Endometriosis Does not Seem to Be an Influencing Factor of Hypertensive Disorders of Pregnancy in IVF / ICSI Cycles

Endometriosis Does not Seem to Be an Influencing Factor of Hypertensive Disorders of Pregnancy in IVF / ICSI Cycles | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Endometriosis Does not Seem to Be an Influencing Factor of Hypertensive Disorders of Pregnancy in IVF / ICSI Cycles Pingyin Lee, Canquan Zhou, Yubin Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1174628/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Mar, 2022 Read the published version in Reproductive Biology and Endocrinology → Version 1 posted 7 You are reading this latest preprint version Abstract Introduction To evaluate whether the incidence of hypertensive disorders of pregnancy (HDP) in pregnant women was related to endometriosis (EM), ovulation and embryo vitrification technology. Methods A retrospective cohort study was conducted on the clinical data of 3674 women who were treated with IVF / ICSI in the Reproductive Medicine Center of the First Affiliated Hospital of Sun Yat-sen University and maintained clinical pregnancy for more than 20 weeks. All pregnancies were followed up until the end of pregnancy. The follow-up consisted of recording the course of pregnancy, pregnancy complications, and basic situation of newborns. Results Compared with NC-FET without EM, HRT-FET without EM was found to have a higher incidence of HDP during pregnancy (2.7% V.S. 6.1%, P0.05). In total frozen-thawed embryo transfer (total-FET), the incidence of HDP in the HRT cycle without ovulation (HRT-FET) was observed to be higher than that in the NC cycle with ovulation (NC-FET) (2.8% V.S. 6.1%, P0.05). Conclusion EM does not seem to have an effect on the occurrence of HDP in assisted reproductive technology. During the FET cycle, the formation of the corpus luteum may play a protective role in the occurrence and development of HDP. Potential damage to the embryo caused by cryopreservation seems to have no effect on the occurrence of HDP. Endocrinology & Metabolism Sexual & Reproductive Medicine Endometriosis Hypertensive disorders of pregnancy In vitro fertilization Frozen-thawed embryo transfer Figures Figure 1 Background Endometriosis (EM) refers to the presence of functional endometrial tissue (glands and stroma) outside the uterus, in which its incidence in women of childbearing age is 5-10%[1] [2]. EM is characterized by estrogen dependent chronic inflammation, which often manifests as dysmenorrhea, lower abdominal pain, dyspareunia and infertility[3]. Many studies have shown that EM can increase the risk of multiple adverse pregnancy outcomes, such as spontaneous abortion, ectopic pregnancy, hypertensive disorders of pregnancy (preeclampsia or gestational hypertension), gestational diabetes mellitus (GDM), preterm birth and low birth weight[4] [5] [6]. In addition, the immune system and inflammation have been considered to serve as pivotal factors in disease progression[7]. Abnormal hormone circulation from EM as well as pathological changes due to chronic inflammation may lead to a higher risk of hypertension[8]. At present, the pathogenesis of hypertensive disorders of pregnancy (HDP) has yet to be fully elucidated. It is generally believed that the occurrence of HDP may be related to immune system disorder, trophoblast or placental ischemia and oxidative stress[9] [10]. Studies have also shown that the incidence of HDP is higher when using assisted reproductive technology (ART), especially in the frozen-thawed embryo transfer (FET) cycle[11], which may be related to the endometrial preparation protocol in the FET cycle[12]. Bellac et al [13] and Lani et al [14] have shown that EM can significantly increase the risk of HDP. However, Hadfield et al [15] found that EM did not increase the risk of HDP, with certain studies showing that EM could reduce the risk of HDP[16]. Different opinions exist regarding EM and HDP, though none are conclusive, and studies pertaining to ART are scarce. Furthermore, both EM and HDP are known to be involved in abnormal immune factors, and immune factors are extremely complex. Accordingly, whether EM has an influence on the occurrence of HDP is worthy of further discussion. Therefore, by analyzing women of more than 20 weeks of clinical pregnancy who were treated with IVF / ICSI (intracytoplasmic sperm injection, ICSI) at our reproductive center in the past 4 years, this study aims to determine whether the risk of HDP is related to EM, ovulation and embryo vitrification technology. Materials And Methods Study design and setting This study was a retrospective cohort study that analyzed the clinical data of 3674 patients treated with IVF / ICSI at the Reproductive Medicine Center of the First Affiliated Hospital of Sun Yat-sen University from January 2017 to June 2021. The protocol was reviewed and approved by the Ethical Committee of The First Affiliated Hospital of Sun Yat-Sen University. The patients/participants provided their written informed consent to participate in this study. The study included 638 cycles of fresh embryo transfer (fresh ET) and 3036 cycles of FET. In order to distinguish FET from HRT-FET and NC-FET, total-FET was used to represent the overall FET cycle (Figure 1). The inclusion criteria of the EM group were as follows: patients aged 20-45 years, diagnosed with endometriosis, has intrauterine gestational sac pregnancy under B-ultrasound 1 month after embryo transfer, and clinical pregnancy status has been maintained for more than 20 weeks. The inclusion criteria of the EM absent group were as follows: patients aged 20-45 years and undergoing IVF / ICSI treatment due to tubal and/or male factors infertility. Exclusion criteria included: diagnosed with PCOS, hyperprolactinemia, abnormal thyroid function, and chromosome abnormalities of one or both of other endocrine related diseases that are not conducive to pregnancy or can cause adverse pregnancy, has underwent ovarian, thyroid, pituitary surgery or antitumor radiotherapy and chemotherapy, undergone oophorectomy due to ovarian malignancy or other reasons. Women were asked whether they had physician diagnosed EM. Participants who responded “yes” indicated the year of diagnosis and whether it had been visually confirmed by laparoscopy, the clinical gold standard for endometriosis diagnosis [17]. The remaining patients who were not diagnosed with EM by laparoscopy and those who were reported as EM by B-ultrasound during the treatment were also classified as EM. This inclusion is based on the comprehensive consideration of the patient's reproductive age and needs. We considered women to have a HDP in a given pregnancy if they had a diagnosis of gestational hypertension, pre-eclampsia, eclampsia, or HELLP syndrome on the medical record at any time between one month before delivery and seven days post partum [18]. To be considered exposed to a HDP in our study, women with diagnoses registered outside this time window also had to have at least one diagnosis registered within the window. (We adopted this restriction to try to ensure that diagnoses of hypertensive disorders of pregnancy reflected true cases.) Stimulation Protocol According to the patient's age, body mass index (BMI), basic sex hormone level, anti-Mullerian hormone (AMH) and antral follicle count (AFC), the appropriate stimulation protocol and starting dose were selected. Ovulation was triggered using 250 µg of recombinant hCG (Ovidrel, Merck-Serono, Switzerland) or 5000-10000 IU hCG (Lizhu, Zhuhai, China) when two follicles reached 18 mm or three follicles reached 17mm in diameter. Transvaginal ultrasound-guided oocyte retrieval was performed 34-36 hours later. Following oocyte retrieval, whether to carry out fresh ET or whole embryo freezing was determined according to whether the patient had high ovarian hyperstimulation syndrome (OHSS) risk, high progesterone level, uterine cavity and condition of endometrium. If fresh ET was planned, Progesterone Sustained-release vaginal gel (Crinone, Merck-Serono, Switzerland) 90mg/d or intramuscular progesterone 40mg/d was given on the day of oocyte retrieval. Dydrogesterone (DydrogesteroneTablets, Abbott biologicals, Netherlands) 10mg was orally administered twice a day until 14 days following embryo transfers. Fertilization and Embryo Culture After culturing 2-6h in vitro, IVF or ICSI was selected according to the condition of the male semen. The number and size of prokaryotes, number and distribution of nucleolar precursor bodies and cytoplasmic distribution were observed 16-18 hours after fertilization. Meanwhile, following 72 h, D3 cleavage embryos were scored according to the number of blastomeres, uniformity of blastomeres size, amount and distribution of fragments. Embryo morphology was evaluated according to the Istanbul Consensus Workshop on Embryo Assessment[19]. Embryo Transfer No more than two cleavage stage embryos were transferred on the morning of the 3rd day after oocyte retrieval. According to our embryo culture strategy, if there were no more than two cleavage stage embryos available after fresh embryo transfer, they were vitrified on the 3rd day. Otherwise, the remainder had blastocyst culture performed. Surplus cleavage stage embryos or blastocysts were vitrified using the Cryotop (Kitazato Supply Co.,Fujinomiya, Japan) method [20] for subsequent FET cycles whenever necessary. Embryo morphology was evaluated according to the Istanbul Consensus Workshop on Embryo Assessment [19]. During the FET cycles, endometrial preparation protocols included hormone therapy (HRT) cycles and natural cycles (NC), as previously described in detail [21]. All embryo transfers were performed under transabdominal ultrasound guidance. Determination of Clinical Pregnancy and Follow-up Serum hCG levels were determined 12-14 days after embryo transfers. A clinical pregnancy was confirmed by transvaginal ultrasound 3 weeks after a positive serum HCG test. Luteal support was continued to the 10th week of gestation. All pregnancies were followed up by our staff until the end of gestation. The details relevant to the follow-up were recorded, including the course of pregnancy, delivery time, mode of delivery, complications during pregnancy, gender, birth weight and congenital abnormalities of newborns. Statistical Analysis Categorical data were presented as numbers and percentages. Continuous variables were given as mean±SD. The chi-square test or Fisher exact probability test was used for categorical variables, while ANOVA was done for continuous variables. Bonferroni method was utilized for pairwise comparison between each group. A p-value < 0.05 was considered to be statistically significant. Results Baseline characteristics and clinical data of patients A total of 3674 patients were included, which included 638 cycles of fresh ET and 3036 cycles of total-FET. No