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The renin-angiotensin system is believed to influence blood pressure (BP) during pregnancy, but the associations between BP during pregnancy and the soluble form of the (pro)renin receptor (s[P]RR), a new component of the tissue renin-angiotensin system, remain undetermined. In this prospective cohort study of 437 pregnant women with normal BP (systolic <140 mm Hg and diastolic <90 mm Hg) during early pregnancy (<16 weeks of gestation) regression analysis was performed to examine the associations between plasma s(P)RR concentrations and BP in 3 gestational stages (20-24, 28-32, and 36-40 weeks of gestation) and logistic regression analysis to evaluate the incidence of preeclampsia. Plasma s(P)RR concentrations at early, middle (16-28 weeks), and late pregnancy (>28 weeks) and at delivery averaged 29.7 ± 10.0, 31.3 ± 12.0, 39.2 ± 8.9, and 40.4 ± 10.2 ng/mL (mean ± SD), respectively. A 1-ng/mL increase in plasma s(P)RR concentration in early pregnancy predicted systolic/diastolic BP elevation in the later 3 gestational stages: 0.11 (95% CI, 0.014-0.20)/0.093 (0.027-0.16) mm Hg for 20 to 24 weeks, 0.11 (0.029-0.19)/0.088 (0.027-0.15) mm Hg for 28 to 32 weeks, and 0.16 (0.058-0.26)/0.12 (0.043-0.19]) mm Hg for 36 to 40 weeks, respectively. Plasma s(P)RR concentrations in middle and late pregnancy were not associated with BP. Adjusted models revealed that women with plasma s(P)RR concentrations above the 75th percentile at delivery had a significantly increased risk of preeclampsia (odds ratio, 22.5 [95% CI, 1.8-279.9]). In conclusion, high circulating levels of s(P)RR at early pregnancy predicted a subsequent elevation in BP, and high concentrations at delivery were significantly associated with preeclampsia. [ABSTRACT FROM AUTHOR]

This multicenter prospective study investigated seasonal variation in home blood pressure (HBP) during pregnancy and its association with the frequency of hypertensive disorders of pregnancy (HDP) and developed trimester-specific upper limits of HBP according to season. Low-risk women with singleton pregnancies were recruited at six university hospitals and three maternity clinics. HBP was measured by a sphygmomanometer twice daily and recorded online using a mobile application. HBP was evaluated according to season (winter, spring, summer, and autumn) and gestational age. Of 705 women recruited, 603 were finally included. Mean diastolic HBP values were lowest in summer and highest in winter throughout pregnancy (mean difference between summer and winter, 3.5-4.6 mmHg). Mean systolic HBP values were also lowest in summer and highest in winter except during the early period of the second trimester (mean difference between summer and the season with the highest value, 2.5-3.4 mmHg). HDP was diagnosed in 32 women (5.3%). The risk of HDP was significantly higher in women who delivered in spring and autumn but not in winter compared with summer. The rounded upper limit of HBP was 120/80 mmHg in the first trimester, 120/75 mmHg in the second trimester, and 125/80 mmHg in the third trimester for summer and 125/85 mmHg, 125/80 mmHg, and 130/85 mmHg, respectively, for other seasons. Systolic and diastolic HBP were lowest in summer throughout pregnancy. Seasonal variation should be considered when interpreting HBP and the risk of HDP during pregnancy., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Objective: To identify any correlations between evidence levels, adoption rates, and additional costs of in vitro fertilization (IVF) add-ons., Design: Online survey., Subjects: The survey was conducted in 621 assisted reproductive technology-registered facilities that are members of the Japanese Society of Obstetrics and Gynecology from December 22, 2021, to February 13, 2022., Exposure: The survey included details regarding the specific add-on modalities employed and their associated costs; inquiries pertained to the fertility healthcare infrastructure in Japan before the implementation of the National Health Insurance scheme., Main Outcome Measures: The correlation between the adoption rate and cost of IVF add-ons and their evidence levels were analyzed. The evidence level of the add-on treatments was classified into Green, Amber, and Red categories based on the United Kingdom's Human Fertilisation and Embryology Authority and Cochrane systematic reviews., Results: A total of 438 eligible responses were analyzed, with clinics constituting 70.9% of the respondents' facilities. A total of 18 add-ons were assessed, and 96.5% (423/438) of facilities used at least one add-on. A positive correlation of the adoption rate and an inverse correlation of the cost with the evidence level of the IVF add-on treatment were observed (not significant). Outpatient clinics, defined as medical facilities with no beds, had a significantly higher adoption rate (Amber, 65.7%; Red, 52.0%) of add-ons than other facilities, regardless of the evidence rating, although the costs were similar across all site attributes., Conclusion: Accumulating evidence on the efficacy and safety of add-ons will lead to the development of medical care with a high-cost benefit, as an increase in the adoption rate and a decrease in cost are expected when limiting to medical care with a high level of evidence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shionoya, Yamada, Harada, Shirasawa, Jwa, Kuroda, Harada and Osuga.)

Objectives: To investigate the association between adenomyosis and placenta accreta spectrum (PAS) and to evaluate the effect of assisted reproductive technology (ART) in mediating this association., Methods: We retrieved data for singleton women from the Japanese nationwide perinatal registry between 2013 and 2019, excluding women with a history of adenomyomectomy. To investigate the association between adenomyosis and PAS among women, we used a multivariable logistic regression model with multiple imputation for missing data. We evaluated mediation effect of ART including in vitro fertilization and intracytoplasmic sperm injection on the association between adenomyosis and PAS using causal mediation analysis based on the counterfactual approach., Results: Of 1 500 173 pregnant women, 1539 (0.10%) had adenomyosis. The number receiving ART was 489/1539 (31.8%) and 117 482/1 498 634 (7.8%) in women with and without adenomyosis, respectively. The proportion of women who developed PAS was 21/1539 (1.4%) in women with adenomyosis and 7530/1 498 634 (0.5%) in women without adenomyosis. Adenomyosis was significantly associated with PAS (odds ratio [OR] 1.95; 95% confidence interval [CI] 1.26-3.00; P = 0.002). Mediation analysis showed that OR of the total effect of adenomyosis on PAS was 1.98 (95% CI 1.13-3.04), OR of natural indirect effect (effect explained by ART) was 1.15 (95% CI 1.01-1.41), and OR of natural direct effect (effect unexplained by ART) was 1.72 (95% CI 0.86-2.82). The proportion mediated (natural indirect effect/total effect) was 26.5%. Adenomyosis was also significantly associated with PAS without previa (OR 1.96; 95% CI 1.23-3.13, P = 0.005)., Conclusion: Adenomyosis was significantly associated with PAS. ART mediated 26.5% of the association between adenomyosis and PAS., (© 2024 International Federation of Gynecology and Obstetrics.)

