Assisted reproductive technology-associated risk factors for placenta accreta spectrum after vaginal delivery.

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.

Assisted reproductive technology-associated risk factors for retained products of conception.

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.

Impact of COVID-19 pandemic on assisted reproductive technology treatment under voluntary lockdown in Japan.

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.

Model-based estimation of the health care expenditure and out-of-pocket payment for assisted reproductive technology: A retrospective linkage study using the Japanese national ART registry.

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.

Postoperative C-reactive protein as a predictive marker for surgical site infection after cesarean section: Retrospective analysis of 748 patients at a Japanese academic institution.

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.

Out-of-pocket payment and patients' treatment choice for assisted reproductive technology by household income: a conjoint analysis using an online social research panel in Japan.

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.

Factors associated with an unfavorable clinical course in hospitalized patients with pelvic inflammatory disease: a retrospective cohort study of 117 patients from a Japanese academic institution.

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.

Down syndrome live births following assisted reproductive technology in Japan: a nationwide survey between 2007 and 2016.

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.

Workflow Optimization for Identification of Female Germline or Oogonial Stem Cells in Human Ovarian Cortex Using Single-Cell RNA Sequence Analysis.

In 2004, the identification of female germline or oogonial stem cells (OSCs) that can support post-natal oogenesis in ovaries of adult mice sparked a major paradigm shift in reproductive biology. Although these findings have been independently verified, and further extended to include identification of OSCs in adult ovaries of many species ranging from pigs and cows to non-human primates and humans, a recent study rooted in single-cell RNA sequence analysis (scRNA-seq) of adult human ovarian cortical tissue claimed that OSCs do not exist, and that other groups working with OSCs following isolation by magnetic-assisted or fluorescence-activated cell sorting have mistaken perivascular cells (PVCs) for germ cells. Here we report that rare germ lineage cells with a gene expression profile matched to OSCs but distinct from that of other cells, including oocytes and PVCs, can be identified in adult human ovarian cortical tissue by scRNA-seq after optimization of analytical workflow parameters. Deeper cell-by-cell expression profiling also uncovered evidence of germ cells undergoing meiosis-I in adult human ovaries. Lastly, we show that, if not properly controlled for, PVCs can be inadvertently isolated during flow cytometry protocols designed to sort OSCs because of inherently high cellular autofluorescence. However, human PVCs and human germ cells segregate into distinct clusters following scRNA-seq due to non-overlapping gene expression profiles, which would preclude the mistaken identification and use of PVCs as OSCs during functional characterization studies.

Optimal individualization of patient-oriented ovarian stimulation in Japanese assisted reproductive technology clinics, a review for unique setting with advanced-age patients.

Ovarian stimulation is a key issue in assisted reproductive technology (ART) treatment. ART practice in Japan is unique with various types of ovarian stimulation protocols, which may contribute to lower pregnancy rates compared to other countries. This review aims to clarify optimal individualized ovarian stimulation for improving the pregnancy rate per one oocyte retrieval cycle in Japan. We performed a literature review to describe ovarian stimulation, classification of infertile women depending on ovarian reserve and response, and Japanese ART data and discussed optimal conventional and mild ovarian stimulation protocols in Japan. According to Japanese ART registry data, the live birth rate of 30-35-year-old women was 32%-37% per ET cycle; therefore, four to five embryos are calculatedly needed when aiming a cumulative live birth rate of ≥80%. Mild stimulation aimed at collecting 5-10 oocytes can be alternative choice as an optimal ovarian stimulation protocol in young women. In 40-year-old women, the live birth rate is 18.8%, resulting in eight or more embryos as necessary. Conventional stimulation must be required in women with advanced age. In poor responders, however, mild stimulation may be sufficient for maximumly extracting their ovarian function. In Japan, mild ovarian stimulation can be selected in patients with a good prognosis and poor responders; however, conventional ovarian stimulation is necessary for women in advanced age.

Comparison of ovarian response to follitropin delta in Japanese and White IVF/ICSI patients.