significant difference was observed between the two groups in regard to age, infertility years, female BMI, gender of live birth (single fetus), number of losses to follow-up, incidence of HDP and EM (P>0.05). There were significant differences between the two groups in the number of gestational sacs and number of live births (P<0.05) (Table 1). Among the 3036 cycles of total-FET, there were 1331 cases of natural cycles (NC-FET) and 1705 cases of hormone therapy cycles (HRT-FET). Moreover, no significant difference was noted between the two groups in terms of age, infertility years, female BMI, number of gestational sacs, number of live births, gender of live birth (single fetus), number of losses to follow-up, incidence of HDP and EM (P>0.05) (Table 2). Relationship between EM, HDP and endometrial preparation protocol during all included cycles In the total-FET cycle, the incidence of HDP in the HRT cycle was found to be higher than that in the NC cycle (P<0.05) (Table 2). After controlling the effects of number of gestational sacs by ultrasound and live births, fresh ET and total-FET were analyzed, in which no significant difference was found in the incidence of HDP during pregnancy in the fresh ET cycle and total-FET cycle, regardless of whether EM was combined (P>0.05) (Table 3). The two types of endometrial preparation protocols were further compared and were analyzed as to whether they had EM. Accordingly, in the total-FET cycle, the incidence of HDP during pregnancy was noted to be higher in the HRT cycle without EM than in the NC cycle without EM (6.1% V.S 2.7%) (P0.05) (Table 4). Relationship between ovulation cycle (fresh ET cycle, NC-FET cycle) and HDP in EM In all cases of ovulation (fresh ET cycle, NC-FET cycle), no significant difference was found in the incidence of HDP during pregnancy between fresh ET cycles with EM and NC-FET cycles with EM (P>0.05) (Table 5). Relationship between EM, embryo transfer methods and HDP in singleton pregnancies According to the previous retrospective analysis of the total population, a few twin pregnancies were present in each group, which may interfere with the results. In order to be more thorough, an analysis of singleton pregnancy was carried out separately. Here, no significant difference was found between the incidence of HDP and whether EM was combined, different embryo transfer methods (fresh ET, total-FET) or the gender of live birth (P>0.05) (Table 6). Discussion EM is known to be common gynecological disease that causes infertility and may lead to adverse pregnancy outcomes, seriously placing the physical and mental health of women of childbearing age at risk along with safety of perinatal mothers and children. However, in recent years, the incidence of HDP in pregnant women with EM has remained controversial. The results of this study demonstrated that no difference in the incidence of HDP was observed in total-FET regardless of whether EM was combined (Table 3). After further cross comparison of the endometrial preparation protocol with EM, the incidence of HDP during pregnancy in HRT cycle without EM (6.1%) was found to be higher than that in the NC cycle without EM (2.7%), though no significant difference was present in the incidence of HDP between NC with EM (4.0%) and HRT with EM (5.7%) (Table 4). Notably, in the corresponding data, the incidence of HDP in all EM groups (4.0% and 5.7%) was within the HDP global incidence rate (5%-10%) [22]. In terms of the results, after adding EM, the HDP incidence that should have been different between NC and HRT exhibited no differences (Table 4), which may suggest that EM improves the incidence of HDP in NC or reduces the incidence in HRT. However, there may be no statistical difference as the present case data are small. Accordingly, in the future, the sample size should be expanded for further research. Nevertheless, the present results suggest that there may be confounding factors in the total-FET cycle. Therefore, it is suggested that when analyzing HDP incidence, it is more appropriate to separate the NC cycle with ovulation from the HRT cycle. Most studies have not confirmed the correlation between EM and HDP. In 2012, Vercellini et al. followed up with pregnancies of patients who underwent EM surgery. Among them, there were 150 patients with deep infiltrating endometriosis (DIE) whose lesions involved the vaginal rectal septum, for which the incidence of HDP did not increase in these patients [23]. Another study on the pregnancy of DIE patients following laparoscopic ureterolysis found that the incidence of HDP was 3.8% [24], which was not higher than the global incidence of HDP of 5% - 10%[22]. However, Nirgianakis et al. put forward that the incidence of HDP in patients with pelvic DIE is higher than that in patients without EM [25]. Exacoustos et al. studied 52 patients with posterior pelvic DIE lesions ≥ 2 cm and found that the risk of HDP in patients with posterior pelvic DIE was increased, about 14.6%, which was significantly higher than that in patients without EM [26], though the baseline of the two groups of patients in terms of age, pregnancy and delivery times and BMI were not consistent, and the study did not exclude interfering factors, such as ART, for pregnancy. Some studies also found that the incidence of pre-eclampsia in EM patients has increased [27] [28], however, these studies did not indicate whether patients assisted by ART were excluded, which cannot present a positive solution between EM and HDP. This study investigated the relationship between EM and HDP in IVF / ICSI. Currently, few articles exist on EM and HDP in ART, which gives the findings of this study more clinical value. Nevertheless, this study did not stratify the severity of EM and did not rule out that different degrees of EM may have different effects on the incidence of HDP, which will be investigated in the next step. In the past decade, FET has significantly increased due to the expansion of surgical indications [29]. At present, numerous studies have shown that the risk of HDP associated with IVF has increased, especially in regard to FET [30] [11]. However, most reports have directly compared fresh ET and FET, where it was found that FET has a higher risk of HDP [31] [32] [33], though it does not clearly indicate which endometrial preparation protocol was used in FET. In this study, no difference was noted in regard to the incidence of HDP between fresh ET and total-FET (Table 1), in which the incidence of HDP in the HRT-FET cycle was found to be higher than that in the NC-FET cycle (Table 2). The results of this study are consistent with that of other research. In a big data retrospective analysis conducted in Japan, it was found that, compared with patients with natural ovulation cycle (NC-FET), patients using HRT-FET had an increased risk of HDP and placental implantation, while the risk of GDM was observed to be reduced [34]. Another retrospective cohort study in China also found that the HRT-FET group had an increased risk of HDP and placenta previa compared to ovarian stimulation in the FET group [12]. These results suggested that endometrial preparation methods may be related to obstetric complications, especially with respect to the development of HDP. This may be due to the increased risk of HDP from the lack of corpus luteum (CL) in patients with HRT-FET [35]. Cryopreserved embryos must be transferred to the uterus during the critical endometrial window that can establish pregnancy [36]. In reproductive women, the common endometrial preparation protocol of FET are NC, stimulated cycle and HRT cycle. In a natural cycle, the major follicle matures and produces E2, which leads to the development and thickening of the endometrium. Ovulation can then occur naturally, and the ovulation site becomes CL, which belongs to a functional ovarian cyst. In the stimulated cycle, ovulation was induced with either clomiphene citrate, letrozole, or gonadotropins, which may lead to one or more CL. However, in the HRT cycle, exogenous E2 and P lead to the development of the endometrium. During this period, the ovary is inhibited, hence, no dominant follicle, ovulation and CL exist. In contrast to the fresh cycle, there may be more CL in light of the role of the stimulation protocol. The hypothesis that the HRT cycle without CL increases the risk of HDP seems to be biologically reasonable. CL can produce E2 and P as well as vasoactive products, such as relaxin, vascular endothelial growth (VEGF) and angiogenic metabolites of estrogen [37] [38] [39]. CL serves as an important source of reproductive hormones before the placenta becomes a source of reproductive hormones (such as P and E2) to maintain pregnancy. Vasoactive products produced by CL are very important for the formation of the initial placenta, and previous studies have proposed that the abnormal formation of early placenta is a critical step in the development of preeclampsia [40] [41] [42]. Since the HRT cycle does not form CL, relaxin and VEGF are not replaced when compared with other endometrial preparation protocols that involves CL formation, which is the pathological basis of subsequent pregnancy complications in women with an HRT cycle. Overall, these studies support the premise that CL deletion is associated with circulatory adaptation defects during pregnancy, in which the formation of CL may play a protective role in the occurrence and development of HDP. However, its mechanism remains unclear and requires further study. In regard to the total-FET cycle, EM does not seem to affect the occurrence and development of HDP, whereas CL may influence them. In order to compare the effect of fresh ET and FET on HDP, EM patients in a fresh ET cycle were compared with EM patients in a total-FET cycle, where no difference in the incidence of HDP was found between the two groups (Table 5). These results suggested that FET does not cause maternal complications during pregnancy due to potential damage from the freeze-thaw process related embryo. The number of FET cases has risen significantly within the past ten years, partly owing to improvements associated with vitrification compared with older slow-freeze methods [29]. However, no final conclusion was reached on whether vitrification technology can cause damage to embryos. Moreover, a cross-sectional analysis of 10744 transfer cycles using single cleavage embryos in Australia found that the live birth rate (LBR) of women receiving freeze-thawed embryos was significantly lower than those receiving fresh embryos, which may be due to embryo damage related to the freeze-thaw process [43], though HDP data were not included. A retrospective cohort study of 560 singleton pregnancies found that the fetal birth weight in the IVF/ICSI group and the artificial insemination group was lower than that in the FET group, and this difference was already present