{"paper_id":"e7dbe6fb-1e87-4293-9d68-3deb588e24b5","body_text":"56\nJournal of Medicine and Pharmacy, Volume 13, No.04, June-2023\nIn vitro fertilization outcomes In infertile women with adenomyosis\nTran Ngoc Ha Giang1, Le Minh Tam1*\n(1) Hue University of Medicine and Pharmacy, Hue University\nAbstract\nObjectives: This study aimed to investigate the efficacy of in vitro fertilization (IVF) in infertile patients \nwith adenomyosis and to identify relevant factors. Subjects and methods: Retrospective descriptive study \nof infertile cases with adenomyosis who received IVF therapy and embryo transfer from November 2013 to \nOctober 2022 at the Center for Reproductive Endocrinology and Infertility, Hue University of Medicine and \nPharmacy Hospital, excluding cases of oocyte donation or surrogacy. The β-hCG test was examined two weeks \nfollowing embryo transfer. Then, women with hCG positive test were followed the pregnancy at 6 weeks, 8 \nweeks, and 12 weeks, and examined some factors that influence the clinical outcome of pregnancy. Results: \nAmong 61 cycles of IVF treatment for infertile patients with adenomyosis, the average number of retrieved \noocytes was 10.9±6.6 oocytes. The percentage of mature oocytes was 82.7%, the fertilization rate was 79.5%, \nthe implantation rate was 16.7%, the clinical pregnancy rate was 19.7%, the miscarriage rate was 6.6%, and \nthe ongoing pregnancy rate was 13.1%. In the group with GnRH agonist administration before embryo transfer, \nthe pregnancy rate was greater than in the group without therapy (29.2% vs. 13.5%), and th e pregnancy rate \nin the group with > 10 oocytes was higher than in the group with ≤ 10 oocytes (28.0% vs 13.5%). However, \nthese differences were not statistically significant (with p > 0.05). The cut-off point of endometrial thickness \non the day of hCG injection, 10.25 mm, had a sensitivity of 58.3%, a specificity of 81.6%, an area under the \ncurve (AUC) of 75.6%, and a p-value of 0.006; the cut-off point of endometrial thickness on the day of embryo \ntransfer, 9.75 mm, had an accuracy of 9.75 mm. sensitivity 75%, specificity 71.4%, AUC 78.50%, p = 0.002 for \nclinical pregnancy prognosis.  Conclusion: The IVF treatment of infertile patients with adenomyosis remains \nchallenging, and additional research is required to explain the influence of this disorder on IVF outcomes.\nKeywords: in vitro fertilization (IVF), adenomyosis, β-hCG.\nCorresponding author: Le Minh Tam, email: leminhtam@hueuni.edu.vn \nRecieved: 29/1/2023; Accepted: 14/3/2023; Published: 10/6/2023\nDOI: 10.34071/jmp.2023.4.8\n1. INTRODUCTION\nEndometriosis is a benign condition characterized \nby the development of endometrial glands and \nstroma outside the uterine cavity [1]. This disease \naffects 6-10% of women, with symptoms ranging \nfrom no symptoms to severe symptoms, and can be \naccompanied by a variety of symptoms, including \ndysmenorrhea, dyspareunia, infertility, and urinary \ntroubles, with the most prevalent symptoms being \ndysmenorrhea, pelvic discomfort, and infertility. Up \nto 25 - 50% of infertile women have endometriosis, \nwhile 30 - 50% of endometriosis-affected women \nare infertile [2]. These findings indicate that \nendometriosis is strongly associated with female \ninfertility.\nAdenomyosis is a form of endometriosis \ncharacterized by the development of localized or \ndiffuse glandular tissue inside the myometrium \n[1]. Despite the benign nature of this invasion, \nectopic glandular tissue can result in dysmenorrhea, \nhypogastric retention, and abnormal uterine \nbleeding. Excessive growth of adenomyosis can \nresult in uterine deformities, constriction of the \nuterine cavity, and decreased fertility by impeding \nembryo implantation and increasing the risk of \nmiscarriage, significantly impacting the quality of \nlife of women [1-2].