Preconception education program for non-invasive prenatal testing focused on interest in genetics among female university students in Japan: a quasi-experimental study comparing pre-intervention, post-intervention, and three-month follow-up results.

BACKGROUND: Non-invasive prenatal testing (NIPT) is offered as a reproductive choice in many countries. However, pregnant women, particularly those who are primipara or lack knowledge of prenatal testing, experience difficulties understanding adequate information and making decisions on NIPT. This study developed a preconception education program about NIPT, focusing on interest in genetics, and aimed to clarify the effectiveness of the program to help women make decisions on future NIPT. METHODS: This was a one-group, quasi-experimental, pre-post-test study. The study population was female undergraduate students in Japan who participated in the education program. This program included two games and was based on the Attention, Relevance, Confidence, and Satisfaction (ARCS) model, which is an instructional design that stimulates learning interest and motivation. The data of 73 pre-pregnant women who completed all three questionnaires-before, immediately after, and three months after the intervention-were analyzed to clarify the time effects. Moreover, all variables were analyzed using logistic regression analysis to investigate factors related to decisional conflict. RESULTS: Interest in genetics, knowledge of genetics and prenatal testing, and indecisive attitudes toward NIPT significantly improved immediately after the intervention, and consequently, these changes and reduction of decisional conflict were maintained at three months. Moreover, low decisional conflict at follow-up was significantly associated with a high interest in genetics (adjusted odds ratio, 3.42). CONCLUSIONS: These findings provide preliminary evidence that this preconception education program, which focused on facilitating interest in genetics, assists pre-pregnant women to reduce decisional conflict about future NIPT. TRIAL REGISTRATION: The trial was registered at the UMIN-CTR registry (January 16, 2023), registration number UMIN000050047.

Prenatal diagnosis of bone dysplasias.

Bone dysplasias are individually rare but collectively common. The prenatal diagnosis of bone dysplasias, especially perinatally lethal dysplasias, is of major interest to obstetric services. The current nosology of genetic skeletal disorders addresses over 400 disorders. However, in clinical practice, we encounter only a limited number of disorders, such as FGFR3-related dysplasias, osteogenesis imperfecta, and type II collagenopathies. The recent development of non-invasive prenatal genetic testing using cell-free fetal DNA in maternal blood samples has had a major impact on the prenatal diagnosis of genetic diseases. However, imaging examinations remain critical for the final diagnosis of bone dysplasias because molecular testing only shows genetic variants, and not their pathogenicity - most variants are clinically insignificant. Bone dysplasias are typically suspected when limb shortening is identified by screening ultrasound. Further assessment can be followed by more detailed ultrasound, magnetic resonance imaging (MRI), and CT. Based on these data, rational decision-making is feasible, even when the definitive prenatal diagnosis is not feasible. Here, we highlight key images of common bone dysplasias obtained by currently available modalities.

Comprehensive Genomic Profiling Detects Hereditary Cancers and Confers Survival Advantage in Patients With Gynaecological Cancers.

BACKGROUND/AIM: The clinical benefits of comprehensive genomic profiling (CGP) of tumours in patients with gynaecological cancers remain unknown. We investigated the utility of CGP in assessing patient survival and its efficacy in detecting hereditary cancers in gynaecological patients. PATIENTS AND METHODS: We retrospectively analysed the medical records of 104 gynaecological patients who underwent CGP between August 2018 and December 2022. The detection of actionable and accessible genomic alterations and administration of targeted therapy, as recommended by the molecular tumour board (MTB), were assessed. The overall survival (after second-line treatment in cervical and endometrial carcinomas and after platinum-resistant recurrence in ovarian carcinoma) was compared between patients with or without administration of MTB-recommended genotype-matched therapy. Germline findings were assessed using a variant allele frequency-tumour content graph. RESULTS: Among 104 patients, actionable and accessible genomic alterations were observed in 53 patients. Matched therapy was applied in 21 patients, comprising administration of repurposing itraconazole (n=7), immune checkpoint inhibitors (n=7), poly (ADP-ribose) polymerase inhibitors (n=5), and others (n=2). The median overall survival of patients receiving and not receiving matched therapy were 19.3 months and 11.2 months, respectively (p=0.036, hazard ratio=0.48). Among 12 patients with hereditary cancers, 11 patients were previously undiagnosed. Seven patients had hereditary breast and ovarian cancer, and five had other cancer. CONCLUSION: The implementation of CGP testing prolonged overall survival in gynaecological cancer as well as provided an opportunity for genetic counselling for newly-diagnosed patients with hereditary cancers and their families.