RESEARCH QUESTION: Is ovarian response associated with individualized follitropin delta dosing regimen comparable across different ethnic populations? DESIGN: Post-hoc analysis of ovarian response in 800 IVF/intracytoplasmic sperm injection (ICSI) patients (170 Japanese women and 630 White women) undergoing stimulation with individualized follitropin delta dosing based on serum anti-Müllerian hormone concentration and body weight in two randomized controlled trials conducted in Japan (NCT03228680) and in Europe, North America and South America (NCT01956110). RESULTS: On average, Japanese women weighed 10 kg less, which affected the total follitropin delta dose, compared with White women (83.5 ± 28.9 versus 90.2 ± 25.2 µg). At the end of stimulation, serum FSH concentrations were not significantly different between Japanese and White women (median 14.3 versus 14.0 IU/l), whereas serum oestradiol concentrations were significantly higher in Japanese women (median 6517 versus 5298 pmol/l, P < 0.0001). Japanese and White women had a similar number of oocytes retrieved with no significant differences among all women who started stimulation (9.3 ± 5.4 versus 9.5 ± 5.7), potential low responders (7.2 ± 3.7 versus 7.6 ± 4.6) or potential high responders (10.8 ± 5.9 versus 11.0 ± 6.0). At each level of ovarian response, serum oestradiol concentrations were significantly higher in Japanese women (P = 0.024). The incidence of early ovarian hyperstimulation syndrome was significantly higher in Japanese women compared with White women; overall (10.0% versus 2.2%, P = 0.0124) and at similar serum oestradiol concentrations (P = 0.0137). CONCLUSIONS: The individualized follitropin delta dosing provides similar serum FSH concentrations and similar oocyte yield in Japanese and White IVF/ICSI patients, but the oestradiol response is higher in Japanese women.

Efficient automated semi-quantitative urine culture analysis via BD Urine Culture App.

We aimed to assess the clinical utility of BD KiestraTM Urine Culture App (UCA). High concordance rates were observed between the urine culture colony counts obtained by medical technologists and those produced using UCA. This application may increase the efficiency of obtaining semi-quantitative urine culture results.

Social capital and use of assisted reproductive technology in young couples: Ecological study using application information for government subsidies in Japan.

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.

Cumulative live birth rate according to the number of receiving governmental subsidies for assisted reproductive technology in Saitama Prefecture, Japan: A retrospective study using individual data for governmental subsidies.

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.

International Committee for Monitoring Assisted Reproductive Technologies world report: assisted reproductive technology, 2014†.

STUDY QUESTION: What were the utilization, effectiveness and safety of practices in assisted reproductive technologies (ART) globally in 2014 and what global trends could be observed? SUMMARY ANSWER: The estimated total number of ART cycles conducted in 76 participating countries in 2014 was 1.93 million representing ∼66% of global activity, with 5-year trends including an increase in success rates and proportion of frozen embryo transfer (FET) cycles, improvement in cumulative live birth rates per aspiration, a continued increase in single embryo transfer (SET) and thus a reduction in multiple birth rates, an increase in preimplantation genetic testing and stabilization in the use of intracytoplasmic sperm injection (ICSI). WHAT IS KNOWN ALREADY: ART is widely practiced throughout the world but continues to be characterized by significant disparities in utilization, practice, effectiveness and safety. The International Committee for Monitoring Assisted Reproductive Technologies (ICMART) annual world report series provides an important instrument for tracking trends in ART treatment and for providing clinical and public health data to ART professionals, health authorities, patients and the general public. STUDY DESIGN, SIZE, DURATION: A retrospective, cross-sectional survey on ART procedures performed globally during 2014 was carried out. A new method for calculating ART utilization rates and number of babies born was introduced in this latest ICMART world report. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 76 countries and 2 746 ART centres submitted data through national and regional ART registries on ART cycles performed during 2014 and their treatment and pregnancy outcomes. ART cycles and outcomes are described at a country level, regionally and globally. Aggregate country data are processed and analyzed based on methods developed by ICMART. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1 629 179 ART cycles were reported for the treatment year 2014. After imputing data for missing values and non-reporting centres in reporting countries, an estimated 1 929 905 cycles resulted in >439 039 babies in reporting countries. From 2010 to 2014, the number of reported non-donor aspirations and FET cycles increased by 37.3% and 67.5%, respectively. The proportion of women aged ≥40 years undergoing non-donor ART increased from 23.2% in 2010 to 27.0% in 2014. ICSI, as a percentage of non-donor aspiration cycles, remained relatively stable at 64.8%. The IVF/ICSI combined delivery rates per fresh aspiration and FET cycle were 19.9% and 24.3%, respectively. In fresh non-donor cycles, SET increased from 30.0% in 2010 to 40.0% in 2014, while the average number of transferred embryos decreased from 1.95 to 1.73-but with wide country variation. The rate of twin deliveries following fresh non-donor transfers continued to decrease, from 20.4% in 2010 to 16.2% in 2014, and the triplet rate decreased from 1.1% to 0.5%. In FET non-donor cycles in 2014, the SET rate was 61.6%, with an average of 1.43 embryos transferred, resulting in twin and triplet rates of 10.1% and 0.2%, respectively. The cumulative delivery rate per aspiration increased from 27.1% in 2010 to 32.1% in 2014. The overall perinatal mortality rate per 1 000 births was 19.4 following fresh IVF/ICSI cycles and 9.5 following FET cycles. Among reporting countries, oocyte donation cycles represented 7.3% of all embryo transfers (89 751 transfer cycles) and resulted in 39 278 babies. LIMITATIONS, REASONS FOR CAUTION: The data presented are dependent on the quality and completeness of data submitted by individual countries to ICMART directly or through regional registries. This report covers approximately two-thirds of world ART activity. China is a major contributor of global cycles missing from this report. Continued efforts to improve the quality and consistency of ART data reported by registries are still needed, including the use of internationally agreed standard definitions (The International Glossary of Infertility and Fertility Care). A new method was introduced in this report to calculate ART utilization and number of babies born following ART; therefore, these results are not directly comparable with previous reports. WIDER IMPLICATIONS OF THE FINDINGS: The ICMART world reports provide the most comprehensive global statistical census and review of ART utilization, effectiveness, safety and quality. While ART treatment effectiveness and safety continue to increase globally, the wide disparities in access to treatment, procedures performed and embryo transfer practices warrant attention by clinicians and policymakers. The new method for estimating ART utilization and number of babies born provided more conservative estimates compared to the previuos method. STUDY FUNDING/COMPETING INTEREST(S): ICMART receives unrestricted grants from Abbott and Ferring Pharmaceuticals. ICMART also acknowledges financial support from the following organizations: American Society for Reproductive Medicine; Asia Pacific Initiative on Reproduction; European Society of Human Reproduction and Embryology; Fertility Society of Australia and New Zealand; Japan Society for Reproductive Medicine; Japan Society of Fertilization and Implantation; Red Latinoamericana de Reproducción Asistida; and the Society for Assisted Reproductive Technology. S.D. reports industry sponsorship for attendance of conference from Ferring, and research grants to support African Network and Registry of ART from Ferring and Merck outside the submitted work. F.Z.-H. reports lectures at organized webinars for Ferring and Merck. O.I. reports honoraria for consulting from Ferring, Merck and ObsEva, as well as honoraria for lectures from Ferring and Merck. G.M.C., J.d.M., M.B., M.S.K. and G.D.A. have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Effect of endometrial preparation protocols on the risk of ectopic pregnancy for frozen embryo transfer.

