Efficacy of Intrauterine Insemination in Women with Endometrioma-Associated Subfertility: Analysis Using Propensity Score Matching

Efficacy of Intrauterine Insemination in Women with Endometrioma-Associated Subfertility: Analysis Using Propensity Score Matching | 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 Efficacy of Intrauterine Insemination in Women with Endometrioma-Associated Subfertility: Analysis Using Propensity Score Matching Jinlin Xie, He Cai, Juanzi Shi, Hui Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-930037/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background : Intrauterine insemination (IUI) treatment is recommended in subfertile women with AFS/ASRM stage I/II endometriosis. However, the efficacy of IUI in women with ovarian endometriomas with tubal patency is uncertain. We explored the efficacy of IUI for the treatment of endometrioma-associated subfertility. Methods : We performed a retrospective matched cohort study using propensity matching (PSM) analysis. Subfertile couples undergoing IUI with and without ovarian stimulation between January 1, 2015, and May 30, 2020 were reviewed. Results : After PSM, 56 women with endometrioma alone were matched to 173 patients with unexplained subfertility. The per-cycle pregnancy rate (PR) was comparable between women with endometrioma-associated subfertility (n=56, 87 cycles) and women with unexplained subfertility (n=173, 280 cycles) (9.2% vs. 17.9%, OR 0.47; 95% CI, 0.21–1.03). Subgroup analyses based on IUI with or without stimulation also resulted in comparable results. A trend toward a lower cumulative pregnancy rates (CPRs) was seen in women with endometrioma (14.3%, 8/56) compared with women with unexplained subfertility (28.9%, 50/173), but the differences were not significant (OR, 0.54; 95% CI, 0.26-1.15). However, patients with endometrioma were nearly twice as likely to converse to IVF treatment compared with those without the disease (60.7% versus 43.9%; OR, 1.97; 95% CI, 1.07-3.65). Conclusion : IUI may be a viable approach for subfertile women with endometrioma and no other identifiable infertility factor. More studies are needed to reassure the findings. Maternal & Fetal Medicine Intrauterine insemination endometrioma subfertility propensity score matching Figures Figure 1 Background Endometriosis is one of the most common chronic gynecologic disorders and is frequently associated with female subfertility (up to 50% subfertile women with endometriosis) [ 1 – 3 ]. Approximately 190 million women worldwide are currently affected by endometriosis [ 4 ] and 30–50% of women with endometriosis are infertile [ 5 – 7 ]. Assisted reproductive technology (ART) frequently is used as the first-line therapy to endometriosis-associated infertility [ 8 – 10 ]. Guidelines of both the European Society of Human Reproduction and Embryology [ 9 ] and American Society for Reproductive Medicine [ 10 ], state that intrauterine insemination (IUI) treatment is only recommended in subfertile women with minimal-to-mild endometriosis. Werbrouck et al. reported no difference in cycle pregnancy rate between women with surgically treated minimal to mild endometriosis and women with unexplained infertility after controlled ovarian hyperstimulation and IUI program. The cumulative live-birth rate within four cycles of IUI was also comparable in women with minimal endometriosis, mild endometriosis, and unexplained infertility (70.2%, 68.2 %, 66.5%, respectively) [ 11 ]. Ovarian endometriomas are found in 17%-44% of women with endometriosis [ 12 – 14 ]. Although the exact pathophysiology of the reduced fertility is not clear, toxic content from an endometrioma may play a crucial role. Endometrioma is also usually overlap with those a more advanced stage of disease (stages III and IV of endometriosis according to the American Society for Reproductive Medicine (ASRM) classification). A significant number of women with endometrioma will eventually seek ART to achieve a pregnancy, which is more often in those with reduced ovarian reserve or other identifiable infertility factor. However, for subfertile patients with presence of endometrioma alone (i.e.normal ovarian reserve and patency of fallopian tubes), is IUI treatment effective for subfertility associated with endometrioma? The optimal management often poses a clinical debate and little evidence exists to provide robust guidance to clinicians. Considering a sequence of IUI cycles is less aggressive and less expensive than an IVF procedure, should IUI treatment be encouraged as a valuable or viable approach to achieve a natural pregnancy? The aim of the present study was to test the efficacy of IUI treatment on women with endometrioma-associated subfertility, comparing the fertility outcomes (per-cycle-pregnancy rate [PR], and cumulative pregnancy rates [CPRs] after IUI treatment in subfertile women with endometrioma and women with unexplained subfertility by using propensity matching (PSM) analysis. Methods Study design We retrospectively analyzed the IUI with the husband’s sperm cycles performed from January 1, 2015 to May 30, 2020. The data were extracted from the database of infertility center of Northwest Women and Children’s Hospital, Xi’an, China. This study was approved by the institutional research ethics review board (2019013). Patients Before reproductive treatment, all subfertile couples underwent a infertility evaluation, including physical examination, transvaginal ultrasound, cycle day 2-3 serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) assays, hysterosalpingography, semen analyses and associated safety tests. The study group consisted of all consecutive subfertile women with the presence of identified endometrioma and no other identifiable infertility factor. Inclusing criteria were failure to conceive for ≥12 months, female age ≤40 years, ovulation demonstrated by appropriately timed mid-luteal progesterone,bilateral tubal patency (demonstrated by hysterosalpingography or laparoscopy); normal semen variables (according to World Health Organization criteria) [ 15 ]. Patients satisfied the above criteria were included whether or not the they had prior surgical treatment for their endometrioma.The endometrioma was diagnosed either by laparoscopy or a combination of physical examination and transvaginal ultrasound. The control group consisted of couples diagnosed with subfertility who were treated during the same period of time and who met the same inclusion criteria except with no evidence of endometrioma. Women were excluded from the study if they had achieved a clinical pregnancy during the previous IUI treatment. Cases from IVF with controlled ovarian stimulation conversion to IUI due to low ovarian response were also excluded.The study and control groups of patients were matched using PSM analysis. IUI Procedures and semen preparation IUI was performed in natural or stimulated cycles [ 16 ]. Briefly, for natural cycles, the ultrasound and serum hormone tests started on the eighth day of the cycle. When the leading follicle was ≥ 14 mm, patients started the test for urinary LH; For stimulation cycles, ovarian stimulation was conducted by either administering letrozole or hMG (Menotropins for Injection, Livzon pharmaceutical group INC., China) or letrozole plus hMG. Ovarian response was monitored by the follicular growth and serum E 2 levels starting on day 5 of stimulation, and then dose of hMG was adjusted accordingly every 1-3 days. IUI was performed 24 hours after detection of LH in the urine. If the leading follicle measured over 18 mm in diameter in the absence of LH in the urine, 10,000 IU of hCG were administrated and insemination was performed the next day. Semen was prepared on the day of insemination by centrifugation on a density gradientas, as previously described [ 17 ]. All women were treated by the same two physicians (HW and JLX ) with the same IUI procedure.The prepared sperm was gently inserted within 1 cm of the fundal extend of the uterine cavity using a soft catheter. Micronized progesterone (200 mg/day) was used for 15 days after IUI. Outcome Measures A serum β-hCG test was performed approximately 16 days after insemination. A clinical pregnancy was diagnosed 2 weeks after a positive test by the presence of a gestational sac on ultrasound. Live birth was defined as a live-born delivery at least 24 weeks after IUI. The primary outcomes of interest were clinical pregnancy rate (PR) per cycle and cumulative pregnancy rates (CPRs) after IUI treatment. A subanalysis was performed based on IUI protocols: natural or stimulation cycle. Statistical analysis PSM was performed to adjust for confounding factors correlated with pregnancy outcomes. The variables in the PSM included female characteristics (i.e., age, gravidity, parity, body mass index (BMI), duration of infertility, antral follicle count (AFC), serum concentrations of FSH and LH, and male characteristics (age, semen parameters). To optimize the precision of the study, patients with endometrioma were matched to patients with unexplained infertility