Analyzing the relationship between feelings about pregnancy and mother-infant bonding with the onset of maternal psychological distress after childbirth: The Japan Environment and Children's Study.

BACKGROUND: Strengthening maternal mental health from early pregnancy is essential. This study investigated the factors affecting the onset of maternal psychological distress at 12 months after childbirth in women who had not experienced it during pregnancy. METHODS: Feelings about pregnancy were assessed using a questionnaire in the first trimester, and maternal mental health was assessed using the 6-Item Kessler Psychological Distress Scale (K6) in the first and second/third trimesters and at 12 months after childbirth. Mother-infant bonding was assessed using the Japanese version of Mother-to-Infant Bonding Scale (MIBS-J) in the first, sixth, and twelfth months after childbirth. This study comprised 46,053 mothers without psychological distress (K6 ≤ 4) during pregnancy from the 97,415 mothers enrolled in the Japan Environment and Children's Study. RESULTS: The onset of psychological distress at 12 months after childbirth was associated with negative maternal feelings about pregnancy, a history of infertility treatment before the current pregnancy, and poor mother-infant bonding after childbirth. Abortion history was not associated with psychological distress. The strongest factor affecting the onset of psychological distress was mother-infant bonding (ß = 0.28), and the indirect effect of feelings about pregnancy was also observed (ß = 0.10). LIMITATIONS: We used the full version of MIBS-J consisting of 10 items at 12 months after childbirth but included only five items in the first and sixth months. CONCLUSIONS: Inadequate mother-infant bonding was associated with the onset of maternal psychological distress after childbirth. Supporting mother-infant bonding is critical throughout the perinatal period, considering maternal feelings about pregnancy.

Factors related to indecisive attitudes toward non-invasive prenatal testing among women of reproductive age in Japan.

AIM: This study aimed to investigate the factors related to indecisive attitudes toward noninvasive prenatal testing (NIPT) among nonpregnant women of reproductive age. METHODS: We conducted an online survey involving nonpregnant Japanese women aged 20-49 years. The questionnaires consisted of a hypothetical question about whether they would decide to undergo NIPT if they were to become pregnant, and responses with "unsure" were defined as indecisive attitudes. RESULTS: Of 1250 participants, 412 (33%) held indecisive attitudes on whether to undergo NIPT. Multivariable logistic regression analysis demonstrated indecisive attitudes were related to a low level of knowledge about prenatal testing (adjusted odds ratio [AOR] 3.89) and preferences for family-driven decisions (AOR 1.44) instead of provider-driven. CONCLUSION: Even though the NIPT is widespread, many nonpregnant women of reproductive age are unable to decide whether to undergo the NIPT or not. Hence, indecisive women toward NIPT require adequate information and communication about future NIPT among their families prior to conception. Therefore, preconception support of providing adequate information about testing and facilitating communication regarding future NIPT among women and their family members may help indecisive women make autonomous decisions on NIPT.

Association of epidural analgesia during labor with neurodevelopment of children during the first three years: the Japan Environment and Children's Study.