when the estimated fetal weight was evaluated in the second trimester of pregnancy (21-23 weeks of pregnancy). The difference of fetal growth dynamics is considered to be due to the influence of the different manners of assisted reproductive technology on the invasiveness of trophoblast [44]. However, as no satisfactory model exists for studying extravillous trophoblasts and the controversial use of trophoblast cell lines, the mechanism of controlling trophoblast invasion and causing placental defects has yet to be fully understood [45]. In this study, the HRT-FET group with CL deletion was excluded, and only the fresh ET cycle and NC-FET were included for comparison (Table 5). In addition, considering that multiple births may affect the incidence of HDP, this study analyzed singleton pregnancies that were delivered alive (Table 6). Accordingly, no difference was found in the incidence of HDP, suggesting that trophoblast damage caused by cryopreservation may not affect the occurrence of HDP. Even when excluding the impact of multiple births on the incidence of HDP, no statistical difference was observed between EM, embryo transfer methods (fresh ET and FET), gender of live birth and incidence of HDP. However, these findings require additional in-depth research for verification. Conclusions In conclusion, EM does not seem to affect the occurrence of HDP in ART. During the total-FET cycle, whether the formation of CL plays a protective role in the occurrence and development of HDP was evaluated. The freeze-thaw process related embryo potential damage caused by cryopreservation has no effect on the occurrence of HDP. However, as the occurrence of HDP in EM is still inconclusive, further studies are needed. These findings also emphasize the potential risk of HDP in patients with HRT-FET cycle during pregnancy follow-up. Therefore, such patients should pay more attention to the occurrence of HDP in order to reduce adverse pregnancy outcomes related to assisted reproductive technology treatment. Abbreviations FET, frozen-thawed embryo transfer, NC-FET, frozen-thawed embryo transfer with natural cycle, HRT-FET, frozen-thawed embryo transfer with hormone therapy Declarations DATA AVAILABILITY STATEMENT The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. ETHICS STATEMENT IEC for clinical research and animal trials of the First Affiliated Hospital of Sun Yat-sen University approved this work under Ref # IIT-2021-824. The patients/participants provided their written informed consent to participate in this study. CONSENT FOR PUBLICATION All the authors consented for the paper publication. AVAILABILITY OF DATA AND MATERIAL The analysed data for the current study will be available from the corresponding author. AUTHOR CONTRIBUTIONS Yubin Li supervised the entire study, including the procedures, conception, design and completion. Pingyin Lee contributed to the data analysis and drafted the article. Pingyin Lee and Canquan Zhou participated in the interpretation of the study data and in revisions to the article. All authors contributed to the article and approved the submitted version. FUNDING National Natural Science Foundation of China Youth Science Foundation (81100470), Natural Science Foundation of Guangdong Province (2021A1515010559), National Key Research and Development Program (2018YFC1003102) and Guangdong Province Key Laboratory of Reproductive Medicine (2012A061400003). 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Ginod P, Choux C, Barberet J, et al. Singleton fetal growth kinetics depend on the mode of conception. Fertil Steril. 2018,110 (6):1109-1117.e1102. Abbas Y, Turco M, Burton G, et al. Investigation of human trophoblast invasion in vitro. Human reproduction update. 2020,26 (4):501-513. Tables TABLE 1. Baseline characteristics and clinical data of all included patients Characteristic Fresh ET cycles Total-FET cycles p-value N 638 3036 Female age (y) 32.30 ± 4.13 32.18 ± 4.39 0.556 Male age (y) 34.81 ± 5.77 34.64 ± 5.36 0.325 History of infertility (y) 3.56 ± 2.76 3.77 ± 2.29 0.785 Female BMI (kg/m2) 21.36 ± 2.68 21.27 ± 3.13 0.946 Number of gestational sac by ultrasound <0.001 1 439 2425 2 196 597 3 3 13 4 0 1 Number of live births <0.001 1 426 2542 2 120 422 3 0 4 During pregnancy 80 0 Middle and late stage abortion or induced labor / Stillbirth 11 59 Gender of live birth (single fetus) 0.682 Male 224 1367 Female 202 1175 loss to follow-up 1 9 0.603 Endometriosis 0.069 Present 163 258 Absent 475 2778 Hypertensive disorders of pregnancy Present 19 (11.9%) 141 (17.6%) 0.061 Absent 619 (88.1%) 2895 (82.4%) Note: Data are presented as mean (standard deviation) or N, unless stated otherwise. TABLE 2. Baseline characteristics and clinical data of patients in total-FET cycles Characteristic NC-FET HRT-FET p-value N 1331 1705 Female age (y) 32.18 ± 4.36 32.18 ± 4.42 0.576 Male age (y) 34.44 ± 5.28 34.80 ± 5.42 0.235 History of infertility (y) 3.46 ± 2.28 3.47 ± 2.49 0.675 Female BMI (kg/m2) 21.37 ± 2.13 21.30 ± 3.06 0.876 Number of gestational sac by ultrasound 0.593 1 1090 1335 2 233 364 3 7 6 4 1 0 Number of live births 0.113 1 1126 1416 2 183 239 3 2 2 During pregnancy 0 0 Middle and late stage abortion or induced labor / Stillbirth 19 40 Gender of live birth (single fetus) 0.447 Male 596 771 Female 530 645 loss to follow-up 1 8 0.113 Endometriosis 0.086 Present 100 158 Absent 1231 1547 Hypertensive disorders of pregnancy Present 37 (2.8%) 104 (6.1%) <0.001 Absent 1294 (97.2%) 1601 (93.9%) Note: Data are presented as mean (standard deviation), or N and incidence (%), unless stated otherwise. TABLE 3. Relationship between EM and HDP in all included cycles Hypertensive disorders of pregnancy Significance (2-sided) Present Absent Fresh ET EM Present 2 (1.4%) 143 (98.6%) 0.181 Absent 17 (4.1%) 395 (95.9%) Total 19 538 Total-FET EM Present 13 (5.0%) 245 (95.0%) 0.763 Absent 128 (4.6%) 2650 (95.4%) Total 141 2895 Note: Data are presented as N and incidence (%), unless stated otherwise. TABLE 4. Relationship between EM, endometrial preparation protocol and HDP in total-FET cycle Hypertensive disorders of pregnancy Significance (2-sided) Present Absent NC 33 (2.7%) b 1198 (97.3%) b <0.001 NC+EM 4 (4.0%) a,b 96 (96.0%) a,b HRT 95 (6.1%) a 1452 (93.9%) a HRT+EM 9 (5.7%) a,b 149 (94.3%) a,b Total 141 2895 Note: Data are presented as N and incidence (%), unless stated otherwise. The letters (a, b) in each footmark are the results of the comparison between the two groups. If the same letters were present, it means that there was no statistical significance between them (P > 0.05). TABLE 5. Relationship between fresh ET cycle, NC-FET cycle and HDP in EM Hypertensive disorders of pregnancy Significance (2-sided)(Fisher) Present Absent Fresh ET + EM 2 (1.2%) 161 (98.8%) 0.205 NC + EM 4 (4.0%) 96 (96.0%) Total 6 257 Note: Data are presented as N and incidence (%), unless stated otherwise. TABLE 6. Relationship between EM, embryo transfer methods, gender of live birth and HDP in singleton pregnancies Hypertensive disorders of pregnancy Significance (2-sided) Present Absent EM Present 11 (3.5%) 303 (96.5%) 0.877 Absent 105 (4.0%) 2548 (96.0%) ET Fresh ET 11 (2.6%) 414 (97.4%) 0.138 Total-FET 105 (4.1%) 2437 (95.9%) Gender of live birth Male 65 (4.1%) 1526 (95.9%) 0.635 Female 51 (3.7%) 1325 (96.3%) Total 116 2851 Note: Data are presented as N and incidence (%), unless stated otherwise. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 25 Mar, 2022 Read the published version in Reproductive Biology and Endocrinology → Version 1 posted Editorial decision: Major revision 17 Jan, 2022 Reviews received at journal 11 Jan, 2022 Reviewers agreed at journal 26 Dec, 2021 Reviewers invited by journal 26 Dec, 2021 Editor assigned by journal 16 Dec, 2021 Submission checks completed at journal 15 Dec, 2021 First submitted to journal 15 Dec, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1174628","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":70491659,"identity":"11909705-1535-4eaa-af34-b29a5b2e394a","order_by":0,"name":"Pingyin Lee","email":"","orcid":"","institution":"First Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Pingyin","middleName":"","lastName":"Lee","suffix":""},{"id":70491660,"identity":"345a552b-54d6-4410-b595-6cc270696700","order_by":1,"name":"Canquan Zhou","email":"","orcid":"","institution":"First Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Canquan","middleName":"","lastName":"Zhou","suffix":""},{"id":70491661,"identity":"d5deac99-e67e-432c-9210-bd9499329f1a","order_by":2,"name":"Yubin Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIiWNgGAWjYBACPmYGBmYGAwY5++ONDQc+GNjYEdTCBtVizHDm8MGHMwrSkglrYQBpYWBIbLiRlmzM8+EQYwNBLew8ZtIFBXcSGxtyzKRtDA4wM7AfProBv8OAWmYYPDNuZjhjJp1jcIePgSct7QZBLTwGh2XbGHtAWp4xM0jwmBGlhbEHxLAAMhqI1aI4g40t2ZiBOC1sxdYzDA4bG/AwH3zYY5CWzEbIL/z8hzfeLvhzWM5A/mHDgR9/bOz42Q8fw6uFgYHDAM1e/MpBgP0BYTWjYBSMglEwsgEAYABDABWnvqcAAAAASUVORK5CYII=","orcid":"","institution":"First Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":true,"prefix":"","firstName":"Yubin","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2021-12-15 16:00:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1174628/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1174628/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12958-022-00922-5","type":"published","date":"2022-03-25T20:02:01+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":16555431,"identity":"11f7c01b-4870-4de1-82ec-c604cdd4b20c","added_by":"auto","created_at":"2021-12-17 15:44:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":58469,"visible":true,"origin":"","legend":"\u003cp\u003eA flow diagram showing the distribution of the study populations.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-1174628/v1/0739d8fb8a7e66147d597d97.png"},{"id":19702449,"identity":"8b379fb4-5886-4037-8ce9-ba0032b9a209","added_by":"auto","created_at":"2022-03-28 20:04:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":387018,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1174628/v1/37a17257-b03c-480e-bbb4-ff002763e9fa.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eEndometriosis Does not Seem to Be an Influencing Factor of Hypertensive Disorders of Pregnancy in IVF / ICSI Cycles\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eEndometriosis (EM) refers to the presence of functional endometrial tissue (glands and stroma) outside the uterus, in which its incidence in women of childbearing age is 5-10%[1]\u0026nbsp;[2]. EM is characterized by estrogen dependent chronic inflammation, which often manifests as dysmenorrhea, lower abdominal pain, dyspareunia and infertility[3].