in a 1:3 matching ratio. The PSM allowed each endometrioma patient undergoing IUI to be matched to a unexplained infertile patient with similar characteristics. PR-per cycle was compared between the two groups (endometrioma-associated subfertility vs. unexplained subfertility). A subanalysis was performed based on IUI protocols: natural or stimulation cycle. As one couple could have more IUI cycles we applied generalized estimating equations (GEE) that took into account this clustering. CPRs were the number of women who achieve a clinical pregnancy after one, two, or three added cycles divided by the number of women who started treatment. Data were expressed as mean ± standard deviation (SD) or n (%). Descriptive data were compared by Student’s T, Mann-Whitney U, Chi-squared or Fishers’ exact tests when appropriate. The number of cycles since first IUI treatment were used as time parameters. The date of entry was the date of the first IUI treatment cycle. Patients were followed up to 1 year after finishing their last IUI treatment. The Kaplan-Meier method was used to estimate the CPRs, and comparisons were made using the log-rank test. Statistical analysis was analyzed using R (v.3.4.3; The R Foundation). P< 0.05 was considered to be significant. Sensitivity analyses were performed on the ovarian endometrioma group versus the unexplained subfertility group with exclusion of patients without surgical diagnosis of endometrioma prior to IUI treatment. Results Patient characteristics Based on inclusion criteria, 58 women with endometrioma and 880 women with unexplained infertility were available for analysis. After PSM, a total of 56 women with endometrioma were successfully matched to 173 women with unexplained infertility. No differences in age (female and male), BMI, duration of infertility, gravity and parity, AFC, basal FSH, LH levels or sperm parameters were found between the two matched groups after matching. Clinical and biological characteristics of patients before and after PSM were shown in Table 1 . For women in the endometrioma group, 22 cases (39.3%) had undergone prior surgery for endometriomas before IUI treatment and the remaining 34 (60.7% ) were diagnosed based on clinical and ultrasound evaluation. Table 1 Patient characteristics before and after propensity score matching (PSM). Before PSM After PSM Endometrioma-associated subfertility (n=58) Unexplained subfertility (n=880) P Endometrioma-associated subfertility (n=56) Unexplained subfertility (n=173) P Maternal age (years) 30.78 (4.02) 30.22 (3.71) 0.272 30.46 (3.72) 30.08 (3.38) 0.466 Paternal age (years) 32.43 (4.67) 31.79 (4.36) 0.283 31.98 (4.10) 31.45 (4.26) 0.409 BMI (kg/m 2 ) 21.86 (2.83) 22.00 (3.21) 0.755 21.85 (2.88) 21.48 (2.77) 0.403 Subfertility time (months) 32.38 (20.26) 33.12 (17.40) 0.756 32.89 (20.40) 32.46 (16.01) 0.833 Primary infertility (%) 40 (69.0) 554 (63.0) 0.358 39 (69.6) 119 (68.8) 0.904 Nulliparity (%) 53 (91.4) 765 (93.5) 0.326 52 (92.9) 158 (91.3) 0.719 AFC (n) 10.00 (4.78) 12.75 (5.58) <0.001 10.21 (4.72) 10.87 (3.79) 0.293 Day-3 FSH (mIU/mL) 7.31 (1.79) 7.04 (1.75) 0.250 7.31 (1.82) 7.32 (1.60) 0.973 Day-3 LH (mIU/mL) 4.39 (1.56) 4.62 (2.29) 0.460 4.40 (1.58) 4.71 (3.26) 0.485 Semen concentration (10 6 /mL) 62.54 (27.01) 62.93 (27.27) 0.916 62.78 (27.36) 62.12 (26.03) 0.872 Semen motility (%) 54.26 (13.77) 57.54 (13.18) 0.067 54.44 (13.93) 54.90 (12.32) 0.815 Normal semen morphology (%) 5.64 (1.66) 5.48 (1.70) 0.493 5.70 (1.66) 5.54 (1.93) 0.594 Treatment outcomes The 56 women from endometrioma group underwent a total of 87 cycles of IUI (range 1-4, a mean of 1.46 attempts per patient), including 45 natural cycles and 42 cycles with stimulation. While the 173 women with unexplained infertility underwent a total of 280 cycles of IUI (range 1-5, a mean of 1.51 attempts per patient), including 152 natural cycles and 128 cycles with stimulation. PR per-cycle The per-cycle clinical PR was lower in women with endometrioma (n=56, 87 cycles) than in the women with unexplained infertility (n=173, 280 cycles), though this was of borderline statistical significance (9.2% vs. 17.9%, OR 0.47; 95% CI, 0.21–1.03, P=0.058). The subgroup analyses based on IUI with or without stimulation also resulted in comparable results (Table 2 ). Table 2 Pregnancy rates in per IUI cycle treatment. Endometrioma- associated subfertility (n=56) Unexplained subfertility (n=173) OR (95% CI) P -value IUI cycles, n 87 280 PR, n (%) 8 (9.2) 50 (17.9) 0.47 (0.21–1.03) 0.058 Subgroups Natural cycles, n 45 152 0.095 PR, n (%) 3 (6.7) 26 (17.1) 0.35 (0.10–1.20) Stimulation cycles, n 42 128 PR, n (%) 5 (11.9) 24 (18.8) 0.59 (0.21–1.65) 0.310 IUI: intrauterine Insemination; PR: Pregnancy rate. The P -value is calculated using GEE taking into account repeated measurements per individual, to correct for the fact that individuals were allowed to participate more than once in this study (see Statistical analysis section). When compared with natural cycles, IUI with stimulation cycles seemed to result in a slightly higher PR per cycle in the group with endometriomas (11.9% vs. 6.7%, P=0.404), though the differences were not significant. No significant difference between the two strategies was observed in the subset of unexplained subfertility (18.8% vs. 17.1%, P=0.720). CPRs In the whole population, the overall CPRs was 15.7% after one IUI cycle, 23.6% after two, 24.9% after three and 25.3% after the final attempt. The specific CPRs at the first IUI cycle in the endometrioma group compared with unexplained infertility group were, respectively, 8.7% versus 18.5%; at the second cycle, 14.3% versus 32.4%; For women with endometrioma-associated subfertility, all pregnancies occurred within the first-two cycles of IUI program. For women with unexplained infertility, three women conceived at the third attempt and one case conceived at the fifth cycle. The CPRs in women with endometrioma-associated subfertility (14.3%, 8/56) were comparable when compared with women with unexplained subfertility (28.9%, 50/173), (OR, 0.54; 95% CI, 0.26-1.15, P=.108) (Fig. 1 ). Women with endometrioma, however, were nearly twice as likely to converse to IVF treatment compared with those without the disease (60.7% versus 43.9%, respectively; OR, 1.97; 95% CI, 1.07–3.65). Amongst those with endometrioma, women who had surgical removal prior to IUI had similar CPRs compared with those women with no surgical treatment (3/22 or 13.6% versus 5/34 or 14.7%). Sensitivity analyses The sensitivity analyses excluding women without surgically confirmed endometrioma (n=34) also resulted in comparable results. The CPRs remained slightly lower in women with cystectomy prior starting IUI treatment (3/22; 13.6%) compared to the unexplained infertility women(50/173; 28.9%), but the difference was not significant. The number of pregnancies in each subgroup or combination, however, was small. Discussion Main findings To our knowledge, this is the first report of a study focusing on the efficacy of IUI program in women with endometrioma-associated subfertility using a PSM technique. Compared with unexplained subfertile women in the matched group, the odds of per-cycle PR in subfertile women with endometriomas were 0.47 (95% CI, 0.21-1.03) and odds of CPRs were 0.54 (95% CI, 0.26-1.15). However, none of the estimations were statistically significant. We found that patients with endometriomas were nearly twice as likely to converse to IVF treatment compared with those without the disease. Subgroup analyses based on with/without prior surgery for endometrioma did not impact the outcomes. Although for women with endometrioma, stimulation cycles seemed to result in a slightly higher PR per cycle than that in natural cycles (11.9% vs. 6.7%, P=0.404), the difference was not significant. Comparison To Other Studies Similar findings have been reported for moderate-to-severe endometriosis. van der Houwen et al. [ 18 ] suggested that IUI was a valuable infertility management in women with more severe endometriosis, namely moderate-to-severe endometriosis. The CPRs of 28% in patients with Stage III and Stage IV endometriosis after six subsequent IUI cycles were reported. In the current study, the CPRs in women with endometrioma were lower than that in women with unexplained infertility (14.3% versus 28.9%; P =0.108), but the difference was not significant. It has been noted that majority couples in the study received no more than 4 cycles of IUI treatment. Although it reflects daily practice, we cannot exclude the possibility that exposure to more cycles of IUI could have led to a significant difference in CPR in both groups. The optimum cycles of IUI attempts has been a pragmatic and challenge question when counseling couples. One previous publishing, concluded that IUI for treatment of unexplained infertility should be limited to a maximum of three cycles [ 19 ]. In the current study, a significant more women with endometrioma resorted to IVF treatment compared with those without the disease. We also found that for women with endometrioma, starting from the third