Prescribing in pregnant women with inflammatory bowel disease and its relationship to congenital malformations in Japan.

BACKGROUND AND AIM: Inflammatory bowel disease (IBD) frequently affects younger patients and poses various challenges concerning pregnancy and childbirth. Maintaining good disease control throughout pregnancy is crucial, but expectant and pregnant patients may worry about the fetal impact of medications, leading to treatment discontinuation due to uncertainty about this issue. This study investigated the real-world drug-prescribing practices for pregnant patients with IBD in Japan and their potential connection to major congenital malformations (MCMs). METHODS: Overall, 277 female IBD patients who gave birth between 2010 and 2019 were selected from the JMDC claims database. The prescribing patterns of IBD medications and MCMs in the patients' offspring were analyzed. RESULTS: Among pregnant IBD patients, 74.4% received at least one medication from 90 days before pregnancy to 90 days after delivery. Trends in medication prescriptions during pregnancy in 2010-2019 revealed consistent use of oral 5-ASA, variable use of topical medications, a decrease in systemic steroids, and an increase in biologics. The prevalence of MCMs in children born to IBD-affected mothers did not differ significantly between those who did and did not receive IBD medications (8.6% vs 6.8%). Although circulatory system MCMs were slightly more common in the IBD medication group (4.9% vs 1.4%), this difference was not significant. Logistic regression analysis did not reveal an association between MCM risk and first-trimester use of IBD medications, including corticosteroids and biologics. CONCLUSIONS: This study provides insights into medication patterns in pregnant IBD patients and suggests no increased risk of MCMs associated with first-trimester IBD medication use.

Real-world prevalence, time of diagnosis, and co-occurrence patterns of birth defects in live-born infants, 2014-2020: A health administrative database study in Japan.

BACKGROUND: A study evaluating the real-world prevalence of birth defects (BDs), including co-occurrence patterns, will provide the information required to estimate Japan's true BD prevalence and monitor it. Information such as when infants are diagnosed with BDs is crucial for defining the study population and data collection period in future administrative database studies. METHODS: This study utilized the DeSC database, a large claims database comprising multiple health insurance schemes. The prevalence of major BDs, including structural congenital malformations (CMs) and chromosomal abnormalities, was determined in infants born between 2014 and 2020 and continuously insured for ≥1 year. The time of the first BD diagnosis and multiple BD patterns were also evaluated. RESULTS: Among 43,147 infants, 3050 (7.07%) were diagnosed with major BDs, and 3002 (6.96%) with major CMs. The circulatory system (2.95%) was the most frequent organ system affected by CMs, followed by CMs and deformations of the musculoskeletal system (1.94%). The cumulative diagnostic rates of BDs and CMs at month 6 were 85.9% and 85.6%, respectively. The EUROCAT BD subgroups diagnosed in more than 1.0% of the infants were atrial septal defects (1.47%) and patent ductus arteriosus (1.07%). Among the 2997 infants with EUROCAT BDs, 241 (8.04%) were classified as having multiple BDs. CONCLUSIONS: A large claims database is a valuable resource for evaluating and monitoring the prevalence of BDs, including multiple patterns. At least 1 year since birth should be considered in future administrative database studies evaluating BDs as outcomes.

No association between major congenital malformations and exposure to Kampo medicines containing rhubarb rhizome: A Japanese database study.