\u003c/p\u003e\n\u003cp\u003eMany studies have shown that EM can increase the risk of multiple adverse pregnancy outcomes, such as spontaneous abortion, ectopic pregnancy, hypertensive disorders of pregnancy (preeclampsia or gestational hypertension), gestational diabetes mellitus (GDM), preterm birth and low birth weight[4]\u0026nbsp;[5]\u0026nbsp;[6]. In addition, the immune system and inflammation have been considered to serve as pivotal factors in disease progression[7]. Abnormal hormone circulation from EM as well as pathological changes due to chronic inflammation may lead to a higher risk of hypertension[8]. At present, the pathogenesis of hypertensive disorders of pregnancy (HDP) has yet to be fully elucidated. It is generally believed that the occurrence of HDP may be related to immune system disorder, trophoblast or placental ischemia and oxidative stress[9]\u0026nbsp;[10]. Studies have also shown that the incidence of HDP is higher when using assisted reproductive technology (ART), especially in the frozen-thawed embryo\u0026nbsp;transfer (FET)\u0026nbsp;cycle[11], which may be related to the endometrial preparation protocol in the FET cycle[12].\u003c/p\u003e\n\u003cp\u003eBellac et al\u0026nbsp;[13]\u0026nbsp;and Lani et al\u0026nbsp;[14]\u0026nbsp;have shown that EM can significantly increase the risk of HDP. However, Hadfield et al\u0026nbsp;[15]\u0026nbsp;found that EM did not increase the risk of HDP, with certain studies showing that EM could reduce the risk of HDP[16]. Different opinions exist regarding EM and HDP, though none are conclusive, and studies pertaining to ART are scarce. Furthermore, both EM and HDP are known to be involved in abnormal immune factors, and immune factors are extremely complex. Accordingly, whether EM has an influence on the occurrence of HDP is worthy of further discussion.\u003c/p\u003e\n\u003cp\u003eTherefore, by analyzing women of more than 20 weeks of clinical pregnancy who were treated with IVF / ICSI (intracytoplasmic sperm injection, ICSI) at our reproductive center in the past 4 years, this study aims to determine whether the risk of HDP is related to EM, ovulation and embryo vitrification technology.\u0026nbsp;\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design and setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was a retrospective cohort study that analyzed the clinical data of 3674 patients treated with IVF / ICSI at the Reproductive Medicine Center of the First Affiliated Hospital of Sun Yat-sen University from January 2017 to June 2021. The protocol was reviewed and approved by the Ethical Committee of The First Affiliated Hospital of Sun Yat-Sen University. The patients/participants provided their written informed consent to participate in this study. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study included 638 cycles of fresh embryo transfer (fresh ET) and 3036 cycles of FET. In order to distinguish FET from HRT-FET and NC-FET, total-FET was used to represent the overall FET cycle (Figure 1). The inclusion criteria of the EM group were as follows: patients aged 20-45 years, diagnosed with endometriosis, has intrauterine gestational sac pregnancy under B-ultrasound 1 month after embryo transfer, and clinical pregnancy status has been maintained for more than 20 weeks. The inclusion criteria of the EM absent group were as follows: patients aged 20-45 years and undergoing IVF / ICSI treatment due to tubal and/or male factors infertility. Exclusion criteria included: diagnosed with PCOS, hyperprolactinemia, abnormal thyroid function, and chromosome abnormalities of one or both of other endocrine related diseases that are not conducive to pregnancy or can cause adverse pregnancy, has underwent ovarian, thyroid, pituitary surgery or antitumor radiotherapy and chemotherapy, undergone oophorectomy due to ovarian malignancy or other reasons.\u003c/p\u003e\n\u003cp\u003eWomen were asked whether they had physician diagnosed\u0026nbsp;EM. Participants who responded \u0026ldquo;yes\u0026rdquo; indicated the year of diagnosis and whether it had been visually confirmed by laparoscopy, the clinical gold standard for endometriosis diagnosis\u0026nbsp;[17]. The remaining patients who were not diagnosed with EM by laparoscopy and those who were reported as EM by B-ultrasound during the treatment were also classified as EM. This inclusion is based on the comprehensive consideration of the patient\u0026apos;s reproductive age and needs. We considered women to have a HDP in a given pregnancy if they had a diagnosis of gestational hypertension, pre-eclampsia, eclampsia, or HELLP syndrome on the medical record at any time between one month before delivery and seven days post partum\u0026nbsp;[18]. To be considered exposed to a HDP in our study, women with diagnoses registered outside this time window also had to have at least one diagnosis registered within the window. (We adopted this restriction to try to ensure that diagnoses of hypertensive disorders of pregnancy reflected true cases.)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStimulation Protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the patient\u0026apos;s age, body mass index (BMI), basic sex hormone level, anti-Mullerian hormone (AMH) and antral follicle count (AFC), the appropriate stimulation protocol and starting dose were selected. Ovulation was triggered using 250 \u0026micro;g of recombinant hCG (Ovidrel, Merck-Serono, Switzerland) or 5000-10000 IU hCG (Lizhu, Zhuhai, China) when two follicles reached 18 mm or three follicles reached 17mm in diameter. Transvaginal ultrasound-guided oocyte retrieval was performed 34-36 hours later. Following oocyte retrieval, whether to carry out fresh ET or whole embryo freezing was determined according to whether the patient had high ovarian hyperstimulation syndrome (OHSS) risk, high progesterone level, uterine cavity and condition of endometrium. If fresh ET was planned, Progesterone Sustained-release vaginal gel (Crinone, Merck-Serono, Switzerland) 90mg/d or intramuscular progesterone 40mg/d was given on the day of oocyte retrieval. Dydrogesterone (DydrogesteroneTablets, Abbott biologicals, Netherlands) 10mg was orally administered twice a day until 14 days following embryo transfers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFertilization and Embryo Culture\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter culturing 2-6h in vitro, IVF or ICSI was selected according to the condition of the male semen. The number and size of prokaryotes, number and distribution of nucleolar precursor bodies and cytoplasmic distribution were observed 16-18 hours after fertilization. Meanwhile, following 72 h, D3 cleavage embryos were scored according to the number of blastomeres, uniformity of blastomeres size, amount and distribution of fragments. Embryo morphology was evaluated according to the Istanbul Consensus Workshop on Embryo Assessment[19].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEmbryo Transfer\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo more than two cleavage stage embryos were transferred on the morning of the 3rd day after oocyte retrieval. According to our embryo culture strategy, if there were no more than two cleavage stage embryos available after fresh embryo transfer, they were vitrified on the 3rd day. Otherwise, the remainder had blastocyst culture performed. Surplus cleavage stage embryos or blastocysts were vitrified using the Cryotop (Kitazato Supply Co.,Fujinomiya, Japan) method\u0026nbsp;[20]\u0026nbsp;for subsequent FET cycles whenever necessary. Embryo morphology was evaluated according to the Istanbul Consensus Workshop on Embryo Assessment\u0026nbsp;[19].\u003c/p\u003e\n\u003cp\u003eDuring the FET cycles, endometrial preparation protocols included hormone therapy (HRT) cycles and natural cycles (NC), as previously described in detail\u0026nbsp;[21]. All embryo transfers were performed under transabdominal ultrasound guidance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDetermination of Clinical Pregnancy and Follow-up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerum hCG levels were determined 12-14 days after embryo transfers. A clinical pregnancy was confirmed by transvaginal ultrasound 3 weeks after a positive serum HCG test. Luteal support was continued to the 10th week of gestation. All pregnancies were followed up by our staff until the end of gestation. The details relevant to the follow-up were recorded, including the course of pregnancy, delivery time, mode of delivery, complications during pregnancy, gender, birth weight and congenital abnormalities of newborns.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCategorical data were presented as numbers and percentages. Continuous variables were given as mean\u0026plusmn;SD. The chi-square test or Fisher exact probability test was used for categorical variables, while ANOVA was done for continuous variables. Bonferroni method was utilized for pairwise comparison between each group. A p-value \u0026lt; 0.05 was considered to be statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline characteristics and clinical data of patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 3674 patients were included, which included 638 cycles of fresh ET and 3036 cycles of total-FET. No significant difference was observed between the two groups in regard to age, infertility years, female BMI, gender of live birth (single fetus), number of losses to follow-up, incidence of HDP and EM (P\u0026gt;0.05). There were significant differences between the two groups in the number of gestational sacs and number of live births (P\u0026lt;0.05) (Table 1). Among the 3036 cycles of total-FET, there were 1331 cases of natural cycles (NC-FET) and 1705 cases of hormone therapy cycles (HRT-FET). Moreover, no significant difference was noted between the two groups in terms of age, infertility years, female BMI, number of gestational sacs, number of live births, gender of live birth (single fetus), number of losses to follow-up, incidence of HDP and EM (P\u0026gt;0.05) (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelationship between EM, HDP and endometrial preparation protocol during all included cycles\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the total-FET cycle, the incidence of HDP in the HRT cycle was found to be higher than that in the NC cycle (P\u0026lt;0.05) (Table 2). After controlling the effects of number of gestational sacs by ultrasound and live births, fresh ET and total-FET were analyzed, in which no significant difference was found in the incidence of HDP during pregnancy in the fresh ET cycle and total-FET cycle, regardless of whether EM was combined (P\u0026gt;0.05) (Table 3). The two types of endometrial preparation protocols were further compared and were analyzed as to whether they had EM. Accordingly, in the total-FET cycle, the incidence of HDP during pregnancy was noted to be higher in the HRT cycle without EM than in the NC cycle without EM (6.1% V.S 2.7%) (P\u0026lt;0.05). Meanwhile, no significant difference was found in the incidence of HDP between the NC and HRT cycles with EM (P\u0026gt;0.05) (Table 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelationship between ovulation cycle (fresh ET cycle, NC-FET cycle) and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eHDP\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;in EM\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn all cases of ovulation (fresh ET cycle, NC-FET cycle), no significant difference was found in the incidence of HDP during pregnancy between fresh ET cycles with EM and NC-FET cycles with EM (P\u0026gt;0.05) (Table 5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelationship between EM, embryo transfer methods and HDP in singleton pregnancies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the previous retrospective analysis of the total population, a few twin pregnancies were present in each group, which may interfere with the results. In order to be more thorough, an analysis of singleton pregnancy was carried out separately. Here, no significant difference was found between the incidence of HDP and whether EM was combined, different embryo transfer methods (fresh ET, total-FET) or the gender of live birth (P\u0026gt;0.05) (Table 6).