Guideline for gynecological practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2023 edition.

Twelve years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 5th Revised Edition was published in 2023. The 2023 Guidelines includes 5 additional clinical questions (CQs), which brings the total to 103 CQ (12 on infectious disease, 30 on oncology and benign tumors, 29 on endocrinology and infertility and 32 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

Japanese Nursing Staff's Knowledge and Attitude toward Bereavement Care for Couples with Miscarriage/Stillbirth and Its Associated Factors.

Bereavement care is conducted to meet the emotional needs of grieving couples who are devastated by the experience of a miscarriage or stillbirth. From January to April 2022, we distributed a questionnaire that assessed the knowledge and attitudes of Japanese nursing staff (nurses and midwives) in Japan's Chugoku-Shikoku region toward bereavement care for couples with miscarriage/stillbirth. The 370 survey respondents' answers revealed that the nursing staff's knowledge regarding recurrent pregnancy loss and subsequent bereavement care was insufficient. About 41.1% and 64.1% of the respondents had received school and on-the-job education in bereavement care, respectively, and 79.2% expressed willingness to provide such care. Our analyses revealed that the following factors were associated with the nursing staff's knowledge level: parent status, age, reproductive history, midwifery license, work experience and environment, and on-the-job education. The following were correlated with the staff's willingness to provide bereavement care: work environment, midwifery license, bereavement care knowledge, and on-the-job education. Together our findings indicate that education plays a significant role in equipping caregivers to provide effective bereavement care for couples who have experienced a miscarriage or stillbirth.

Anti-ß2-glycoprotein I/HLA-DR Antibody and Adverse Obstetric Outcomes.

Anti-ß2-glycoprotein I/HLA-DR (anti-ß2GPI/HLA-DR) antibody has been reported to be associated with antiphospholipid syndrome and recurrent pregnancy loss (RPL). We conducted a prospective multicenter cross-sectional study aimed at evaluating whether the anti-ß2GPI/HLA-DR antibody is associated with adverse obstetric outcomes and RPL. From 2019 to 2021, serum anti-ß2GPI/HLA-DR antibody levels (normal, <73.3 U) were measured in 462 women with RPL, 124 with fetal growth restriction (FGR), 138 with hypertensive disorders of pregnancy (HDP), 71 with preterm delivery before 34 gestational weeks (preterm delivery (PD) ≤ 34 GWs), and 488 control women who experienced normal delivery, by flow cytometry analysis. The adjusted odds ratios (aORs) of anti-ß2GPI/HLA-DR antibody positivity for adverse obstetric outcomes and RPL were evaluated on the basis of comparisons between the control and each patient group, using multivariable logistic regression analysis. The following were the positivity rates for the anti-ß2GPI/HLA-DR antibody in the patient and control groups: RPL, 16.9%; FGR, 15.3%; HDP, 17.4%; PD ≤ 34 GWs, 11.3%; and the control, 5.5%. It was demonstrated that anti-ß2GPI/HLA-DR antibody positivity was a significant risk factor for RPL (aOR, 3.3 [95% confidence interval {CI} 1.9-5.6], p < 0.001), FGR (2.7 [1.3-5.3], p < 0.01), and HDP (2.7 [1.4-5.3], p < 0.01) although not for PD ≤ 34 GWs. For the first time, our study demonstrated that the anti-ß2GPI/HLA-DR antibody is involved in the pathophysiology underlying FGR and HDP, as well as RPL.

Gestational Outcomes and Birth Weight in Japanese Women at the Upper and Lower limits of the Normal BMI range.