Aim: To investigate variation in the diagnosis and treatment of chronic endometritis (CE) at the national level in Japan., Methods: We performed a nationwide survey targeting all assisted reproductive technology (ART) facilities across Japan between 2021 and 2022. Diagnostic methods, criteria, and first- and second-line treatment protocols for CE were collected via a questionnaire., Results: Among 616 ART facilities, 437 responded to the survey (response rate: 70.9%) of which 339 (77.6%) implemented diagnosis and treatment of CE. In the diagnosis of CE, 214 (63.1%) facilities used CD138 immunohistochemical staining of endometrial tissue, while hysteroscopy was the most frequently used as an adjunct diagnostic method (241 facilities, 71.1%). The most frequent cutoff value of CD138-positive cells for diagnosing CE was 3-5 cells/20 high-power fields (50%), but 7.9% (17 facilities) and 5.1% (11 facilities) used cutoff values of 1 and 2 cells, respectively. The most common first- and second-line treatment methods were doxycycline (210 facilities, 61.9%) and ciprofloxacin + metronidazole (164 facilities, 48.0%), respectively., Conclusions: There is considerable variation in the number of CD138-positive cells used for diagnosing CE. Establishing unified diagnostic criteria and therapeutic methods for CE is essential to provide standardized medicine for CE at the national level., (© 2024 The Author(s). Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Aims: This study aims to comprehensively examine the employment and practices of embryologists in Japan's assisted reproductive technology (ART) laboratories, focusing on the impact of various factors such as ART cycle numbers, add-ons, and regional differences. Additionally, it seeks to assess the extent to which Japanese ART facilities meet international minimum standards set by the American Society for Reproductive Medicine (ASRM)., Methods: A survey was conducted from December 2021 to February 2022 among 621 ART facilities in Japan. The study categorized facilities into five ART cycle groups and compared the number of embryologists across these groups. It also examined the correlation between the number of embryologists, ART cycles, add-ons, and regional differences. Data were analyzed using linear regression and multiple linear regression analyses., Results: The study's findings revealed a significant correlation between the total number of embryologists at each facility and the ART cycles. Notably, there were significant differences in the number of embryologists across all ART cycle categories. Of the 435 facilities, only 44.6% met the ASRM minimum embryologist staffing requirement. The regression analysis further highlighted the significance of ART cycles and preimplantation genetic testing for aneuploidies as factors. Moreover, the number of embryologists stationed at urban facilities was significantly higher than at nonurban facilities, indicating a potential regional disparity., Conclusion: In Japan, it was first found that more than 50% of ART facilities do not have sufficient embryologists in place relative to the number of ART cycles. Furthermore, the add-ons and regional differences affect the placement of embryologists., (© 2024 The Author(s). Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Objective: To report utilization, effectiveness, and safety of assisted reproductive technologies in 2015 and 2016., Design: A retrospective, cross-sectional survey of 3,103 assisted reproductive technology clinics in 74 countries in 2015 and 3,249 clinics in 79 countries in 2016 that submitted cycle and pregnancy outcome data through national and regional registries., Setting: Seventy-nine countries and >3,000 assisted reproductive technology clinics., Patient(s): Patients undergoing assisted reproductive technology procedures., Intervention(s): Assisted reproductive technology., Main Outcome Measure(s): Outcomes on country, regional, and global levels., Result(s): Reported for 2015: 2,358,239 cycles with 548,652 infants born; for 2016: 2,807,963 cycles with 647,188 infants born. Estimated in 2015, ≥2,683,677 cycles resulted in >675,134 infants; in 2016, ≥3,100,448 cycles resulted in ≥723,026 infants. Reported cycles represent approximately 80% of global utilization. In 2015 and 2016, 27.6% and 27.8%, respectively, of women undergoing fresh autologous treatment cycles were aged ≥40 years. Frozen-thawed embryo transfer (ET) cycles accounted for 47.0% and 51.9%, respectively, of all ETs in 2015 and 2016. Oocyte donation cycles accounted for 6.7% and 7.1% of all ETs in 2015 and 2016. Intracytoplasmic sperm injection was performed in 57.7% and 56.4% of autologous aspiration cycles in 2015 and 2016, respectively. The cumulative delivery rate per aspiration cycle for fresh and frozen-thawed ET was 32.4% in 2015 and 33.1% in 2016, respectively. The average number of transferred embryos was 1.70 in 2015 and 1.69 in 2016. The proportion of single ETs in fresh autologous cycles increased from 42.1% in 2015 to 44.0% in 2016. The twin delivery rate decreased from 16.0% in 2015 to 14.7% in 2016, and the triplet rate decreased from 0.6% in 2015 to 0.4% in 2016. The proportion of single ETs in frozen-thawed ET autologous treatment cycles was 62.2% in 2015 and 64.2% in 2016, with twin and triplet rates of 10.1% and 0.3% in 2015 and 10.0% and 0.2% in 2016, respectively., Conclusion(s): Utilization of assisted reproductive technology treatment and births per cycle increased from 2015 to 2016, although multiple births were reduced. An increasing proportion of frozen-thawed ET cycles, continuing wide variation in use of intracytoplasmic sperm injection, and an increase in single ET rates are reported., Competing Interests: Declaration of Interests M.S.K. reports travel support from Ferring, IBSA, and Merck, outside the submitted work. G.M.C. reports funding from the International Committee for Monitoring Assisted Reproductive Technologies (ICMART). The National Perinatal Epidemiology and Statistics Unit (NPESU) of the University of New South Wales, Sydney (UNSW) received funding. S.D. has nothing to disclose. F.Z.H. reports travel expenses to give a scientific lecture from Ferring Pharma, Director, responsible for the Latin American Registry of ART, Chair Committee of Ethics and Public Policies; Chilean Society of Obstetrics and Gynecology, Vice Chair ICMART, outside the submitted work. J.D.M. is Chair of Société de Médecine de la Reproduction, France, unpaid, outside the submitted work. O.I. has nothing to disclose. M.B. reports consulting fees from ABBOTT INIDA; honoraria from BAZEL PHARMA and MERCK SPEC; Board of Director, Pacific Rim Society of Reproductive Medicine; Board of Director, POSEIDON Group; Regional Director, IFFS Triennial Report, outside the submitted work. S.C.J. reports travel fee for lectures supported by Ferring; travel support from the Japan Society for Reproductive Medicine for attending meetings, outside the submitted work. B.F. has nothing to disclose. E.E. has nothing to disclose. V.B. reports consulting fees from Organon, Society for Assisted Reproductive Technology Executive Council, not paid, outside the submitted work. G.D.A. reports honoraria from Organon; travel support from ESHRE; Chair, International Committee for Monitoring ART. unpaid; President, World Endometriosis Research Foundation, unpaid; ICMART NGO Liaison Observer, Board of the International Federation of Fertility Societies, unpaid; ASRM: Member, Global Health Committee, American Society for Reproductive Medicine, unpaid; founder and CEO of Advanced Reproductive Care, Inc. (d/b/a ARC®Fertility), outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate whether conisation increases chorioamnionitis (CAM) and assess whether this risk differs between preterm and term periods. Furthermore, we estimated mediation effects of CAM between conisation and preterm birth (PTB)., Design: A nationwide observational study., Setting: Japan., Population: Singleton pregnant women derived from the perinatal registry database of the Japan Society of Obstetrics and Gynaecology between 2013 and 2019., Methods: The association between a history of conisation and clinical CAM was examined using a multivariable logistic regression model with multiple imputation. We conducted mediation analysis to estimate effects of CAM on PTB following conisation., Main Outcome Measures: Clinical CAM., Results: Of 1 500 206 singleton pregnant women, 6961 (0.46%) underwent conisation and 1 493 245 (99.5%) did not. Clinical CAM occurred in 150 (2.2%) and 11 484 (0.8%) women with and without conisation, respectively. Conisation was associated with clinical CAM (odds ratio [OR] 3.09; 95% confidence interval (CI) 2.63-3.64; p < 0.001) (risk difference 1.57%; 95% CI 1.20-1.94). The association was detected among 171 440 women with PTB (OR 3.09; 95% CI 2.57-3.71), whereas it was not significant among 1 328 284 with term birth (OR 0.88; 95% CI 0.58-1.34). OR of total effect of conisation on PTB was 2.71, OR of natural indirect effect (effect explained by clinical CAM) was 1.04, and OR of natural direct effect (effect unexplained by clinical CAM) was 2.61. The proportion mediated was 5.9%., Conclusions: Conisation increased CAM occurrence. Obstetricians should be careful regarding CAM in women with conisation, especially in preterm period. Bacterial infections may be an important cause of PTB after conisation., (© 2023 John Wiley & Sons Ltd.)

To assess the risk of major birth defects after first-trimester exposure to carbocisteine and ambroxol during pregnancy, we conducted a prospective cohort study using counseling data for drug use during pregnancy provided by the Japan Drug Information Institute in Pregnancy and Toranomon Hospital. Counseling information, including drug usage and participants' demographic information, was collected between April 1988 and December 2017. Pregnancy outcome data, including major birth defects, were obtained using a questionnaire administered 1 month after delivery. The risks of major birth defects after first-trimester exposure to carbocisteine (n = 588) and ambroxol (n = 341) were compared with those of nonteratogenic drug use during the first trimester (n = 1525). The adjusted odds ratio (aORs) for major birth defects was calculated using a multiple logistic regression analysis adjusted for confounders. The incidence of major birth defects was 1.2% (7/588) and 2.1% (7/341) in the carbocisteine and ambroxol groups, respectively, which was comparable to the control group (26/1525, 1.7%). Results of multiple logistic regression demonstrated similar nonsignificant risks for both carbocisteine (aOR: 0.66, 95% confidence interval [CI]: 0.40-1.1, p = 0.11) and ambroxol (aOR: 1.1, 95% CI: 0.18-7.2, p = 0.88). No specific major birth defects were reported in the carbocisteine or ambroxol groups. This study demonstrated that carbocisteine and ambroxol exposure during the first trimester was not associated with an increased risk of major birth defects. These results could help in counseling for the use of these drugs during pregnancy and further alleviate anxiety in patients., (© 2024 The Authors. Congenital Anomalies published by John Wiley & Sons Australia, Ltd on behalf of Japanese Teratology Society.)

