The Appropriate Time Interval Between Hysteroscopic Polypectomy and the Start of FET : A Retrospective Corchort Study

Objective: To investigate when is the appropriate time interval between hysteroscopic polypectomy and the start of FET cycles Design: Retrospective cohort study. Setting: Academic center. Patient(s): All patients diagnosed with endometrial polyps undergoing hysteroscopic polypectomy before FET. Intervention(s): Hysteroscopic polypectomy. MainOutcomeMeasure(s): Patients were divided into four groups based on the time interval between hysteroscopic polypectomy and the start of FET Demographics, baseline FET characteristics, pregnancy outcomes after FET were compared among the groups. A total of 1703 patients met inclusion criteria: 547 patients in group 1 who underwent FET after hysteroscopic polypectomy 1-3menses cycles, 389 patients in group 2 who underwent FET after hysteroscopic polypectomy 4-6 menses cycles, 421 patients in group 3 who underwent FET after hysteroscopic polypectomy 7-12menses cycles, and 373 patients in group 4 who underwent FET after hysteroscopic polypectomy more than 12 menses cycles, whats more the group 1 were divided into 3 groups depend on the time interval between hysteroscopic polypectomy and the start of FET. The FET outcomes were compared. Result(s): There were no differences in the mean number of embryos transferred. The overall pregnancy outcomes were similar for groups 1, 2, 3,and 4: implantation rate (38%, 38.2%, 39.5%and 36.8, respectively), clinical pregnancy rate (51.9%, 48%, 53.2and 50%), spontaneous miscarriage rate (8.4%,8.4%, 12.2and 8.9%), and live birth rate (42.4%. 40.4%, 42.8% and 40.9%). Conclusion(s): IVF outcomes seem to be unrelated to the time interval between the hysteroscopic polyp resection and the initiation of the FET; The abortion rates may be lower if the treatment is started in the rst few months post operatively.


Introduction
Embryo quality and uterine receptivity are the two most important factors for a successful implantation in in vitro fertilization (IVF) cycles. Although localized lesions of the endometrium that are commonly seen in women of reproductive age (1). It is clear that removal of endometrial polyps can help to increase natural conception rates as well as increase pregnancy rates with the use of assisted reproduction (2)(3)(4)(5)(6)(7). But the best appropriate interval between the hysteroscopic polyp resection there are less data regarding the appropriate time interval between polyp resection and start of assisted reproduction treatment (8). In our study , we aimed to compared the FET outcomes of the time interval between hysteroscopic polypectomy and the start of Frozen-embryo transfer (FET) cycles.

Materials And Methods
Inclusion and Exclusion Criteria in The Third A liated Hospital of Zhengzhou university College Institutional Review Board approved the study protocol. All patients diagnosed with endometrial polyps undergoing hysteroscopic polypectomy before FET cycles from January 2016 to December 2019 were analyzed for potential inclusion. Inclusion criteria includede Endometrial polyps were diagnosed by hysteroscopy.
Endometrial polyp was usually suspected by hyperechoic with regular occupied the uterine cavity either partially or fully (7,9).we selected patients who were not older than 43 years during the FET cycles and patients who BMI were less than 30 kg/m2 Exclusion criteria included donor oocyte cycles, PGD/PGS who had systemic health problems or who were using antidiabetic, antihypertensive, or steroid-type medications were not included the study. Cycles and patients with recurrent IVF failure.

Hysteroscopic polypectomy
Hysteroscopic polypectomy was carried out in the follicular phase of the subsequent menstrual cycle by the same physician with bearing an outer diameter of 8 mm The surgery was undertaken using a cutting-loop without the application of diathermy. All visible endometrial polyps were bluntly removed under direct hysteroscopic vision.