To examine the outcome of gestational blood pressure and birth weight in women with normal pre-pregnancy BMI (18.5-25 kg/m2) who are at the lower and upper limits of this range, i.e., slightly underweight or slightly overweight. Overall, 2,038 Japanese women with low -risk who had delivered during January 2014-December 2016 were classified according to their pre-pregnancy BMI: underweight (< 18.5 kg/m2), slightly underweight (18.5≤BMI<21 kg/m2), normal (21≤BMI<23 kg/m2), slightly overweight (23≤BMI<25 kg/m2) and overweight (≤ 25 kg/m2). Their blood pressure during each trimester and birth weight was evaluated. The slightly overweight group showed a significantly higher blood pressure than the underweight and slightly underweight groups. Birth weight was lower in the slightly underweight than in the slightly overweight group (p<0.01). The incidence rate of "heavy for dates" (HFD) infants was significantly higher in the slightly overweight and overweight groups than in the other groups (p<0.05 and p<0.01, respectively). Weight gain of < 7 kg significantly increased the rate of "light for dates" (LFD) infants, while a weight gain of ≥13 kg significantly increased the rate of HFD infants (p<0.05 and p<0.01, respectively). Blood pressure during pregnancy was ssociated with pre-pregnancy BMI. The birth weight of infants of low-risk pregnant women is affected by both pre-pregnancy BMI and gestational weight gain.

Inflammation of the adipose tissue in the retroperitoneal cavity adjacent to pelvic endometriosis.

AIM: Peritoneal endometriosis is a chronic inflammatory disease particularly associated with macrophages. Of note, adipose tissues with fibrotic changes in the context of peritoneal endometriotic lesions are often observed during surgery. However, the characteristics of fibrotic adipose tissues in endometriosis are still unknown. In this study, we investigated the inflammatory status of retroperitoneal adipose tissues adjacent to pelvic endometriotic lesions. METHODS: Thirty-two patients who underwent surgical treatment were assigned to either the endometriosis (n = 16) or the control (n = 16) groups. Retroperitoneal adipose tissues around the uterus were collected from patients in both groups. Fibrosis was evaluated via Masson's trichrome staining. Macrophage infiltration, the expression of fatty acid-binding protein 4 (FABP4), and angiogenesis in the retroperitoneal adipose tissues were evaluated via immunohistochemistry. The mRNA expression levels of cytokines was also evaluated in the adipose tissues using real-time PCR. RESULTS: There was more fibrosis and angiogenesis in the adipose tissues adjacent to the endometriotic lesions with a significantly higher level of infiltration of macrophages and a predominance of the M1 type in the endometriosis group compared to the control group. In addition, FABP4 positivity in the adipose tissues of the peritoneum was significantly higher in the endometriosis group versus the control group. Moreover, the mRNA expression levels of FABP4, VEGF, and proinflammatory cytokines were also significantly higher in the endometriosis group. CONCLUSION: Altogether, our results showed that the adipose tissue adjacent to endometriotic lesions are inflamed with fibrosis and angiogenesis.

Relation Between Identity Disclosure to Family Members and Mental Health in Japanese Transgender People.

Family members are critical mediators of the experiences of transgender people. We studied whether transgen-der subjects had disclosed their identity to their families and their families' reactions after the disclosure. We also evaluated the subjects' mental state and its association with disclosure status. Transgender people were recruited for this anonymous questionnaire survey in the Okayama University Hospital gender clinic. Subjects disclosed their identity to family members at the following rates: 68.7% to the father, 89.1% to the mother, 59.1% to a brother, 77.8% to a sister, and 47.6% to grandparents. Fathers had the lowest rate (26.7%) of posi-tive reactions, while over 50% of fathers showed an ambiguous response. Approximately 20% of parents showed a negative response. The majority of parents agreed to hormonal treatment and sex-reassignment sur-gery and that the transgender child should live with the gender they wanted to express. However, the rate of subjects with mood and anxiety disorders according to the Kessler 6 scale was significantly higher in those who experienced negative or ambiguous reactions from family members compared to those who experienced posi-tive reactions. Educational and mental health professionals should support the disclosure process of transgen-der people as well as their family members.

Gender Expression among Transgender Women in Japan: Support Is Needed to Improve Social Passing as a Woman.

Gender expression is important for transgender women to improve their social passing as women. Herein, a questionnaire about the status of gender expression and support needs was distributed to 54 transgender women aged 17-71 in Japan. Most of the respondents noted that they had found it relatively difficult to handle physical changes and weight gain due to hormone treatment. They also found it difficult to enact and sustain practices such as a feminine use of voice and to use women-only services, whereas practicing and continuing with routine skin and hair care and feminine mannerisms were relatively easy for them. In the questionnaire regarding the support for gender transitioning, many items showed only a small percentage of the transgender women had received the support that they were looking for, and most of their needs for support were not addressed. Some of the factors that increased the respondents' needs and achievement of gender expression as women included estrogen treatment, sex reassignment surgery, and living as a woman; these aspects met their support needs as well. Gender support professionals need to coordinate and collaborate with specialists in areas such as nutritional guidance and voice training to enable transgender women to improve the extent to which they can socially 'pass' as women.