BACKGROUND: Epidural analgesia relives pain during labor. However, the long-term effects on neurodevelopment in children remain unclear. We explored associations between exposure to epidural analgesia during labor and childhood neurodevelopment during the first 3 years of life, in the Japan Environment and Children's Study (JECS), a large-scale birth cohort study. METHODS: Pregnant women were recruited between January 2011 and March 2014, and 100,304 live births of singleton children born at full-term by vaginal delivery, and without congenital diseases were analyzed. Data on mothers and children were collected using a self-administered questionnaires and medical record transcripts. The children's neurodevelopment was repeatedly assessed for five domains (communication, gross motor, fine motor, problem solving, and personal-social), using the Ages and Stages Questionnaires, Third Edition, at six time points from age 6 to 36 months. After adjusting for potential confounders, the associations between exposure to epidural analgesia during labor and children's neurodevelopment at each time point were assessed. RESULTS: Of the 42,172 children with valid data at all six time points, 938 (2.4%) were born to mothers who received epidural analgesia during labor. Maternal exposure to epidural analgesia was associated with neurodevelopmental delays during the first 3 years after birth. Delay risks in gross and fine motor domains were the greatest at 18 months (adjusted odds ratio (aOR) [95% confidence interval (CI)]: 1.40 [1.06, 1.84] and 1.54 [1.17, 2.03], respectively), subsequently decreasing. Delay risks in communication and problem-solving domains were significantly high at 6 and 24 months, and remained significant at 36 months (aOR [95% CI]: 1.40 [1.04, 1.90] and 1.28 [1.01, 1.61], respectively). Exposure to epidural analgesia was also associated with the incidence of problem solving and personal-social delays from 18 to 24 months old. Neurodevelopmental delay risks, except for communication, were dominant in children born to mothers aged ≥30 years at delivery. CONCLUSIONS: This study showed that maternal exposure to epidural analgesia during labor was associated with neurodevelopmental delays in children during the first 3 years after birth.

Development of individuals with thanatophoric dysplasia surviving beyond infancy.

BACKGROUND: This study aimed to analyze the physical and psychosocial development of long-term survivors (age >1 year) of thanatophoric dysplasia (TD). METHODS: The participants were 20 long-term survivors recruited from a cohort obtained through a nationwide survey for TD conducted across 147 pediatric departments in Japan between 2012 and 2016. Their guardians consented to participate in this study. Medical and psychosocial information was collected through questionnaires and interviews with primary physicians and guardians. RESULTS: The participants were 1.2-27.8 years old, and all showed marked growth deficiency. The mean length at birth was 36 cm (-3.4 SD to -7.9 SD). The adult height (age >16 years) was <-15.2 SD. All individuals showed severely delayed psychomotor development. The highest level of psychosocial development was equivalent to that at 2 years of age. Skin disorders (acanthosis nigricans and seborrheic keratoses) were common. Eleven subjects had been hospitalized or institutionalized consistently after birth, and nine had been moved to home care, and four were exclusively orally fed. All individuals required assisted ventilation. CONCLUSIONS: Long-term survival of TD individuals is common. Some individuals enjoy home-based lives; however, they are severely psychosocially and physically disabled and require meticulous respiratory and nutritional support.

Evaluation of the clinical performance of noninvasive prenatal testing at a Japanese laboratory.

AIM: We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high-risk pregnant women. METHODS: Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age-specific PPV and NPV were estimated. RESULTS: Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78-99.96), 99.12% (95% CI: 96.83-99.76), and 100% (95% CI: 88.30-100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age-specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively. CONCLUSION: The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high-risk pregnant women, and maternal age-specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan.

Feelings about pregnancy and mother-infant bonding as predictors of persistent psychological distress in the perinatal period: The Japan Environment and Children's Study.

Feelings about pregnancy and mother-infant bonding are associated with maternal mental health before and after childbirth. The current study examined factors associated with persistent distress at 12 months after childbirth among mothers with psychological distress in the first trimester, using data from the Japan Environment and Children's Study (JECS). Feelings about pregnancy were assessed using a questionnaire in the first trimester, and maternal mental health was assessed using the Kessler 6 (K6) in the first trimester and at 12 months after childbirth. In addition, mother-infant bonding was assessed using the Mother-to-Infant Bonding Scale Japanese version (MIBS-J) at 12 months after childbirth, and 5 items from the MIBS-J at one and six months after childbirth. Among the 97,415 mothers registered in the JECS, 24,324 mothers with psychological distress (K6 ≥ 5) in the first trimester were included in this analysis. The relationships between persistence of psychological distress at 12 months after childbirth with feelings about pregnancy and mother-infant bonding were analyzed. Both maternal negative feelings about pregnancy in the first trimester and mother-infant bonding after childbirth were significantly associated with persistent psychological distress at 12 months after childbirth (ß = 0.02, p = 0.001 and ß = 0.35, p < 0.001, respectively). The indirect effect of feelings about pregnancy on persistent distress through mother-infant bonding was also observed (ß = 0.06, p < 0.001). These findings indicate that mother-infant bonding after childbirth may be important for improving the mental health of mothers with prenatal psychological distress.

