Tacrolimus treatment in women with repeated implantation failures.

Background: Tacrolimus is an immunosuppressive drug that works as a calcineurin inhibitor to improve the reproductive outcomes for women who have experienced multiple implantation failures (RIF) and show elevated type 1 helper T (Th1)/Th2 cell ratios. Methods: In the first part of this review, we indicate how we re-evaluated the cut-off index for selecting the participants in a tacrolimus regimen via transferred euploid blastocysts. In the second part, we cite cases where tacrolimus has improved the live birth rate for women who have experienced recurrent pregnancy losses (PRL) and we introduce the utility of tacrolimus treatment to prevent obstetrical complications. Main Findings: After reconsideration of the cut-off index (Th1/Th2 ≥ 11.8), however, the pregnancy rates of women with tacrolimus were significantly higher than those of women without tacrolimus. The PRL women treated with tacrolimus showed significantly lower rates of biochemical pregnancy, but higher live-birth rates compared with women who were not treated with tacrolimus. Moreover, prior severe obstetrical complications could be controlled via the administration of tacrolimus during pregnancy. Conclusion: Tacrolimus has become indispensable in the field of solid-organ transplantation, and in the near future, it should become an essential agent in the reproductive field, as well.

Therapeutic efficacy of the optimization of thyroid function, thrombophilia, immunity and uterine milieu (OPTIMUM) treatment strategy on pregnancy outcomes after single euploid blastocyst transfer in advanced age women with recurrent reproductive failure.

Purpose: To clarify the efficacy of the OPtimization of Thyroid function, Thrombophilia, IMmunity and Uterine Milieu (OPTIMUM) treatment strategy on pregnancy outcomes after euploid blastocyst transfer in advanced age women with recurrent implantation failure (RIF) and/or recurrent pregnancy loss (RPL). Methods: Between January 2019 and May 2022, 193 consecutive women aged ≥40 years with RIF and/or RPL received single euploid blastocyst transfer. Before embryo transfer, 127 women underwent RIF/RPL testing. Chronic endometritis was treated with mainly antibiotics, aberrant high Th1/Th2 cell ratios with vitamin D and/or tacrolimus, overt/subclinical hypothyroidism with levothyroxine, and thrombophilia with low-dose aspirin. We compared pregnancy outcomes in the women who did and did not receive the OPTIMUM treatment strategy. Results: Women with RIF/RPL in the OPTIMUM group had significantly higher clinical pregnancy and livebirth rates than did those in the control group (clinical pregnancy rate of 71.7% and 45.5%, p < 0.001; livebirth rate of 64.6% and 39.4%, p = 0.001, respectively). However, preimplantation genetic testing for aneuploidy with and without OPTIMUM promoted low miscarriage rates with no significant difference between them (9.9%, and 13.3%, respectively; p = 0.73). Conclusions: The OPTIMUM treatment strategy improved clinical pregnancy rates after single euploid blastocyst transfer; but not miscarriage rates.

Risk Factors for Alcohol Consumption after Starting Assisted Reproductive Technology Treatment among Japanese Women: Japan-Female Employment and Mental Health in Assisted Reproductive Technology (J-FEMA) Study.

AIMS: To determine the association between drinking habits and social factors among women undergoing assisted reproductive technology (ART) treatment in Japan. METHODS: The study participants who provided answers for the questionnaire concerning alcohol consumption were 1017 female patients undergoing ART treatment were enrolled in the Japan-Female Employment and Mental Health in assisted reproductive technology (J-FEMA) study between August and December 2018. Patient characteristics, including demographic, clinical, and socioeconomic status, were assessed using a self-administered questionnaire which was distributed only once during the period, regardless of their first or follow-up examination. We defined current drinkers who drank ≥46 g of ethanol per week as the habitual drinking group. The risk factors for habitual drinking were analyzed using multivariable-adjusted logistic regression. RESULTS: The proportion of habitual drinkers was 15.5% in this study population. The multivariable-adjusted odds ratios (95% confidence interval) for habitual drinking were 2.27 (0.99-5.21) for women aged ≥35 years versus those <35 years, 4.26 (1.98-9.16) for women having partners who currently drink compared to those with partners without current drinking, 1.84 (1.08-3.12) for women without a history of childbirth versus those with, and 1.77 (1.00-3.14) for working women compared with those not working. CONCLUSIONS: In our study, habitual drinking among women undergoing ART treatment was significantly associated with older age, no history of childbirth, partner's current drinking status, and working.