Clinical and Laboratory Protocols
For the preparation of patients in the natural cycle group, the follicles were followed up with USG at intervals of 3 to 4 days from the beginning of the cycle. When the dominant follicle was greater than 17 mm, u-hCG 10000 U or r-hCG 250 ug was administered. Progesterone was started 36 hours later, and natural progesterone (Crinone vaginal gel, Merck Serono, Switzerland) was used for 3 days in patients whose embryos were frozen on the third day and for 5 days in patients whose embryos were frozen on the fth day, at 90 mg once a day.
The embryos were transferred on the following day, and progesterone was continued in the women who became pregnant until the 10th to 12th week of pregnancy. The patients in the HRT cycle group were administered transdermal estrogen The patients, whose doses were increased by 1 patch at intervals of 4 days, underwent USG on the 14th day of their cycle. The patients with an endometrial thickness of more than 8 mm started to receive vaginal natural progesterone (Crinone vaginal gel, Merck Serono) in the morning and at night on the following day (day 15).
Following the 3-day progesterone (90 mg twice a day) use in patients whose embryos were frozen on the third day before transfer and 5-day progesterone use for those whose embryos were frozen on the fth day before transfer, the embryos were thawed and transferred on the following day. After the transfer, estrogen and progesterone use was continued for 14 days until the beta-hCG test. Estrogen and progesterone use was continued in women who became pregnant until the 10th-12th week of pregnancy.

Outcome Variables
Demographic characteristics recorded included age, body mass index (BMI; kg/m2). Baseline FET characteristics recorded were FSH (mIU/mL) and E2 (pg/mL) level at cycle start , peak endometrial stripe (mm), mean number of embryos transferred (10). Pregnancy outcomes after FET were also recorded. Implan tation rate was de ned as the mean number of gestational sacs seen with the use of transvaginal ultrasonography divided by the number of embryos transferred for each patient. Clinical pregnancy rate was de ned as the number of intrauterine gestations with fetal cardiac activity per FET cycle. A biochemical pregnancy was de ned as positive hCG level . Any pregnancy loss after visualization of an intrauterine gestation was considered to be a spontaneous miscarriage, and any birth after 24 weeks of gestation was considered to be a live birth.

Statistical Analyses
All statistical analyses were performed with the use of SPSS 23 Continuous variables were checked for normality and expressed as mean±SD. Categoric variables were expressed as n (%). By study design, patients were as signed to four groups based on the time interval between hysteroscopic polypectomy and the start of a FET cycle: Group 1 consisted of patients who underwent FET after their 1-3menses, group 2 after 4-6 menstrual cycles, group 3after 7-12 menstrual cycles group 4 after more than 12menstrual cycles. Analysis of variance and chi-square tests were used to compare means and percentages of recorded parameters among the four groups. Statistical signi cance was set at P<0.05.

Results
A total of 1977 patients underwent hysteroscopies during the study period. The 1703 patients who met inclusion criteria were grouped as follows: 547 in group 1 389 in group 2 421 in group 3and 373 in group 4.Whats more the group 1were divided into 3 groups depend on the time interval between hysteroscopic polypectomy and the start of FET The FET outcomes were compared.