This study aimed to investigate assisted reproductive technology (ART) factors associated with placenta accreta spectrum (PAS) after vaginal delivery. This was a registry-based retrospective cohort study using the Japanese national ART registry. Cases of live singleton infants born via vaginal delivery after single embryo transfer (ET) between 2007 and 2020 were included (n = 224,043). PAS was diagnosed in 1412 cases (0.63% of deliveries), including 1360 cases (96.3%) derived from frozen-thawed ET cycles and 52 (3.7%) following fresh ET. Among fresh ET cycles, assisted hatching (AH) (adjusted odds ratio [aOR], 2.5; 95% confidence interval [CI] 1.4-4.7) and blastocyst embryo transfer (aOR, 2.2; 95% CI 1.3-3.9) were associated with a significantly increased risk of PAS. For frozen-thawed ET cycles, hormone replacement cycles (HRCs) constituted the greatest risk factor (aOR, 11.4; 95% CI 8.7-15.0), with PAS occurring in 1.4% of all vaginal deliveries following HRC (1258/91,418 deliveries) compared with only 0.11% following natural cycles (55/47,936). AH was also associated with a significantly increased risk of PAS in frozen-thawed cycles (aOR, 1.2; 95% CI 1.02-1.3). Our findings indicate the need for additional care in the management of patients undergoing vaginal delivery following ART with HRC and AH., (© 2024. The Author(s).)

Objective: To evaluate assisted reproductive technology-associated risk factors for retained products of conception among live births., Design: Registry-based retrospective cohort study., Setting: Not applicable., Patient(s): Cycle-specific data for a total of 369,608 singleton live births after fresh and frozen-thawed embryo transfers (FETs) between 2007 and 2017 were obtained from the Japanese assisted reproductive technology registry., Intervention(s): None., Main Outcome Measure(s): Retained products of conception after delivery. Odds ratios and 95% confidence intervals for risk factors associated with retained products of conception during fresh and frozen cycles., Result(s): In total, 132 deliveries (0.04% of eligible assisted reproductive technology registry deliveries) had retained products of conception; 122 (92.4%) of these deliveries occurred after FET transfer cycles. Cases with retained products of conception were significantly more likely to have undergone vaginal delivery than cases without retained products of conception (78.0% vs. 61.1%); they were also more likely to have been complicated with the placenta accreta spectrum (24.2% vs. 0.45%). Among patients undergoing FETs, factors associated with a significantly increased risk of retained products of conception were embryo stage at transfer, use of hormone replacement cycles, and assisted hatching. Use of hormone replacement cycles represented the largest risk factor (adjusted odds ratio, 4.9; 95% confidence interval, 2.0-12.4), such that retained products of conception occurred in 0.05% (51 of 97,958) of deliveries after hormone replacement cycles but only 0.01% (5 of 47,079) of deliveries after natural cycles. Subgroup analysis showed that hormone replacement cycles and assisted hatching remained significant risk factors for retained products of conception in cases without polycystic ovary syndrome and anovulation and cases with vaginal delivery, but not cases with cesarean section. Among fresh embryo transfers, an increased number of retrieved oocytes was the only significant risk factor for retained products of conception., Conclusion(s): Our analyses demonstrated that most of the cases involving retained products of conception were derived from FETs, and we identified the use of hormone replacement cycles as the largest risk factor for retained products of conception within this group., Competing Interests: Declaration of interests S.C.J. is a board member of the International Committee for Monitoring Assisted Reproductive Technologies (ICMART). H.T. has nothing to disclose. S.T. has nothing to disclose. M.T. has nothing to disclose. A.N. has nothing to disclose. T.K. has nothing to disclose. O.I. has received consultation fees from Organon, an honorarium from Ferring Pharmaceuticals and Nippon Shinyaku Pharma and advisory board members for Ferring Pharmaceuticals and Merck biopharma and a board member of ICMART. Y.K. has nothing to disclose., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: The Japan Society of Obstetrics and Gynecology (JSOG) registry gathers comprehensive data from registered assisted reproductive technology (ART) facilities in Japan. Herein, we report 2021 ART cycle characteristics and outcomes., Methods: Descriptive statistics were used to summarize and analyze 2021 data., Results: In 2021, 625 ART facilities participated in the registry; 27 facilities did not conduct ART cycles and 598 registered treatment cycles. In total, 498 140 cycles were registered, and there were 69 797 neonates (increases of 10.7% and 15.5%, respectively, from the previous year). The number of freeze-all in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles decreased in 2021; the number of neonates born was 2268 for IVF-embryo transfer (ET) cycles and 2850 for ICSI cycles. Frozen-thawed ET (FET) cycles increased markedly from 2020 (11.2% increase). In 2021, 239 428 FET cycles were conducted, resulting in 87 174 pregnancies and 64 679 neonates. For fresh transfers, the total single ET, singleton pregnancy rate, and singleton live birth rates were 82.7%, 97.0%, and 97.3%; for FET, these rates were 84.9%, 96.9%, and 97.1%., Conclusions: The 2021 Japanese ART registry analysis showed marked increases in both total treatment cycles and live births from the previous year., Competing Interests: “Iwase, Akira” is an Editorial Board member of Reproductive Medicine and Biology and a coauthor of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication. The authors have no conflict of interest to disclose in relation to this work., (© 2023 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Purpose: To evaluate clinical outcomes after endometrial receptivity analysis (ERA)., Methods: This was a multicenter, retrospective cohort study involving 861 women who underwent ERA testing at certified fertility clinics in Japan, and who received subsequent personalized blastocyst embryo transfers (ET) between 2018 and 2020. Clinical outcomes, including pregnancies, miscarriages, and live births, were evaluated according to receptivity status for ERA., Results: Mean patient age was 37.7 years (SD = 4.0), and the median number of previous ETs was 2 (interquartile range, 2-3). 41.0% (353/861) of patients were non-receptive for ERA testing. Clinical pregnancy, miscarriage, and live birth rates for personalized blastocyst ET were 44.5% (226/508), 26.1% (59/226), and 26.8% (136/508) for receptive patients, and 43.1% (152/353), 28.3% (43/152), and 28.9% (102/353) for non-receptive patients, all statistically nonsignificant. Multiple logistic regression demonstrated similar nonsignificant associations between receptivity and clinical outcomes. Greater patient age, smoking, and longer duration of infertility were significantly and negatively associated with receptivity, whereas a history of delivery was positively associated and statistically significant., Conclusions: Clinical outcomes after ERA testing were similar between receptive and non-receptive patients. Further prospective study including an appropriate comparison group are warranted to evaluate the efficacy of ERA testing., Competing Interests: Yutaka Osuga and Hiroaki Yoshida are Editorial Board members of Reproductive Medicine and Biology and co‐authors of this article. To minimize bias, they were excluded from all editorial decision‐making related to acceptance of this article for publication., (© 2023 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Aims: In anticipation of the future development of assisted reproductive technology (ART) and to smoothly introduce new technology, it is necessary to understand the current staffing status of the medical system and the current state of treatment, as well as the status of in vitro fertilization add-ons, where the need for insurance coverage is currently a matter of debate., Methods: ART facilities in Japan were surveyed (437 valid responses, response rate: 71%). Current staffing status of the medical system, implementation rates of ART, add-on treatments, and medical supplies were investigated., Results: Despite the abundance of embryologists, nurses, and obstetricians and gynecologists in facilities, the majority of facilities lacked counselors, anesthesiologists, and other essential medical professionals. Conventional ovarian stimulation was widely adopted (median 120 [interquartile range 60-300] cycles), followed by mild ovarian simulation (60 [30-200]). Additionally, freeze-thaw embryo transfer cycles (300 [120-750]) were performed more frequently than fresh embryo transfer cycles (30 [30-60]). Among the add-ons, assisted hatching (85.1%), chronic endometritis examination (77.2%) and treatment (76.9%), artificial oocyte activation (67.3%), endometrial receptivity analysis (64.2%), and endometrial microbiome analysis (58.9%) were relatively widely employed., Conclusions: The implementation of frozen-thawed embryo transfer cycles, freeze-all strategies, and add-on treatments have become popular and widely accepted despite the lack of robust evidence regarding their safety and efficacy., (© 2023 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