Traditional Japanese (Kampo) medicines containing rhubarb rhizome are prescribed for constipation during pregnancy; however, detailed safety information of their use for pregnant women is lacking. The aim of current study was to clarify the association between prescription Kampo-containing rhubarb rhizome (KRR) in the first trimester of pregnancy and congenital malformations in newborns. Using a large Japanese health insurance claims database, we included pregnant women who enrolled the same health insurance society from 3 months before pregnancy to the delivery date, who gave birth between 2010 and 2019, and those with data related to their infants. Pregnant women who were prescribed magnesium oxide (MgO), commonly used for constipation, during the first trimester of pregnancy and their infants were extracted as controls. Associations between KRR prescribed in the first pregnancy trimester and major congenital malformations (MCM) in the infants were examined using multivariate logistic regression analysis. Of 75,398 infants, 4,607 (6.1%) were diagnosed with MCMs within the first year after birth. Furthermore, 9,852 infants were born to women prescribed MgO, among whom 680 (6.9%) had MCMs; 450 infants were born to women prescribed KRR, among whom 28 (6.2%) had MCMs. Multivariate logistic regression analysis identified no difference in MCM risk between the two types of prescriptions [crude odds ratio (OR) 0.895, 95% confidence interval (CI) 0.606-1.322, adjusted OR 0.889, 95% CI 0.599-1.320]. In conclusion, the risk of MCMs did not differ between those prescribed KRR or MgO in the first trimester of pregnancy.

Risk of major congenital malformations associated with first-trimester antihypertensives, including amlodipine and methyldopa: A large claims database study 2010-2019.

OBJECTIVES: To evaluate the major congenital malformation (MCM) risk of first-trimester antihypertensive exposure, specifically of amlodipine and methyldopa. STUDY DESIGN: A large administrative claims database was used. MAIN OUTCOME MEASURES: The prevalence of antihypertensive prescriptions during pregnancy was described in 91,390 women giving birth between 2010 and 2019. The MCM risk of first-trimester antihypertensives was evaluated in 1,185 women diagnosed with hypertensive disorders in the first trimester. The MCM risk of first-trimester amlodipine and methyldopa was evaluated in 178 women who were prescribed antihypertensives in the first trimester. RESULTS: Antihypertensives were prescribed to 278 (0.30%) women during their first trimester. The prescription prevalence in the first trimester was highest for methyldopa (115, 0.13%), followed by amlodipine (55, 0.06%). Antihypertensives were prescribed to 2,955 (3.23%) women during pregnancy. Nifedipine (903, 0.99%) and nicardipine (758, 0.83%) were the most frequently prescribed oral and injectable antihypertensives during pregnancy, both with a significant increase in annual prevalence. Of the 1,185 women diagnosed with hypertensive disorders in the first trimester, antihypertensives were prescribed to 178 women. The adjusted odds ratio (aOR) of MCMs in the first-trimester prescription of any antihypertensive medication was 1.124 (95% confidence interval [CI], 0.618-2.045). Amlodipine and methyldopa were prescribed to 44 and 93 of the 178 women, respectively. The aORs of MCMs in the first-trimester prescription of amlodipine and methyldopa were 1.219 (95% CI, 0.400-3.721) and 0.921 (0.331-2.564), respectively. CONCLUSIONS: The MCM risk of first-trimester exposure to antihypertensives, including amlodipine and methyldopa, was not suggested.

Development and validation of claims-based algorithms to identify pregnancy based on data from a university hospital in Japan.

OBJECTIVE: When using administrative data, validation is essential since these data are not collected for research purposes and misclassification can occur. Thus, this study aimed to develop algorithms identifying pregnancy and to evaluate the validity of administrative claims data in Japan. METHODS: All females who visited the Tohoku University Hospital Department of Obstetrics in 2018 were included. The diagnosis, medical procedure, medication, and medical service addition fee data were utilized to identify pregnancy, with the electronic medical records set as the gold standard. Combination algorithms were developed using predefined pregnancy-related claims data with a positive predictive value (PPV) ≥80%. Sensitivity (SE), specificity (SP), PPV, and negative predictive value (NPV) with their corresponding 95% confidence intervals (CIs) were calculated for these combination algorithms. RESULTS: This study included 1757 females with a mean age of 32.8 (standard deviation: 5.9) years. In general, the individual claims data were able to identify pregnancy with a PPV ≥80%; however, the number of pregnancies identified using a single claims data was limited. Based on the combination algorithm with all of the categories, including diagnosis, medical procedure, medication, and medical service addition, the calculated SE, SP, PPV, and NPV were 73.4% (95% CI: 71.2%-75.4%), 96.9% (95% CI: 89.3%-99.6%), 99.8%,(95% CI: 99.4%-100.0%), and 12.3% (95% CI: 9.6%-15.4%), respectively. CONCLUSIONS: The combination algorithm to identify pregnancy demonstrated a high PPV and moderate SE. The algorithm validated in this study is expected to accelerate future studies that aim to identify pregnancies and evaluate pregnancy outcome.