cycle onward, additional attempts have only rarely increased fecundability. Although these could be attributed by chance, the results also suggested that women with subfertility and endometrioma may be reassured by more active and aggressive reproductive technology. we assume this information will be helpful in the counselling process. Some selected patients may be better served by IVF procedure if they fail to conceive after two cycles of IUI. Further data on this issue are needed. It is still debatable whether IUI with stimulation is superior to unstimulated IUI. A pragmatic randomised controlled trial failed to show any advantage of superovulation over unstimulated IUI in couples with unexplained infertility [ 20 ]. While the Cochrane view supported clomifene citrate administration and suggested it had a beneficial effect in unexplained infertility [ 21 ]. In a recent study, an increased cumulative pregnancy rate has been shown in patients receiving IUI with stimulation up to six cycles compared to three times IUI without stimulation followed by up to three times IUI with stimulation, which endorsed the cochrane view [ 18 ]. In our study, when compared to IUI without stimulation, ovarian stimulation seemed to result in a slightly higher PR per cycle in women with subfertility and endometrioma (11.9% vs. 6.7%, P =.404). Differences in the two protocols that are close to statistical significance, increasing the sample size of patients may reveal meaningful role of ovarian stimulation in IUI program. The rationale for ovarian stimulation in women with endometrioma has been to correct potential disorders of endocrine and ovulation, including luteinized unruptured follicle syndrome, abnormal follicular growth, and premature LH surges [ 22 ]. However, ovarian stimulation may cause some concerns among patients. Impact of ovarian stimulation on the progression of endometriosis or its recurrence was recently summarized in a systematic review [ 23 ]. According to their report, impact of ovarian stimulation on ovarian endometrioma, if present, is clinically unremarkable. In the present study with multiple simulated IUI cycles, no bleeding, infection and other related complications was reported. All these results can be used to reassure patients. Strengths And Limitations One of the major strengths of this study was the use of PSM analysis to achieve matched groups. Evaluating and comparing treatment strategies for subfertile women with endometrioma alone is limited by heterogeneous practices between clinicians and centers. We specifically focused on this point by matching multiple clinical covariates in patients performing IUI. Secondly, at the present study, we compared the effectiveness of IUI on women with endometrioma alone versus women with unexplained subfertility. The assessment was specifically confined to the impact of ovarian endometrioma alone. Definition of the “true” unexplained infertility is still controversial. Some women in the unexplained subfertility group might have undetected minimal or mild endometriosis. However, that inclusion of the control group means that our results reflect the true contributory effect of the endometrioma alone with. This study had some limitations deserve to be underlined. The relatively small sample size of the present study, may be underpowered to detect a significant difference in reproductive outcomes. Hence the results should be interpreted with caution. Our choice of clinical protocols for the management of subfertile women with endometrioma reflects current practice in our center and the rest of the China, but the results might not be generalizable to other populations and alternative national funding strategy. The inclusion of women with endometrioma could be diagnosed by laparoscopy or imaging detection might have introduced an factor of heterogeneity. Not reliably imaging peritoneal implants of endometriosis, however, transvaginal ultrasound have shown to have good accuracy for ovarian endometioma (95.1%~96% specificity and 93~94.7% sensitivity) [ 24 , 25 ], which is also recommended by ARSM [ 10 ]. There were few pregnancies within each subgroup (endometrioma diagnosed with/without prior surgery), sensitivity analyses indicate similar IUI treatment effects. We did not find any RCTs comparing reproductive outcomes after endometrioma cystectomy versus no treatment in women with endometrioma and addressing if IUI procedure is more successful post cystectomy compared to untreated. Future research should focus on more uniform control group and addressing the issues. Conclusion The choice of the best treatment for endometrioma-assocaited subfertility remains a challenge. In the current study, IUI treatment may be a viable option to achieve spontaneous pregnancy for endometrioma subfertility. These findings must be confirmed by further studies. Individualized treatment based on the patient's age, clinical condition, costs and insurances is is highlighted. Abbreviations AFC Antral follicle count ART Assisted reproductive technology ASRM American Society for Reproductive Medicine CPR Cumulative pregnancy rates FSH Follicle-stimulating hormone GEE Generalized estimating equations (GEE) IUI Intrauterine insemination LH luteinizing hormone PSM Propensity score matching PR Pregnancy rate. Declarations Acknowledgement The authors thank Professor Stephan Gordts for help with linguistic modification. We are very grateful to our volunteer patients for taking part in our research. Without the efforts, this research would not have been possible. Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Availability of data and material Data available on request corresponding author due to privacy and ethical restrictions. Author contributions HC and JZS participated on the design of the study. HW and JLX collected the data. HC conducted the statistical analyses and drafted the initial version of the manuscript. JZS provided important guidance throughout the study process and the manuscript preparation. All authors contributed in the interpretation of the data, revised the manuscript and approved the final article. Ethics approval and consent to participate All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. This study was approved by the Ethics Review Board of the Northwest Women’s and Children’s Hospital, Xi’an, China (2019013). Consent for publication Not applicable since there are no details, images, or videos relating to an individual person. Conflict of interest The authors declare that there is no conflict of interest. References Eisenberg, V.H., Weil, C., Chodick, G., Shalev, V. Epidemiology of endometriosis: a large population-based database study from a healthcare provider with 2 million members. BJOG,2018; 125: 55–62. Somigliana E, Vigano P, Benaglia L, Busnelli A, Berlanda N, Vercellini P. Management of Endometriosis in the Infertile Patient. Semin Reprod Med. 2017;35(1):31–37. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020;382: 1244–1256. Hamdan M, Dunselman G, Li TC, Cheong Y. The impact of endometrioma on IVF/ICSI outcomes: a systematic review and meta-analysis. Hum Reprod Update. 2015 21(6):809–825. Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D'Hooghe T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril 2009;92: 68–74. Redwine DB. Ovarian endometriosis: a marker for more extensive pelvic and intestinal disease. Fertil Steril. 1999;72(2):310–315. Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Marshall LM,Hunter DJ. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol 2004;160:784–796. Kennedy S, Bergqvist A, Chapron C, D'Hooghe T, Dunselman G, Greb R et al.; ESHRE Special Interest Group for Endometriosis and Endometrium Guideline Development Group. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20(10):2698–2704 Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D'Hooghe T, De Bie B et al; European Society of Human Reproduction and Embryology. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400–412. Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fertil Steril. 2012;98(3):591–598. Werbrouck E, Spiessens C, Meuleman C, D'Hooghe T. No difference in cycle pregnancy rate and in cumulative live-birth rate between women with surgically treated minimal to mild endometriosis and women with unexplained infertility after controlled ovarian hyperstimulation and intrauterine insemination. Fertil Steril. 2006;86(3):566–571. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–1799. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279. Alborzi S, Zahiri Sorouri Z, Askari E, Poordast T, Chamanara K. The success of various endometrioma treatments in infertility: A systematic review and meta-analysis of prospective studies. Reprod Med Biol. 2019;19;18(4):312–322. World Health Organization. WHO laboratory manual for the examination and processing of human semen; Switzerland: World Health Organization; 2010. p. 1–286. Mu X, Wang H, Liu PJ, Shi JZ. The interval between insemination and ovulation predicts outcome after intrauterine insemination with donor sperm (IUI-D). Int J Gynaecol Obstet. 