To investigate the impact of a state of emergency (i.e., voluntary lockdown) during the COVID-19 epidemic, we conducted a retrospective cohort study using the Japanese nationwide registry. In comparison with those during 2019, the number of treatment cycles decreased in April 2020 (-9.5%) to its lowest point in May (-24.1%). The magnitude of the decline was three times larger for frozen cycles (-37.0%) than for fresh cycles (-12.4%). The decrease was significantly smaller for women aged <35 years (-31.0%) than for the older groups (-39.0% to -39.7%). Under voluntary lockdown, a considerable decrease was observed especially for frozen cycles and older women., Competing Interests: Dr. Seung Chik Jwa received a payment and travel fees for lectures from Merck biopharma, participated in advisory meetings for Ferring Pharmaceuticals and Merck biopharma, and is a board member of the International Committee for Monitoring Assisted Reproductive Technologies (ICMART). Dr. Osamu Ishihara has received an honorarium and consulting fees from Ferring Pharmaceuticals and Merck biopharma and is a board member of ICMART and the International Federation of Fertility Societies., (© 2023 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Aim: From April 2022, the Japanese government funding system for assisted reproductive technology (ART) has shifted from government subsidies to universal health insurance. To date, studies estimating the health care expenditure for ART are scarce. We estimated health care expenditures for ART cycles and compared the proportion of patients' out-of-pocket payment by ovarian stimulation protocols under the Japanese government subsidy system., Methods: We linked payment information for government subsidies in Saitama Prefecture during 2016 and 2017 with the Japanese ART registry. Health care expenditures for all treatment cycles in Japan during 2017 among women aged <43 years (n = 369 757) were estimated using a generalized linear model., Results: We linked 6269 subsidy applications to the Japanese ART registry. The average treatment fee for a fresh cycle was 376 434 JPY (standard deviation = 159 581). However, significant variation was observed across ovarian stimulation protocols. The estimated health care expenditure for ART during 2017 was 101 278 629 888 JPY (920 714 817 USD), leading to a 0.24% increase in the national health care expenditure for fiscal year 2017. Fresh cycles accounted for 70% of the expenditure. The proportion of the average patient out-of-pocket payment for one treatment cycle was smaller for natural (0%) and mild ovarian stimulation using clomiphene citrate (4.5%-20.7%) than those of conventional stimulation (30.3%-32.4%)., Conclusions: Health insurance coverage for ART would increase national health care expenditure by 0.24%. Under the subsidy system, the proportion of the average patient out-of-pocket payment was smaller for natural and mild ovarian stimulation than conventional stimulations., (© 2023 Japan Society of Obstetrics and Gynecology.)

This large multi-center retrospective study examined whether artificial oocyte activation (AOA) using Ca 2+ ionophore following ICSI improves the live birth rate for couples with previous ICSI cycles of unexplained low fertilization rate. In this large-scale multi-center retrospective study conducted in Japan, data were collected from Keio University and 17 collaborating institutions of the Japanese Institution for Standardizing Assisted Reproductive Technology. Between January 2015 and December 2019, 198 couples were included in this study. Oocytes for both the intervention and control groups were procured from the same pool of couples. Oocytes obtained from ICSI cycles with no or low fertilization rate (<50%) with unknown causes were included in the control (conventional ICSI) group while oocytes procured from ICSI cycles followed by performing AOA were assigned to the intervention (ICSI-AOA) group. Those fertilized with surgically retrieved sperm were excluded. ICSI-AOA efficacy and safety were evaluated by comparing these two groups. Live birth rate was the primary outcome. The ICSI-AOA group (2,920 oocytes) showed a significantly higher live birth per embryo transfer rate (18.0% [57/316]) compared to that of the conventional ICSI group with no or low fertilization rate (1,973 oocytes; 4.7% [4/85]) (odds ratio 4.5, 95% confidence interval 1.6-12.6; P<0.05). A higher live birth rate was observed in younger patients without a history of oocyte retrieval. Miscarriage, preterm delivery, and fetal congenital malformation rates were similar between the two groups. ICSI-AOA may reduce fertilization failure without increasing risks during the perinatal period. AOA may be offered to couples with an ICSI fertilization rate < 50%., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Akashi, Yamada, Jwa, Utsuno, Kamijo, Hirota, Tanaka, Osuga and Kuji.)

Surgical site infection (SSI) is a common but potentially serious maternal complication of cesarean section (CS). C-reactive protein (CRP) can be used in early detection of SSI. However, its predictive value for post-cesarean SSI has never been investigated. This study aims to evaluate the predictive value of CRP for the development of SSI. This was a hospital-based retrospective cohort study of 748 pregnant women who underwent CS at our university hospital between January 2017 and December 2019. CRP was measured on postoperative days 1, 3, and 6. The predictive values of CRP for SSI were evaluated using receiver operating characteristics analysis. Forty-seven (6.3%) patients developed SSI, of whom 38 (80.9%) underwent emergency CS. Serum CRP levels were significantly higher in the SSI group than in the non-SSI group from postoperative day 1 (64 vs. 81 mg/L, p = 0.001); the difference became more evident on postoperative days 3 and 6. The area under the receiver operating characteristic curve (AUC) for CRP on days 1, 3, and 6 was 0.58 (95% confidence interval [CI], 0.49 to 0.68), 0.70 (0.62 to 0.78) and 0.73 (0.65 to 0.81), respectively. The optimal cutoff value for day 3 and 6 CRP was 66.4 mg/L (sensitivity = 76.1% and specificity = 54.4%) and 22.2 mg/L (sensitivity = 76.5% and specificity = 63.2%), respectively. CRP on postoperative days 3 and 6 can be used as a predictive marker for the development of SSI after CS. Further studies to validate the predictive value in different populations is essential., Competing Interests: The authors have declared that no competing interests exist.

Background: Economic disparities affect access to assisted reproductive technology (ART) treatment in many countries. At the time of this survey, Japan provided partial reimbursement for ART treatment only for those in low- or middle-income classes due to limited governmental budgets. However, the optimal level of financial support by income class remains unclear., Methods: We conducted a conjoint analysis of ART in Japan in January 2020. We recruited 824 women with fertility problems aged 25 to 44 years via an online social research panel. They completed a questionnaire of 16 hypothetical scenarios measuring six relevant ART attributes (i.e., out-of-pocket payment, pregnancy rate, risk of adverse effects, number of visits to outpatient clinics, consultation hours and kindness of staff) and their relations to treatment choice., Results: Mixed-effect logistic regression models showed that all six attributes significantly influenced treatment preferences, with participants valuing out-of-pocket payment the most, followed by pregnancy rates and kindness of staff. Significant interactions occurred between high household income (≥ 8 million JPY) and high out-of-pocket payment (≥ 500,000 JPY). However, the average marginal probability of the highest-income patients (i.e., ≥ 10 million JPY, ineligible for the subsidy) receiving ART treatment at the average cost of 400,000 JPY was 47%, compared to 56 - 61% of other income participants, who opted to receive ART at an average cost of 100,000 JPY after a 300,000 JPY subsidy., Conclusion: Our results suggest that out-of-pocket payment is the primary determinant in patients' decision to opt for ART treatment. High-income patients were more likely to choose treatment, even at a high cost, but their income-based ineligibility for government financial support might discourage some from receiving treatment., (© 2022. The Author(s).)

Background: This study aimed to determine the factors associated with an unfavorable clinical course (emergency surgery and/or prolonged hospitalization) in patients requiring hospitalization owing to pelvic inflammatory disease (PID)., Methods: A retrospective study was performed on 117 patients diagnosed with PID who were admitted to our hospital between January 2014 and December 2018. Multivariate regression analysis was conducted to determine the factors associated with emergency surgical intervention, and prolonged hospitalization in a subgroup of successful expectant management (n = 93)., Results: The average age (mean ± standard deviation) of the patients was 41.2 ± 12.5 years; 16 (13.7%) were postmenopausal; 81 patients (69.2%) complicated with a tubo-ovarian abscess (TOA) of which 59 (72.9%) had an ovarian endometrioma; and 19 patients (16.2%) had a history of various intrauterine manipulations. Emergency surgery was performed in 24 patients (20.5%), and patients with TOA underwent emergency surgery more often than did patients without TOA (25.9% vs. 8.3%, p = 0.03), and TOA was associated with longer length of hospital stay (17.1 days vs. 8.0 days, p = 0.01). Smoking, postmenopausal status, past medical history of PID, and high C-reactive protein (CRP) level at admission were significantly associated with emergency surgery. In patients with successful expectant management, obesity (body mass index ≥ 30) and high WBC and CRP level at admission were significantly associated with prolonged hospitalization., Conclusions: Of the patients requiring hospitalization owing to PID, TOA was associated with both emergency surgery and prolonged hospital stay. Patients with increased inflammatory markers and obesity should be considered to be at a high risk for unfavorable clinical course in the management of PID., (© 2022. The Author(s).)