Validity of Administrative Data for Identifying Birth-Related Outcomes with the End Date of Pregnancy in a Japanese University Hospital.

This study aimed to develop and validate claims-based algorithms for identifying live birth, fetal death, and cesarean section by utilizing administrative data from a university hospital in Japan. We included women who visited the Department of Obstetrics at a university hospital in 2018. The diagnosis, medical procedures, and medication data were used to identify potential cases of live birth, fetal death, and cesarean section. By reviewing electronic medical records, we evaluated the positive predictive values (PPVs) and the accuracy of the end date of pregnancy for each claims datum. "Selected algorithm 1" based on PPVs and "selected algorithm 2" based on both the PPVs and the accuracy of the end date of pregnancy were developed. A total of 1757 women were included, and the mean age was 32.8 years. The PPVs of "selected algorithm 1" and "selected algorithm 2" were both 98.1% for live birth, 99.0% and 98.9% for fetal death, and 99.7% and 100.0% for cesarean section, respectively. These findings suggest that the developed algorithms are useful for future studies for evaluating live birth, fetal death, and cesarean section with an accurate end date of pregnancy.

Long-Term Safety and Effectiveness of PF-05280014 (a Trastuzumab Biosimilar) Treatment in Patients with HER2-Positive Metastatic Breast Cancer: Updated Results of a Randomized, Double-Blind Study.

BACKGROUND: PF-05280014 was compared with trastuzumab sourced from the European Union (trastuzumab-EU), each plus paclitaxel, as first-line treatment for human epidermal growth factor receptor 2-positive metastatic breast cancer in a phase III study. Equivalence between treatment groups was demonstrated. OBJECTIVE: The aim of this study was to report long-term safety and overall survival (OS) over 6 years after the first patient was screened. PATIENTS AND METHODS: Randomized patients received intravenous PF-05280014 or trastuzumab-EU, each plus paclitaxel, until objective disease progression. OS, long-term safety, subgroup safety (patients ongoing after day 378), and time-to-treatment discontinuation (TTD) were assessed based on the final statistical analysis plan amended for the ad-hoc analyses. RESULTS: Of 707 randomized patients (n = 352, PF-05280014; n = 355, trastuzumab-EU), 252 (71.6%) in the PF-05280014 and 251 (70.7%) in the trastuzumab-EU group discontinued treatment due to objective progression. Overall, 451 (63.8%) patients completed the study. Between groups (PF-05280014; trastuzumab-EU), estimated median TTDs were 12.25 and 12.06 months (p = 0.692); 61 (17.3%) and 67 (18.9%) patients died; stratified hazard ratio for OS was 0.929 (95% confidence interval 0.656-1.316; p = 0.339); estimated survival rates were 82.3 and 77.4% at 2 years and 77.2 and 75.3% at 3 years. The incidences of treatment-emergent adverse events (TEAEs) overall (98.6%; 96.6%) and for grades ≥3 (41.0%; 43.1%) were comparable between groups. In patients (n = 265; n = 264) ongoing after day 378, the incidences of any TEAEs, grade ≥3 TEAEs, and serious TEAEs were comparable between the treatment groups. CONCLUSION: Long-term safety and OS were consistent with previous results and demonstrated no clinically meaningful differences between treatment groups. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01989676 (21 November 2013); and EudraCT: 2013-001352-34 (18 December 2013).

Risk of major congenital malformations associated with first-trimester exposure to propulsives: A health administrative database study in Japan.