2021 Feb 6. Cai H, Gordts S, Sun J, Meng B, Shi J. Reproductive outcomes with donor sperm in couples with severe male-factor infertility after intracytoplasmic sperm injection failures. J Assist Reprod Genet. 2020;37(8):1883–1893. van der Houwen LE, Schreurs AM, Schats R, Heymans MW, Lambalk CB, Hompes PG, Mijatovic V. Efficacy and safety of intrauterine insemination in patients with moderate-to-severe endometriosis. Reprod Biomed Online. 2014;28(5):590–598. Aboulghar M, Mansour R, Serour G, Abdrazek A, Amin Y, Rhodes C. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of unexplained infertility should be limited to a maximum of three trials. Fertil Steril. 2001;75(1):88–91. Bhattacharya S, Harrild K, Mollison J, Wordsworth S, Tay C, Harrold A, McQueen D, Lyall H, Johnston L, Burrage J, Grossett S, Walton H, Lynch J, Johnstone A, Kini S, Raja A, Templeton A. Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: pragmatic randomised controlled trial. BMJ. 2008,7;337:a716. Hughes E, Collins J, Vanderkerckhove P. Clomiphene citrate for infertility in women. Cochrane Database Syst Rev 2000;(2):CD 000057. Schenken RS, Asch RH, Williams RF, Hodgen GD. Etiology of infertility in monkeys with endometriosis: luteinized unruptured follicles, luteal phase defects, pelvic adhesions, and spontaneous abortions. Fertil Steril 1984; 41:122–130. Somigliana E, Viganò P, Benaglia L, Busnelli A, Paffoni A, Vercellini P. Ovarian stimulation and endometriosis progression or recurrence: a systematic review. Reprod Biomed Online. 2019;38(2):185–194. Nisenblat V, Bossuyt PMM, Farquhar C, Johnson N, Hull ML. Imaging modalities for the non-invasive diagnosis of endometriosis. Cochrane Database of Systematic Reviews 2016. Goncalves MO, Siufi Neto J, Andres MP, Siufi D, de Mattos LA, Abrao MS. Systematic evaluation of endometriosis by transvaginal ultrasound can accurately replace diagnostic laparoscopy, mainly for deep and ovarian endometriosis. Hum Reprod. 2021 17;36(6):1492–1500. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 16 Nov, 2021 Reviews received at journal 14 Nov, 2021 Reviewers agreed at journal 09 Nov, 2021 Reviews received at journal 19 Oct, 2021 Reviewers agreed at journal 06 Oct, 2021 Reviewers invited by journal 06 Oct, 2021 Editor assigned by journal 06 Oct, 2021 Editor invited by journal 05 Oct, 2021 Submission checks completed at journal 05 Oct, 2021 First submitted to journal 23 Sep, 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-930037","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":55575832,"identity":"40797aed-60cc-4cc2-9e54-d73e976c0198","order_by":0,"name":"Jinlin Xie","email":"","orcid":"","institution":"Northwest Women’s and Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jinlin","middleName":"","lastName":"Xie","suffix":""},{"id":55575833,"identity":"e211e7b8-d2d1-4efe-9a6f-fdbdf4adafe7","order_by":1,"name":"He Cai","email":"","orcid":"","institution":"Northwest Women’s and Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"He","middleName":"","lastName":"Cai","suffix":""},{"id":55575834,"identity":"326b5d71-6c30-4957-a960-570951526a88","order_by":2,"name":"Juanzi Shi","email":"","orcid":"","institution":"Northwest Women’s and Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Juanzi","middleName":"","lastName":"Shi","suffix":""},{"id":55575835,"identity":"963fc3e8-e560-45cb-a3a3-a37b7af29c2f","order_by":3,"name":"Hui Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYJACZgYGCRB14MCHCpK0sLElHpxxhngtQMDGY3yYt4UI5QbHzx5+XdhmIW8+v+fDAd4GBnl+sQMEtJzJS7Oe2SZhOOcY74YDkjsYDGfOTsCvxexAjpkxb5sE4ww2oBbDMwwJBrcJaTn/BqzFfgYbz4MDiW3EaLmRY/wYqCURqIXhwEFitNjfeGPGzHNOInkGW5rBwYYzEoT9ItmfY/yZp6zOdgbz4cef/1TYyPNLE9ACBGwSSBwJnMqQAfMHopSNglEwCkbByAUAb8hEKR5XFtUAAAAASUVORK5CYII=","orcid":"","institution":"Northwest Women’s and Children’s Hospital","correspondingAuthor":true,"prefix":"","firstName":"Hui","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2021-09-23 12:29:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-930037/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-930037/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":14799858,"identity":"2616d929-b2a1-4a2b-93d0-8d6f07350438","added_by":"auto","created_at":"2021-10-22 14:37:31","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":28132,"visible":true,"origin":"","legend":"Kaplan–Meier curves of cumulative pregnancy rates after IUI treatment in subfertile women of the two groups (P=.108). ","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-930037/v1/b0e2de2cb536c84cb4ee0c65.jpg"},{"id":14799862,"identity":"e54b17c7-fdd6-4ca7-8593-2d629ea05eba","added_by":"auto","created_at":"2021-10-22 14:37:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":357858,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-930037/v1/ec74fa08-060e-4c01-a816-17451badef50.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eEfficacy of Intrauterine Insemination in Women with Endometrioma-Associated Subfertility: Analysis Using Propensity Score Matching\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eEndometriosis is one of the most common chronic gynecologic disorders and is frequently associated with female subfertility (up to 50% subfertile women with endometriosis) [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Approximately 190 million women worldwide are currently affected by endometriosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] and 30\u0026ndash;50% of women with endometriosis are infertile [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Assisted reproductive technology (ART) frequently is used as the first-line therapy to endometriosis-associated infertility [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Guidelines of both the European Society of Human Reproduction and Embryology [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and American Society for Reproductive Medicine [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], state that intrauterine insemination (IUI) treatment is only recommended in subfertile women with minimal-to-mild endometriosis. Werbrouck et al. reported no difference in cycle pregnancy rate between women with surgically treated minimal to mild endometriosis and women with unexplained infertility after controlled ovarian hyperstimulation and IUI program. The cumulative live-birth rate within four cycles of IUI was also comparable in women with minimal endometriosis, mild endometriosis, and unexplained infertility (70.2%, 68.2 %, 66.5%, respectively) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOvarian endometriomas are found in 17%-44% of women with endometriosis [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Although the exact pathophysiology of the reduced fertility is not clear, toxic content from an endometrioma may play a crucial role. Endometrioma is also usually overlap with those a more advanced stage of disease (stages III and IV of endometriosis according to the American Society for Reproductive Medicine (ASRM) classification).\u003c/p\u003e \u003cp\u003eA significant number of women with endometrioma will eventually seek ART to achieve a pregnancy, which is more often in those with reduced ovarian reserve or other identifiable infertility factor. However, for subfertile patients with presence of endometrioma alone (i.e.normal ovarian reserve and patency of fallopian tubes), is IUI treatment effective for subfertility associated with endometrioma? The optimal management often poses a clinical debate and little evidence exists to provide robust guidance to clinicians.\u003c/p\u003e \u003cp\u003eConsidering a sequence of IUI cycles is less aggressive and less expensive than an IVF procedure, should IUI treatment be encouraged as a valuable or viable approach to achieve a natural pregnancy? The aim of the present study was to test the efficacy of IUI treatment on women with endometrioma-associated subfertility, comparing the fertility outcomes (per-cycle-pregnancy rate [PR], and cumulative pregnancy rates [CPRs] after IUI treatment in subfertile women with endometrioma and women with unexplained subfertility by using propensity matching (PSM) analysis.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed the IUI with the husband\u0026rsquo;s sperm cycles performed from January 1, 2015 to May 30, 2020. The data were extracted from the database of infertility center of Northwest Women and Children\u0026rsquo;s Hospital, Xi\u0026rsquo;an, China. This study was approved by the institutional research ethics review board (2019013).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eBefore reproductive treatment, all subfertile couples underwent a infertility evaluation, including physical examination, transvaginal ultrasound, cycle day 2-3 serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) assays, hysterosalpingography, semen analyses and associated safety tests.