Immunosuppressive therapy with tacrolimus is a potential drug candidate for the prevention of unexplained or preeclamptic stillbirths with Th1-dominant immune states: a case series of five patients.

Some of obstetrical complications such as unexplained pregnancy loss and preeclampsia (PE) are associated with maternal-fetal immune abnormalities, leading to uteroplacental dysfunction, insufficient fetal immune tolerance, or fetal rejection. Immunosuppressants with calcineurin inhibitors could be useful for the prevention of these complications by modulating the cellular immune balance by directly inhibiting activated T-helper (Th) 1 and natural killer (NK)/NKT cells. We present our experience with the immunosuppressant tacrolimus in five pregnant women who had a previous pregnancy history of unexplained or preeclamptic stillbirth. Th1 and Th2 cell populations and NK cell activities in peripheral blood were measured as clinical parameters during pregnancy. Case 1-3 achieved suppressions of predominant Th1 immunity and live births without pregnancy-related complications. In case 4, increased tacrolimus dose after a miscarriage resulted in her first live birth; however, she developed PE and severe fetal growth restriction with elevated Th1/Th2 cell ratios at 26 weeks of gestation. Case 5 had a previous history of early onset PE and the hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, and an emergency cesarean section was needed for maternal safety at 20 weeks of gestation. The course of the next pregnancy was stable under tacrolimus treatment; however, the HELLP syndrome recurred after PE at 33 weeks of gestation. Although an imbalance in the Th1/Th2 cell ratio was not observed during pregnancy, NK cell activity was markedly elevated before delivery. In conclusion, tacrolimus is a potential drug candidate for the prevention of unexplained or preeclamptic stillbirth with Th1-dominant immune states.

Gene expression signatures associated with chronic endometritis revealed by RNA sequencing.

Introduction: Chronic endometritis (CE) is a persistent inflammatory condition of the endometrium characterized by the infiltration of plasma cells in the endometrial stroma. CD138 immunohistochemistry is considered to improve the CE diagnosis rate. Methods: Using the number of CD138-positive cells equal or greater than five as a diagnostic criterion for CE, we identified 24 CE and 33 non-CE cases among women with infertility. We conducted RNA-sequencing analysis for these 57 cases in total as an attempt to elucidate the molecular pathogenesis of CE and to search for new biomarkers for CE. Results and Discussion: By comparing CE and non-CE groups, we identified 20 genes upregulated in the endometria of CE patients, including 12 immunoglobulin-related genes and eight non-immunoglobulin genes as differentially expressed genes. The eight genes were MUC5AC, LTF, CAPN9, MESP1, ACSM1, TVP23A, ALOX15, and MZB1. By analyzing samples in the proliferative and secretory phases of the menstrual cycle separately, we also identified four additional non-immunoglobulin genes upregulated in CE endometria: CCDC13 by comparing the samples in the proliferative phase, and OVGP1, MTUS2, and CLIC6 by comparing the samples in the secretory phase. Although the genes upregulated in CE may serve as novel diagnostic markers of CE, many of them were upregulated only in a limited number of CE cases showing an extremely high number of CD138-positive cells near or over one hundred. Exceptionally, TVP23A was upregulated in the majority of CE cases regardless of the number of CD138-positive cells. The upregulation of TVP23A in the endometria of CE cases may reflect the pathophysiology of a cell-type or cell-types intrinsic to the endometrium rather than the accumulation of plasma cells. Our data, consisting of clinical and transcriptomic information for CE and non-CE cases, helped us identify gene expression signatures associated with CE.

Therapeutic efficacy of gentle endometrial curettage on antibiotic-resistant chronic endometritis in infertile women.