PURPOSE: To evaluate the risk of major congenital malformations (MCMs) associated with first-trimester exposure to propulsives with a special focus on domperidone using a large administrative database in Japan. METHODS: A large claims database was used from January 2005 to August 2016. The dates of pregnancy onset and delivery were estimated using the developed algorithms. MCMs were defined according to the International Classification of Diseases, 10th revision codes. We compared the infants' risk of overall MCMs between women with or without first-trimester prescriptions of propulsives and estimated the odds ratios (ORs) with unadjusted and adjusted analyses. We also compared the risk of overall MCMs between women with domperidone prescriptions and those with other propulsive prescriptions during the first trimester. RESULTS: Among 38 270 women, propulsives were prescribed to 3197 women (8.4%) in the first trimester, including domperidone to 371 women (1.0%). Propulsive prescriptions in the first trimester were not significantly associated with an increased risk of overall MCMs (adjusted OR [aOR] 1.030, 95% confidence interval [CI] 0.843-1.257). Compared to the prescription of other propulsives in the first trimester, the prescription of domperidone in the first trimester was not associated with an increased risk of overall MCMs (aOR 0.724, 95% CI 0.363-1.447). CONCLUSIONS: The first-trimester prescription of propulsives, including domperidone, was not associated with an increased risk of overall MCMs.

Prescription of Kampo Formulations for Pre-natal and Post-partum Women in Japan: Data From an Administrative Health Database.

Introduction: Traditional Japanese (Kampo) medicines are often prescribed for women in Japan before, during, and after pregnancy. However, detailed information on the actual frequency of use and safety of Kampo preparations during pregnancy is lacking. Aim: To investigate the frequency of prescription of Kampo medicines for pregnant women in Japan. Methods: Information on Kampo medicines prescribed during outpatient care and hospitalization of selected mothers from January 2005 to August 2016 were extracted from the Japan Medical Data Center (Tokyo, Japan), which is a large claims database. Results: Of the 33,941 subscribers identified from the database, 16,294 (48%) received at least one prescription of a Kampo medicine. Kakkonto was the formula most prescribed during the study period, followed by shoseiryuto and tokishakuyakusan. In the 180 days before pregnancy, the most prescribed medicine was tokishakuyakusan, followed by kakkonto and shoseiryuto. Shoseiryuto, tokishakuyakusan, and kakkonnto were the formulae most prescribed during pregnancy. The most prescribed medicines during the 180 days postpartum were kakkonto, shoseiryuto, and saireito. Conclusions: Information in the Japanese insurance system shows that Kampo medicines are often prescribed during pregnancy. Most of these prescriptions are generally used for the treatment of common cold. Tokishakuyakusan in particular is usually used in the treatment of various symptoms of pregnancy. Further research is needed to clarify the relationship between the use of Kampo medicines during pregnancy and adverse events in infants in Japan.

Validity of congenital malformation diagnoses in healthcare claims from a university hospital in Japan.

PURPOSE: This study aimed to assess the validity of diagnoses of congenital malformations (CMs) recorded in claims of a university hospital in Japan. METHODS: Congenital malformations were identified according to Code Q00-Q89 of the International Classification of Diseases, 10th revision. All the children who had been diagnosed with CMs based on their claims in 2015 and within 1 year from their birth month were selected for this study. The infants' medical records were considered as a gold standard. Positive predictive values (PPVs) for CMs were calculated. RESULTS: This study included 227 infants who had a CM diagnosis in their claims. Based on the algorithms established by the Quebec Pregnancy Cohort study group, the PPV for any CM was 90.7% and that for major CMs (MCMs) was 91.5%. Concerning MCMs of specific organ systems, those of the circulatory system (PPV 85.1%) were the most frequent, followed by cleft lip and cleft palate (PPV 100.0%), and other CMs of the digestive system (PPV 96.4%). Based on the EUROCAT classification, the PPV for any MCM was 88.5%. Specific MCMs reported in ≥20 infants were ventricular septal defect (PPV 96.0%), patent ductus arteriosus (PPV 72.7%) and cleft lip with or without cleft palate (PPV 100.0%). CONCLUSIONS: The PPVs for CMs in the Japanese administrative data were high enough to suggest that these data could be utilized for perinatal pharmacoepidemiological evaluations. The results were from a single center, and further validation studies are needed.