Increased Plasma Levels of Platelet Factor 4 and ß-thromboglobulin in Women with Recurrent Pregnancy Loss.

Thrombosis in decidual vessels is one of the mechanisms of pregnancy loss. However, few studies have assessed the relation between platelet activation, which is known to cause of thrombosis, and recurrent pregnancy loss (RPL). We investigated platelet activation in women with RPL compared to controls by measuring plasma levels of platelet factor 4 (PF4) and ß-thromboglobulin (ßTG), and assessed correlations between PF4/ßTG and coagulative risk factors associated with RPL. The study group included 135 women who had experienced two or more consecutive pregnancy losses. The control group included 28 age-matched healthy women who had never experienced pregnancy loss. PF4 and ßTG plasma levels were significantly higher in the women with RPL than controls (PF4: 14.0 [8.0-20.0] vs. 9.0 [6.0-12.0] ng/ml, p=0.043; ßTG: 42.0 [24.3-59.8] vs. 31.5 [26.6-36.4] ng/ml, p=0.002). There was a significant association between ßTG and anti-phosphatidylethanolamine antibody immunoglobulin M (aPE IgM) (p=0.048). Among the women with RPL, 18 of those who were positive for PF4 (45%) and 18 of those who were positive for ßTG (37%) were negative for all known coagulative risk factors associated with RPL. Measurements of PF4 and ßTG may be important because they help identify women who are at risk of RPL.

Risk Factors and Outcomes of Recurrent Pregnancy Loss in Japan.

AIM: To clarify the risk factors and pregnancy outcomes for each risk factor of recurrent pregnancy loss (RPL) in Japan. METHODS: Using a prospective RPL database collected from 16 facilities in Japan, the prevalence of risk factors for RPL, their treatments and pregnancy outcomes were examined. RESULTS: Of 6663 patients registered in our database, 5708 patients had RPL. All examinations for risk factors were performed for 1340 patients (23.5%). The prevalences of positive antiphospholipid antibodies (aPL), malformation of the uterus, thyroid dysfunction, parental karyotype abnormality, factor XII deficiency, protein S deficiency and unknown risk factors were 8.7%, 7.9%, 9.5%, 3.7%, 7.6%, 4.3% and 65.1%, respectively. Although factor XII deficiency and protein S deficiency are not recognized as risk factors for RPL in general, low-dose aspirin (LDA) or unfractionated heparin + LDA therapy improved live birth rates. In transiently aPL-positive patients, the live birth rate with LDA therapy was similar to that with heparin + LDA. For unknown risk factors of RPL, the live birth rate in normal fetal karyotype in the none treatment group was similar to that in all other treatments group (81.3% vs 86.0%). Of 5708 RPL patients, pregnancy outcomes were known for 2261 patients and 1697 patients (75.1%) had at least one live birth. CONCLUSION: The risk factors and pregnancy outcomes for each risk factor of RPL are useful for clinicians and patients. Factor XII deficiency and protein S deficiency may be risk factors of RPL.

Thyroid Function Decline and Diet in Female High School Long-distance Runners.

We aimed to clarify the state of thyroid function in female high school long-distance runners. We evaluated the associations between thyroid function and menstrual condition, bone mineral density (BMD), nutritious status, and body composition. The subjects' height and weight were measured, along with fat percentage, fat mass, muscle mass, and BMD with dual-energy X-ray absorptiometry. A nutrition and dietary survey measured the subjects' intake of energy and nutrients based on meals provided at the subjects' dorm for 3 days in July of 2016 and 2017. Blood parameters including thyroid hormone and estradiol were measured. Most of the subjects (81.3%) were underweight (body mass index <18.5). The thyroid hormone free T3 value was decreased, but TSH was not increased and was similar to that observed in individuals with anorexia nervosa. In our subjects, thyroid hormone was associated with BMD and nutritional intake. To improve the menstruation abnormality of female athletes and to increase their bone density, the athletes' weight should be managed by proper nutrient intake and the maintenance of their thyroid function.