Purpose: To identify the efficacy of endometrial curettage on antibiotic-resistant chronic endometritis (CE) in infertile women. Methods: Of 1580 women with CE, 87 with antibiotic-resistant CE after two to five cycles of antibiotic treatment were recruited between 2019 and 2021. The women who underwent endometrial curettage without applying any force and, in the subsequent menstrual cycle, endometrial sampling for CD138 immunostaining without antibiotic use. Pregnancy outcomes after in vitro fertilization treatment were analyzed in women who did not desire endometrial curettage and in those with cured and persistent CE after endometrial curettage. Results: In 64 women who underwent endometrial curettage, the number of CD138-positive cells decreased from 28.0 ± 35.3 to 7.7 ± 14.0 (p < 0.0001), and CE in 41 women (64.1%) was cured (<5 CD138-positive cells). The pathological findings detected 3.1% of endometrial hyperplasia and 1.6% of endometrial cancer. The ongoing pregnancy rates in women aged ≤42 without endometrial curettage were significantly lower than those of women with cured and persistent CE (26.7%, 67.6%, and 57.1%, respectively, p = 0.03). Conclusions: Gentle endometrial curettage for antibiotic-resistant CE significantly decreased the number of CD138-positive cells, resulting in improved pregnancy outcomes regardless of remaining CE. Endometrial curettage is also important as a screening for endometrial malignancy.

Hyaluronan-enriched transfer medium (HETM) can improve the implantation rate in morphologically poor euploid blastocyst transfer.

PURPOSE: Hyaluronan-enriched transfer medium (HETM) could improve the clinical pregnancy rate (CPR) for patients with repeated implantation failures (RIF). In contrast, there have been seldom reports addressing the potentially beneficial effects of HETM for morphologically poor blastocysts (MPBLs). Our study aimed to evaluate whether the use of HETM would improve the CPR for the patients who were transferred with euploid MPBLs. METHODS: Patients who underwent single euploid blastocyst transfer between July 2020 and June 2022 were enrolled. We included only those blastocysts confirmed as euploid by PGT-A, and those blastocysts were transferred after thawing. The natural ovulatory cycle or hormone replacement cycle (HRC) protocol were used for endometrial preparation for frozen embryo transfer (FET). A total of 1,168 FET cycles were performed in the study period, including 954 cycles of morphologically good blastocysts (≥ 4BB in Gardner's classification), and 85 cycles of MPBLs, of which 47 were transferred using HETM in FET (the HETM group), and the remaining 38 were transferred with the medium without hyaluronan (the control group). We compared the CPR between these two groups. RESULTS: The characteristics of patients were similar between the HETM and control groups. The CPR in the HETM group was significantly higher than the control group (47.4% and 21.5%, respectively, p = 0.019). The multiple logistic regression analysis found that the use of HETM was a predictive factor of positive pregnancy outcomes (OR = 5.08, 95% CI = 1.62-16.0, p = 0.019). CONCLUSION: Our data suggests that HETM used in the euploid blastocyst transfer can improve the clinical pregnancy rates of morphologically poor blastocysts.

Transcriptomic profiling analysis of human endometrial stromal cells treated with autologous platelet-rich plasma.

Purpose: To clarify the mechanisms of intrauterine platelet-rich plasma (PRP) infusion that support embryo implantation in in vitro fertilization treatment. Methods: Blood and endometrial samples were collected from four infertile women. Human endometrial stromal cells (HESCs) were cultured and passaged equally into four cell culture dishes in each patient. Two were treated with PRP twice, and the other two were treated with vehicle. Subsequently, two cultures with and without PRP were decidualized with 8-bromoadenosine 3',5'-cyclic AMP and progesterone for 5 days. Results: The gene expression in undifferentiated or decidualized HESCs with and without PRP was compared. In the microarray analysis, 381 and 63 differentially expressed genes were detected in undifferentiated and decidualized HESCs, respectively. In the undifferentiated HESCs, PRP was found to promote the gene expression associated with cell growth, tissue regeneration, proinflammatory response, and antibiotic effects. In decidualized HESCs, PRP was found to attenuate the gene expression involved in cell proliferation and inflammation by inhibiting the expression of phosphoinositide 3-kinase signaling. Conclusions: Platelet-rich plasma regulates the reprogramming of cell proliferation and inflammation depending on menstrual cycle phases in an appropriate manner, suggesting that PRP has the potential to increase endometrial thickness in the proliferative phase and improve immune tolerance in the secretory phase.