Real-world anticancer medications for reproductive-age women with breast cancer by using a claims database in Japan.

Aim: To describe real-world breast cancer medications among reproductive-age women. Patients & methods: Using data from a Japanese claims database, anticancer prescriptions were classified into seven categories of amenorrhea risk based on fertility preservation guidelines. Results: We identified 2999 women with records of breast cancer and anticancer prescription from 2005 to 2018. The proportions of prescriptions were as follows: high, 4.1-12.9%; intermediate: 6.0-16.3%; low: 0.4-2.3%; very low/no: 0.3-12.2%; unknown: 33.9-45.5%; unlisted combination: 12.2-23.4%; and unlisted drug: 12.5-26.7%. The common drugs in the unknown category were trastuzumab (n = 1527), docetaxel (n = 1014), and paclitaxel (n = 995). For medications unlisted in the guidelines, various drugs and drug combinations were observed. Conclusion: Numerous anticancer drugs are currently being prescribed with insufficient evidence regarding amenorrhea risk.

Lay abstract The ability to have children for breast cancer patients is one of the key issues of cancer survivorship, especially because recent progress in anticancer treatments has enabled patients to achieve longer survival. The fertility preservation guidelines of the American Society of Clinical Oncology (2006) introduce some anticancer treatments that carry potential risks to future fertility. In this study, the anticancer prescriptions of 2999 patients with breast cancer aged between 15 and 49 years were examined. Results showed that several medications are prescribed despite the lack of information on the risk of infertility. This suggests that further research is required to fill the evidence gap, and that decision aid through adequate counseling should be undertaken.

Folic acid prescribed to prenatal and postpartum women who are also prescribed antiepileptic drugs in Japan: Data from a health administrative database.

BACKGROUND: The aim of this study was to evaluate the prevalence of folic acid (FA) prescription to prenatal and postpartum women who have also been prescribed antiepileptic drugs (AED) in Japan. METHODS: The data set used in this study included women covered by health insurance between 2005 and 2016. The prevalence of FA prescriptions between 180 days before pregnancy and 180 days postpartum was determined from a large administrative database, with the FA prescription classified according to dose and timing. RESULTS: For 33,941 women meeting our eligibility criteria, the mean maternal age at delivery was 32.3 years. At least one AED was prescribed to 225 of 33,941 women between 180 days before pregnancy and 180 days postpartum. FA was prescribed to 32 of 225 women (14.2%) during the same period. FA was prescribed to 8.8% of women with AED within 90 days before pregnancy and to 19.8% during the first trimester. FA was prescribed to 10.9% during the first 30 days after conception, all of whom were prescribed FA before the pregnancy. The maximum FA dose prescribed within 90 days before pregnancy was 5 mg/day for 5 of 12 women (41.7%) and >5 mg/day for 4 of 12 women (33.3%). The maximum FA dose prescribed during the first trimester was 5 mg/day for 14 of 22 women (63.6%) and >5 mg/day for 8 of 22 women (36.4%). CONCLUSIONS: The concurrent prescription of FA with AEDs in Japan was an uncommon therapeutic approach both before and during pregnancy.

Antidepressant prescriptions for prenatal and postpartum women in Japan: A health administrative database study.

