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.

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.

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.

Clinical outcomes of assisted reproductive technology treatment by using a self-injection of recombinant human chorionic gonadotropin as the final maturation trigger.

PURPOSE: To evaluate the efficacy and safety of self-injections of the prefilled recombinant human chorionic gonadotropin (r-hCG) in a syringe in assisted reproductive technology (ART) treatment for the maturation trigger (MT), as compared to self-injections of conventional hCG and intranasal administration of gonadotropin-releasing hormone agonist (GnRH-a). METHODS: Between January and April, 2017, 396 patients who underwent oocyte retrieval were recruited. Of these, 396 patients were classified into three groups, according to the types of MT: (1) the urinary human chorionic gonadotropin (u-hCG) group that consisted of patients who had a self-injection of u-hCG (n = 127); (2) the GnRH-a group that received nasal administration of GnRH-a (n = 159); and (3) the r-hCG group that had a self-injection of r-hCG (n = 110). Several ART outcomes were evaluated. RESULTS: The mature oocyte retrieval rate was not different between the u-hCG, r-hCG, and GnRH-a groups and the fertilization and cleavage rates were similar between the three groups. The clinical pregnancy rates did not significantly differ between the GnRH-a group and the u-hCG group; however, it was significantly lower in the GnRH-a group, compared to the r-hCG group. No difference was observed in the incidence of moderate or more severe ovarian hyperstimulation syndrome among the three groups. CONCLUSION: The self-injection of the prefilled r-hCG is a favorable MT for ART patients.

Perinatal outcomes of patients who achieved pregnancy with a morphologically poor embryo via assisted reproductive technology.

PURPOSE: To learn more about the perinatal outcomes of conception via the use of low-grade embryos, we evaluated the relationship between the status of transferred embryos and the resultant perinatal outcomes. METHODS: A total of 340 patients who achieved pregnancy via ART treatment and consequently delivered in our clinic between April 2009 and March 2014 were recruited for this study. Patients were divided into two groups according to a morphological assessment of the transferred embryos, which relegated 79 patients into a poor-embryo group with the remainders (n = 261) placed into a good-embryo group. RESULTS: The mean maternal age for the poor-embryo group was 36.0 years, which was similar to the good-embryo group (36.8). In both groups, the percentages of fresh ET cycles were similar. The values for the mean birth weight and birth height of infants in the poor-embryo group were 3055 g and 50.3 cm, respectively, and there were no significant differences with the good-embryo group. The umbilical blood gas analysis in the poor-quality group was similar to that in the good-embryo group. There were no obvious major anomalies among the infants of either group. CONCLUSIONS: The perinatal outcomes of the poor-embryo group were comparable to those of the good-embryo group. Based on these results, we can provide qualified assurance for a normal perinatal outcome to patients who had no choice but to undergo embryo transfer with a poor-quality embryo.

Prostaglandin therapy during the proliferative phase improves pregnancy rates following frozen embryo transfer in a hormone replacement cycle.

AIM: To determine the efficacy of prostaglandin administration during the proliferative phase in order to improve pregnancy rates following frozen embryo transfer during a hormone replacement cycle (HRC). METHODS: From September 2010 through March 2012, patients (n = 135) were recruited who had undergone oocyte retrieval during a stimulation cycle with clomiphene and had deferred fresh embryo transfer (ET) due to a thin uterine endometrium. All patients were less than 40 years of age and underwent thawed ET following all embryo cryopreservation, and were randomly divided into two groups for thawed ET using a conventional hormone replacement cycle with or without prostaglandin derivatives (prostaglandin or conventional group). Prostaglandin derivatives were administrated during the proliferative phase. Pregnancy and implantation rates following frozen ET were compared between the two groups. RESULTS: Although the endometrial thickness on the day of ET was similar for the prostaglandin and conventional groups, the pregnancy and implantation rates for the prostaglandin group were 40.0% and 22.0%, respectively, which was significantly higher than the rates for the conventional group (P < 0.01). CONCLUSION: Among patients who avoided fresh ET due to a thin endometrium, the pregnancy rate following a thawed cycle was low. However, it was improved when prostaglandin derivatives were used during the proliferative phase.

Using a mild stimulation protocol combined with clomiphene citrate and recombinant follicle-stimulating hormone to determine the optimal number of oocytes needed to achieve pregnancy and reduce the concerns of patients.

PURPOSE: The purpose of this study was to investigate how many oocytes are needed to achieve an adequate pregnancy rate per 1 oocyte retrieval cycle in mild ovarian stimulation. METHODS: This protocol consisted of clomiphene citrate and recombinant-follicle-stimulating hormone injection without a gonadotropin-releasing hormone-antagonist. From January 2009 through December 2010, there were 1,227 women who underwent assisted reproductive technologies treatment with mild stimulation at the Sugiyama Clinic. The overall pregnancy rate per single oocyte retrieval cycle was evaluated using both fresh and cryopreserved-and-thawed embryos according to the retrieved oocyte number. RESULTS: According to the retrieved oocyte number, a total of 1,227 cycles were divided into 4 groups: group A (the oocyte number <4; 433 cycles), group B (the oocyte number = 4, 5; 317 cycles), group C (the oocyte number = 6, 7; 206 cycles), and group D (the oocyte number ≥8; 271 cycles). The overall pregnancy rates for groups A, B, C, and D were 22.2, 42.9, 52.4, and 56.0 %, respectively, the rates for groups C and D were significantly higher than that for group A (p < 0.01). CONCLUSIONS: The optimal number of retrieved oocytes proved to be between 6 and 7 for the patients who received our milder stimulation protocol and experienced no reduction in their overall pregnancy rate.