Purpose: The use of assisted reproductive technology (ART) and prenatal genetic testing have become more widespread in line with an increase in maternal age. However, the effect of the introduction of non-invasive prenatal testing (NIPT) in April 2013 on pregnancy outcomes in Japan, including the prevalence of Down syndrome live births following ART, has not been investigated. This study aimed to evaluate the trends in the prevalence of Down syndrome live births following ART in Japan., Methods: This population-based retrospective study used the Japanese nationwide ART registry. All clinical pregnancies resulting in live births, stillbirths, and termination of pregnancy (TOP) following ART from 2007 to 2016 were included. Pregnancy outcomes involving infants with Down syndrome were evaluated., Results: Among 351,808 pregnancies, the proportion of mothers with advanced age increased significantly from 2007 to 2016 (from 49.5 to 62.4% and 8.9 to 17.8% for mothers aged ≥ 35 and ≥ 40 years, respectively). The proportion of live births with Down syndrome was 77.3% in 2007, which remained consistent until 2012, but then decreased significantly to 45.1% after 2013 (P < 0.001). The prevalence of Down syndrome live births increased up to 2012 (19.5/10,000 live births), decreased significantly in 2013 (12.1/10,000 live births), and then remained almost stable (11.1-14.7/10,000 live births)., Conclusion: The introduction of NIPT balanced the prevalence of Down syndrome live births following ART with recent increasing maternal age in Japan., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To clarify risk factors and clinical outcomes for placenta accreta spectrum (PAS) stratified by placenta previa., Methods: We conducted registry-based multicenter cross-sectional study including 472,301 singleton deliveries between 2013 and 2015. PAS was considered as a primary outcome, as well as maternal age, parity, history of cesarean section, history of miscarriage, and assisted reproductive technology (ART) were considered as potential exposures. A multivariable Poisson regression analysis was conducted to assess the risk for PAS, stratified by placenta previa. In addition, the risk for subsequent blood transfusion and hysterectomy by each exposure using multivariable Poisson regression analysis was conducted., Results: There were 426 and 1827 cases of PAS with and without placenta previa. Among cases with placenta previa, the number of previous cesarean sections was the most powerful predictor for PAS [adjusted risk ratio (aRR) for one previous cesarean section 5.34, 95% confidence interval (CI) 3.70-7.71; aRR for two or more previous cesarean section 16.5, 95% CI 11.5-23.6]. Among cases without placenta previa, previous cesarean section was not a significant predictor, whereas the strongest predictor was conception through ART (aRR 5.05, 95% CI 4.50-5.66). Although the risks of PAS for blood transfusion and hysterectomy were higher among cases with placenta previa, those without placenta previa also demonstrated non-negligible risks., Conclusion: The current study demonstrated that history of cesarean section was the strongest risk factor for PAS among women with placenta previa. Among those without placenta previa, ART was an important predictor, but not cesarean section., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: This study aimed to clarify the feasibility of a mobile cardiotocogram (CTG) device for self-monitoring fetal heart rate (FHR) in low-risk singleton pregnant women., Methods: This study was conducted at six university hospitals and seven maternity clinics in Japan. Using a mobile cardiotocogram device (iCTG, Melody International Ltd., Kagawa, Japan), participants of more than 34 gestational weeks measured the FHR by themselves at least once a week until hospitalization for delivery. We evaluated the acquisition rate of evaluable FHR recordings and the frequency of abnormal FHR patterns according to the CTG classification system of the Japan Society of Obstetrics and Gynecology (JSOG). The participants also underwent a questionnaire survey after delivery to evaluate their satisfaction level of self-monitoring FHR using the mobile CTG device., Results: A total of 1278 FHR recordings from 101 women were analyzed. Among them, 1276 (99.8%) were readable for more than 10 min continuously, and the median percentage of the total readable period in each recording was 98.9% (range, 51.4-100). According to the JSOG classification system, 1245 (97.6%), 9 (0.7%), 18 (1.4%), and four (0.3%) FHR patterns were classified as levels 1, 2, 3, and 4, respectively. The questionnaire survey revealed high participant satisfaction with FHR self-monitoring using the iCTG., Conclusion: The mobile CTG device is a feasible tool for self-monitoring FHR, with a high participant satisfaction level., (© 2021 Japan Society of Obstetrics and Gynecology.)

Purpose: The Japan Society of Obstetrics and Gynecology records online annual cycle-based information for assisted reproductive technology (ART). This report presents the characteristics and treatment outcomes of ART cycles registered during 2019., Methods: The Japanese ART registry includes cycle-specific information from 619 participating facilities, including treatment and pregnancy outcomes. Descriptive analyses were conducted for cycles registered during 2019., Results: In 2019, 458 101 treatment cycles and 60 598 neonates were reported, both of which increased from 2018. The number of fresh cycles, including in vitro fertilization and intracytoplasmic sperm injection, decreased, while frozen-thawed embryo transfer (ET) cycles increased. The mean maternal age was 37.9 years (standard deviation ± 4.7). Of 239 348 oocyte retrievals, 123 690 (51.7%) involved freeze-all-embryos cycles; fresh ET was performed in 41 831 cycles (a decreasing trend since 2015). In 2019, there were 211 597 frozen-thawed ET cycles, resulting in 74 882 pregnancies and 54 168 neonates born. Single ET was performed in 82.6% of fresh transfers and 85.1% of frozen-thawed cycles, with singleton live birth rates of 97.3% for both., Conclusions: The number of fresh cycles decreased but frozen cycles increased in 2019. Single ET was performed in >80% of cases, and the proportion of babies born from frozen-thawed ET increased., Competing Interests: There is no conflict of interest regarding the publication of this study., (© 2021 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Background: Assisted reproductive technology (ART) is a globally established treatment; however, large disparities exist in ART use among young couples. We investigated regional-level factors associated with ART use in Japan., Methods: We calculated the use rate of ART using the number of women aged <35 years who applied for government subsidies in 2017; we divided that figure by the number of women aged 20-35 years in each prefecture. Prefectural-level average household income; social capital indicators including voting rate, volunteer rate, and move-in rate; and Gini coefficients as indicators of income inequality were linked to ART use, adjusting for prefectural size, the mean age of women at first marriage, number of ART facilities, and additional prefectural subsidies., Results: The rate of ART use (per 10,000 women) varied significantly from 22.0 to 58.8 across Japan's 47 prefectures. Multivariate analysis demonstrated that the use rate increased by 0.048 (95% confidence interval [CI], 0.007 to 0.088) for each 10,000-yen increase in average household income and 1.5 (95% CI, 0.65 to 2.3) for each 1% increase in volunteer rate. Conversely, the use rate decreased by 18.4 (95% CI, -28.6 to -8.1) for each 1% increase in the move-in rate. There was no significant association between ART use and income inequality., Conclusion: Although we cannot infer causal relationships, the findings suggest that improving financial access and enhancing social capital may increase access to ART. Further research, particularly multilevel analysis using individual data, is required to confirm these findings., Competing Interests: Dr. Osamu Ishihara has received an honorarium from Ferring Pharmaceuticals., (© 2021 The Authors. Published by Elsevier Ltd.)

Studies have consistently reported a significantly reduced incidence of ectopic pregnancy (EP) for frozen-thawed embryo transfer (ET) cycles compared with fresh cycles. However, only a few studies reported an association between endometrial preparation protocols on EP and results were conflicting. A registry-based retrospective cohort study of 153,354 clinical pregnancies following frozen single ETs between 2014 and 2017 were conducted, of which 792 cases of EP (0.52%) were reported. Blastocyst embryo transfers accounted for 87% of the total sample and were significantly associated with a decreased risk for EP compared with early cleavage ET (0.90% vs. 0.46%, adjusted OR = 0.50, 95% CI, 0.41 to 0.60). Compared with natural cycles, hormone replacement cycles (HRC) demonstrated a similar risk for EP (0.53% vs. 0.47%, adjusted OR = 1.12, 95% CI, 0.89 to 1.42). Subgroup analysis with or without tubal factor infertility and early cleavage/blastocyst ETs demonstrated similar non-significant associations. Endometrial preparation protocols using clomiphene (CC) were associated with a significantly increased risk for EP (1.12%, adjusted OR = 2.34; 95% CI, 1.38 to 3.98). These findings suggest that HRC and natural cycles had a similar risk for EP. Endometrial preparation using CC was associated with an increased risk of EP in frozen embryo transfer cycles., (© 2021. The Author(s).)