Discussion
Endometrial polyps are localized overgrowths of endometrial glands and stroma within the uterine cavity.In determining uterine receptivity, the endometrium and uterine cavity are two important factors that are most successfully evaluated by hysteroscopy 11, 12 . They are frequently asymptomatic and therefore may remain undetected 13 .
The prevalence of endometrial polyps is considered to be higher in infertile women (1,14).The polyps can be millimeters to centimeters in size, single or multiple, and sessile or pedunculated, ( 15). Some studies suggest that polyps are associated with infertility (15), but only one randomized controlled trial con rms the association. (7). It seems that many of the risk factors for endometrial polyps can be underlied by unopposed or excess estrogen exposure,as in the case of ovarian stimulation during IVF (4,9,10). Molecular mechanisms, containing the over expression of estrogen and progesterone receptors (25), Polyps may adversely affect fertility by mechanically interfering with sperm transportation or as space-occupying lesions impeding embryo implantation (4,5). Endometrial polyps may also induce local in ammatory changes (19,20) or produce glycodelin (21), The glands and stroma in endometrial polyps are unresponsive to progesterone stimulation, leading to defective implantation at the site of the polyp (20,22)With respect to endometrial receptivity, HOXA10 and HOXA11 mRNA expression are decreased in endometrium obtained from uterine cavities containing polyps compared with normal cavities, (15).
In this context, hysteroscopic polypectomy remains the criterion standard for both diagnosis and treatment of endometrial polyps (1,15). Previous studies have shown that resection of endometrial polyps can improve natural conception rates, particularly in patients with unexplained infertility (16). In one retrospective study of 78 patients by Varasteh et al , a pregnancy rate of 78.3% was noted after polypectomy compared with a pregnancy rate of 42.1% in patients with normal uterine cavities (6). Removal of polyps at the uterotubal junction results in the greatest chance of pregnancy (57.4%) based on a retrospective study of polyp location in 230 infertile women [23]. The best evidence for polyps as a cause for infertility comes from a well designed RCT of 215 infertile women with polyps planning to undergo intrauterine insemination (IUI) [24]..Signi cantly higher pregnancy rates were demonstrated in women who had hysteroscopic polypectomy Pregnancy rates are also improved in patients undergoing hysteroscopic polypectomy before undergoing intrauterine insemination (IUI) (9 ,15).Similarly, a previous retrospective study showed that natural conception rates were increased among infertile women who had hysteroscopic polypectomy compared with those who had hysteroscopy, but were found to have a normal cavity (78 versus 42.1%) 25 .These ndings were con rmed by another independent study, which reported pregnancy rates of 40.7% and 22.3% in patients who, respectively, did and did not undergo polypectomy before IUI (2). The resection of endometrial polyps diagnosed before starting IVF-ET cycles are suppored by current evidence. (1). However, there is limited evidence about the optimal time interval between hysteroscopic polypectomy and initiation of a FET cycle. In a retrospective study of 60 patients, Eryilmaz et al. compared the ovarian stimulation and pregnancy outcomes of 29 and 31 patients who got IVF <6 months and 6 months, respectively, after hysteroscopic polypectomy . It is concluded that there is no relation between the IVF outcomes of the study cohort and the initiation time of the IVF after the hysteroscopic polypectomy (8). Whereas our study strati ed the time period between polypectomy and FET cycle start by the number of intervening menstrual cycles. It is suggested by some studies that higher implantation and pregnancy rates after mild endometrial injury in the menstrual cycle preceding IVF (27 ). Group 1 in the present study represents such a clinical scenario, but the implantation and pregnancy rates of group 1 were similar to those of groups 2 3 and4. The present study is not without limitations. All hysteroscopic polypectomy cases were performed in the operating room with the use of a monopolar resectoscope. It remains to be con rmed whether the observed IVF-ET cycle outcomes would remain unchanged if polypectomy were operated in the o ce setting or with other resection methods, such as bipolar electrode excision (29) or hysteroscopic morcellation (30,31). Although our analysis of FETcycle outcomes was strati ed on the basis of the number of menstrual cycles between hysteroscopic polypectomy and FET cycle start, Furthermore, it must be noted that reasons for delaying FET were largely logistical or personal. Finally, its conclusions should be interpreted with caution and should be subject to larger prospective settings, because the study was retrospective in nature.

Conclusion
The data from this study suggest that FET outcomes seem to be unrelated to the time interval between the hysteroscopic polyp resection and the initiation of the FET; The abortion rates may be lower if the treatment is started in the rst few months post operatively. This approach may be especially bene cial in patients who require speci c timing of FET cycles.

Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate
The study was performed in accordance with guidelines outlined in the Declaration of Helsinki. All the methods and information collection protocols were approved by the institutional review board of Zhengzhou University Third Hospital and Henan Province Women and Children's Hospital, China. Our research has obtained the waiver from institutional review board for the medical review for selective variable analysis in the center.

Competing interests
The authors declare no competing interests.  Figure 1 Design routes Figure 1 Design routes