A programmed schedule of oocyte retrieval using mild ovarian stimulation (clomiphene citrate and recombinant follicle-stimulating hormone).

PURPOSE: The purpose was to establish a mild ovarian stimulation protocol that would help assisted reproductive technology (ART) units to avoid scheduling on weekends. METHODS: This protocol directed patients to take 50 mg/day of clomiphene citrate between days 3 and 7 of the menstrual cycle: 225 IU of recombinant follicle-stimulating hormone (rec-FSH) were administered on days 3, 5 and 7; human chorionic gonadotropin (hCG) was administered on day 9; and, oocyte pick-up (OPU) was planned for day 11. From October 2008 through October 2009, 514 women underwent ART treatment with mild stimulation at the Sugiyama Clinic, and we evaluated whether OPU was accomplished on the planned day. RESULTS: Of all the treatment cycles, 419 (81.5%) underwent OPU on day 11 (scheduled group). Additional rec-FSH administration was needed in 83 cycles, in which case OPU was performed on day 12 or later. In 12 cycles, OPU was canceled. The unscheduled group (n = 95) consisted of delayed OPU cycles and canceled cycles. Of all treatment cycles, 332 cycles in the scheduled group and 68 cycles in the unscheduled group underwent embryo transfer, with 81 and 16, respectively, resulting in pregnancies. CONCLUSIONS: Using this protocol, OPU was performed on the scheduled day in about 80% of the cycles. Most weekend scheduling of OPU can be avoided using this mild stimulation.

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.

Impact of chronic endometritis on endometrial receptivity analysis results and pregnancy outcomes.

BACKGROUND: The aim of this study is to evaluate the relationship between chronic endometritis (CE) and a personalized window of implantation (WOI), identified by results of endometrial receptivity analysis (ERA), and pregnancy outcomes following embryo transfer (ET) based on the ERA outcomes. METHODS: The single-center, cross-sectional study was designed. The study population consisted of 101 infertile women who underwent endometrial sampling between June 2018 and February 2020. We recruited 88 patients who underwent ERA testing and immunohistochemistry of the plasma cell marker CD138 to diagnose CE within 3 months of testing. Subjects were divided into three groups as follows: 33 without CE (non-CE group); 19 with untreated CE at ERA testing (CE group); and 36 successfully treated for CE before ERA testing (cured-CE group). CE diagnosis was defined as ≥5 CD138-positive plasma cells per 10 random stromal areas at ×400 magnification. RESULTS: In non-CE, CE, and cured-CE groups, the numbers of CD138-positive cells were 0.7 ± 1.0, 28.5 ± 30.4, and 1.3 ± 1.3, respectively (p < .001). The rates of "receptive" endometrium in non-CE and cured-CE groups were 57.6% (19 women) and 50.0% (18 women), respectively; however, in the CE group, this rate was significantly lower than the other two groups (p = .009) at only 15.8% (3 women). After CE were treated prior or posterior to the ERA test in cured-CE or CE groups, the clinical pregnancy rates at the first ET in non-CE, CE, and cured-CE groups were 77.8% (21/27 cycles), 22.2% (4/18 cycles), and 51.7% (15/29 cycles), respectively (p < 0.001). CONCLUSION: CE had detrimental effects on the individual WOI, leading to embryo-endometrial asynchrony; therefore, diagnosis and treatment of CE should be done before ERA testing.

Physicians' perception of the "Guidelines for Obstetrical Practice in Japan" and the reasons for different compliances.

The "Guidelines for Obstetrical Practice in Japan" are the first consensus-based guidelines in the field of obstetrics and were published in 2008 owing to an obstetric medical care crisis in Japan. The Guidelines describe appropriate methods for obstetric care and were based on consensus among obstetricians in Japan. Originally, the Guidelines were not intended to be a rulebook to limit physician discretion; however, from a medical care litigation standpoint, medical practices that conform to the Guidelines are following the "medical standard". The present study aimed to investigate obstetricians' perceptions of the Guidelines, to assess the degree of compliance, and to consider the implication of physician discretion in medical litigation. A questionnaire exploring the perception of the Guidelines was completed by 341 obstetricians was conducted from February 2009 until May 2009; questionnaires were evaluated using simple aggregation, correlation analysis, and principal component analysis. Although more than 80% of physicians responded that content of the Guidelines was appropriate, only 34.7% complied with recommendation level A. Our findings suggest that the rate of compliance to the Guidelines should be improved, reasons for noncompliance should be clarified, and Guidelines that are easier for patients to understand should be drafted.