\nIn vitro fertilization (IVF) is one of the best \noptions for treating infertility and is a fairly common \nmethod for infertility caused by endometriosis. Up \nto now, studies on the impact of adenomyosis on IVF \noutcomes have not been consistent. Some reports \nsuggest that IVF reduces the ability of embryo \nimplantation and pregnancy development, so the \nclinical pregnancy rate, the live birth rate after IVF \nin these patients is lower than in the control group \n[3-4]. Meanwhile, another study reported that IVF \ndid not affect pregnancy outcomes after IVF [5-6].\nAlthough assisted reproduction techniques \nare growing day by day, IVF treatment in infertile \npatients with adenomyosis is still a challenge. This \nstudy aimed to evaluate the results of IVF and to find \nout some factors affecting the treatment outcomes \nin infertile patients with adenomyosis.\n\n57\nJournal of Medicine and Pharmacy, Volume 13, No.04, June-2023\n2. METHODS\nInfertility cases with adenomyosis who got IVF \ntreatment and embryo transfer from November \n2013 to October 2022 at the Center for Reproductive \nEndocrinology and Infertility, Hue University of \nMedicine and Pharmacy Hospital, were recruited. \nDonor oocyte and surrogacy instances were omitted \nfrom the research group. The study sample included \n61 cycles of IVF-embryo transfer that matched the \ninclusion criteria. \nThe patient underwent a general examination, \nbaseline hormone testing (LH, FSH, Estradiol, \nProlactin), AMH at the beginning of the menstrual \ncycle and the CA-125 test, a gynecologic \nultrasound. Uterine saline infusion sonography and \nhysterosalpingography (HSG) were indicated within \nthe first three to five days after menstruation. The \npatient received ovarian stimulation in accordance \nwith the GnRH antagonist protocol, with a starting \ndose of FSH between 150 - 300 UI. Embryos were \ncultured and transferred using the same methods. \nThe β-hCG test was conducted two weeks following \nembryo transfer. Then, in the sixth week of \npregnancy, a clinical pregnancy will be reported if an \nultrasound reveals the presence of a gestational sac \nin the uterus. Follow-up will continue for another \neight weeks, and the on-going pregnancy will be \nrecorded at 12 weeks. \nThe primary outcomes were the clinical \npregnancy outcomes, and the secondary outcome \nincluded maternal age, obstetric history (type of \ninfertility, mean duration of infertility), history of \nlong-term GnRH agonist therapy, diameter anterior-\nposterior of the uterus (DAP) and adenomyosis \npattern, mean CA-125, number of oocytes obtained \n(> 10 oocytes and ≤ 10 oocytes), and endometrial \nthickness on the day of embryo transfer. All \nembryos were evaluated according to the Istanbul \nconsensus [7]. At the blastocyst stage (day 5), 1 - \n2 embryos per transfer were conducted. In the \nabsence of embryos of grade A, grade B embryos \nwere selected for transfer.\nSPSS 20.0 was used for statistical analysis, data \nwere cleaned and examined. The quantitative \nvariable findings is reported as the mean ±standard \ndeviation. Examine the association between \nvariables using the Chi-Square test and the Fisher’s \nExact test. Using the Mann-Whitney test, compare \nthe mean of a quantitative, non-normally distributed \nvariable with a qualitative variable. The ROC curve \nwas produced to determine the cut-off point with \nthe best sensitivity and specificity for predicting \nclinical pregnancy outcomes based on endometrial \nthickness on the day of hCG injection and the day of \nembryo transfer. A p-value less than or equal to 0.05 \nwas considered statistically significant.