Comparison of Pregnancy Outcomes Between Fresh Embryo Transfer in a Natural IVF Cycle and IUI Cycle Among Infertile Young Women.

Background: The purpose of the current study was comparing pregnancy outcomes for natural cycle in vitro fertilization (IVF) per fresh embryo transfer (ET) and oocyte pick-up (OPU) in intrauterine insemination (IUI). Methods: This was a retrospective cohort study of women who underwent either IUI (n=246) or OPU with fresh ET for natural cycle IVF (n=291), conducted between April 2017 and February 2018 at the Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan. Patients in both groups did not receive ovarian stimulation and luteal support; gonadotropin-releasing agonist spray was administered 35 hr before OPU or IUI. The clinical pregnancy rate was compared between the IUI and IVF groups. Data analysis was based on the number of cycles. The p≦0.05 was considered significant. Results: The clinical pregnancy rate per OPU in the IVF group was higher than the one in IUI group (20.6% vs. 10.1%), and the difference was significant (p<0.01). The pregnancy rate for natural cycle IVF calculated per fresh ET was 36.8%. The miscarriage rate did not significantly differ between the IVF (4.1%) and IUI (8.0%) groups. Conclusion: Fresh ET in natural cycle IVF provides a higher implantation rate than IUI.

Prevalence of and risk factors for chronic endometritis in patients with intrauterine disorders after hysteroscopic surgery.

OBJECTIVE: To identify the prevalence of and risk factors for chronic endometritis (CE) in patients with intrauterine disorders and the therapeutic efficacy of hysteroscopic surgery in the treatment of CE without antibiotic therapy. DESIGN: Prospective cohort study. SETTING: Hospital specializing in reproductive medicine. PATIENT(S): The study population consisted of 350 women with infertility, of whom 337 were recruited, who underwent hysteroscopic surgery between November 2018 and June 2021. Eighty-nine consecutive patients without intrauterine disorders were also recruited as controls. INTERVENTION(S): Endometrial samples were collected during the surgery for CD138 immunostaining for the diagnosis of CE. In women diagnosed with CE, endometrial biopsy was performed without antibiotic use in the subsequent menstrual cycle. MAIN OUTCOME MEASURE(S): Prevalence of and risk factors for CE in intrauterine disorders and therapeutic effects of hysteroscopic surgery on CE. RESULT(S): The prevalence of CE with ≥5 CD138-positive cells in women with no intrauterine disorder and with endometrial polyps, myomas, intrauterine adhesions (IUAs), and septate uterus was 15.7%, 85.7%, 69.0%, 78.9%, and 46.2%, respectively. A multivariate analysis revealed that CE was diagnosed significantly more often in the endometrial polyp (odds ratio, 27.69; 95% confidence interval, 15.01-51.08) and IUA groups (odds ratio, 8.85; 95% confidence interval, 3.26-24.05). The rate of recovery from CE with surgery in women with endometrial polyps, myomas, IUA, and septate uterus was 89.7%, 100%, 92.8%, and 83.3%, respectively. CONCLUSION(S): Endometrial polyp and IUA were risk factors for CE. Most CE cases with intrauterine disorders were cured with hysteroscopic surgery without antibiotic therapy, regardless of the type of intrauterine abnormalities.

Risk factors for infertility treatment-associated harassment among working women: a Japan-Female Employment and Mental health in assisted reproductive technology (J-FEMA) study.