Fertility preservation in adolescent and young adult cancer patients: From a part of a national survey on oncofertility in Japan.

PURPOSE: This study evaluated the current status of reproductive disorders and provision of information on oncofertility to female adolescent and young adult (AYA) cancer patients in Japan. METHODS: A national survey of AYA cancer survivors was conducted. Children were <15 years old, and AYAs were 15-39 years old. Results from the survivors of other than gynecological disease who underwent chemotherapy were analyzed. RESULTS: Among the survivors, 41.4% were concerned about their reproductive function and infertility, and 36.2% were aware of menstrual cycle abnormalities. Among them, 15.5% (n = 20) of all and 21.2% (n = 17) of the AYA-onset survivors suffered infertility due to chemo- or radiotherapy and gave up childbearing. These rates were significantly higher than those of healthy AYAs. Although 80.8% of AYA-onset survivors answered that they had received information on reproductive function and infertility, only 55.8% had received information on fertility preservation methods. Furthermore, only 22.4% of all and 42.3% of AYA-onset survivors had received pretreatment information on fertility preservation methods. CONCLUSIONS: Not a few AYA cancer survivors reported reproductive dysfunction. These findings indicate that information provided on therapy-related problems before cancer treatment in Japan was insufficient and highlight the need to improve patient decision-making and support systems for fertility preservation.

Problems of reproductive function in survivors of childhood- and adolescent and young adult-onset cancer revealed in a part of a national survey of Japan.

PURPOSE: This study aimed to evaluate the current status of reproductive disorders as long-term complications in adolescent and young adult (AYA) cancer patients by comparing survivors of childhood-onset with those of AYA-onset cancer in Japan. METHODS: We conducted a national survey of AYA cancer survivors and healthy AYAs and analyzed the results from survivors who underwent chemotherapy and reported fertility problems as their current concern. RESULTS: Among all of the childhood-onset survivors, 27 (35.5%; nine males [28.1%] and 18 females [40.9%]) listed reproduction fertility problems as their current concern. Among all AYA-onset survivors, 25 (69.5%; 1/4 males [25.0%] and 24/32 females [75.0%]) listed these problems as a current concern. In contrast, 96.3% (26/27) of all childhood-onset cancer survivors and 68.0% (17/25) of all AYA-onset cancer survivors who received chemotherapy listed these problems as a current concern. CONCLUSIONS: A considerable number of both childhood-onset and AYA-onset cancer survivors, and especially those who had undergone chemotherapy, reported reproductive dysfunction as a delayed complication. It is vitally important to establish a supportive care system both for the patients whose fertility was abolished after the completion of cancer treatment and prophylactically for patients before they begin treatment.

Descriptive Study of Gender Dysphoria in Japanese Individuals with Male-to-Female Gender Identity Disorder.

We focus on Japanese individuals with gender identity disorder (GID), especially male-to-female (MTF) GID, who have experienced difficulty in adapting to social life. We clarify what gender dysphoria is, and we examine methods of intervention. Semi-structured interviews were conducted with 11 individuals with MTF-GID from August 2015 to April 2017. We categorized the subjects'experiences regarding dysphoria into the 'Onset of gender dysphoria,' 'Experience of feeling gender dysphoria,' and 'Changes due to receiving medical care.' The subjects reported experiencing great pain and distress because they did not fully understand that they were experiencing dysphoria and could not align their gender identity and their self-identity. All subjects described their experiences of dysphoria as negative. Additionally, all said that the dysphoria was alleviated by a medical intervention such as visiting a gender clinic, receiving a diagnosis and treatment, and changing their physical sex to the sex congruent with their gender identity. The provision of information at the gender clinic and the physical changes achieved by medical intervention exerted a positive effect both mentally and socially on the subjects, who suffered various physical, mental and social problems.

Women with Recurrent Pregnancy Loss : Their Psychology During Late Pregnancy and the Supportive Behavior of Their Partners.

