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.

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.

Factors that affect menarche in Japanese national-level track-and-field athletes.

OBJECTIVES: The minimum body mass index (BMI) required to menarche and the relationship between the training onset age of sports and menarche is not fully understood. The aim of this study is to elucidate the minimum BMI required to attain menarche in female adolescent athletes competing at a national level, and to determine how the occurrence of menarche is associated with training onset age in track-and-field athletes. METHODS: Overall, 134 sprinters and 44 long-distance (LD) runners of ninth-grade females at a national level were enrolled and an anonymous questionnaire was administered. RESULTS: As BMI increased, the proportion of athletes who had attained menarche increased. The BMI cutoff values for menarche were 17.3 and 17.1 kg/m2 for sprinters and LD runners, respectively. Menarche had not occurred in almost 50% of the LD runners who began training at elementary school, and among LD runners, those who began training at elementary school had 18.4 higher odds of not attaining menarche until the age of 15 years as opposed to those who started training after elementary school. CONCLUSIONS: The BMI cutoff values could be an indicator for menarche in sprinters and LD runners. For LD runners, starting to compete at elementary school could be a risk factor for delayed menarche.

Prenatal diagnosis of severe mitochondrial diseases caused by nuclear gene defects: a study in Japan.

Prenatal diagnoses of mitochondrial diseases caused by defects in nuclear DNA (nDNA) or mitochondrial DNA have been reported in several countries except for Japan. The present study aimed to clarify the status of prenatal genetic diagnosis of mitochondrial diseases caused by nDNA defects in Japan. A comprehensive genomic analysis was performed to diagnose more than 400 patients, of which, 13 families (16 cases) had requested prenatal diagnoses. Eight cases diagnosed with wild type homozygous or heterozygous variants same as either of the heterozygous parents continued the pregnancy and delivered healthy babies. Another eight cases were diagnosed with homozygous, compound heterozygous, or hemizygous variants same as the proband. Of these, seven families chose to terminate the pregnancy, while one decided to continue the pregnancy. Neonatal- or infantile-onset mitochondrial diseases show severe phenotypes and lead to lethality. Therefore, such diseases could be candidates for prenatal diagnosis with careful genetic counseling, and prenatal testing could be a viable option for families.

Differences in the birthweight of infants born to patients with early- or mid-to-late-detected gestational diabetes mellitus who underwent guideline-based glycemic control.

AIMS: To examine the effects of strict glycemic control on the birthweight of infants born to Japanese patients with early- or mid-to-late-detected gestational diabetes mellitus (ed- or md-GDM). METHODS: We retrospectively examined the characteristics of 101 patients with GDM who underwent guideline-based glycemic control. A 75-g oral glucose tolerance test was conducted to diagnose GDM at gestational weeks 11-15 (ed-GDM subgroup) and 24-28 (md-GDM subgroup). RESULTS: Infant birthweight was significantly lower in the ed-GDM subgroup (n = 25) than in the md-GDM subgroup (n = 76) (2688.3 ±â€¯470.4 g vs. 3052.4 ±â€¯383.1 g, p < 0.05), and the proportion of low-birthweight infants (<2500 g) was significantly higher in the ed-GDM subgroup than in the md-GDM subgroup (32.0% vs. 5.3%, p < 0.005). Fasting plasma glucose (FPG) levels during early treatment and before delivery were significantly lower in the ed-GDM subgroup than in the md-GDM subgroup (76.1 ±â€¯10.4 mg/dL vs. 85.5 ±â€¯9.6 mg/dL, p < 0.001; 80.5 ±â€¯10.4 mg/dL vs. 90.4 ±â€¯10.3 mg/dL, p < 0.0001). CONCLUSIONS: Patients with ed-GDM showed significantly lower FPG levels during treatment compared to those with md-GDM, presumably indicating an association with the delivery of low-birthweight infants.

Retrospective details of false-positive and false-negative results in non-invasive prenatal testing for fetal trisomies 21, 18 and 13.