PURPOSE: This study aims to elucidate the risk factors of infertility treatment-associated harassment (I-harassment) among Japanese working women. METHODS: The study participants were 1103 female patients who enrolled in the Japan-Female Employment and Mental Health in artificial reproductive technology (J-FEMA) study. Of the 1727 female patients, 1103 female patients were working during the initiation of infertility treatment and were still working during the survey. Risk factors for I-harassment were analyzed using a multivariable logistic regression model. RESULTS: In this study, 82 female patients (7.4%) experienced I-harassment. The risk was significantly higher in those who had more in vitro fertilization (IVF) cycles than those who had fewer IVF cycles (OR, 1.06; 95% CI, 1.01-1.10). Similarly, those who disclosed their infertility treatment to their workplace were at significantly higher risk for I-harassment than those who did not (OR, 1.80; 95% CI, 1.03-3.15). CONCLUSION: This study found that 7.4% of female patients experienced I-harassment after infertility treatment initiation. Those female patients who "experienced more IVF cycles," and "disclosed their infertility treatment in their workplace" should be carefully followed up by healthcare professionals to prevent I-harassment.

Changes in the T-helper 1 and 2 cell populations during pregnancy in tacrolimus-treated women with repeated implantation failure and recurrent pregnancy loss.

Tacrolimus has received considerable attention as a treatment approach for infertility associated with maternal-foetal immune abnormalities, such as repeated implantation failure (RIF) and recurrent pregnancy loss (RPL). This study examined the changes in T-helper (Th) 1 and 2 cell populations during pregnancy in peripheral blood of tacrolimus-treated RIF patients who delivered a liveborn infant from August 2012 to February 2020 at the National Centre for Child Health and Development. A total of 58 eligible study subjects were divided into two groups according to the presence of a history of RPL: (i) RIF-alone group (n = 31); and (ii) RIF-plus-RPL group (n = 27). In a flow cytometric analysis, the Th1/Th2 cell ratios were significantly higher before pregnancy than after pregnancy, and during the first trimester than the second trimester in the RIF-alone group (p = 0.0071 and p = 0.0087, respectively). However, no significant differences were present in the RIF-plus-RPL group. Although the Th1 immunity was suppressed under tacrolimus treatment in both groups, a delayed reduction in the Th1 cell percentage after initiation of treatment was observed in the RIF-plus-RPL group. In conclusion, the cellular immune alterations in tacrolimus-treated patients with RIF were different depending on the presence or absence of a history of RPL.

Therapeutic effects of an oral gonadotropin-releasing hormone receptor antagonist, relugolix, on preventing premature ovulation in mild ovarian stimulation for IVF.

PURPOSE: Can relugolix, a novel oral gonadotropin-releasing hormone receptor (GnRH) antagonist, function as an alternative ovulation inhibitor to GnRH antagonist injections? METHODS: This single-center, cross-sectional retrospective study compared premature ovulation rates and clinical outcomes in IVF treatment after mild ovarian stimulation with 40 mg of relugolix (relugolix group) or 0.25-mg injections of ganirelix acetate or cetrorelix acetate (injection group) between March 2019 and January 2020. Of 247 infertile women (256 IVF cycles) aged ≤42 years, 223 women (230 cycles) were evaluated. In the relugolix and injection groups, we compared 104 and 85 cycles after GnRH antagonist use before the LH surge (LH levels <10 mIU/ml) and 22 and 19 cycles during the LH surge (LH levels ≥10 mIU/ml), respectively. RESULTS: Before the LH surge, the ovulation rates in the two groups were very low (p = 0.838), however; during the LH surge, the cycles using relugolix had a high ovulation rate of 40.9% compared with no ovulation in the injection group (p = 0.002). There were no significant differences in embryo culture findings and pregnancy outcomes between the two groups. CONCLUSIONS: Although relugolix had a high ovulation suppressive effect, when the LH surge occurred, its effect was insufficient.

Novel approaches to the management of recurrent pregnancy loss: The OPTIMUM (OPtimization of Thyroid function, Thrombophilia, Immunity, and Uterine Milieu) treatment strategy.