To elucidate the psychiatric characteristics of mothers and the supportive behavior of their partners during late pregnancy, 131 mothers who gave birth at 2 general hospitals in City A between August 2009 and September 2010 (control group: n=90; recurrent pregnancy loss (RPL) group: n=41) completed a self-administered questionnaire on four separate occasions: during late pregnancy, during hospitalization, at 1-month postpartum, and at 3-months postpartum. The RPL group had significantly (p=0.03) lower anxiety regarding potential change in their appearance than the controls, but were more likely to worry about losing their baby (58% vs. 38%) (p=0.021). At 3-months postpartum, the RPL group reported having had more stress during pregnancy than the controls (49% vs. 31%; p=0.041). There were no significant differences in state or trait anxiety (State-Trait Anxiety Inventory) between the 2 groups at any of the four measurements. However, state anxiety decreased significantly throughout the hospitalization for controls (p <0.001), but did not decrease significantly for the RPL group until 3 months postpartum (p<0.05). RPL participants who expressed high satisfaction with their partners' supportive behavior received significantly greater psychological support than did participants with low satisfaction. Healthcare professionals should attempt to support both members of RPL couples.

Slow Fetal Heart Rate before Miscarriage in the Early First Trimester Predicts Fetal Aneuploidy in Women with Recurrent Pregnancy Loss.

Establishing whether miscarriages result from fetal aneuploidy or other factors is important for treating recurrent pregnancy loss. We examined the relationship between fetal heart rate (FHR) before miscarriage in the early first trimester and fetal karyotype, analyzing 223 pregnant women with recurrent pregnancy loss. Among the pregnancies, 110 resulted in live births regarded as normal karyotype (the Norm-group). The other 113 pregnancies ended in miscarriage, and we categorized them into groups based on fetal karyotype, determined by chorionic villus sampling: the Misc-NK (normal karyotype) group, n=35 euploid cases; the Misc-CA1 (chromosomal abnormality) group, n=18 cases of aneuploidy with trisomies 13/18/21, Turner's syndrome, or Klinefelter's syndrome; and the Misc-CA2 subgroup, n=60 cases of other aneuploidies excluding those in the Misc-CA1 group. We compared the groups' regression line slopes and intercepts for FHR by an analysis of covariance. The FHRs of the Norm, Misc-NK and Misc-CA1 groups increased from 36 to 49 days after fertilization, but did not significantly differ across these groups. The Misc-CA2 group's FHR did not increase and significantly differed from the other three groups (p<0.01). These results suggest that the absence of an increase in FHR in early pregnancy may indicate the presence of chromosomal abnormalities causing miscarriage.

Current Multidisciplinary Approach to Fertility Preservation for Breast Cancer Patients.

Adverse effects on fertility are a significant problem for premenopausal breast cancer patients. Since April 2009, we have been referring young patients for fertility counseling provided by a multidisciplinary team. Here we evaluated the efficacy and safety of our current fertility preservation approach. We retrospectively analyzed the cases of 277 patients < 45 years old at diagnosis, which was made between 2009 and 2016. Seventy-two (26%) patients received fertility counseling. Seventeen (6%) of the 277 patients decided to preserve their fertility before starting adjuvant systemic therapy. Six (35%) patients underwent oocyte cryopreservation, and 11 (65%) married patients opted for embryo cryopreservation. There were no pregnancies among the patients undergoing oocyte cryopreservation, whereas 3 (27%) of the patients who opted for embryo cryopreservation became pregnant. Two (12%) patients stopped endocrine therapy after 2 years in an effort to become pregnant, but their breast cancers recurred. Though the problem of fertility loss for breast cancer patients is important and we should assess the infertility risk for all patients, we should also consider the prognosis. In June 2016, we launched a prospective multicenter cohort study to evaluate the efficacy and safety of fertility preservation in greater detail.

[Current Status of Oncofertility in Adolescent and Young Adult (AYA) Generation Cancer Patients in Japan - National Survey of Oncologists].