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.

Household income and medical help-seeking for fertility problems among a representative population in Japan.

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.

Fertility treatments have helped millions of people to have a child. Although financial factors are known to play an important role in the decision to use fertility treatments, no previous studies have investigated how socioeconomic factors affect medical help-seeking for fertility in Japan. Therefore, we assessed the association between household income and medical help-seeking among couples with fertility problems in Japan, using nationally representative data from the National Fertility Survey 2015. Of the 6598 respondents (married women under 50 years old), one-third (2253) reported worrying about fertility problems, and half of those women (1154) sought medical help for fertility-related issues. The proportion of help-seekers was highest (59%) among those with high household income and lowest (43%) among those with low household income with a significant linear trend. Even after accounting for age, length of marriage, educational level, employment status, and other possibly related factors, those with higher household income were more likely to seek medical help for fertility tests and treatments. Japan provides various sources of financial support for fertility-related care, such as health insurance coverage for tests and early-stage treatments and partial subsidies for assisted reproductive technology treatments. However, the results indicate that further policy discussion about additional financial support and further studies focusing on barriers to care in Japan could help improve the situations for those with fertility problems.

Lactobacillus crispatus promotes invasion of the HTR-8/SVneo trophoblast cell line.

INTRODUCTION: Recent studies have shown that the endometrium possesses unique microbiomes, including Lactobacillus. However, the roles of these microbes are currently unknown, especially in placentation and the early stage of pregnancy. METHODS: The immortalized human first-trimester trophoblast cell line HTR-8/SVneo was cultured in the presence or absence of Lactobacillus crispatus. Invasive and migrative activities were directly evaluated using an optical microscope and a time-lapse imaging system. Protein levels of the invasion-related protein matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9 were evaluated using ELISA. RESULTS: Matrigel invasion of HTR-8/SVneo cells was significantly increased by L. crispatus, though migration was not affected. The culture supernatant of L. crispatus also promoted invasion. Additionally, levels of the active forms of MMP-1 and MMP-2 in the cell culture medium were upregulated by L. crispatus treatment, but that of MMP-9 was not changed. DISCUSSION: L. crispatus promotes trophoblast invasion with an increase in MMP-1 and MMP-2 activation. Our results might explain why Lactobacillus dominance in the endometrium seems beneficial for implantation. Nevertheless, further research is required to determine whether the promotion of trophoblast invasion by L. cripatus is favorable for successful placentation at the early stage of pregnancy.