\n3. RESULTS\nTable 1. Demographic and baseline characteristics of study population\nFactors Number Percentage (%)\nAge ≤ 35 34 55.7\n> 35 27 44.3\nMean ± SD 35.2 ± 4.8\nBMI (kg/m2) < 18.5 14 23.0\n18.5 - 22.9 42 68.9\n23 - 24.9 4 6.6\n≥ 25 1 1.5\nMean ± SD 19.9 ± 2.0\nInfertility type Primary 36 59.0\nSecondary 25 41.0\nInfertility duration < 5 years 28 45.9\n5 - 10 years 28 45.9\n> 10 years 5 8.2\nMean ±  SD 5.3 ± 3.3\n\n58\nJournal of Medicine and Pharmacy, Volume 13, No.04, June-2023\nOther causes Abnormal semen parameters 58 95.1\nEndometrioma 34 55.7\nLow ovarian reserve 28 45.9\nPCOS 9 14.8\nTubal disorders 11 18.0\nFibroids 6 9.8\nEndometrial polyp 8 13.1\n    The mean age of the study group was 35.2 ± 4.8 years, in which, the group ≤ 35 years accounted for \n55.7%. The mean BMI was 19.9 ± 2.0 kg/m2, of which, 68.9% had mean BMI of 18.5 - 22.9, and 8.1% were \noverweight or obese. 59.0% of cases are primary infertility. The mean duration of infertility was 5.3 ± 3.3 \nyears, of which, infertility ≥ 5 years accounted for 54.1%. Other causes of infertility accompanied by abnormal \nsemen analysis 95.1%, endometrioma was 55.7%, low ovarian reserve was 45.9%.\nTable 2. Hormone testing and characteristics of the cycles with ovarian stimulation\nCharacteristics Results\nBaseline FSH (mIU/ml) 7.0 ± 2.5\nBaseline LH (mIU/ml) 5.7 ± 2.2\nBaseline Estradiol (pg/ml) 44.8 ± 21.8\nProlactin (µUI/ml) 415.4 ± 200.1\nAMH (ng/ml) 3.6 ± 3.2\nCA-125 (UI/ml) 54.9 ± 47.5\nAFC (follicles) 9.2 ± 6.0\nDays of stimulation (days) 8.9 ± 1.4\nTotal dose of Gonadotropin (UI) 2324.2 ± 576.7\nEndometrial thickness on the day of hCG (mm) 9.3 ± 1.7\nRetrieved oocytes 10.9 ± 6.6\n    The basal hormone and AMH levels were within normal limits. The mean CA-125 was 54.9 ± 47.5 UI/ml. \nThe basic parameters of the ovarian stimulation cycle are recorded in Table 2. Accordingly, the mean number \nof oocytes obtained was 10.9 ± 6.6 oocytes.\nTable 3. The in-vitro fertiliazation outcomes\nCharacteristics Percentage (%)\nMature oocyte rate 82.7\nFertilization rate 79.6\nEmbryo quality\n   Grade A\n   Grade B\n   Grade C\n45.9\n28.9\n25.2\nImplantation rate 16.7\nClinical pregnancy rate 19.7\nMiscarriage rate 6.6\nOn-going pregnancy rate 13.1\n    In this study, the rate of mature oocytes was 82.7%, fertilization rate was 79.6%, in which, embryos of type \nA, B, and C were 45.9%, 28.9% and 25.2%, respectively. Implantation rate was 16.7%, clinical pregnancy rate \nwas 19.7%, miscarriage rate was 6.6% and on-going pregnancy rate was 13.1%.\n\n59\nJournal of Medicine and Pharmacy, Volume 13, No.04, June-2023\nTable 4. Some related factors affecting clinical pregnancy outcome\nCharacteristics Pregnancy p\nYes No\nMaternal age (years)\n   ≤ 35\n   > 35\n9 (26.5%)\n3 (11.1%)\n25 (73.5%)\n24 (88.9%)\np = 0.134\nInfertility type\n   Primary \n   Secondary\n7 (19.4%)\n5 (20.0%)\n29 (80.6%)\n20 (80.0%)\np = 1.0\nInfertility duration 5.3 ± 3.2 5.3 ± 3.3 p = 0.729\nGnRHa administration\n   Yes\n   No\n7 (29.2%)\n5 (13.5%)\n17 (70.8%)\n32 (86.5%)\np = 0.189\nCA-125 (mean±SD) 64.7 ± 74.6 52.6 ± 38.9 p = 0.849\nRetrieved oocytes\n   > 10\n   ≤ 10\n7 (28.0%)\n5 (13.9%)\n18 (72.0%)\n31 (86.1%)\np = 0.203\nDAP (mm)\n   < 40\n   40 – 50\n   > 50\n2 (15.4%)\n7 (18.4%)\n3 (30.0%)\n11 (84.6%)\n31 (81.6%)\n7 (70.0%)\np = 0.655\nAdenomyosis pattern\n   Local\n   Diffuse\n4 (16.7%)\n8 (21.6%)\n20 (83.3%)\n29 (78.4%)\np = 0.749\nCA-125: cancer antigen 125; DAP: anterior-posterior diameter of the uterus.