\u003c/p\u003e \u003cp\u003eThe study group consisted of all consecutive subfertile women with the presence of identified endometrioma and no other identifiable infertility factor. Inclusing criteria were failure to conceive for \u0026ge;12 months, female age \u0026le;40 years, ovulation demonstrated by appropriately timed mid-luteal progesterone,bilateral tubal patency (demonstrated by hysterosalpingography or laparoscopy); normal semen variables (according to World Health Organization criteria) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Patients satisfied the above criteria were included whether or not the they had prior surgical treatment for their endometrioma.The endometrioma was diagnosed either by laparoscopy or a combination of physical examination and transvaginal ultrasound.\u003c/p\u003e \u003cp\u003eThe control group consisted of couples diagnosed with subfertility who were treated during the same period of time and who met the same inclusion criteria except with no evidence of endometrioma. Women were excluded from the study if they had achieved a clinical pregnancy during the previous IUI treatment. Cases from IVF with controlled ovarian stimulation conversion to IUI due to low ovarian response were also excluded.The study and control groups of patients were matched using PSM analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eIUI Procedures and semen preparation\u003c/h2\u003e \u003cp\u003eIUI was performed in natural or stimulated cycles [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Briefly, for natural cycles, the ultrasound and serum hormone tests started on the eighth day of the cycle. When the leading follicle was \u0026ge; 14 mm, patients started the test for urinary LH; For stimulation cycles, ovarian stimulation was conducted by either administering letrozole or hMG (Menotropins for Injection, Livzon pharmaceutical group INC., China) or letrozole plus hMG. Ovarian response was monitored by the follicular growth and serum E\u003csub\u003e2\u003c/sub\u003e levels starting on day 5 of stimulation, and then dose of hMG was adjusted accordingly every 1-3 days. IUI was performed 24 hours after detection of LH in the urine. If the leading follicle measured over 18 mm in diameter in the absence of LH in the urine, 10,000 IU of hCG were administrated and insemination was performed the next day.\u003c/p\u003e \u003cp\u003eSemen was prepared on the day of insemination by centrifugation on a density gradientas, as previously described [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. All women were treated by the same two physicians (HW and JLX ) with the same IUI procedure.The prepared sperm was gently inserted within 1 cm of the fundal extend of the uterine cavity using a soft catheter. Micronized progesterone (200 mg/day) was used for 15 days after IUI.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eOutcome Measures\u003c/h2\u003e \u003cp\u003eA serum β-hCG test was performed approximately 16 days after insemination. A clinical pregnancy was diagnosed 2 weeks after a positive test by the presence of a gestational sac on ultrasound. Live birth was defined as a live-born delivery at least 24 weeks after IUI. The primary outcomes of interest were clinical pregnancy rate (PR) per cycle and cumulative pregnancy rates (CPRs) after IUI treatment. A subanalysis was performed based on IUI protocols: natural or stimulation cycle.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003ePSM was performed to adjust for confounding factors correlated with pregnancy outcomes. The variables in the PSM included female characteristics (i.e., age, gravidity, parity, body mass index (BMI), duration of infertility, antral follicle count (AFC), serum concentrations of FSH and LH, and male characteristics (age, semen parameters). To optimize the precision of the study, patients with endometrioma were matched to patients with unexplained infertility in a 1:3 matching ratio. The PSM allowed each endometrioma patient undergoing IUI to be matched to a unexplained infertile patient with similar characteristics.\u003c/p\u003e \u003cp\u003ePR-per cycle was compared between the two groups (endometrioma-associated subfertility vs. unexplained subfertility). A subanalysis was performed based on IUI protocols: natural or stimulation cycle. As one couple could have more IUI cycles we applied generalized estimating equations (GEE) that took into account this clustering. CPRs were the number of women who achieve a clinical pregnancy after one, two, or three added cycles divided by the number of women who started treatment.\u003c/p\u003e \u003cp\u003eData were expressed as mean \u0026plusmn; standard deviation (SD) or n (%). Descriptive data were compared by Student\u0026rsquo;s T, Mann-Whitney U, Chi-squared or Fishers\u0026rsquo; exact tests when appropriate. The number of cycles since first IUI treatment were used as time parameters. The date of entry was the date of the first IUI treatment cycle. Patients were followed up to 1 year after finishing their last IUI treatment. The Kaplan-Meier method was used to estimate the CPRs, and comparisons were made using the log-rank test. Statistical analysis was analyzed using R (v.3.4.3; The R Foundation). P\u0026lt; 0.05 was considered to be significant.\u003c/p\u003e \u003cp\u003eSensitivity analyses were performed on the ovarian endometrioma group versus the unexplained subfertility group with exclusion of patients without surgical diagnosis of endometrioma prior to IUI treatment.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eBased on inclusion criteria, 58 women with endometrioma and 880 women with unexplained infertility were available for analysis. After PSM, a total of 56 women with endometrioma were successfully matched to 173 women with unexplained infertility. No differences in age (female and male), BMI, duration of infertility, gravity and parity, AFC, basal FSH, LH levels or sperm parameters were found between the two matched groups after matching. Clinical and biological characteristics of patients before and after PSM were shown in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. For women in the endometrioma group, 22 cases (39.3%) had undergone prior surgery for endometriomas before IUI treatment and the remaining 34 (60.7% ) were diagnosed based on clinical and ultrasound evaluation.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics before and after propensity score matching (PSM).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eBefore PSM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eAfter PSM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndometrioma-associated subfertility\u003c/p\u003e \u003cp\u003e(n=58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUnexplained subfertility\u003c/p\u003e \u003cp\u003e(n=880)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEndometrioma-associated subfertility\u003c/p\u003e \u003cp\u003e(n=56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUnexplained subfertility (n=173)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal age (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.78 (4.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.22 (3.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.272\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30.46 (3.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30.08 (3.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.466\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePaternal age (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.43 (4.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.79 (4.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.283\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.98 (4.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e31.45 (4.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.409\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.86 (2.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.00 (3.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.755\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21.85 (2.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21.48 (2.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.403\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubfertility time (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.38 (20.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.12 (17.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.756\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32.89 (20.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32.46 (16.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.833\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary infertility (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (69.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e554 (63.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.358\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39 (69.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e119 (68.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.904\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNulliparity (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (91.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e765 (93.