A national survey conducted in 2016 aimed to evaluate the current status and needs of the field of oncofertility and to consider optimized medical delivery systems. A total of 739 oncologists, excluding gynecological and urological specialists, were surveyed. Of these, 99.2% thought that providing information on fertility preservation was important. Of the surveyed oncologists, 48% were affiliated with facilities providing assisted reproductive technology, and 79.3% practiced in university hospitals. Of 238 (32.2%) specialists who provided information on the risk of reproductive damage resulting from treatment in their facility, 163 (44.9%) and 75 (19.9%) practiced in university hospitals (n=363) and non-university hospitals (n= 376), respectively. In contrast, 14.3% and 32.7% of oncologists who practiced in university hospitals and non-university hospitals, respectively, collaborated with local obstetricians and gynecologists. Among oncologists who use a gradually expanding regional oncofertility network, 0.6% practice in university hospitals and 2.7% practice in non-university hospitals. Patients were advised that the risk of infertility was 92.3% and the likelihood of fertility preservation was 66.9%. Furthermore, as an ideal way of providing information on preservation of fertility, 22.9% of oncologists collaborate with local gynecologists, and 26.3% do so at a public cancer and reproductive medical counseling center. In addition, 34.7% and 55.1% of oncologists at university and non-university hospitals, respectively, thought that implementation of a fertility preservation program at a public facility would be desirable. Although most oncologists recognize the importance of providing information on reproductive medicine, the support system for reproductive function and fertility in adolescent and young adult (AYA) generation cancer patients is limited because of the lack of agreement on patient referral. The limited number of referrals in turn limits data collection in the field of oncofertility. Grant: A Health and Labour Sciences Research Grant: H27-Cancer Control-Ippan.

Increased Anti-HSP60 and Anti-HSP70 Antibodies in Women with Unexplained Recurrent Pregnancy Loss.

　Vascular dysfunction has been reported in women with recurrent pregnancy loss (RPL). We investigated the severity of vascular dysfunction in non-pregnant women with RPL and its correlation with anti-heat shock protein (HSP) antibodies that are known to induce arteriosclerosis. We measured the serum anti-HSP60 antibodies, anti-HSP70 antibodies, and anti-phospholipid antibodies (APA) in 68 women with RPL and 29 healthy controls. Among the women with RPL, 14 had a diagnosis of antiphospholipid syndrome (APS), and in the remaining 54, the causes for RPL were unexplained. Compared to the controls, the brachial-ankle pulse wave velocity (baPWV), carotid augmentation index (cAI), and uterine artery pulsatility index (PI) were all significantly higher in the women with both APS and unexplained RPL. Compared to the controls, the anti-HSP60 antibody levels were significantly higher in the APA-positive group of women with unexplained RPL, and the anti-HSP70 antibody levels were significantly higher in APS and APA-positive group of women with unexplained RPL. However, the anti-HSP60 and anti-HSP70 antibody levels did not correlate with the values of baPWV or cAI. Our results demonstrated anti-HSP60 and anti-HSP70 antibodies are increased in women with unexplained RPL. Further studies are needed to elucidate the roles of anti-HSP antibodies and their pathophysiology in unexplained RPL.

Altered autonomic nervous system activity in women with unexplained recurrent pregnancy loss.

AIM: Autonomic nervous system activity was studied to evaluate the physical and mental state of women with unexplained recurrent pregnancy loss (RPL). METHODS: Heart rate variability (HRV) is a measure of beat-to-beat temporal changes in heart rate and provides indirect insight into autonomic nervous system tone and can be used to assess sympathetic and parasympathetic tone. We studied autonomic nervous system activity by measuring HRV in 100 women with unexplained RPL and 61 healthy female volunteers as controls. The degree of mental distress was assessed using the Kessler 6 (K6) scale. RESULTS: The K6 score in women with unexplained RPL was significantly higher than in control women. HRV evaluated on standard deviation of the normal-to-normal interval (SDNN) and total power was significantly lower in women with unexplained RPL compared with control women. These indices were further lower in women with unexplained RPL ≥4. On spectral analysis, high-frequency (HF) power, an index of parasympathetic nervous system activity, was significantly lower in women with unexplained RPL compared with control women, but there was no significant difference in the ratio of low-frequency (LF) power to HF power (LF/HF), an index of sympathetic nervous system activity, between the groups. CONCLUSIONS: The physical and mental state of women with unexplained RPL should be evaluated using HRV to offer mental support. Furthermore, study of HRV may elucidate the risk of cardiovascular diseases and the mechanisms underlying unexplained RPL.