International Committee for Monitoring Assisted Reproductive Technologies (ICMART): world report on assisted reproductive technologies, 2013.

OBJECTIVE: To report the utilization, effectiveness, and safety of practices in assisted reproductive technology (ART) globally in 2013 and assess global trends over time. DESIGN: Retrospective, cross-sectional survey on the utilization, effectiveness, and safety of ART procedures performed globally during 2013. SETTING: Seventy-five countries and 2,639 ART clinics. PATIENT(S): Women and men undergoing ART procedures. INTERVENTION(S): All ART. MAIN OUTCOME MEASURE(S): The ART cycles and outcomes on country-by-country, regional, and global levels. Aggregate country data were processed and analyzed based on methods developed by the International Committee for Monitoring Assisted Reproductive Technology (ICMART). RESULT(S): A total of 1,858,500 ART cycles were conducted for the treatment year 2013 across 2,639 clinics in 75 participating countries with a global participation rate of 73.6%. Reported and estimated data suggest 1,160,474 embryo transfers (ETs) were performed resulting in >344,317 babies. From 2012 to 2013, the number of reported aspiration and frozen ET cycles increased by 3% and 16.4%, respectively. The proportion of women aged >40 years undergoing nondonor ART increased from 25.2% in 2012 to 26.3% in 2013. As a percentage of nondonor aspiration cycles, intracytoplasmic sperm injection (ICSI) was similar to results for 2012. The in vitro fertilization (IVF)/ICSI combined delivery rates per fresh aspiration and frozen ET cycles were 24.2% and 22.8%, respectively. In fresh nondonor cycles, single ET increased from 33.7% in 2012 to 36.5% in 2013, whereas the average number of transferred embryos was 1.81-again with wide country variation. The rate of twin deliveries after fresh nondonor transfers was 17.9%; the triplet rate was 0.7%. In frozen ET cycles performed in 2013, single ET was used in 57.6%, with an average of 1.49 embryos transferred and twin and triplet rates of 10.8% and 0.4%, respectively. The cumulative delivery rate per aspiration was 30.4%, similar to that in 2012. Perinatal mortality rate per 1,000 births was 22.2% after fresh IVF/ICSI and 16.8% after frozen ET. The data presented depended on the quality and completeness of the data submitted by individual countries. This report covers approximately two-thirds of world ART activity. Continued efforts to improve the quality and consistency of reporting ART data by registries are still needed. CONCLUSION(S): Reported ART cycles, effectiveness, and safety increased between 2012 and 2013 with adoption of a better method for estimating unreported cycles.

Cesarean delivery rates for overall and multiple pregnancies in Japan: A descriptive study using nationwide health insurance claims data.

AIM: Due to the lack of national perinatal registries, population-wide descriptive statistics on cesarean deliveries in Japan are unknown. We aim to describe cesarean deliveries for overall and multiple pregnancies using the Japan National Database of health insurance claims. METHODS: We calculated the national and prefectural cesarean delivery rates for overall and multiple pregnancies in 2014. We described maternal morbidities (e.g., blood transfusion) and the place and type of the institutions providing prenatal and perinatal care. RESULTS: The national cesarean delivery rates were 18.6% overall and 82.7% for women with multiple pregnancies. Prefectural cesarean delivery rates for overall and multiple pregnancies varied from 12.5% to 24.2% and from 49.2% to 100%, respectively, showing a moderate positive correlation (r = 0.59, p < 0.001). Overall, 1.4% of cesarean patients received an allogeneic blood transfusion, compared to 3.2% for those with multiple pregnancies. In addition, 65.9% of overall cesarean deliveries occurred at hospitals with ≥20 beds, whereas 94.6% of cesarean patients with multiple pregnancies delivered at hospitals. Older patients were more likely to receive their cesarean section at a different institution than their first visit within the same prefecture, but trans-prefectural movement during pregnancy covered by health insurance was most frequent among those in their early thirties: 7.0% overall and 10.7% for multiple pregnancies. CONCLUSIONS: The overall cesarean delivery rate in Japan was optimal, but the rate was high for multiple pregnancies, with large regional differences. Data on patient movement across institutions and areas would help to improve the perinatal care system.