Association between the serum insulin-like growth factor-1 concentration in the first trimester of pregnancy and postpartum depression.

AIM: Patients with major depression present with an increased serum insulin-like growth factor-1 (IGF-1) concentration. However, the longitudinal relationship between serum IGF-1 levels and depression development remains unclear. This study aimed to investigate the longitudinal association between the serum IGF-1 concentration in the first trimester of pregnancy and postpartum depression development using data obtained from the Japan Environment and Children's Study (JECS). METHODS: The JECS included 97 415 pregnant women; among them, 8791 were enrolled in this study. Data regarding depression in the first trimester, postpartum depression development at 1 month after childbirth, and other covariates were collected using a self-administered questionnaire. Serum IGF-1 levels were measured in the first trimester of pregnancy. The participants were divided into four groups according to the serum IGF-1 level. RESULTS: In the first trimester, serum IGF-1 levels were not significantly associated with psychological distress in pregnant women. In the longitudinal analyses, however, postpartum depression development in mothers within the highest quartile for serum IGF-1 concentration in the first trimester was significantly less common than in those within the lowest quartile (odds ratio 0.48, 95% confidence interval 0.30-0.79). CONCLUSION: Pregnant women with a high serum IGF-1 concentration in the first trimester were less likely to develop postpartum depression than those with a low concentration. A high serum IGF-1 concentration during pregnancy may help to protect against postpartum depression development.

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.

Qualitative investigation of the factors that generate ambivalent feelings in women who give birth after receiving negative results from non-invasive prenatal testing.

BACKGROUND: Women who receive negative results from non-invasive prenatal genetic testing (NIPT) may find that they later have mixed or ambivalent feelings, for example, feelings of accepting NIPT and regretting undergoing the test. This study aimed to investigate the factors generating ambivalent feelings among women who gave birth after having received negative results from NIPT. METHODS: A questionnaire was sent to women who received a negative NIPT result, and a contents analysis was conducted focusing on ambivalent expressions for those 1562 women who responded the questionnaire. The qualitative data gathered from the questionnaire were analyzed using the N-Vivo software package. RESULTS: Environmental factors, genetic counseling-related factors, and increased anticipatory anxiety, affected the feeling of ambivalence among pregnant women. Furthermore, pregnant women desired more information regarding the detailed prognosis for individuals with Down syndrome and living with them and/or termination, assuming the possibility that they were positive. CONCLUSIONS: Three major interrelated factors affected the feeling of ambivalence in women. Highlighting and discussing such factors during genetic counseling may resolve some of these ambivalences, thereby enhancing the quality of decisions made by pregnant women.

Clinical Practice Guidelines for Hypophosphatasia.

Hypophosphatasia (HPP) is a rare bone disease caused by inactivating mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). Patients with HPP have varied clinical manifestations and are classified based on the age of onset and severity. Recently, enzyme replacement therapy using bone-targeted recombinant alkaline phosphatase (ALP) has been developed, leading to improvement in the prognosis of patients with life-threatening HPP. Considering these recent advances, clinical practice guidelines have been generated to provide physicians with guides for standard medical care for HPP and to support their clinical decisions. A task force was convened for this purpose, and twenty-one clinical questions (CQs) were formulated, addressing the issues of clinical manifestations and diagnosis (7 CQs) and those of management and treatment (14 CQs). A systematic literature search was conducted using PubMed/MEDLINE, and evidence-based recommendations were developed. The guidelines have been modified according to the evaluations and suggestions from the Clinical Guideline Committee of The Japanese Society for Pediatric Endocrinology (JSPE) and public comments obtained from the members of the JSPE and a Japanese HPP patient group, and then approved by the Board of Councils of the JSPE. We anticipate that the guidelines will be revised regularly and updated.

Association of ALPL variants with serum alkaline phosphatase and bone traits in the general Japanese population: The Nagahama Study.