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eEM is known to be common gynecological disease that causes infertility and may lead to adverse pregnancy outcomes, seriously placing the physical and mental health of women of childbearing age at risk along with safety of perinatal mothers and children. However, in recent years, the incidence of HDP in pregnant women with EM has remained controversial. The results of this study demonstrated that no difference in the incidence of HDP was observed in total-FET regardless of whether EM was combined (Table 3). After further cross comparison of the endometrial preparation protocol with EM, the incidence of HDP during pregnancy in HRT cycle without EM (6.1%) was found to be higher than that in the NC cycle without EM (2.7%), though no significant difference was present in the incidence of HDP between NC with EM (4.0%) and HRT with EM (5.7%) (Table 4). Notably, in the corresponding data, the incidence of HDP in all EM groups (4.0% and 5.7%) was within the HDP global incidence rate (5%-10%)\u0026nbsp;[22].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn terms of the results, after adding EM, the HDP incidence that should have been different between NC and HRT exhibited no differences (Table 4), which may suggest that EM improves the incidence of HDP in NC or reduces the incidence in HRT. However, there may be no statistical difference as the present case data are small. Accordingly, in the future, the sample size should be expanded for further research. Nevertheless, the present results suggest that there may be confounding factors in the total-FET cycle. Therefore, it is suggested that when analyzing HDP incidence, it is more appropriate to separate the NC cycle with ovulation from the HRT cycle. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMost studies have not confirmed the correlation between EM and HDP. In 2012, Vercellini et al. followed up with pregnancies of patients who underwent EM surgery. Among them, there were 150 patients with deep infiltrating endometriosis (DIE) whose lesions involved the vaginal rectal septum, for which the incidence of HDP did not increase in these patients\u0026nbsp;[23]. Another study on the pregnancy of DIE patients following laparoscopic ureterolysis found that the incidence of HDP was 3.8%\u0026nbsp;[24], which was not higher than the global incidence of HDP of 5% - 10%[22]. However, Nirgianakis et al. put forward that the incidence of HDP in patients with pelvic DIE is higher than that in patients without EM\u0026nbsp;[25]. Exacoustos et al. studied 52 patients with posterior pelvic DIE lesions\u0026nbsp;\u0026ge;\u0026nbsp;2 cm and found that the risk of HDP in patients with posterior pelvic DIE was increased, about 14.6%, which was significantly higher than that in patients without EM\u0026nbsp;[26], though the baseline of the two groups of patients in terms of age, pregnancy and delivery times and BMI were not consistent, and the study did not exclude interfering factors, such as ART, for pregnancy. Some studies also found that the incidence of pre-eclampsia in EM patients has increased\u0026nbsp;[27]\u0026nbsp;[28], however, these studies did not indicate whether patients assisted by ART were excluded, which cannot present a positive solution between EM and HDP. This study investigated the relationship between EM and HDP in IVF / ICSI. Currently, few articles exist on EM and HDP in ART, which gives the findings of this study more clinical value. Nevertheless, this study did not stratify the severity of EM and did not rule out that different degrees of EM may have different effects on the incidence of HDP, which will be investigated in the next step.\u003c/p\u003e\n\u003cp\u003eIn the past decade, FET has significantly increased due to the expansion of surgical indications\u0026nbsp;[29]. At present, numerous studies have shown that the risk of HDP associated with IVF has increased, especially in regard to FET\u0026nbsp;[30]\u0026nbsp;[11]. However, most reports have directly compared fresh ET and FET, where it was found that FET has a higher risk of HDP\u0026nbsp;[31]\u0026nbsp;[32]\u0026nbsp;[33], though it does not clearly indicate which endometrial preparation protocol was used in FET. In this study, no difference was noted in regard to the incidence of HDP between fresh ET and total-FET (Table 1), in which the incidence of HDP in the HRT-FET cycle was found to be higher than that in the NC-FET cycle (Table 2). The results of this study are consistent with that of other research. In a big data retrospective analysis conducted in Japan, it was found that, compared with patients with natural ovulation cycle (NC-FET), patients using HRT-FET had an increased risk of HDP and placental implantation, while the risk of GDM was observed to be reduced\u0026nbsp;[34]. Another retrospective cohort study in China also found that the HRT-FET group had an increased risk of HDP and placenta previa compared to ovarian stimulation in the FET group\u0026nbsp;[12]. These results suggested that endometrial preparation methods may be related to obstetric complications, especially with respect to the development of HDP. This may be due to the increased risk of HDP from the lack of corpus luteum (CL) in patients with HRT-FET\u0026nbsp;[35].\u003c/p\u003e\n\u003cp\u003eCryopreserved embryos must be transferred to the uterus during the critical endometrial window that can establish pregnancy\u0026nbsp;[36]. In reproductive women, the common endometrial preparation protocol of FET are NC, stimulated cycle and HRT cycle. In a natural cycle, the major follicle matures and produces E2, which leads to the development and thickening of the endometrium. Ovulation can then occur naturally, and the ovulation site becomes CL, which belongs to a functional ovarian cyst. In the stimulated cycle, ovulation was induced with either clomiphene citrate, letrozole, or gonadotropins, which may lead to one or more CL. However, in the HRT cycle, exogenous E2 and P lead to the development of the endometrium. During this period, the ovary is inhibited, hence, no dominant follicle, ovulation and CL exist. In contrast to the fresh cycle, there may be more CL in light of the role of the stimulation protocol.\u003c/p\u003e\n\u003cp\u003eThe hypothesis that the HRT cycle without CL increases the risk of HDP seems to be biologically reasonable. CL can produce E2 and P as well as vasoactive products, such as relaxin, vascular endothelial growth (VEGF) and angiogenic metabolites of estrogen\u0026nbsp;[37]\u0026nbsp;[38]\u0026nbsp;[39]. CL serves as an important source of reproductive hormones before the placenta becomes a source of reproductive hormones (such as P and E2) to maintain pregnancy. Vasoactive products produced by CL are very important for the formation of the initial placenta, and previous studies have proposed that the abnormal formation of early placenta is a critical step in the development of preeclampsia\u0026nbsp;[40]\u0026nbsp;[41]\u0026nbsp;[42]. Since the HRT cycle does not form CL, relaxin and VEGF are not replaced when compared with other endometrial preparation protocols that involves CL formation, which is the pathological basis of subsequent pregnancy complications in women with an HRT cycle. Overall, these studies support the premise that CL deletion is associated with circulatory adaptation defects during pregnancy, in which the formation of CL may play a protective role in the occurrence and development of HDP. However, its mechanism remains unclear and requires further study.\u003c/p\u003e\n\u003cp\u003eIn regard to the total-FET cycle, EM does not seem to affect the occurrence and development of HDP, whereas CL may influence them. In order to compare the effect of fresh ET and FET on HDP, EM patients in a fresh ET cycle were compared with EM patients in a total-FET cycle, where no difference in the incidence of HDP was found between the two groups (Table 5). These results suggested that FET does not cause maternal complications during pregnancy due to potential damage from the freeze-thaw process related embryo.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe number of FET cases has risen significantly within the past ten years, partly owing to improvements associated with vitrification compared with older slow-freeze methods\u0026nbsp;[29]. However, no final conclusion was reached on whether vitrification technology can cause damage to embryos. Moreover, a cross-sectional analysis of 10744 transfer cycles using single cleavage embryos in Australia found that the live birth rate (LBR) of women receiving freeze-thawed embryos was significantly lower than those receiving fresh embryos, which may be due to embryo damage related to the freeze-thaw process\u0026nbsp;[43], though HDP data were not included.\u003c/p\u003e\n\u003cp\u003eA retrospective cohort study of 560 singleton pregnancies found that the fetal birth weight in the IVF/ICSI group and the artificial insemination group was lower than that in the FET group, and this difference was already present when the estimated fetal weight was evaluated in the second trimester of pregnancy (21-23 weeks of pregnancy). The difference of fetal growth dynamics is considered to be due to the influence of the different manners of assisted reproductive technology on the invasiveness of trophoblast [44]. However, as no satisfactory model exists for studying extravillous trophoblasts and the controversial use of trophoblast cell lines, the mechanism of controlling trophoblast invasion and causing placental defects has yet to be fully understood [45]. In this study, the HRT-FET group with CL deletion was excluded, and only the fresh ET cycle and NC-FET were included for comparison (Table 5). In addition, considering that multiple births may affect the incidence of HDP, this study analyzed singleton pregnancies that were delivered alive (Table 6). Accordingly, no difference was found in the incidence of HDP, suggesting that trophoblast damage caused by cryopreservation may not affect the occurrence of HDP. Even when excluding the impact of multiple births on the incidence of HDP, no statistical difference was observed between EM, embryo transfer methods (fresh ET and FET), gender of live birth and incidence of HDP. However, these findings require additional in-depth research for verification.