PURPOSE: Does the OPtimization of Thyroid function, Thrombophilia, Immunity, and Uterine Milieu (OPTIMUM) treatment strategy, developed for treating repeated implantation failure (RIF), contribute to improving pregnancy outcomes in patients with a history of recurrent pregnancy loss (RPL)? METHODS: Between 2018 and 2019, women with RPL after two or more clinical pregnancy losses underwent RPL testing. We treated chronic endometritis with antibiotics, high Th1/Th2 cell ratios with vitamin D and/or tacrolimus, overt/subclinical hypothyroidism with levothyroxine, and thrombophilia with low-dose aspirin. Of 168 consecutive women aged ≤43 years, 115 underwent RPL testing. We compared 100 pregnancies (90 women) and 46 pregnancies (41 women) with and without the OPTIMUM treatment strategy, respectively. RESULTS: RPL testing identified intrauterine abnormalities in 66 (57.4%), elevated Th1/Th2 cell ratios in 50 (43.5%), thyroid dysfunction in 33 (28.7%), and thrombophilia in 33 (28.7%). The live birth rate in the OPTIMUM group was significantly higher than that in the control group among women aged <40 years (78.1% and 42.3%, respectively; p = 0.002), but no significant difference was observed in women aged ≥40 years (55.6% and 30.0%, respectively; p = 0.09). CONCLUSIONS: The OPTIMUM treatment strategy improved pregnancy outcomes in patients with not only RIF but also RPL.

Effects of Periconceptional Multivitamin Supplementation on Folate and Homocysteine Levels Depending on Genetic Variants of Methyltetrahydrofolate Reductase in Infertile Japanese Women.

Methylenetetrahydrofolate reductase (MTHFR) has various polymorphisms, and the effects of periconceptional folic acid supplementation for decreasing neural tube defects (NTDs) risk differ depending on the genotypes. This study analyzed the effectiveness of multivitamin supplementation on folate insufficiency and hyperhomocysteinemia, depending on MTHFR polymorphisms. Of 205 women, 72 (35.1%), 100 (48.8%) and 33 (16.1%) had MTHFR CC, CT and TT, respectively. Serum folate and homocysteine levels in women with homozygous mutant TT were significantly lower and higher, respectively, than those in women with CC and CT. In 54 women (26.3% of all women) with a risk of NTDs, multivitamin supplementation containing folic acid and vitamin D for one month increased folate level (5.8 ± 0.9 to 19.2 ± 4.0 ng/mL, p < 0.0001) and decreased the homocysteine level (8.2 ± 3.1 to 5.8 ± 0.8 nmol/mL, p < 0.0001) to minimize the risk of NTDs in all women, regardless of MTHFR genotype. Regardless of MTHFR genotype, multivitamin supplements could control folate and homocysteine levels. Tests for folate and homocysteine levels and optimal multivitamin supplementation in women with risk of NTDs one month or more before pregnancy should be recommended to women who are planning a pregnancy.

Increasing number of implantation failures and pregnancy losses associated with elevated Th1/Th2 cell ratio.

PROBLEM: We aimed to assess whether an imbalance of T-helper (Th) 1 and Th2 cells contributes to implantation failure and pregnancy loss. METHOD OF STUDY: In this cross-sectional study, 197 consecutive patients with a history of repeated implantation failure (RIF) after three or more embryo transfer (ET) cycles and/or recurrent pregnancy loss (RPL) after two or more clinical pregnancy losses underwent Th cell testing. After excluding 42 women aged ≥44 and 9 with vitamin D supplementation, we recruited 146 women including 79 with RIF and 81 with RPL. Fourteen women had a history of both RIF and RPL. We also recruited 45 fertile women and 40 general infertile women without a history of in vitro fertilization treatment. This study was approved by the local ethics committee. RESULTS: There was no significant difference in IFN-γ-producing Th1 and IL-4-producing Th2 cell levels between the fertile and general infertile women, but Th1 cell levels and the Th1/Th2 cell ratio were significantly higher in the women with ≥4 ET cycles and ≥2 pregnancy losses than in the fertile and general infertile women. In the general infertile women, the total livebirth rates including natural conception after two ET cycles in the normal and high Th1/Th2 groups (Th1/Th2 <11.8 and ≥11.8, respectively) were 66.7% and 87.5%, respectively (p = .395). CONCLUSIONS: A high Th1/Th2 cell ratio was linked to ≥4 implantation failure cycles and ≥2 pregnancy losses but not to general infertility.