\nThe pregnancy rate in the group ≤ 35 years old was higher than that in the group > 35 years old (26.5% \nvs 11.1%), the group with GnRH agonist treatment had a higher pregnancy rate than the group without \ntreatment 29.2% vs. 13.5%) and the pregnancy rate in the group obtained > 10 oocytes was higher than \nin the group obtained ≤ 10 oocytes (28.0% vs 13.9%). However, these differences were not statistically \nsignificant with p > 0.05. Other factors such as infertility type, mean duration of infertility, mean CA-125, \nanterior-posterior diameter of the uterus or type of adenomyosis were not associated with clinical pregnancy \noutcome with p > 0.05.\nFigure 1. Relationship of endometrial thickness on the day of hCG injection and\ndate of embryo transfer with clinical pregnancy outcome\n\n\n60\nJournal of Medicine and Pharmacy, Volume 13, No.04, June-2023\nAUC (%) Endometrial \nthickness Se Sp p\nDay of hCG 75.6 10.25 58.3 81.6 0.006\nDay of embryo transfer 78.5 9.75 75.0 71.4 0.002\nThe area under the ROC curve on the relationship between endometrial thickness on the day of hCG \ninjection and the day of embryo transfer with clinical pregnancy outcome is 75.6% and 78.5%, respectively, \nso it has a predictive value for clinical pregnancy, at the moderate level, with p < 0.05. The cut-off point of \nendometrial thickness on the day of hCG injection (10.25 mm) had a sensitivity of 58.3% and a specificity of \n81.6%. The cut-off point of endometrial thickness on the day of embryo transfer of 9.75 mm had a sensitivity \nof 75.0% and a specificity of 71.4%.\n4. DISCUSSION\n4.1. Results of IVF in infertile patients with \nadenomyosis\nThe percentage of mature oocytes, fertilization \nrate in this study were similar to those in Chan \nWoo Park’s study (2016) [8], Sunita Sharma (2019) \nand Chloe’s study [3, 8,9]. Regarding the quality \nof embryos obtained, the percentage of embryos \ngrade A, B, and C were 45.9%, 28.9% and 25.2%, \nrespectively. The percentage of embryo A was \nhigher than that of Chloe Higgins (2021). 29.2% may \nbe due to differences in improved embryo culture \ntechniques [9].\nThe implantation rate in the study group was \n16.7%, lower than that in the study of Jiaxin Zhang \n(2021) at 31.91% [10]. However, other reports by \nMartínez-Conejero (2011), Tasuku Harada (2016) \ndemonstrated that adenomyosis does not affect \nimplantation rates, especially in those who received \nlong-term GnRH agonist therapy before embryo \ntransfer. Based on its ability to inhibit proliferation of \nectopic endometrial cells, reduce negative effects of \ncytotoxic cytokines and oxidative stress, and clearly \nimprove pregnancy outcomes of patients with \nadenomyosis [5-6, 11-12]. The clinical pregnancy \nrate in this study was 19.7%, lower than the results \nof Chan Woo Park (2016) with a clinical pregnancy \nrate of 25.2 - 39.5% and Sunita Sharma (2019) with \na clinical pregnancy rate of 25.2 - 39.5%.\nThe miscarriage rate as reported by Sunita \nSharma (2019) in the 2 groups of adenomyosis and \nendometrioma was 9.38% and 7.95%, respectively \n[3], even up to 15.69% [10], higher than those in our \nstudy.