Although alkaline phosphatase (ALP) activity is relatively low in carriers of recessive type hypophosphatasia (HPP), most are asymptomatic and therefore do not undergo medical evaluations. We analyzed the association of ALP-encoding ALPL variants with serum ALP and bone traits in the general Japanese population. Study participants (n = 9671) were from the Nagahama Study, which was a longitudinal cohort study of an apparently healthy general Japanese population. ALPL variants were analyzed by whole-genome sequencing or TaqMan probe assays using DNA extracted from peripheral blood samples. The speed of sound in calcaneal bone was assessed by quantitative ultrasound (QUS) and used as surrogate measures of bone mineral density. We identified 13 ALPL variants. Minor allele frequencies of three variants were higher than expected. Variant c.529G > A has been reported as a possible pathogenic variant for adult type HPP. Variants c.979C > T and c.1559delT are reported as pathogenic variants for perinatal severe HPP or infantile HPP. The allele frequencies of c.529G > A, c.979C > T, and c.1559delT were 0.0107, 0.0040, and 0.0014, respectively. Serum ALP activity was significantly lower and differed among the three variants (P < 0.001), as well as between individuals with and without any of the three variants (P < 0.001). Serum ALP activity was inversely associated with QUS values, although no direct association was observed between the ALPL variants and QUS values. An association between serum ALP activity and QUS was confirmed; however, we failed to detect an association between ALPL variants and bone traits in the general Japanese population.

Paternal occupational exposure to chemicals and secondary sex ratio: results from the Japan Environment and Children's Study.

BACKGROUND: Declining proportions of male births have been reported in several industrialised countries. Previous reports have shown that exposure to certain chemical substances might influence the secondary sex ratio (SSR). We assessed the associations between paternal occupational exposure to chemicals and the SSR of their children using the Japan Environment and Children's Study (JECS), a large-scale birth cohort study. METHODS: Data on paternal occupational exposure to various agents and other covariates were collected using a self-administered questionnaire to partners of pregnant female participants enrolled in the JECS. After adjusting for potential confounders, multivariable modified Poisson regression models were used to evaluate associations between paternal occupational exposures and the SSR of their children. This study was registered in the UMIN Clinical Trials Registry, number UMIN000030786. FINDINGS: The JECS study gathered data on 103 062 pregnancies, 104 065 fetuses, and 51 898 partners of pregnant women. Among 50 283 children with data on paternal occupational exposures, 25 657 were male and 24 626 were female. The proportion of boys whose fathers were regularly occupationally exposed to insecticides was 0·445 (males, n=293; females, n=366; 95% CI 0·406-0·483), which was lower than the proportion of boys whose fathers were not exposed to insecticides. After adjusting for confounding factors, regular paternal occupational exposure to insecticides (adjusted relative risk 0·86, 95% CI 0·78-0·96) and medical disinfectants (0·95, 0·90-1·00) were significantly associated with lower SSRs among their offspring compared with the offspring of fathers not exposed to these substances. INTERPRETATION: A declining proportion of boys could potentially be due to fathers working in environments in which they are exposed to chemicals. The associations between poorer semen quality and levels of reproductive and thyroid hormones require investigation. FUNDING: Ministry of the Environment of Japan.

Challenges in Managing Patients with Hereditary Cancer at Gynecological Services.

AIM: To reveal current problems and challenges faced by our gynecologic services department in managing patients with hereditary cancers. METHODS: We collected clinical data of patients with hereditary cancers, identified via genetic testing (or clinically diagnosed in cases of Cowden syndrome or Peutz-Jeghers syndrome), and treated in our gynecological department from 2012 to 2018. RESULTS: Fifteen patients had hereditary breast and ovarian cancer (HBOC), 6 had Lynch syndrome, 2 had Cowden syndrome, and 2 had Peutz-Jeghers syndrome. Five patients diagnosed with HBOC were younger than 40 years at diagnosis. Risk-reducing salpingo-oophorectomy (RRSO) was performed on 1 patient with a BRCA1 mutation at age 38 years. Seven patients overall underwent RRSO, and none had malignancies on pathological examinations. Peritoneal washing cytology (PWC) was suspicious for malignancy in one patient; however, subsequent PWC at 6 months after RRSO was negative. A patient with endometrial cancer and Lynch syndrome and a patient with atypical endometrial hyperplasia (AEH) and Cowden syndrome strongly desired fertility preservation. They achieved remission after medroxyprogesterone acetate treatment and multiple dilations and curettages, respectively. One patient with Lynch syndrome developed AEH after 11 years of surveillance. Laparotomy revealed adjacent low-grade and high-grade serous ovarian cancer with positive ascites cytology. She had no recurrence during 7-year follow-up after laparotomy. CONCLUSION: Managing patients with hereditary cancer, positive or false-positive ascites cytology discovered during RRSO, and desired preservation of fertility is highly challenging.