Analysis of severe psychological stressors in women during fertility treatment: Japan-Female Employment and Mental health in Assisted reproductive technology (J-FEMA) study.

PURPOSE: To identify risk factors for severe psychological stress in women undergoing fertility treatment. METHODS: This cross-sectional, multi-center study was conducted from August to December 2018. We recruited 1672 subjects who completed an anonymous, self-reported questionnaire regarding fertility treatment, conditions at work and home, and psychological stress using K6 score, which estimates psychological distress during the previous 30 days. We further focused our analysis on 1335 subjects who were working when starting fertility treatment. RESULTS: Of 1672 women, mean K6 score (range 0-24) was 4.8 ± 4.4, including 103 women (6.2%) with K6 score ≥ 13 (high K6), and classified as probable severe psychological distress. Multivariate logistic regression analysis showed that high K6 was strongly associated with low annual family income of ≤ USD55,700 (JPY6 million) (odds ratio [OR] 1.89, 95% confidence interval [CI] 1.04-3.42), infertility duration of ≥ 2 years (OR 1.87, 95% CI 1.08-3.25), and no experience of childbirth (OR 2.04, 95% CI 1.05-3.97). Focusing on 1335 working women, 266 (19.9%) experienced resignation from work. High K6 was strongly associated with low family income (OR 2.83, 95% CI 1.52-5.28), cessation of professional duties (OR 2.08, 95% CI 1.05-4.14), infertility-related harassment in the workplace (OR 2.07, 95% CI 1.08-3.98), and perceived difficulties to continue working during fertility treatment (OR 2.94, 95% CI 1.15-7.50). CONCLUSION: Severe psychological stressors in women during fertility treatment included low family income, long infertility duration, childlessness, infertility-related harassment, and perceived difficulty in working conditions or cessation from work. Establishment of mental health care support systems is urgently required in this population.

Analysis of the therapeutic effects of hysteroscopic polypectomy with and without doxycycline treatment on chronic endometritis with endometrial polyps.

PROBLEM: We aimed to compare the therapeutic effects of hysteroscopic polypectomy with and without doxycycline treatment on chronic endometritis (CE) with endometrial polyps. METHOD OF STUDY: DESIGN: A cross-sectional study was conducted on 267 infertile patients, of whom 243 were recruited, who underwent hysteroscopic polypectomy between March 2019 and March 2020. During surgery, the endometrial specimens for the immunohistochemistry analysis of the plasma cell marker CD138 and for the intrauterine bacterial culture were obtained to diagnose CE, and the prevalence of CE was analyzed. Of the 222 women who were diagnosed with CE after polypectomy, we treated 62 women with doxycycline (antibiotic group) and did not provide antibiotics in 160 women (non-antibiotic group). RESULTS: Most of the infertile patients with endometrial polyps had CE (92.6%). The recovery rate from CE by hysteroscopic polypectomy was significantly higher in the non-antibiotic group than in the antibiotic group (88.8% and 58.1%, respectively, p < 0.0001). The duration of recovery from CE in the non-antibiotic group was shorter than that in the antibiotic group (42.6 ± 41.0 and 56.5 ± 32.3 days, respectively, p < 0.0001). The clinical pregnancy rate within 6 months in non-antibiotic group was higher than that in the antibiotic group (63.2% and 43.8%, respectively, p = 0.034). CONCLUSION: Endometrial polyps are significantly associated with CE. Most CE patients with endometrial polyps had been cured by polypectomy without doxycycline. Inappropriate antibiotic therapy may delay recovery from CE and decrease the efficacy of polypectomy on CE and pregnancy rates.

Incidences and risk factors of moderate-to-severe ovarian hyperstimulation syndrome and severe hemoperitoneum in 1,435,108 oocyte retrievals.