Background: Fertility treatments help many infertile couples to have children. However, disparities exist in access to fertility tests and treatments. We investigated the association between household income and medical help-seeking for fertility in Japan., Methods: We conducted a cross-sectional study using nationally representative data from the National Fertility Survey 2015. Respondents were 6598 married women younger than 50 years old. The primary outcome was medical help-seeking for fertility among those who experienced fertility problems. Multiple logistic regression models were used to assess the association between household income and medical help-seeking, adjusting for age, length of marriage, educational level, employment status, number of children, childbearing desires, living with parents, and region of residence., Results: Among 2253 (34%) women who experienced fertility problems, 1154 (51%) sought medical help. The proportion of help-seekers increased linearly from 43% in the low-income group (< 4 million Japanese yen [JPY]) to 59% in the high-income group (≥ 8 million JPY) (P for trend < 0.001). Respondents with upper-middle (6-8 million JPY) or high household income were more likely to seek medical help, compared to those with low household income: adjusted odds ratio [aOR] 1.37 (95% confidence interval [CI]: 1.00-1.86) and aOR 1.78 (95% CI: 1.29-2.47), respectively., Conclusions: We found that higher household income was associated with a higher probability of seeking medical help among Japanese women who experienced fertility problem. Along with policy discussion about additional financial support, further studies from societal, cultural, or psychological views are required., (© 2021. The Author(s).)

Purpose: We investigated the cumulative live birth rate (CLBR) in women receiving governmental subsidies for assisted reproductive technology (ART) in Saitama Prefecture, Japan., Methods: Women who applied for subsidies from Saitama Prefectural Government for the first time in 2016 were enrolled and followed up until the end of 2017. Treatment information, including live birth, was obtained from the Japanese ART registry by linking it with unique identification numbers for treatment. Patients' factors associated with having a live birth were investigated., Results: Of 1,072 women (2,513 applications), 495 (46.2%) had a live birth with 8 (1.6%) twin pregnancies. The CLBR over six subsidized cycles was 53.7% for women aged <40 years, and 17.2% over three subsidized cycles for women 40-42 years; highest among women <35 years (58.4%), followed by those aged 35-39 years (49.3%). Multivariate analysis revealed patient age as the only independent factor for having a live birth., Conclusions: The CLBR of women receiving subsidies for ART was greatest in women aged <35 years. Effective policies for promoting ART among younger couples who seek infertility treatment are essential., Competing Interests: Dr Osamu Ishihara has received an honorarium from Ferring Pharmaceuticals., (© 2021 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Objective: To evaluate the risk of ectopic pregnancies (EPs) for fresh cycles according to different ovarian stimulation protocols., Design: Registry-based retrospective cohort study., Setting: Not applicable., Patient(s): A total of 68,851 clinical pregnancies after fresh single embryo transfer between 2007 and 2015., Intervention (s): None MAIN OUTCOME MEASURE(S): Ectopic pregnancies. Odds ratios and 95% confidence intervals for EPs were calculated by using generalized estimating equations adjusted for potential maternal and treatment characteristics., Result(s): Among 68,851 clinical pregnancies, 1,049 (1.46%) cases of EP were reported. Compared with natural cycles, all ovarian stimulation protocols were associated with a significantly increased risk of EP. Ovarian stimulation with clomiphene (CC) demonstrated the highest odds ratios for EPs. Significant associations between ovarian stimulation protocols and EP compared with natural cycles were prominent when the number of retrieved oocytes was low (1-3) to moderate (4-7), but there were no significant associations when the number of retrieved oocytes was high (≥8)., Conclusion(s): Ovarian stimulation protocols were significantly associated with an increased risk of EP. In particular, ovarian stimulation with CC had the highest risk of EP compared with other stimulation protocols. Further studies are essential to investigate possible confounding factors for different ovarian stimulation protocols, especially CC, and the risk of EP., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Since 2007, the Japan Society of Obstetrics and Gynecology (JSOG) has collected cycle-based data for assisted reproductive technology (ART) in an online registry. Here, we present the characteristics and treatment outcomes of ART cycles registered during 2018., Methods: The Japanese ART registry consists of cycle-specific information for all ART treatment cycles implemented at 621 participating facilities. We conducted descriptive analyses for such cycles registered for 2018., Results: In total, 454 893 treatment cycles and 56 979 neonates were reported in 2018: both increased from 2017. The mean maternal age was 38.0 years (standard deviation ± 4.7). Of 247 402 oocyte retrievals, 118 378 (47.8%) involved freeze-all-embryos cycles; fresh embryo transfer (ET) was performed in 50 463 cycles: a decreasing trend since 2015. A total of 199 914 frozen-thawed ET cycles were reported, resulting in 69 357 pregnancies and 49 360 neonates born. Single ET (SET) was performed in 82.2% of fresh transfers and 83.4% of frozen-thawed cycles, with singleton pregnancy/live birth rates of 97.2%/97.2% and 97.0%/97.2%, respectively., Conclusions: Total ART cycles and subsequent live births increased in 2018. SET was performed in over 80% of cases, and the mode of ET has shifted continuously from using fresh embryos to frozen-thawed ones compared with previous years., Competing Interests: Conflict of interest: There is no conflict of interest regarding the publication of this study. Human rights statement and informed consent: All procedures were performed in accordance with the ethical standards of the relevant committees on human experimentation (institutional and national) and the Helsinki Declaration of 1964 and its later amendments. Animal rights: This report does not contain any studies performed by any of the authors that included animal participants., (© 2020 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Purpose: The Japan Society of Obstetrics and Gynecology (JSOG) has collected cycle-based assisted reproductive technology (ART) data in an online registry since 2007. Herein, we present the characteristics and treatment outcomes of ART cycles registered during 2017., Methods: We collected cycle-specific information for all ART cycles implemented at participating facilities and performed descriptive analysis., Results: In total, 448,210 treatment cycles and 56,617 neonates (1 in 16.7 neonates born in Japan) were reported in 2017, increased from 2016; the number of initiated fresh cycles decreased for the first time ever. The mean patient age was 38.0 years (standard deviation 4.6). A total 110,641 of 245,205 egg retrieval cycles (45.1%) were freeze-all cycles; fresh embryo transfer (ET) was performed in 55,720 cycles. A total 194,415 frozen-thawed ET cycles were reported, resulting in 66,881 pregnancies and 47,807 neonates born. Single ET (SET) was performed in 81.8% of fresh transfers and 83.4% of frozen cycles, with singleton pregnancy/live birth rates of 97.5%/97.3% and 96.7%/96.6%, respectively., Conclusions: Total ART cycles and subsequent live births increased continuously in 2017, whereas the number of initiated fresh cycles decreased. SET was performed in over 80% of cases, and ET shifted from using fresh embryos to frozen ones., Competing Interests: There is no conflict of interest regarding the publication of this study., (© 2019 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Background: Children born after intracytoplasmic sperm injection (ICSI) are at increased risk of specific major birth defects compared with children born after in vitro fertilization (IVF). However, whether this risk is due to the treatment itself (i.e., IVF or ICSI) or underlying male subfertility is unknown. This study investigated the associations between male subfertility and the risk of major birth defects in children born after IVF and ICSI., Methods: We conducted a retrospective cohort study using data from the Japanese assisted reproductive technology registry between 2007 and 2014. Fresh embryo transfer cycles registered from 2007 to 2014 that resulted in singleton live births, still births, or selective terminations were included (n = 59,971). Major birth defects were defined by the US Centers for Disease Control and Prevention guidelines, excluding chromosomal abnormalities. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using generalized estimating equations adjusting for potential confounders., Results: Major birth defects were reported in 626/59,971 (1.04%) cases. Among IVF cycles, male subfertility was associated with significantly greater risks of hypospadias (3/3163 [0.09%] vs 4/28,671 [0.01%], adjusted OR = 6.85, 95% CI 2.05-22.9, P = 0.002) and atrial septal defects (4/3163 [0.13%] vs 9/28,671 [0.03%], adjusted OR = 3.98, 95% CI 1.12-14.1, P = 0.03) compared with fertile men. Subgroup analysis using sperm parameters showed that oligozoospermia (i.e., sperm concentrations < 15 million/mL) was significantly associated with a greater risk of ventricular septal defects compared with normal sperm concentrations in IVF pregnancies (5/868 [0.58%] vs 60/28,090 [0.21%], adjusted OR = 2.68, 95% CI 1.15-6.27, P = 0.02), and severe oligozoospermia (i.e., sperm concentrations < 5 million/mL) was significantly associated with an increased risk of hypospadias compared with normal sperm concentrations in ICSI pregnancies (5/3136 [0.16%] vs 5/16,865 [0.03%], adjusted OR = 3.88, 95% CI 1.14-13.2, P = 0.03)., Conclusions: The results of this exploratory study suggest that underlying male subfertility may play a role in the risk of major birth defects related to ICSI and IVF. Further research, including systematic reviews adjusting for confounders, is required to confirm the associations between male subfertility and major cardiac and urogenital birth defects.