BACKGROUND: The prevalence and pattern of perinatal antidepressant prescriptions in Japan are unknown. METHODS: The prevalence of antidepressant prescriptions between 180 days before pregnancy onset and 180 days postpartum was evaluated using a large administrative database. The dates of pregnancy onset and delivery were estimated using developed algorithms. RESULTS: Of 33,941 women, at least one antidepressant was prescribed to 451 (133/10,000 deliveries) between 180 days before pregnancy and 180 days postpartum and to 241 (71/10,000 deliveries) during pregnancy. The prevalence of antidepressant prescriptions decreased during the first and second trimesters and increased in the postpartum period. Of 339 women with antidepressant prescriptions before pregnancy, 151 (44.5%) discontinued it during pregnancy. Selective serotonin-reuptake inhibitors were the most frequently prescribed class of antidepressants in the time period studied (356 women, 105/10,000 deliveries), followed by tricyclic/non-tricyclic antidepressants (101 women, 30/10,000 deliveries). Of the 57 women who had at least one record of paroxetine prescription in the first trimester, 13 (22.8%) were prescribed >25 mg/day. Fifty-seven women (17/10,000 deliveries) were concurrently prescribed two or more classes of antidepressants between 180 days before pregnancy and 180 days postpartum. LIMITATIONS: It may not always have been the case that the prescribed antidepressants were used. Women whose pregnancy ended in an abortion or stillbirth were not included. CONCLUSIONS: Various antidepressants were prescribed to prenatal and postpartum women in Japan. Approximately half of pregnant women discontinued treatment with antidepressants after becoming pregnant. Women of childbearing age should select an appropriate antidepressant considering the risk/benefit profile.

Update on the prevalence and determinants of folic acid use in Japan evaluated with 91,538 pregnant women: the Japan Environment and Children's Study.

Objective: To provide the latest and most promising evidence on the prevalence and determinants for folic acid supplementation in pregnant women in Japan, including differences in prevalence between interview years and determinants across regions.Materials and methods: The study participants were enrolled from 15 regional centers across Japan between January 2011 and March 2014. Information on the use of folic acid supplementation before and during pregnancy and the characteristics of the participants were collected using questionnaires, medical chart reviews, and interviews by research coordinators.Results: Data for 91,538 women who provided sufficient data on folic acid supplementation were analyzed. The prevalence of adequate users was 8.0%, which, although low, tended to improve over the 4-year recruitment period. Various kinds of sociodemographic factors, lifestyle habits, and obstetrical and medication use history were significant and independent determinants for folic acid use. Associations between adequate preconception folic acid use and its major determinants tended to be similar across regions.Conclusions: Although the prevalence of adequate folic acid use was low, it increased from 2011 to 2014. Reproductive-aged women who have determinants for inadequate folic acid use should be informed about the need for preconception folic acid supplementation to help prevent neural tube defects.

Examination of the prescription of antiepileptic drugs to prenatal and postpartum women in Japan from a health administrative database.

PURPOSE: To evaluate the prevalence and patterns of prescriptions of antiepileptic drugs (AEDs) to prenatal and postpartum women in Japan using a large administrative database. METHODS: The dates of pregnancy onset and delivery were estimated using published algorithms and infant birth months. The prevalence of prescribed AEDs, the maximum dose of some AEDs, and the frequency of potential combination therapy with AEDs were evaluated for the 180 days before pregnancy onset, during pregnancy, and at 180-day postpartum. RESULTS: In total, 33 941 pregnant women were eligible for analysis. At least one AED was prescribed to 225 women (66 per 10 000 deliveries) between 180 days before pregnancy and 180-day postpartum and for 135 women (40 per 10 000 deliveries) during pregnancy. The prevalence of AED prescription declined during the first and second trimesters and increased in the third trimester and postpartum. Valproate was the most frequently prescribed drug, followed by clonazepam, lamotrigine, and carbamazepine. Nine (18.4%) of the 49 women with at least one prescription record of valproate in the first trimester were prescribed more than 600 mg/day of valproate. Concerning potential combination therapy, 40 (12 per 10 000 deliveries) concurrently received two or more AEDs between 180 days before pregnancy and 180-day postpartum, respectively, 31 (9 per 10 000 deliveries) women received these drugs during pregnancy. CONCLUSIONS: Various AEDs were prescribed to pregnant Japanese women. Women of reproductive age should select the appropriate AED before becoming pregnant, depending on the risk benefit profile.