RESEARCH QUESTION: What are the risk factors affecting the incidences of moderate-to-severe ovarian hyperstimulation syndrome (OHSS) and severe hemoperitoneum in assisted reproductive technology (ART) treatment cycles? DESIGN: A retrospective cohort study was conducted on 1,435,108 oocyte retrieval cycles among Japanese ART registry data between 2007 and 2015. The study included 11,378 cycles with moderate-to-severe OHSS, 1182 cycles with severe hemoperitoneum, including 27 cycles with both conditions, and 1,422,575 cycles without moderate-to-severe OHSS and severe hemoperitoneum. RESULTS: The incidences of moderate-to-severe OHSS and severe hemoperitoneum were 0.79% and 0.08%, respectively, and decreased by 0.57-fold and 0.29-fold from 2007 to 2015, respectively. In cycles with OHSS and cycles with hemoperitoneum women were younger (odds ratios [OR] 0.91 and 0.95, respectively) and had more retrieved oocytes (OR 1.09 and 1.01, respectively) compared with cycles without both complications. The use of a gonadotrophin-releasing hormone (GnRH) agonist protocol for ovarian stimulation was the highest risk factor in cycles with OHSS and hemoperitoneum (OR 1.83 and 1.24, respectively), followed by GnRH antagonist protocol (reference), gonadotrophin with or without oral medicine (OR 0.45 and 0.56, respectively) and natural or oral medicine (OR 0.02 and 0.19, respectively). In fresh embryo transfer, clinical pregnancy was associated with an increased risk of OHSS and hemoperitoneum (OR 1.19 and 2.34, respectively). CONCLUSIONS: The highest risk factors affecting OHSS and hemoperitoneum were the use of a GnRH agonist protocol and clinical pregnancy following fresh embryo transfer. The incidences of OHSS and hemoperitoneum have decreased yearly with a reduction of GnRH agonist use and fresh embryo transfer.

Analysis of the risk factors and treatment for repeated implantation failure: OPtimization of Thyroid function, IMmunity, and Uterine Milieu (OPTIMUM) treatment strategy.

PROBLEM: What are the pregnancy outcomes after the OPtimization of Thyroid function, Immunity, and Uterine Milieu (OPTIMUM) treatment strategy in patients with repeated implantation failure (RIF)? METHOD OF STUDY: Infertile women with a history of RIF after more than three embryo transfer (ET) cycles underwent implantation testing, including a hysteroscopy, endometrial biopsy for CD138 immunostaining and bacterial culture, and serum 25-hydroxyvitamin D3 , interferon-γ-producing helper T (Th1) cell, IL-4-producing helper T (Th2) cell, thyroid-stimulating hormone, thyroid peroxidase antibody, and thrombophilia screening between April 2017 and August 2018. We treated chronic endometritis with antibiotics, aberrant high Th1/Th2 cell ratios with vitamin D and/or tacrolimus intake, overt/subclinical hypothyroidism with levothyroxine, and thrombophilia with low-dose aspirin. Of the 116 RIF women, 88 women with 133 ET cycles were recruited from a questionnaire-based survey regarding pregnancy outcomes. Fifty-nine consecutive RIF patients without the OPTIMUM treatment strategy were also recruited as a control. RESULTS: The 116 women with RIF after the OPTIMUM treatment strategy were 38.3 ± 3.8 years old and had an implantation failure history over 5 (3-19) ET cycles. Implantation testing identified impaired intrauterine circumstances in 75 women (64.7%), an aberrant elevated Th1/Th2 cell ratio in 56 women (48.3%), and thyroid abnormalities in 33 women (28.4%). Cumulative ongoing pregnancy rates including spontaneous pregnancy in the patients aged < 40 and ≥ 40 years were 72.7% and 45.5% within two ET cycles, respectively. The pregnancy outcomes in the OPTIMUM group were significantly higher than those in the control. CONCLUSIONS: The OPTIMUM treatment strategy improved pregnancy outcomes in patients with RIF.