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, EM does not seem to affect the occurrence of HDP in ART. During the total-FET cycle, whether the formation of CL plays a protective role in the occurrence and development of HDP was evaluated. The freeze-thaw process related embryo potential damage caused by cryopreservation has no effect on the occurrence of HDP. However, as the occurrence of HDP in EM is still inconclusive, further studies are needed. These findings also emphasize the potential risk of HDP in patients with HRT-FET cycle during pregnancy follow-up. Therefore, such patients should pay more attention to the occurrence of HDP in order to reduce adverse pregnancy outcomes related to assisted reproductive technology treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eFET, frozen-thawed embryo transfer, NC-FET, frozen-thawed embryo transfer with natural cycle, HRT-FET, frozen-thawed embryo transfer with hormone therapy\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY STATEMENT\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICS STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIEC for clinical research and animal trials of the First Affiliated Hospital of Sun Yat-sen University approved this work under Ref # IIT-2021-824. The patients/participants provided their written informed consent to participate in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONSENT FOR PUBLICATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors consented for the paper publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAVAILABILITY OF DATA AND MATERIAL\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe analysed data for the current study will be available from the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYubin Li supervised the entire study, including the procedures, conception, design and completion. Pingyin Lee contributed to the data analysis and drafted the article. Pingyin Lee and Canquan Zhou participated in the interpretation of the study data and in revisions to the article. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNational Natural Science Foundation of China Youth Science Foundation (81100470), Natural Science Foundation of Guangdong Province (2021A1515010559), National Key Research and Development Program (2018YFC1003102) and Guangdong Province Key Laboratory of Reproductive Medicine (2012A061400003).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD\u003c/strong\u003e\u003cstrong\u003eECLARATION\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eOF\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCOMPETING\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;I\u003c/strong\u003e\u003cstrong\u003eNTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZondervan KT, Becker CM, Missmer SA. Endometriosis. The New England journal of medicine. 2020,382 (13):1244-1256.\u003c/li\u003e\n\u003cli\u003eMorassutto C, Monasta L, Ricci G, et al. Incidence and Estimated Prevalence of Endometriosis and Adenomyosis in Northeast Italy: A Data Linkage Study. PloS one. 2016,11 (4):e0154227.\u003c/li\u003e\n\u003cli\u003eSchleedoorn MJ, Nelen WLDM, Dunselman GAJ, et al. Selection of key recommendations for the management of women with endometriosis by an international panel of patients and professionals. Human reproduction (Oxford, England). 2016,31 (6):1208-1218.\u003c/li\u003e\n\u003cli\u003eFarland L, Prescott J, Sasamoto N, et al. Endometriosis and Risk of Adverse Pregnancy Outcomes. Obstet Gynecol. 2019,134 (3):527-536.\u003c/li\u003e\n\u003cli\u003eFarella M, Chanavaz-Lacheray I, Verspick E, et al. Pregnancy outcomes in women with history of surgery for endometriosis. Fertil Steril. 2020,113 (5):996-1004.\u003c/li\u003e\n\u003cli\u003eYi K, Cho G, Park K, et al. 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BJOG : an international journal of obstetrics and gynaecology. 2012,119 (12):1538-1543.\u003c/li\u003e\n\u003cli\u003eUccella S, Cromi A, Casarin J, et al. Laparoscopy for ureteral endometriosis: surgical details, long-term follow-up, and fertility outcomes. Fertil Steril. 2014,102 (1):160-166.e162.\u003c/li\u003e\n\u003cli\u003eNirgianakis K, Gasparri M, Radan A, et al. Obstetric complications after laparoscopic excision of posterior deep infiltrating endometriosis: a case-control study. Fertil Steril. 2018,110 (3):459-466.\u003c/li\u003e\n\u003cli\u003eExacoustos C, Lauriola I, Lazzeri L, et al. Complications during pregnancy and delivery in women with untreated rectovaginal deep infiltrating endometriosis. Fertil Steril. 2016,106 (5):1129-1135.e1121.\u003c/li\u003e\n\u003cli\u003eGlavind M, Forman A, Arendt L, et al. Endometriosis and pregnancy complications: a Danish cohort study. Fertil Steril. 2017,107 (1):160-166.\u003c/li\u003e\n\u003cli\u003ePan M, Chen L, Tsao H, et al. Risk of gestational hypertension-preeclampsia in women with preceding endometriosis: A nationwide population-based study. PloS one. 2017,12 (7):e0181261.\u003c/li\u003e\n\u003cli\u003eRienzi L, Gracia C, Maggiulli R, et al. Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance. Human reproduction update. 2017,23 (2):139-155.\u003c/li\u003e\n\u003cli\u003eIshihara O, Araki R, Kuwahara A, et al. 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):128-133.\u003c/li\u003e\n\u003cli\u003eRoque M, Haahr T, Geber S, et al. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Human reproduction update. 2019,25 (1):2-14.\u003c/li\u003e\n\u003cli\u003eSha T, Yin X, Cheng W, et al. 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.e339.\u003c/li\u003e\n\u003cli\u003eMaheshwari A, Pandey S, Amalraj Raja E, et al. Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer? Human reproduction update. 2018,24 (1):35-58.\u003c/li\u003e\n\u003cli\u003eSaito K, Kuwahara A, Ishikawa T, 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 reproduction (Oxford, England). 2019,34 (8):1567-1575.\u003c/li\u003e\n\u003cli\u003eSingh B, Reschke L, Segars J, et al. Frozen-thawed embryo transfer: the potential importance of the corpus luteum in preventing obstetrical complications. Fertil Steril. 2020,113 (2):252-257.\u003c/li\u003e\n\u003cli\u003eBergh P, Navot D. The impact of embryonic development and endometrial maturity on the timing of implantation. Fertil Steril. 1992,58 (3):537-542.\u003c/li\u003e\n\u003cli\u003evon Versen-H\u0026ouml;ynck F, Strauch N, Liu J, et al. Effect of Mode of Conception on Maternal Serum Relaxin, Creatinine, and Sodium Concentrations in an Infertile Population. Reproductive sciences (Thousand Oaks, Calif). 2019,26 (3):412-419.\u003c/li\u003e\n\u003cli\u003eJohnson M, Abdalla H, Allman A, et al. Relaxin levels in ovum donation pregnancies. Fertil Steril. 1991,56 (1):59-61.\u003c/li\u003e\n\u003cli\u003eKnobil E, Neill J, Greenwald G, et al. The Physiology of Reproduction, Second Edition. The Endocrinologist. 1995,5 77-78.\u003c/li\u003e\n\u003cli\u003eWeissgerber T, Milic N, Milin-Lazovic J, et al. Impaired Flow-Mediated Dilation Before, During, and After Preeclampsia: A Systematic Review and Meta-Analysis. Hypertension (Dallas, Tex : 1979). 2016,67 (2):415-423.\u003c/li\u003e\n\u003cli\u003eKhaw A, Kametas N, Turan O, et al. Maternal cardiac function and uterine artery Doppler at 11-14 weeks in the prediction of pre-eclampsia in nulliparous women. BJOG : an international journal of obstetrics and gynaecology. 2008,115 (3):369-376.\u003c/li\u003e\n\u003cli\u003eDe Paco C, Kametas N, Rencoret G, et al. Maternal cardiac output between 11 and 13 weeks of gestation in the prediction of preeclampsia and small for gestational age. Obstet Gynecol. 2008,111 292-300.\u003c/li\u003e\n\u003cli\u003eTinn Teh W, Polyakov A, Garrett C, et al. Reduced live birth rates in frozen versus fresh single cleavage stage embryo transfer cycles: A cross -sectional study. International journal of reproductive biomedicine. 2020,18 (7):491-500.\u003c/li\u003e\n\u003cli\u003eGinod P, Choux C, Barberet J, et al. Singleton fetal growth kinetics depend on the mode of conception. Fertil Steril. 2018,110 (6):1109-1117.e1102.\u003c/li\u003e\n\u003cli\u003eAbbas Y, Turco M, Burton G, et al. Investigation of human trophoblast invasion in vitro. Human reproduction update. 2020,26 (4):501-513.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTABLE 1. Baseline characteristics and clinical data of all included patients\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003eFresh\u0026nbsp;ET\u0026nbsp;cycles\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003eTotal-FET\u0026nbsp;cycles\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e638\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e3036\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eFemale age (y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e32.30 \u0026plusmn; 4.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e32.18 \u0026plusmn; 4.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e0.556\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eMale age (y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e34.81 \u0026plusmn; 5.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e34.64 \u0026plusmn; 5.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e0.325\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eHistory of infertility (y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e3.56 \u0026plusmn; 2.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e3.77 \u0026plusmn; 2.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e0.785\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eFemale BMI (kg/m2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e21.36 \u0026plusmn; 2.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e21.27 \u0026plusmn; 3.