National survey of prevalence and prognosis of thanatophoric dysplasia in Japan.

BACKGROUND: Thanatophoric dysplasia (TD) is a rare congenital disease of the skeletal system, with an incidence of 1.68-8.3 per 100 000 births, but statistical data on the estimated number of TD patients across Japan are not available. The aim of this study was therefore to investigate the prevalence and prognosis of TD in Japan. METHODS: A nationwide primary questionnaire survey was conducted. RESULTS: A total of 127 obstetric, 186 pediatric, and 115 orthopedic facilities provided responses. Excluding duplications, we identified 73 patients with TD. Of the 73 cases, 15 were abortions, four were stillbirths, 51 were live births, and three had unknown details. Of the 51 live newborns, 27 died ≤7 days after birth, with an early neonatal mortality rate of 56%. Of the 24 newborns who survived the early neonatal period, 16 survived for ≥1 year. All of the 24 newborns received respiratory management and survived during the early neonatal period. Of the 51 live newborns, 25 did not receive respiratory management and died ≤2 days after birth. CONCLUSIONS: The prevalence of TD in Japan is estimated to be at 1.1 (95%CI: 0.84-1.37) per 100 000 births, but the actual incidence is expected to be higher. To our knowledge, we have confirmed for the first time that newborns with TD may not always die during the early neonatal period but can survive the early neonatal period with appropriate respiratory management. Therefore, the term "thanatophoric dysplasia" does not accurately reflect the nature of the disease.

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.

Correction: Nationwide survey for current clinical status of amniocentesis and maternal serum marker test in Japan.

Since the publication of this paper, the authors noticed that Yosuke Fujii was assigned to the incorrect affiliation. The affiliation information is provided correctly, above.

A Case of a Pregnant Woman with Thrombosis in an Artificial Aortic Valve Resulting in Severe Cerebral Hemorrhage in the Newborn.

Many patients, after artificial valve replacement surgery, receive warfarin anticoagulant therapy. However, it has been reported that warfarin administration during pregnancy can cause fetal teratogenicity. With reference to this case, we will discuss how warfarin administration in mid-pregnancy caused severe cerebral hemorrhage in the newborn child. The 36-year-old patient in this case underwent aortic valve replacement surgery when she was 11 years old; this requires the continued use of warfarin after surgery. Although she was advised otherwise, the patient became pregnant. The warfarin treatment was discontinued at 5 weeks of gestation and she began self-injection of heparin; however, her health quickly deteriorated requiring an emergency, warfarin treatment. On gestation week 21, she was admitted to our hospital with a high likelihood of a spontaneous abortion. A week later, transesophageal ultrasonography revealed a thrombus in the patient's aortic valve. Because of this finding, we re-started warfarin administration. At 32 weeks of gestation, cardiotocography showed decreased fetal heart rate; thus, an emergency Cesarean section was performed. A baby was delivered, weighing 1,702 g with an Apgar Score of 1 at 1 minute and 4 at 5 minutes. Cranial computed tomography of the infant showed bilateral intraventricular hemorrhage and ventricular dilation. In order to protect the mother and prevent hemorrhage in the newborn, it is recommended that a continuous heparin infusion should be administered to the pregnant woman after the 36th week of gestation. Regarding the impact on the infant, it is considered that continuous intravenous administration of heparin is safer during the third trimester of pregnancy. However, administration of heparin alone makes the preventive effect of thrombosis uncertain. When warfarin is administered in pregnancy, pregnancy management should be performed bearing the risk of fetal cerebral hemorrhage in mind.