OBJECTIVE: Maternal characteristics and neonatal outcomes associated with cell-free DNA (cfDNA) results were analysed retrospectively to assess the details of false-positive and false-negative results after initial blood sampling in non-invasive prenatal testing (NIPT). STUDY DESIGN: A multicentre retrospective study was performed for women undergoing NIPT who received discordant cfDNA results between April 2013 and March 2018. The NIPT data obtained using massive parallel sequencing were studied in terms of maternal background, fetal fraction, z-scores, invasive procedure results and neonatal outcomes after birth. RESULTS: Of the 56,545 women who participated in this study, 54 false-positive (0.095 %) and three false-negative (0.006 %) cases were found. Seven of the 54 false-positive cases (13.0 %) had vanishing twin on ultrasonography. Among the 18 false-positive cases of trisomy 18, confined placental mosaicism (CPM) was confirmed in three cases (16.7 %), while CPM was present in one of the three false-negative cases of trisomy 21. CONCLUSION: These data suggest that the incidence of women with false-positive or false-negative results is relatively low, that such false results can often be explained, and that vanishing twin and CPM are potential causes of NIPT failure. Genetic counselling with regard to false results is important for clients prior to undergoing NIPT.

Use of nutritional supplements by elite Japanese track and field athletes.

BACKGROUND: While scientific evidence supports the efficacy of only limited nutritional supplements (NS) on sports performance, the use of NS is widespread in athletes. Given the serious issues of health damage or unintended Anti-Doping Rule Violations due to ingestion of contaminated NS in sports, accurately understanding NS practices by athletes is crucial. This study therefore elucidated the use of NS by elite Japanese track and field (TF) athletes. METHODS: The subjects were 574 Japanese TF athletes, including 275 junior athletes (under 20 years) and 299 senior athletes, who participated in international competitions from 2013 to 2018. Data on NS use were collected through pre-participation medical forms obtained from all entrants before their participation in competitions. NS users were requested to report the product names and primary components of all NS they were taking. RESULTS: The overall prevalence of NS use was 63.9%. The mean number of NS products used per athlete was 1.4. The prevalence was significantly higher in women (69.2%) than in men (59.6%) (p = 0.018) and significantly higher in senior athletes (68.9%) than in junior athletes (58.9%) (p = 0.012). The prevalence of NS use was higher in long-distance runners (75.8%) and lower in jumpers (52.3%) and throwers (49.2%) than other disciplines (p < 0.001). The most prevalent components were amino acids (49.3%), followed by vitamins (48.3%), minerals (22.8%), and protein (17.8%). CONCLUSIONS: Approximately two-thirds of elite Japanese TF athletes reported the use of NS, and NS practices varied by gender, age, and discipline.

Classification of factors involved in nonreportable results of noninvasive prenatal testing (NIPT) and prediction of success rate of second NIPT.

OBJECTIVE: To evaluate the reasons for nonreportable cell-free DNA (cfDNA) results in noninvasive prenatal testing (NIPT), we retrospectively studied maternal characteristics and other details associated with the results. METHODS: A multicenter retrospective cohort study in pregnant women undergoing NIPT by massively parallel sequencing (MPS) with failed cfDNA tests was performed between April 2013 and March 2017. The women's data and MPS results were analyzed in terms of maternal characteristics, test performance, fetal fraction (FF), z scores, anticoagulation therapy, and other details of the nonreportable cases. RESULTS: Overall, 110 (0.32%) of 34 626 pregnant women had nonreportable cfDNA test results after an initial blood sampling; 22 (20.0%) cases had a low FF (<4%), and 18 (16.4%) cases including those with a maternal malignancy, were found to have altered genomic profile. Approximately half of the cases with nonreportable results had borderline z score. Among the women with nonreportable results because of altered genomic profile, the success rate of retesting using a second blood sampling was relatively low (25.0%-33.3%). Thirteen (11.8%) of the women with nonreportable results had required hypodermic heparin injection. CONCLUSIONS: The classification of nonreportable results using cfDNA analysis is important to provide women with precise information and to reduce anxiety during pregnancy.

Weight control before and during pregnancy for patients with gestational diabetes mellitus.