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.326\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e52 (92.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e158 (91.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.719\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFC (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.00 (4.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.75 (5.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.21 (4.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10.87 (3.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.293\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay-3 FSH (mIU/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.31 (1.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.04 (1.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.31 (1.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7.32 (1.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.973\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay-3 LH (mIU/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.39 (1.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.62 (2.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.460\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.40 (1.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.71 (3.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.485\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSemen concentration (10\u003csup\u003e6\u003c/sup\u003e/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.54 (27.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.93 (27.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.916\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.78 (27.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e62.12 (26.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.872\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSemen motility (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54.26 (13.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57.54 (13.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e54.44 (13.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e54.90 (12.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.815\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNormal semen morphology (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.64 (1.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.48 (1.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.493\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.70 (1.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.54 (1.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.594\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eTreatment outcomes\u003c/h2\u003e \u003cp\u003eThe 56 women from endometrioma group underwent a total of 87 cycles of IUI (range 1-4, a mean of 1.46 attempts per patient), including 45 natural cycles and 42 cycles with stimulation. While the 173 women with unexplained infertility underwent a total of 280 cycles of IUI (range 1-5, a mean of 1.51 attempts per patient), including 152 natural cycles and 128 cycles with stimulation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePR per-cycle\u003c/h2\u003e \u003cp\u003eThe per-cycle clinical PR was lower in women with endometrioma (n=56, 87 cycles) than in the women with unexplained infertility (n=173, 280 cycles), though this was of borderline statistical significance (9.2% vs. 17.9%, OR 0.47; 95% CI, 0.21\u0026ndash;1.03, P=0.058). The subgroup analyses based on IUI with or without stimulation also resulted in comparable results (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePregnancy rates in per IUI cycle treatment.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndometrioma-\u003c/p\u003e \u003cp\u003eassociated subfertility\u003c/p\u003e \u003cp\u003e(n=56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUnexplained subfertility\u003c/p\u003e \u003cp\u003e(n=173)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIUI cycles, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e280\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (17.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.47 (0.21\u0026ndash;1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubgroups\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNatural cycles, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.095\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.35 (0.10\u0026ndash;1.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStimulation cycles, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (11.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.59 (0.21\u0026ndash;1.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.310\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eIUI: intrauterine Insemination; PR: Pregnancy rate.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eThe \u003cem\u003eP\u003c/em\u003e-value is calculated using GEE taking into account repeated measurements per individual, to correct for the fact that individuals were allowed to participate more than once in this study (see \u003cspan refid=\"Sec7\" class=\"InternalRef\"\u003eStatistical analysis\u003c/span\u003e section).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWhen compared with natural cycles, IUI with stimulation cycles seemed to result in a slightly higher PR per cycle in the group with endometriomas (11.9% vs. 6.7%, P=0.404), though the differences were not significant. No significant difference between the two strategies was observed in the subset of unexplained subfertility (18.8% vs. 17.1%, P=0.720).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCPRs\u003c/h2\u003e \u003cp\u003eIn the whole population, the overall CPRs was 15.7% after one IUI cycle, 23.6% after two, 24.9% after three and 25.3% after the final attempt. The specific CPRs at the first IUI cycle in the endometrioma group compared with unexplained infertility group were, respectively, 8.7% versus 18.5%; at the second cycle, 14.3% versus 32.4%; For women with endometrioma-associated subfertility, all pregnancies occurred within the first-two cycles of IUI program. For women with unexplained infertility, three women conceived at the third attempt and one case conceived at the fifth cycle.\u003c/p\u003e \u003cp\u003eThe CPRs in women with endometrioma-associated subfertility (14.3%, 8/56) were comparable when compared with women with unexplained subfertility (28.9%, 50/173), (OR, 0.54; 95% CI, 0.26-1.15, P=.108) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Women with endometrioma, however, were nearly twice as likely to converse to IVF treatment compared with those without the disease (60.7% versus 43.9%, respectively; OR, 1.97; 95% CI, 1.07\u0026ndash;3.65). Amongst those with endometrioma, women who had surgical removal prior to IUI had similar CPRs compared with those women with no surgical treatment (3/22 or 13.6% versus 5/34 or 14.7%).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analyses\u003c/h2\u003e \u003cp\u003eThe sensitivity analyses excluding women without surgically confirmed endometrioma (n=34) also resulted in comparable results. The CPRs remained slightly lower in women with cystectomy prior starting IUI treatment (3/22; 13.6%) compared to the unexplained infertility women(50/173; 28.9%), but the difference was not significant. The number of pregnancies in each subgroup or combination, however, was small.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eMain findings\u003c/h2\u003e \u003cp\u003eTo our knowledge, this is the first report of a study focusing on the efficacy of IUI program in women with endometrioma-associated subfertility using a PSM technique. Compared with unexplained subfertile women in the matched group, the odds of per-cycle PR in subfertile women with endometriomas were 0.47 (95% CI, 0.21-1.03) and odds of CPRs were 0.54 (95% CI, 0.26-1.15). However, none of the estimations were statistically significant. We found that patients with endometriomas were nearly twice as likely to converse to IVF treatment compared with those without the disease. Subgroup analyses based on with/without prior surgery for endometrioma did not impact the outcomes. Although for women with endometrioma, stimulation cycles seemed to result in a slightly higher PR per cycle than that in natural cycles (11.9% vs. 6.7%, P=0.404), the difference was not significant.\u003c/p\u003e \u003c/div\u003e\n\u003ch2\u003eComparison To Other Studies\u003c/h2\u003e\n\u003cp\u003eSimilar findings have been reported for moderate-to-severe endometriosis. van der Houwen et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] suggested that IUI was a valuable infertility management in women with more severe endometriosis, namely moderate-to-severe endometriosis. The CPRs of 28% in patients with Stage III and Stage IV endometriosis after six subsequent IUI cycles were reported. In the current study, the CPRs in women with endometrioma were lower than that in women with unexplained infertility (14.3% versus 28.9%; \u003cem\u003eP\u003c/em\u003e=0.108), but the difference was not significant. It has been noted that majority couples in the study received no more than 4 cycles of IUI treatment. Although it reflects daily practice, we cannot exclude the possibility that exposure to more cycles of IUI could have led to a significant difference in CPR in both groups.