\n4.2. Some related factors affecting the outcome \nof IVF in infertile patients with adenomyosis\nPregnancy rates in this study were associated \nwith maternal age, GnRH agonist treatment group \nand number of oocytes obtained. The study of \nsome other authors also noted the difference in the \npregnancy rate when the mother’s age gets older \n[14-15]. The study of Houwen (2014) and Chan \nWoo Park (2016) also reported the benefit of GnRH \nagonist treatment before embryo transfer compared \nwith no treatment and similar to the results of the \nmeta-analysis by Loendersloot (2010). There was a \npositive correlation between the number of oocytes \nobtained and the pregnancy rate following IVF, with \nOR = 1.04 (95% CI: 1.02 - 1.07) [7,16,17]. However, \nthese differences are not statistically significant with \np > 0.05, possibly because our sample size is still \nlimited. Other factors such as infertility classification, \nmean duration of infertility were not associated with \nclinical pregnancy outcome. This result is similar to \nthe studies of Matalliotakis (2008), Liao (2019), and \nLoendersloot (2010) [17-19].\nCA-125 is an important marker in suggesting \nthe diagnosis of endometriosis. In this study, the \nmean CA-125 concentration in the pregnant group \nand the non-pregnant group did not differ, with p \n> 0.05. According to a study by Ling Huang (2021) \nconducted on 84 infertile patients with adenomyosis, \nthere was no association between CA-125 levels \nand pregnancy outcomes [20]. Similarly, KE Fish \n(2004) also found that CA-125 levels had no value \nin predicting pregnancy outcomes (AUC = 0.63) [21].\nHong Gao (2019) and colleagues concluded that \npatients with uterine anteroposterior diameter \n< 30mm have a higher live birth rate than the \ngroup with DAP ≥ 50 mm (RR = 1.636) and Yaoqiu \nWu’s study (2019) performed on patients with \nadenomyosis after frozen embryo transfer showed \nthat the mean DAP in the live-birth group (4.97 \n± 0.86 cm) was lower than that in the non-live-\npregnant group (5.34 ± 1.17 cm), with p < 0.05 \n[15,22]. Our study did not record this difference, \npossibly due to the treatment of GnRH agonists 3 \nmonths before embryo transfer, which improved \nthe size of the uterus and improved the pregnancy \nrate [11,15]. Regarding the type of adenomyosis, in \n\n61\nJournal of Medicine and Pharmacy, Volume 13, No.04, June-2023\nour study the number of cases of diffuse was more \nthan that of focal pattern, however, there was no \ndifference in the clinical pregnancy rate between \nthese two groups, with p > 0.05 . This result is similar \nto the studies of Chan Woo Park (2016) and Laura \nBenaglia (2014), and Yaoqiu Wu (2022) [7,15,23].\nVaginal ultrasound assessment of endometrial \nthickness on the day of hCG injection and the day \nof embryo transfer is an indispensable step in IVF \ntreatment. Many authors believe that the ideal \nendometrial thickness at embryo transfer from \n8-14mm helps to increase the clinical pregnancy \nrate, live birth rate and reduce the miscarriage rate \n[27-28]. In this study, the endometrial thickness on \nthe day of embryo transfer ranged from 7-13mm and \nwe investigated that the cut-off point of endometrial \nthickness of 9.75 mm had 75% sensitivity and 71.4% \nspecificity in predicting the probability of miscarriage \nand clinical pregnancy. Research by Georg Griesinger \n(2018) also recorded a cut-off point of ≥ 9 mm, or by \nNeal Mahutte (2022) if endometriosis 10 - 12 mm \nthe live birth rate is better [29-30]. More studies \nwith a larger sample and other confounding factors \nsuch as embryo transfer quality, embryo transfer \ntechnique, are needed to be able to agree on the \noptimal cut-off points.\n5. CONCLUSION\nThis study evaluated the results of in vitro \nfertilization (IVF) in infertile patients with \nadenomyosis and noted several factors related to \nthe success rate such as maternal age, the number \nof oocytes obtained. 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