Previous studies suggested ovarian stimulation was associated with lower birth weight and higher risk of preterm delivery (PTD) from fresh embryo transfers (ETs). However, whether the increased risk differs between distinct ovarian stimulation protocols remains unknown. A retrospective cohort study of 38,220 singleton deliveries after fresh single ETs from 2007 to 2013 was conducted. Main outcomes were birth weight and gestational length. Compared with the natural cycle, all ovarian stimulation protocols were associated with a significantly increased risk for PTD, low birth weight (LBW) and small for gestational age (SGA). In subgroup analysis of maternal age under 35 years, luteal support using progesterone, and early cleavage ETs, the significant associations remained for LBW and SGA in gonadotropin-releasing hormone (GnRH) antagonist protocol and for LBW in GnRH agonist protocol. Ovarian stimulation using clomiphene citrate (CC) had the highest increased risks for LBW (Adjusted odds ratio [AOR], 1.58, 95% confidence interval [95% CI], 1.43-1.73) and SGA (AOR, 1.65, 95% CI, 1.50-1.82) compared with natural cycles, and was further associated with PTD and cesarean section. These findings suggest ovarian stimulation was associated with lower birth weight, and CC may have adverse effect on neonatal outcomes in fresh cycles.

Purpose: The Japan Society of Obstetrics and Gynecology started an online cycle-based assisted reproductive technology (ART) registry system in 2007. This report presents the characteristics and treatment outcomes of ART registered for the cycles practiced during 2016., Methods: Cycle-specific information for all ART cycles implemented in participating ART facilities were collected. A descriptive analysis was conducted for the registry database of 2016., Results: In total, 447 790 treatment cycles and 54 110 neonates (one in 18.1 neonates born in Japan) were reported in 2016. The mean patients' age was 38.1 years (SD = 4.5). Among the egg retrieval cycles, 104 575 of 251 399 (41.6%) were freeze-all cycles without fresh embryo transfers (ET), while fresh ET was performed in 64 497 cycles (58.4%). A total of 187 132 frozen-thawed ET cycles were reported, resulting in 62 432 pregnancies and 44 484 neonates born. Single ET was selected for 81.0% of fresh transfers and 82.7% of frozen cycles, resulting in singleton pregnancy/live birth rates of 97.0%/96.4% and 96.7%/96.4%, respectively., Conclusion: The total ART cycles and subsequent live births continued to increase in 2016. Single ET was performed more than 80%, and ET has shifted from using fresh embryos to frozen ones.

Background/objectives: Vegetable intake during childhood may reduce the risk of subsequent asthma. We verified the effect of maternal intake during pregnancy on asthma risk in offspring, which has rarely been studied., Subjects/methods: In a hospital-based birth cohort study conducted in Tokyo, we administered a food frequency questionnaire at two periods during the respondents' pregnancy: early and mid to late periods. In addition, a questionnaire including the International Study of Asthma and Allergies in Childhood questionnaire was conducted when the offspring were 2 years old. Multivariate Poisson regression adjusting for maternal baseline demographics was used to elucidate the association between maternal vegetable intake and the incidence of wheeze in the offspring., Results: Among 310 singletons, 82 (26.5%) experienced wheeze at 2 years of age. Women with the highest intake of cruciferous, and folate-rich vegetables during early pregnancy reported a significantly lower prevalence of wheeze in their child at 2 years of age in comparison with those who reported the lowest intake (adjusted risk ratio: 0.48 and 0.47, 95% confidence interval: 0.26-0.89, and 0.25-0.87, respectively). In trend analysis, a higher maternal intake of cruciferous, folate-rich vegetables, and total vegetables during early pregnancy was less likely to be associated with wheeze in the offspring at 2 years old (p for trend: 0.038, <0.001, and 0.028, respectively). Maternal vegetable intake during mid to late pregnancy was not associated with wheeze in the offspring., Conclusions: Maternal vegetable intake during early pregnancy may have a protective effect against asthma in offspring at 2 years of age.

Purpose: The Japan Society of Obstetrics and Gynecology (JSOG) implemented an assisted reproductive technology (ART) registry system in 1986. Here are reported the characteristics and treatment outcomes of ART cycles that were registered in 2015., Methods: JSOG has requested all participating ART facilities to register cycle-specific information for all ART cycles since 2007. A descriptive analysis was performed by using the registry database for 2015., Results: In total, 424 151 cycles and 51 001 neonates (1 in 19.7 neonates born in Japan) were registered in 2015. The patients' mean age was 38.2 years (standard deviation = 4.5). Among the fresh cycles, 94 158 of 244 718 (38.5%) egg retrieval cycles were cycles with freeze-all embryos or oocytes, while fresh embryo transfer (ET) was performed in 70 254 cycles, signaling a decrease from 2014. There were 169 898 frozen-thawed ET cycles, resulting in 56 355 pregnancies and 40 599 neonates. Single ET was performed at a rate of 79.7% for fresh and 81.8% for frozen cycles and the singleton pregnancy/live birth rates were 96.9%/96.5% and 96.8%/96.4% for the respective cycles., Conclusion: The total ART cycles and live births resulting from ART has been increasing in Japan. Single ET was performed at a rate of almost 80% and ET cycles have shifted from fresh to frozen cycles.

Background: The Institute of Medicine (IOM) guidelines are the most widely used guidelines on gestational weight gain; however, accumulation of evidence that body composition in Asians differs from other races has brought concern regarding whether their direct application is appropriate. We aimed to study to what extent optimal gestational weight gain among women in Japan differs by pre-pregnancy body mass index (BMI) and to compare estimated optimal gestational weight gain to current Japanese and Institute of Medicine (IOM) recommendations., Methods: We retrospectively studied 104,070 singleton pregnancies among nulliparous women in 2005-2011 using the Japanese national perinatal network database. In five pre-pregnancy BMI sub-groups (17.0-18.4, 18.5-19.9, 20-22.9, 23-24.9, and 25-27.4 kg/m 2 ), we estimated the association of the rate of gestational weight gain with pregnancy outcomes (fetal growth, preterm delivery, and delivery complications) using multivariate regression., Results: Weight gain rate associated with the lowest risk of adverse outcomes decreased with increasing BMI (12.2 kg, 10.9 kg, 9.9 kg, 7.7 kg, and 4.3 kg/40 weeks) for the five BMI categories as described above, respectively. Current Japanese guidelines were lower than optimal gains, with the lowest risk of adverse outcomes for women with BMI below 18.5 kg/m 2 , and current IOM recommendations were higher than optimal gains for women with BMI over 23 kg/m 2 ., Conclusion: Optimal weight gain during pregnancy varies largely by pre-pregnancy BMI, and defining those with BMI over 23 kg/m 2 as overweight, as proposed by the World Health Organization, may be useful when applying current IOM recommendations to Japanese guidelines., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Objectives: To determine the characteristics, outcomes, and prognostic factors of fetal hydrothorax (FHT) with trisomy 21., Methods: A nationwide survey was conducted on FHT fetuses with trisomy 21 delivered after 22 weeks' gestation between January 2007 and December 2011 at perinatal centers., Results: The 91 cases of FHT with trisomy 21 included 28 (30.8%) diagnosed in utero and 63 (69.2%) diagnosed after birth. The natural remission rate was 6.6% (6/91). Thoracoamniotic shunting was performed in 14.3% (13/91) of cases. The survival rates of the hydropic, nonhydropic, and total cases were 47.0% (31/66), 84.0% (21/25), and 57.1% (52/91), respectively. The crude odds ratio for death was 8.2 (p = 0.003) for fetuses diagnosed at 26-30 weeks of gestational age (vs ≥30 weeks), 5.9 (p = 0.003) for hydrops, 4.0 (p = 0.04) for bilateral pleural effusion, 0.68 (p = 0.42) for associated cardiovascular anomalies, and 2.1 (p = 0.26) for thoracoamniotic shunting (vs no fetal therapy)., Conclusions: The prognosis of FHT with trisomy 21 was not very poor, but it was still worse than that of primary FHT. Hydrops, an early gestational age at the diagnosis and bilateral effusion, but not associated anomalies, were risk factors for death. Fetal therapy showed no survival benefit for FHT with trisomy 21. © 2017 John Wiley & Sons, Ltd., (© 2017 John Wiley & Sons, Ltd.)