\u003c/p\u003e \u003cp\u003eThe optimum cycles of IUI attempts has been a pragmatic and challenge question when counseling couples. One previous publishing, concluded that IUI for treatment of unexplained infertility should be limited to a maximum of three cycles [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In the current study, a significant more women with endometrioma resorted to IVF treatment compared with those without the disease. We also found that for women with endometrioma, starting from the third cycle onward, additional attempts have only rarely increased fecundability. Although these could be attributed by chance, the results also suggested that women with subfertility and endometrioma may be reassured by more active and aggressive reproductive technology. we assume this information will be helpful in the counselling process. Some selected patients may be better served by IVF procedure if they fail to conceive after two cycles of IUI. Further data on this issue are needed.\u003c/p\u003e \u003cp\u003eIt is still debatable whether IUI with stimulation is superior to unstimulated IUI. A pragmatic randomised controlled trial failed to show any advantage of superovulation over unstimulated IUI in couples with unexplained infertility [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. While the Cochrane view supported clomifene citrate administration and suggested it had a beneficial effect in unexplained infertility [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In a recent study, an increased cumulative pregnancy rate has been shown in patients receiving IUI with stimulation up to six cycles compared to three times IUI without stimulation followed by up to three times IUI with stimulation, which endorsed the cochrane view [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In our study, when compared to IUI without stimulation, ovarian stimulation seemed to result in a slightly higher PR per cycle in women with subfertility and endometrioma (11.9% vs. 6.7%, \u003cem\u003eP\u003c/em\u003e=.404). Differences in the two protocols that are close to statistical significance, increasing the sample size of patients may reveal meaningful role of ovarian stimulation in IUI program. The rationale for ovarian stimulation in women with endometrioma has been to correct potential disorders of endocrine and ovulation, including luteinized unruptured follicle syndrome, abnormal follicular growth, and premature LH surges [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, ovarian stimulation may cause some concerns among patients. Impact of ovarian stimulation on the progression of endometriosis or its recurrence was recently summarized in a systematic review [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. According to their report, impact of ovarian stimulation on ovarian endometrioma, if present, is clinically unremarkable. In the present study with multiple simulated IUI cycles, no bleeding, infection and other related complications was reported. All these results can be used to reassure patients.\u003c/p\u003e\n\u003ch2\u003eStrengths And Limitations\u003c/h2\u003e\n\u003cp\u003eOne of the major strengths of this study was the use of PSM analysis to achieve matched groups. Evaluating and comparing treatment strategies for subfertile women with endometrioma alone is limited by heterogeneous practices between clinicians and centers. We specifically focused on this point by matching multiple clinical covariates in patients performing IUI. Secondly, at the present study, we compared the effectiveness of IUI on women with endometrioma alone versus women with unexplained subfertility. The assessment was specifically confined to the impact of ovarian endometrioma alone. Definition of the \u0026ldquo;true\u0026rdquo; unexplained infertility is still controversial. Some women in the unexplained subfertility group might have undetected minimal or mild endometriosis. However, that inclusion of the control group means that our results reflect the true contributory effect of the endometrioma alone with.\u003c/p\u003e \u003cp\u003eThis study had some limitations deserve to be underlined. The relatively small sample size of the present study, may be underpowered to detect a significant difference in reproductive outcomes. Hence the results should be interpreted with caution. Our choice of clinical protocols for the management of subfertile women with endometrioma reflects current practice in our center and the rest of the China, but the results might not be generalizable to other populations and alternative national funding strategy. The inclusion of women with endometrioma could be diagnosed by laparoscopy or imaging detection might have introduced an factor of heterogeneity. Not reliably imaging peritoneal implants of endometriosis, however, transvaginal ultrasound have shown to have good accuracy for ovarian endometioma (95.1%~96% specificity and 93~94.7% sensitivity) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], which is also recommended by ARSM [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. There were few pregnancies within each subgroup (endometrioma diagnosed with/without prior surgery), sensitivity analyses indicate similar IUI treatment effects. We did not find any RCTs comparing reproductive outcomes after endometrioma cystectomy versus no treatment in women with endometrioma and addressing if IUI procedure is more successful post cystectomy compared to untreated. Future research should focus on more uniform control group and addressing the issues.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe choice of the best treatment for endometrioma-assocaited subfertility remains a challenge. In the current study, IUI treatment may be a viable option to achieve spontaneous pregnancy for endometrioma subfertility. These findings must be confirmed by further studies. Individualized treatment based on the patient's age, clinical condition, costs and insurances is is highlighted.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAFC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAntral follicle count\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eART\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAssisted reproductive technology\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eASRM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican Society for Reproductive Medicine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCPR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCumulative pregnancy rates\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFSH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFollicle-stimulating hormone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGEE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGeneralized estimating equations (GEE)\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIUI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntrauterine insemination\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eluteinizing hormone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePSM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePropensity score matching\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePregnancy rate.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Professor Stephan Gordts for help with linguistic modification. We are very grateful to our volunteer patients for taking part in our research. Without the efforts, this research would not have been possible.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData available on request corresponding author due to privacy and ethical restrictions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHC and JZS participated on the design of the study. HW and JLX collected the data. HC conducted the statistical analyses and drafted the initial version of the manuscript. JZS provided important guidance throughout the study process and the manuscript preparation. All authors contributed in the interpretation of the data, revised the manuscript and approved the final article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. This study was approved by the Ethics Review Board of the Northwest Women\u0026rsquo;s and Children\u0026rsquo;s Hospital, Xi\u0026rsquo;an, China (2019013).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable since there are no details, images, or videos relating to an individual person.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there is no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEisenberg, V.H., Weil, C., Chodick, G., Shalev, V. Epidemiology of endometriosis: a large population-based database study from a healthcare provider with 2 million members. BJOG,2018; 125: 55\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSomigliana E, Vigano P, Benaglia L, Busnelli A, Berlanda N, Vercellini P. Management of Endometriosis in the Infertile Patient. Semin Reprod Med. 2017;35(1):31\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020;382: 1244\u0026ndash;1256.