AIMS/INTRODUCTION: The aim of the present study was to examine the associations of pregestational body mass index (BMI) and gestational weight change with birthweight for gestational age in Japanese mothers with gestational diabetes mellitus (GDM). MATERIALS AND METHODS: We retrospectively examined the clinical and laboratory characteristics of 101 mothers with GDM (pregestational BMI 24.7 ± 5.8 kg/m2 ; maternal age at delivery 34.7 ± 5.1 years; gestational age 38.5 ± 1.4 weeks) at a single center from January 2011 to December 2016. RESULTS: Gestational weight changes were 6.22 ± 5.39 kg, and infant birthweights were 2,987.3 ± 393.6 g. Multivariable analysis showed that, in all mothers, pregestational BMI and gestational weight change were positively associated with infant birthweight (P < 0.001 and P = 0.007, respectively). Pregestational BMI, but not gestational weight change, was positively associated with infant birthweight (P = 0.007) in 31 mothers with GDM who had pregestational BMI ≥25 kg/m2 ; in 68 mothers with GDM who had pregestational BMI 18.5-24.9 kg/m2 , only gestational weight gain was positively associated with infant birthweight (P = 0.039). Two mothers had pregestational BMI <18.5 kg/m2 . No statistically significant interactions of pregestational BMI with gestational weight change were found (P = 0.158). CONCLUSIONS: In mothers with GDM, pregestational BMI ≥25 kg/m2 and excessive gestational weight gain were significantly associated with increased infant birthweight. A prospective multicenter clinical study enrolling a larger number of mothers with GDM will be required to verify the effects of adequately controlling pregestational and gestational weights on infant birthweight for gestational age.

Fetal cell-free DNA fraction in maternal plasma for the prediction of hypertensive disorders of pregnancy.

OBJECTIVE: The purpose of this study is to compare the fetal fractions during non-invasive prenatal testing (NIPT) in singleton pregnancies according to gestational age and maternal characteristics to evaluate the utility of this parameter for the prediction of pregnancy complications including gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP). STUDY DESIGN: This study was a multicenter prospective cohort study. The present data were collected from women whose NIPT results were negative. The relationships between the fetal fractions and the gestational age, maternal weight and height, and incidences of miscarriage, preterm delivery, and pregnancy complications including GDM, HDP and placental abruption were assessed. RESULTS: A total of 5582 pregnant women with verified NIPT negative results were registered in the study. The demographic characteristics of the study populations were statistically analyzed, and the women with HDP tended to have a low fetal fraction in samples taken during early gestation. The area under the curve (AUC) in a receiver operating characteristic curve (ROC) analysis was 0.608 for women with HDP. CONCLUSION: A low fetal fraction on NIPT might be correlated with future HDP. However, predicting HDP during early pregnancy in women with a low fetal fraction might be difficult.

Current status of non-invasive prenatal testing in Japan.

AIM: The purpose of this study was to report the 3-year experience of a nationwide demonstration project to introduce non-invasive prenatal testing (NIPT) of maternal plasma for aneuploidy, and review the current status of NIPT in Japan. METHODS: Tests were conducted to detect aneuploidy in high-risk pregnant women, and adequate genetic counseling was provided. The clinical data, test results, and pregnancy outcomes were recorded. We discuss the problems of NIPT on the basis of published reports and meta-analyses. RESULTS: From April 2013 to March 2016, 30 613 tests were conducted at 55 medical sites participating in a multicenter clinical study. Among the 30 613 women tested, 554 were positive (1.81%) and 30 021 were negative (98.1%) for aneuploidy. Of the 289, 128, and 44 women who tested positive for trisomies 21, 18, and 13, respectively, and underwent definitive testing, 279 (96.5%), 106 (82.8%), and 28 (63.6%) were determined to have a true-positive result. For the 13 481 women with negative result and whose progress could be traced, two had a false-negative result (0.02%). The tests were performed on the condition that a standard level of genetic counseling be provided at hospitals. CONCLUSION: Here, we report on the 3-year nationwide experience with NIPT in Japan. It is important to establish a genetic counseling system to enable women to make informed decisions regarding prenatal testing. Moreover, a welfare system is warranted to support women who decide to give birth to and raise children with chromosomal diseases.

Factors affecting parental decisions to terminate pregnancy in the presence of chromosome abnormalities: a Japanese multicenter study.