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e0.946\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eNumber of gestational sac by ultrasound\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e439\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e2425\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e196\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e597\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eNumber of live births\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e426\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e2542\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e422\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eDuring pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eMiddle and late stage abortion or induced labor / Stillbirth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eGender of live birth (single fetus)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e0.682\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e224\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e1367\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e202\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e1175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eloss to follow-up\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e0.603\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eEndometriosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e0.069\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e258\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e475\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e2778\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eHypertensive disorders of pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e19 (11.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e141 (17.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e0.061\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.14991181657848%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e619 (88.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.929453262786595%\"\u003e\n \u003cp\u003e2895 (82.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: Data are presented as mean (standard deviation) or N, unless stated otherwise.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp id=\"isPasted\"\u003eTABLE\u0026nbsp;2. Baseline characteristics and clinical data of patients in total-FET cycles\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003eNC-FET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003eHRT-FET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e1331\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e1705\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eFemale age (y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e32.18\u0026nbsp;\u0026plusmn; 4.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e32.18\u0026nbsp;\u0026plusmn;\u0026nbsp;4.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e0.576\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eMale age (y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e34.44\u0026nbsp;\u0026plusmn;\u0026nbsp;5.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e34.80\u0026nbsp;\u0026plusmn; 5.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e0.235\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eHistory of infertility (y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e3.46 \u0026plusmn; 2.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e3.47 \u0026plusmn; 2.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e0.675\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eFemale BMI (kg/m2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e21.37\u0026nbsp;\u0026plusmn; 2.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e21.30\u0026nbsp;\u0026plusmn; 3.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e0.876\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eNumber of gestational sac by ultrasound\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e0.593\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e1090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e1335\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e233\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e364\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eNumber of live births\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e1126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e1416\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e183\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e239\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eDuring pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eMiddle and late stage abortion or induced labor / Stillbirth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eGender of live birth (single fetus)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e0.447\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e596\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e771\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e530\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e645\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eloss to follow-up\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eEndometriosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e0.086\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e158\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e1231\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e1547\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eHypertensive disorders of pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e37 (2.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e104 (6.1%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"44.36619718309859%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e1294 (97.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.54225352112676%\"\u003e\n \u003cp\u003e1601 (93.9%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.549295774647888%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: Data are presented as mean (standard deviation), or N and incidence (%), unless stated otherwise.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp id=\"isPasted\"\u003eTABLE 3. Relationship between EM and\u0026nbsp;HDP\u0026nbsp;in all included cycles\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.3265306122449%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.224489795918368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"43.87755102040816%\"\u003e\n \u003cp\u003eHypertensive disorders of pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003eSignificance (2-sided)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.402061855670103%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.463917525773196%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.49484536082474%\"\u003e\n \u003cp\u003eFresh ET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.34020618556701%\"\u003e\n \u003cp\u003eEM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.402061855670103%\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003e2 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003e143 (98.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.463917525773196%\"\u003e\n \u003cp\u003e0.181\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.402061855670103%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003e17 (4.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003e395 (95.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.463917525773196%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.34020618556701%\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.402061855670103%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003e538\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.463917525773196%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.49484536082474%\"\u003e\n \u003cp\u003eTotal-FET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.34020618556701%\"\u003e\n \u003cp\u003eEM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.402061855670103%\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003e13 (5.0%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003e245 (95.0%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.463917525773196%\"\u003e\n \u003cp\u003e0.763\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.402061855670103%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003e128 (4.6%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003e2650 (95.4%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.463917525773196%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.34020618556701%\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.402061855670103%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003e141\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.649484536082475%\"\u003e\n \u003cp\u003e2895\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.463917525773196%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: Data are presented as N and incidence (%), unless stated otherwise.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp id=\"isPasted\"\u003eTABLE 4. Relationship between EM, endometrial preparation protocol and\u0026nbsp;HDP\u0026nbsp;in total-FET\u0026nbsp;cycle\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"63.63636363636363%\"\u003e\n \u003cp\u003eHypertensive disorders of pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003eSignificance (2-sided)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.3265306122449%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.632653061224488%\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.632653061224488%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.408163265306122%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.3265306122449%\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.632653061224488%\"\u003e\n \u003cp\u003e33 (2.7%) b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.632653061224488%\"\u003e\n \u003cp\u003e1198 (97.3%) b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.408163265306122%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.3265306122449%\"\u003e\n \u003cp\u003eNC+EM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.632653061224488%\"\u003e\n \u003cp\u003e4 (4.0%) a,b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.632653061224488%\"\u003e\n \u003cp\u003e96 (96.0%) a,b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.408163265306122%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.3265306122449%\"\u003e\n \u003cp\u003eHRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.632653061224488%\"\u003e\n \u003cp\u003e95 (6.1%) a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.632653061224488%\"\u003e\n \u003cp\u003e1452 (93.9%) a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.408163265306122%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.3265306122449%\"\u003e\n \u003cp\u003eHRT+EM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.632653061224488%\"\u003e\n \u003cp\u003e9 (5.7%) a,b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.632653061224488%\"\u003e\n \u003cp\u003e149 (94.3%) a,b\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.408163265306122%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.3265306122449%\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.632653061224488%\"\u003e\n \u003cp\u003e141\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.632653061224488%\"\u003e\n \u003cp\u003e2895\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.408163265306122%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: Data are presented as N and incidence (%), unless stated otherwise. The letters (a, b) in each footmark are the results of the comparison between the two groups. If the same letters were present, it means that there was no statistical significance between them (P \u0026gt; 0.05).