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHamdan M, Dunselman G, Li TC, Cheong Y. The impact of endometrioma on IVF/ICSI outcomes: a systematic review and meta-analysis. Hum Reprod Update. 2015 21(6):809\u0026ndash;825.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D'Hooghe T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril 2009;92: 68\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRedwine DB. Ovarian endometriosis: a marker for more extensive pelvic and intestinal disease. Fertil Steril. 1999;72(2):310\u0026ndash;315.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMissmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Marshall LM,Hunter DJ. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol 2004;160:784\u0026ndash;796.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKennedy S, Bergqvist A, Chapron C, D'Hooghe T, Dunselman G, Greb R et al.; ESHRE Special Interest Group for Endometriosis and Endometrium Guideline Development Group. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20(10):2698\u0026ndash;2704\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D'Hooghe T, De Bie B et al; European Society of Human Reproduction and Embryology. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400\u0026ndash;412.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePractice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fertil Steril. 2012;98(3):591\u0026ndash;598.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWerbrouck E, Spiessens C, Meuleman C, D'Hooghe T. No difference in cycle pregnancy rate and in cumulative live-birth rate between women with surgically treated minimal to mild endometriosis and women with unexplained infertility after controlled ovarian hyperstimulation and intrauterine insemination. Fertil Steril. 2006;86(3):566\u0026ndash;571.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789\u0026ndash;1799.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBulun SE. Endometriosis. N Engl J Med. 2009;360(3):268\u0026ndash;279.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlborzi S, Zahiri Sorouri Z, Askari E, Poordast T, Chamanara K. The success of various endometrioma treatments in infertility: A systematic review and meta-analysis of prospective studies. Reprod Med Biol. 2019;19;18(4):312\u0026ndash;322.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization. WHO laboratory manual for the examination and processing of human semen; Switzerland: World Health Organization; 2010. p.\u0026nbsp;1\u0026ndash;286.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMu X, Wang H, Liu PJ, Shi JZ. The interval between insemination and ovulation predicts outcome after intrauterine insemination with donor sperm (IUI-D). Int J Gynaecol Obstet. 2021 Feb 6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCai H, Gordts S, Sun J, Meng B, Shi J. Reproductive outcomes with donor sperm in couples with severe male-factor infertility after intracytoplasmic sperm injection failures. J Assist Reprod Genet. 2020;37(8):1883\u0026ndash;1893.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan der Houwen LE, Schreurs AM, Schats R, Heymans MW, Lambalk CB, Hompes PG, Mijatovic V. Efficacy and safety of intrauterine insemination in patients with moderate-to-severe endometriosis. Reprod Biomed Online. 2014;28(5):590\u0026ndash;598.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAboulghar M, Mansour R, Serour G, Abdrazek A, Amin Y, Rhodes C. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of unexplained infertility should be limited to a maximum of three trials. Fertil Steril. 2001;75(1):88\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhattacharya S, Harrild K, Mollison J, Wordsworth S, Tay C, Harrold A, McQueen D, Lyall H, Johnston L, Burrage J, Grossett S, Walton H, Lynch J, Johnstone A, Kini S, Raja A, Templeton A. Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: pragmatic randomised controlled trial. BMJ. 2008,7;337:a716.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHughes E, Collins J, Vanderkerckhove P. Clomiphene citrate for infertility in women. Cochrane Database Syst Rev 2000;(2):CD 000057.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchenken RS, Asch RH, Williams RF, Hodgen GD. Etiology of infertility in monkeys with endometriosis: luteinized unruptured follicles, luteal phase defects, pelvic adhesions, and spontaneous abortions. Fertil Steril 1984; 41:122\u0026ndash;130.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSomigliana E, Vigan\u0026ograve; P, Benaglia L, Busnelli A, Paffoni A, Vercellini P. Ovarian stimulation and endometriosis progression or recurrence: a systematic review. Reprod Biomed Online. 2019;38(2):185\u0026ndash;194.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNisenblat V, Bossuyt PMM, Farquhar C, Johnson N, Hull ML. Imaging modalities for the non-invasive diagnosis of endometriosis. Cochrane Database of Systematic Reviews 2016.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoncalves MO, Siufi Neto J, Andres MP, Siufi D, de Mattos LA, Abrao MS. Systematic evaluation of endometriosis by transvaginal ultrasound can accurately replace diagnostic laparoscopy, mainly for deep and ovarian endometriosis. Hum Reprod. 2021 17;36(6):1492\u0026ndash;1500.\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Intrauterine insemination, endometrioma, subfertility, propensity score matching","lastPublishedDoi":"10.21203/rs.3.rs-930037/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-930037/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Intrauterine insemination (IUI) treatment is recommended in subfertile women with AFS/ASRM stage I/II endometriosis. However, the efficacy of IUI in women with ovarian endometriomas with tubal patency is uncertain. We explored the efficacy of IUI for the treatment of endometrioma-associated subfertility.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We performed a retrospective matched cohort study using propensity matching (PSM) analysis. Subfertile couples undergoing IUI with and without ovarian stimulation between January 1, 2015, and May 30, 2020 were reviewed.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: After PSM, 56 women with endometrioma alone were matched to 173 patients with unexplained subfertility. The per-cycle pregnancy rate (PR) was comparable between women with endometrioma-associated subfertility (n=56, 87 cycles) and women with unexplained subfertility (n=173, 280 cycles) (9.2% vs. 17.9%, OR 0.47; 95% CI, 0.21–1.03). Subgroup analyses based on IUI with or without stimulation also resulted in comparable results. A trend toward a lower cumulative pregnancy rates (CPRs) was seen in women with endometrioma (14.3%, 8/56) compared with women with unexplained subfertility (28.9%, 50/173), but the differences were not significant (OR, 0.54; 95% CI, 0.26-1.15). However, patients with endometrioma were nearly twice as likely to converse to IVF treatment compared with those without the disease (60.7% versus 43.9%; OR, 1.97; 95% CI, 1.07-3.65).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: IUI may be a viable approach for subfertile women with endometrioma and no other identifiable infertility factor. More studies are needed to reassure the findings.\u003c/p\u003e","manuscriptTitle":"Efficacy of Intrauterine Insemination in Women with Endometrioma-Associated Subfertility: Analysis Using Propensity Score Matching","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-10-22 14:37:29","doi":"10.21203/rs.3.rs-930037/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-11-16T09:24:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-11-15T02:52:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"754b917b-b4de-43a3-825d-12ac1b6f2739","date":"2021-11-09T23:26:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-10-19T07:18:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"4f6466dc-13e9-4ad9-a352-ab071fcffb37","date":"2021-10-06T15:45:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-10-06T11:57:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-10-06T11:45:12+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-10-05T13:25:34+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-10-05T11:39:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2021-09-23T12:25:04+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"104fef49-97e2-4876-8676-c9dac069582c","owner":[],"postedDate":"October 22nd, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":8028961,"name":"Maternal \u0026 Fetal Medicine"}],"tags":[],"updatedAt":"2021-12-15T10:29:04+00:00","versionOfRecord":[],"versionCreatedAt":"2021-10-22 14:37:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-930037","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-930037","identity":"rs-930037","version":["v1"]},"buildId":"0U-iFTyB6qxOgVj8rjrZV","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}