7):CD003414-CD.

      ,
      • Yarali H.
      • Polat M.
      • Mumusoglu S.
      • Yarali I.
      • Bozdag G.
      Preparation of endometrium for frozen embryo replacement cycles: a systematic review and meta-analysis.
      ,

      Glujovsky D, Pesce R, Sueldo C, Quinteiro Retamar AM, Hart RJ, Ciapponi A. Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes. Cochrane Database Syst Rev 2020; 10(10):Cd006359.

      ]. In terms of LBR per cycle, the largest multi-centre RCT (ANTARCTICA trial) reported comparable LBR in NC-FET compared to HRC-FET; however, more cycles were cancelled in HRC-FET with a dropout rate of > 10 % and the overall success rate was low and miscarriage rate high [

      Groenewoud ER, Cohlen BJ, Al-Oraiby A, Brinkhuis EA, Broekmans FJ, de Bruin JP, et al. A randomized controlled, non-inferiority trial of modified natural versus artificial cycle for cryo-thawed embryo transfer. Human Reproduct (Oxford, England). 2016;31(7):1483-92.

      ]. The latest Cochrane review [

      Glujovsky D, Pesce R, Sueldo C, Quinteiro Retamar AM, Hart RJ, Ciapponi A. Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes. Cochrane Database Syst Rev 2020; 10(10):Cd006359.

      ] stated insufficient evidence on the use of any particular intervention for endometrial preparation. The main limitations in the evidence were poor reporting of study methods and lack of precision in pregnancy outcomes.
      Prospective multi-centre randomized control trials with standard endometrial preparation protocols and definitions are required to determine the best method of endometrial preparation for optimal pregnancy outcomes. Besides the emotional implications of bleeding and miscarriages, interventions such as curettage might lead to intrauterine infection or adhesion which could, in turn, have a negative impact on further embryo transfers. With regard to the high incidence of early pregnancy complications and, moreover, lower LBR per pregnancy in HRC-FET, clinicians should prefer cycle regimens in which the corpus luteum is not suppressed.

      Conclusion

      This is the latest large European register study evaluating early pregnancy complications and LBR per pregnancy after FET between all three cycle regimens. Miscarriage rate was higher in HRC-FET which could be translated into lower LBR. Thus, NC-FET or SC-FET should be preferred if medically possible. Further research is necessary to clarify the potential mechanism underlying the influence of FET regimens with or without corpus luteum affecting early pregnancy complications.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgement

      Statistical calculation was financially supported by IBSA Institut Biochimique SA, which did not have any role in designing or conducting the study and the calculations, nor in the decision on preparation or publication of the manuscript. We thank all 29 Swiss ART centres who gave consent for this research project. We thank Dr. Elizabeth Krämer for linguistic revision.

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