OBJECTIVE: To investigate the rates of termination of pregnancy (TOP) for fetal chromosomal abnormalities and factors related to such parental decision in Japan. METHODS: A multicenter retrospective cohort study of chromosomal abnormalities diagnosed before 22 weeks of gestation between April 2008 and March 2015. The pregnancy outcomes and parental decisions were investigated. RESULTS: Among 931 fetuses with chromosome abnormalities, the total TOP rate was 75.1% (699/931). TOP rates were 89.3% (585/655) in autosomal aneuploidies and 40.8% (51/125) in sex chromosome aneuploidies. Trisomy 21 showed the highest TOP rate (93.8% [390/416]) followed by trisomy 18 (84.5% [163/193]) and trisomy 13 (71.9% [23/32]). Indications for karyotyping were related to a parental decision for TOP (p < 0.01): in cases of autosomal aneuploidy, with fetal abnormal ultrasound findings as the reference value, diagnoses made following positive results at non-invasive prenatal testing (adjusted odds ratio [OR]: 13.7, 95% confidence interval [CI] 4.07-45.9) and those because of advanced maternal age (adj. OR 2.91, 95% CI 1.15-7.35) were significantly more frequent. CONCLUSIONS: In Japan, pregnancies with fetal trisomy 21 are more likely to result in TOP when diagnosed in utero than any other chromosome anomaly. The indications for prenatal karyotyping strongly affect the decision to TOP. © 2016 John Wiley & Sons, Ltd.

A survey on awareness of genetic counseling for non-invasive prenatal testing: the first year experience in Japan.

The purpose of this study is to summarize the results from a survey on awareness of genetic counseling for pregnant women who wish to receive non-invasive prenatal testing (NIPT) in Japan. As a component of a clinical study by the Japan NIPT Consortium, genetic counseling was conducted for women who wished to receive NIPT, and a questionnaire concerning both NIPT and genetic counseling was given twice: once after pre-test counseling and again when test results were reported. The responses of 7292 women were analyzed. They expressed high satisfaction with the genetic counseling system of the NIPT Consortium (94%). The number of respondents who indicated that genetic counseling is necessary for NIPT increased over time. Furthermore, they highly valued genetic counseling provided by skilled clinicians, such as clinical geneticists or genetic counselors. The vast majority (90%) responded that there was sufficient opportunity to consider the test ahead of time. Meanwhile, women who received positive test results had a poor opinion and expressed a low-degree satisfaction. We confirmed that the pre-test genetic counseling that we conducted creates an opportunity for pregnant women to sufficiently consider prenatal testing, promotes its understanding and has possibilities to effectively facilitate informed decision making after adequate consideration. A more careful and thorough approach is considered to be necessary for women who received positive test results.

Prenatal diagnosis of complex rearrangement of chromosome 21: The significance of interphase and metaphase fluorescence in situ hybridization and comparative genomic hybridization.

KEY CLINICAL MESSAGE: Maternal serum screening-positive patient had prenatal diagnosis with amniotic fluid, which showed inconsistent results between interphase fluorescence in situ hybridization (three signals of 21q22.13-21q22.2) and G-banding analysis (46,XY). Further analyses proved that the fetus had extremely complex rearrangements of chromosome 21, including the interstitial duplication of Down syndrome critical region.

Prenatal molecular diagnosis of a severe type of L1 syndrome (X-linked hydrocephalus).

OBJECT: The aim of this study was to evaluate the feasibility of prenatal L1CAM gene testing for X-linked hydrocephalus (XLH). METHODS: In a nationwide study conducted in Japan between 1999 and 2009, the authors identified 51 different L1CAM gene mutations in 56 families with XLH. Of these 56 families, 9 obligate carriers requested prenatal gene mutation analysis for the fetal L1CAM gene in 14 pregnancies. RESULTS: In 2004, new clinical guidelines for genetic testing were established by 10 Japanese genetic medicine-related societies. These guidelines stated that the genetic testing of carriers should be done only with their consent and with genetic counseling. Therefore, because females are carriers, since 2004, L1CAM gene analysis has not been performed for female fetuses. The authors report on 7 fetal genetic analyses that were performed at the request of families carrying L1CAM mutations, involving 3 female (prior to 2004) and 4 male fetuses. Of the 7 fetuses, 3 (1 male and 2 female) carried L1CAM mutations. Of these 3, 1 pregnancy (the male fetus) was terminated; in the other cases, the pregnancies continued, and 3 female and 3 male babies without the XLH phenotype were born. CONCLUSIONS: Prenatal L1CAM gene testing combined with genetic counseling was beneficial for families carrying L1CAM mutations.