Extrauterine choriocarcinoma in the fallopian tube is very rare and is often diagnosed and treated as an ectopic tubal pregnancy. A 34-year-old woman who initially became pregnant after infertility treatment using ovulation induction with clomiphene citrate and intrauterine insemination was later diagnosed with an extrauterine choriocarcinoma in the left fallopian tube. Because of suspected left ectopic tubal pregnancy based on ultrasonography findings and a high level of β-human chorionic gonadotropin (β-hCG; 7054.3 mIU/mL), the patient underwent diagnostic laparoscopy at a gestational age of 6 weeks. Left salpingectomy was performed based on the operative diagnosis of an ectopic tubal pregnancy. No signs of tubal rupture or leakage of contents from the fallopian tube were observed during the operation. Her serum β-hCG dropped to 10.3 mIU/mL at 15 days postoperatively. Histopathology demonstrated an extrauterine choriocarcinoma in the removed fallopian tube, and the patient was referred to a regional oncologic hospital to receive additional adjuvant chemotherapy. This case indicates that conservative treatment for ectopic pregnancy should be chosen carefully, and that histopathology diagnosis and appropriate β-hCG monitoring following treatment are important not only to diagnose persistent ectopic pregnancy, but also to rule out the possibility of a tubal choriocarcinoma., (Copyright © 2017 AAGL. Published by Elsevier Inc. All rights reserved.)

Study Question: Are pregnancy and neonatal outcomes following letrozole use comparable with natural and HRT cycles in patients undergoing single frozen-thawed embryo transfer (FET)?, Summary Answer: Letrozole use was significantly associated with higher rates of clinical pregnancy, clinical pregnancy with fetal heart beat and live birth, and with a lower rate of miscarriage, compared with natural and HRT cycles., What Is Known Already: Letrozole is the most commonly used aromatase inhibitor for mild ovarian stimulation in ART. However, the effect of letrozole on pregnancy and neonatal outcomes in FET are not well known., Study Design Size, Duration: A retrospective cohort study was conducted using data from the Japanese national ART registry between 2012 and 2013., Participants/materials Setting Methods: A total of 110 722 single FET cycles with letrozole (n = 2409), natural (n = 41 470) or HRT cycles (n = 66 843) were included. The main outcomes were the rates of clinical pregnancy, clinical pregnancy with fetal heart beat, miscarriage and live birth. Adjusted odds ratios and relative risks (RRs) were calculated using a generalized estimating equation adjusting for correlations within clinics., Main Results and the Role of Chance: The rates of clinical pregnancy, clinical pregnancy with fetal heart beat, and live birth were significantly higher, while the rate of miscarriage was significantly lower in the letrozole group compared with the natural and HRT groups. In blastocyst stage transfers, the adjusted RRs for clinical pregnancy with fetal heart beat of letrozole compared with natural and HRT cycles were 1.48 (95% CI: 1.41-1.55) and 1.62 (95% CI: 1.54-1.70), respectively. Similarly, the adjusted RRs of letrozole for miscarriage compared with natural and HRT cycles were 0.91 (95% CI: 0.88-0.93) and 0.84 (95% CI: 0.82-0.87), respectively. Neonatal outcomes were mostly similar in letrozole, natural and HRT cycles., Limitations Reasons for Caution: Important limitations of this study included the lack of information concerning the reasons for selecting the specific FET method, parity, the number of previous ART failures, embryo quality and the dose and duration of letrozole intake., Wider Implications of the Findings: These results suggest that letrozole use may improve clinical pregnancy, clinical pregnancy with fetal heart beat, and live births and reduce the risk of miscarriage in patients undergoing single FET cycles., Study Funding/competing Interest(s): No external funding was used for this study. There are no conflicts of interest., Trial Registration Number: Not applicable., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Background: No previous study has shown the validity of a food frequency questionnaire (FFQ) in early pregnancy with consideration of nausea and vomiting during pregnancy (NVP). The aim of this study was to evaluate the validity of a FFQ in early pregnancy for Japanese pregnant women., Method: We included 188 women before 15 weeks of gestation and compared estimated nutrient intake and food group intake based on a modified FFQ with that based on 3-day dietary records (DRs). Spearman's rank correlation coefficients, adjusting energy intake and attenuating within-person error, were calculated. Subgroup analysis for those with and without NVP was conducted. We also examined the degree of appropriate classification across categories between FFQ and DRs through division of consumption of nutrients and food groups into quintiles., Results: Crude Spearman's correlation coefficients of nutrients ranged from 0.098 (sodium) to 0.401 (vitamin C), and all of the 36 nutrients were statistically significant. In 27 food groups, correlation coefficients ranged from -0.015 (alcohol) to 0.572 (yogurt), and 81% were statistically significant. In subgroup analysis, correlation coefficients in 89% of nutrients and 70% of food groups in women with NVP and 97% of nutrients and 74% of food groups in women without NVP were statistically significant. On average, 63.7% of nutrients and 60.4% of food groups were classified into same or adjacent quintiles according to the FFQ and DRs., Conclusions: The FFQ is a useful instrument, regardless of NVP, for assessing the diet of women in early pregnancy in Japan., (Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Caesarean section (CS) is increasing globally, and women with prior CS are at higher risk of uterine rupture in subsequent pregnancies. However, little is known about the incidence, risk factors, and outcomes of uterine rupture in women with prior CS, especially in developing countries. To investigate this, we conducted a secondary analysis of the World Health Organization Multicountry Survey on Maternal and Newborn Health, which included data on delivery from 359 facilities in 29 countries. The incidence of uterine rupture among women with at least one prior CS was 0.5% (170/37,366), ranging from 0.2% in high-Human Development Index (HDI) countries to 1.0% in low-HDI countries. Factors significantly associated with uterine rupture included giving birth in medium- or low-HDI countries (adjusted odds ratio [AOR] 2.0 and 3.88, respectively), lower maternal educational level (≤6 years) (AOR 1.71), spontaneous onset of labour (AOR 1.62), and gestational age at birth <37 weeks (AOR 3.52). Women with uterine rupture had significantly higher risk of maternal death (AOR 4.45) and perinatal death (AOR 33.34). Women with prior CS, especially in resource-limited settings, are facing higher risk of uterine rupture and subsequent adverse outcomes. Further studies are needed for prevention/management strategies in these settings.

Objectives: This study aims to determine the prognostic factors and outcomes of primary fetal hydrothorax (FHT) and investigate the effects of fetal therapy., Methods: A nationwide survey was conducted on fetuses with primary FHT delivered after 22 weeks of gestation between January 2007 and December 2011 at perinatal centers., Results: Among the 287 cases of primary FHT, the survival rates for those with and without hydrops were 58.0% (113/195) and 97.8% (90/92), respectively. The survival rates in the no-therapy, thoracocentesis, and thoracoamniotic shunting (TAS) groups in the hydropic cases and the non-hydropic cases were 59.7% (40/67), 51.5% (35/68), and 63.3% (38/60) and 98.1% (53/54), 96.3% (26/27), and 100% (11/11), respectively. The crude relative risk for death was 2.1 (p = 0.005) for fetuses diagnosed at 26 to 30 weeks of gestational age (vs ≥30 weeks), 2.3 (p = 0.001) for both skin edema and ascites, and 3.1 (p = 0.02) for bilateral pleural effusion. TAS was associated with a significant risk reduction for death in hydropic cases [adjusted relative risk 0.61, p = 0.01 (vs no fetal therapy)]., Conclusions: Hydrops and an early gestational age at diagnosis (<30 weeks of gestation), skin edema with ascites, and bilateral effusion predicted a poor prognosis in primary FHT cases. TAS was associated with a higher survival rate. © 2016 John Wiley & Sons, Ltd., (© 2016 John Wiley & Sons, Ltd.)

Background: The relative validity of food frequency questionnaires for estimating long-chain polyunsaturated fatty acid (LC-PUFA) intake among pregnant Japanese women is currently unclear. The aim of this study was to verify the external validity of a food frequency questionnaire, originally developed for non-pregnant adults, to assess the dietary intake of LC-PUFA using dietary records and serum phospholipid levels among Japanese women in early and late pregnancy., Methods: A validation study involving 188 participants in early pregnancy and 169 participants in late pregnancy was conducted. Intake LC-PUFA was estimated using a food frequency questionnaire and evaluated using a 3-day dietary record and serum phospholipid concentrations in both early and late pregnancy., Results: The food frequency questionnaire provided estimates of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake with higher precision than dietary records in both early and late pregnancy. Significant correlations were observed for LC-PUFA intake estimated using dietary records in both early and late pregnancy, particularly for EPA and DHA (correlation coefficients ranged from 0.34 to 0.40, p < 0.0001). Similarly, high correlations for EPA and DHA in serum phospholipid composition were also observed in both early and late pregnancy (correlation coefficients ranged 0.27 to 0.34, p < 0.0001)., Conclusions: Our findings suggest that the food frequency questionnaire, which was originally designed for non-pregnant adults and was evaluated in this study against dietary records and biological markers, has good validity for assessing LC-PUFA intake, especially EPA and DHA intake, among Japanese women in early and late pregnancy., (Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)