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp id=\"isPasted\"\u003eTABLE 5. Relationship between fresh ET cycle, NC-FET cycle and\u0026nbsp;HDP\u0026nbsp;in EM\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25.510204081632654%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"54.08163265306123%\"\u003e\n \u003cp\u003eHypertensive disorders of pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.408163265306122%\"\u003e\n \u003cp\u003eSignificance (2-sided)(Fisher)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25.77319587628866%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.804123711340207%\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.804123711340207%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.61855670103093%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25.77319587628866%\"\u003e\n \u003cp\u003eFresh\u0026nbsp;ET + EM\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.804123711340207%\"\u003e\n \u003cp\u003e2 (1.2%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.804123711340207%\"\u003e\n \u003cp\u003e161 (98.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.61855670103093%\"\u003e\n \u003cp\u003e0.205\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25.77319587628866%\"\u003e\n \u003cp\u003eNC + EM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.804123711340207%\"\u003e\n \u003cp\u003e4 (4.0%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.804123711340207%\"\u003e\n \u003cp\u003e96 (96.0%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.61855670103093%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25.77319587628866%\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.804123711340207%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.804123711340207%\"\u003e\n \u003cp\u003e257\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.61855670103093%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: Data are presented as N and incidence (%), unless stated otherwise.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp id=\"isPasted\"\u003eTABLE 6. Relationship between EM, embryo transfer methods, gender of live birth and HDP in singleton pregnancies\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"22.448979591836736%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"45.91836734693877%\"\u003e\n \u003cp\u003eHypertensive disorders of pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.367346938775512%\"\u003e\n \u003cp\u003eSignificance (2-sided)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"22.448979591836736%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.53061224489796%\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.387755102040817%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.367346938775512%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"22.448979591836736%\"\u003e\n \u003cp\u003eEM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.53061224489796%\"\u003e\n \u003cp\u003e11 (3.5%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.387755102040817%\"\u003e\n \u003cp\u003e303 (96.5%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.367346938775512%\"\u003e\n \u003cp\u003e0.877\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"22.448979591836736%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.53061224489796%\"\u003e\n \u003cp\u003e105 (4.0%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.387755102040817%\"\u003e\n \u003cp\u003e2548 (96.0%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.367346938775512%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"22.448979591836736%\"\u003e\n \u003cp\u003eET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003eFresh\u0026nbsp;ET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.53061224489796%\"\u003e\n \u003cp\u003e11 (2.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.387755102040817%\"\u003e\n \u003cp\u003e414 (97.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.367346938775512%\"\u003e\n \u003cp\u003e0.138\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"22.448979591836736%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003eTotal-FET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.53061224489796%\"\u003e\n \u003cp\u003e105 (4.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.387755102040817%\"\u003e\n \u003cp\u003e2437 (95.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.367346938775512%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"22.448979591836736%\"\u003e\n \u003cp\u003eGender of live birth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.53061224489796%\"\u003e\n \u003cp\u003e65 (4.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.387755102040817%\"\u003e\n \u003cp\u003e1526 (95.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.367346938775512%\"\u003e\n \u003cp\u003e0.635\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"22.448979591836736%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.53061224489796%\"\u003e\n \u003cp\u003e51 (3.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.387755102040817%\"\u003e\n \u003cp\u003e1325 (96.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.367346938775512%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"22.448979591836736%\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.53061224489796%\"\u003e\n \u003cp\u003e116\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.387755102040817%\"\u003e\n \u003cp\u003e2851\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.367346938775512%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: Data are presented as N and incidence (%), unless stated otherwise.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"reproductive-biology-and-endocrinology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rbej","sideBox":"Learn more about [Reproductive Biology and Endocrinology](http://rbej.biomedcentral.com)","snPcode":"12958","submissionUrl":"https://submission.nature.com/new-submission/12958/3","title":"Reproductive Biology and Endocrinology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Endometriosis, Hypertensive disorders of pregnancy, In vitro fertilization, Frozen-thawed embryo transfer","lastPublishedDoi":"10.21203/rs.3.rs-1174628/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1174628/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction\u003c/p\u003e\u003cp\u003eTo evaluate whether the incidence of hypertensive disorders of pregnancy (HDP) in pregnant women was related to endometriosis (EM), ovulation and embryo vitrification technology.\u0026nbsp;\u003c/p\u003e\u003cp\u003eMethods\u003c/p\u003e\u003cp\u003eA retrospective cohort study was conducted on the clinical data of 3674 women who were treated with IVF / ICSI in the Reproductive Medicine Center of the First Affiliated Hospital of Sun Yat-sen University and maintained clinical pregnancy for more than 20 weeks. All pregnancies were followed up until the end of pregnancy. The follow-up consisted of recording the course of pregnancy, pregnancy complications, and basic situation of newborns.\u003c/p\u003e\u003cp\u003eResults\u003c/p\u003e\u003cp\u003eCompared with NC-FET without EM, HRT-FET without EM was found to have a higher incidence of HDP during pregnancy (2.7% V.S. 6.1%, P\u0026lt;0.001); however, no significant difference was found in the incidence of HDP between NC-FET and HRT-FET combined with EM (4.0% V.S. 5.7%, P\u0026gt;0.05). In total frozen-thawed embryo transfer (total-FET), the incidence of HDP in the HRT cycle without ovulation (HRT-FET) was observed to be higher than that in the NC cycle with ovulation (NC-FET) (2.8% V.S. 6.1%, P\u0026lt;0.001). In patients with EM, no significant difference was found in the incidence of HDP between fresh ET and NC-FET (1.2% V.S. 4.0%, P\u0026gt;0.05). \u0026nbsp;\u003c/p\u003e\u003cp\u003eConclusion\u003c/p\u003e\u003cp\u003eEM does not seem to have an effect on the occurrence of HDP in assisted reproductive technology. During the FET cycle, the formation of the corpus luteum may play a protective role in the occurrence and development of HDP. Potential damage to the embryo caused by cryopreservation seems to have no effect on the occurrence of HDP.\u0026nbsp;\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Endometriosis Does not Seem to Be an Influencing Factor of Hypertensive Disorders of Pregnancy in IVF / ICSI Cycles","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-12-17 15:44:45","doi":"10.21203/rs.3.rs-1174628/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2022-01-17T23:10:23+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-01-11T13:25:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"912357b9-eca4-4b28-bbdc-e1fe564d9772","date":"2021-12-26T09:14:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-12-26T05:58:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-12-16T11:03:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-12-16T03:54:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Reproductive Biology and Endocrinology","date":"2021-12-15T15:47:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"reproductive-biology-and-endocrinology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rbej","sideBox":"Learn more about [Reproductive Biology and Endocrinology](http://rbej.biomedcentral.com)","snPcode":"12958","submissionUrl":"https://submission.nature.com/new-submission/12958/3","title":"Reproductive Biology and Endocrinology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3835ef14-be10-45dc-b557-3b52a349acfd","owner":[],"postedDate":"December 17th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":9218018,"name":"Endocrinology \u0026 Metabolism"},{"id":9218019,"name":"Sexual \u0026 Reproductive Medicine"}],"tags":[],"updatedAt":"2022-03-28T20:02:01+00:00","versionOfRecord":{"articleIdentity":"rs-1174628","link":"https://doi.org/10.1186/s12958-022-00922-5","journal":{"identity":"reproductive-biology-and-endocrinology","isVorOnly":false,"title":"Reproductive Biology and Endocrinology"},"publishedOn":"2022-03-25 20:02:01","publishedOnDateReadable":"March 25th, 2022"},"versionCreatedAt":"2021-12-17 15:44:45","video":"","vorDoi":"10.1186/s12958-022-00922-5","vorDoiUrl":"https://doi.org/10.1186/s12958-022-00922-5","workflowStages":[]},"version":"v1","identity":"rs-1174628","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1174628","identity":"rs-1174628","version":["v1"]},"buildId":"k6vKHA0u1VdKjwwnw531e","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}