Antihypertensives prescribed for pregnant women in Japan: Prevalence and timing determined from a database of health insurance claims.

PURPOSE: The purpose of the study is to evaluate the status of prescribed antihypertensives primarily during pregnancy, but also before pregnancy and after delivery, using a large claims database in Japan. METHODS: The dates of pregnancy onset and delivery were identified using reported algorithms and the birth months of infants. The prevalence and timing of prescribed antihypertensives during pregnancy were descriptively evaluated. Time trends in prescriptions were evaluated using multivariate logistic regression analyses. We also evaluated the prevalence of antihypertensives prescribed within 180 days before pregnancy and 180 days after delivery among women who were covered by health insurers during the entire period. RESULTS: At least one antihypertensive agent was prescribed for 1144 (2.74%) of 41 693 pregnant women. The most frequently prescribed oral antihypertensive during pregnancy was nifedipine, followed by methyldopa, hydralazine, and furosemide. Drugs targeting the renin-angiotensin system were prescribed for 21 pregnant women (0.05%), including angiotensin II receptor blockers that were prescribed for 19 (0.05%) of them. Nicardipine was the most frequently prescribed injectable antihypertensive during pregnancy, followed by furosemide, hydralazine, and nitroglycerin. Annual prescription trends remained similar except for a significant decrease in those for oral and injectable furosemide and an annual increase in those for organic nitrate. Based on an evaluation of 33 941 pregnant women, the number of prescriptions for antihypertensives increased particularly during the third trimester, then decreased from 91 to 180 days after delivery. CONCLUSIONS: Various types of antihypertensives are prescribed for Japanese pregnant women. The effects of exposing pregnant Japanese women to these agents should be evaluated.

Development of algorithms to determine the onset of pregnancy and delivery date using health care administrative data in a university hospital in Japan.

PURPOSE: To develop and assess algorithms to determine the onset of pregnancy and delivery date using health administrative data from a university hospital in Japan. METHODS: All women who were hospitalized in the maternity ward and had at least one pregnancy that ended with a delivery during the period of January 2014 and December 2015 were included in this study. The true delivery date was obtained from the electronic medical records and was used as a gold standard. The onset of pregnancy was calculated by subtracting the gestational age at birth from the delivery date based on the electronic medical records and was also used as a gold standard. The administrative data-based algorithms to identify (1) the onset of pregnancy estimated from the gestational age recorded as part of a diagnosis during a specific visit and (2) the delivery date estimated using the delivery-related diagnosis, procedure, or prescription were compared with the gold-standard data. RESULTS: Of the 1705 women included in this study, the onset of pregnancy was determined in 1704 subjects with 1582 (92.8%) within ± 7 days from the gold-standard date of pregnancy onset. The delivery date was determined in 1654 subjects, and 1594 (96.4%) were within ± 7 days before the true delivery date using the algorithm of "selected" diagnosis and a surgical procedure followed by some other delivery-related data. CONCLUSIONS: The algorithms developed in this study are expected to accelerate future studies for real-world exposure and quantify drug safety during pregnancy using Japanese health care administrative databases.

Individual assessment of inherent arterial stiffness using nomogram and pulse wave velocity index: the Ohasama study.

We measured the brachial-ankle pulse wave velocity (baPWV) in 491 normotensives and determined the "PWV index" (measured baPWV-theoretical baPWV) in 491 normotensives and 83 controlled hypertensives. Linear regression analysis revealed that the theoretical baPWV (cm/sec) was 0.21 × age(2) (years(2))-13.73 × age (years) + 0.05 × mean arterial pressure(2) (mmHg(2)) + 3.95 × heart rate (bpm) + 36.49 × gender (1 male; 0 female) + 733 (R(2) = 0.53). The calculated PWV index was significantly higher in 13 smokers than 70 nonsmokers among controlled hypertensives. The calculated PWV index might provide more precise information about inherent arterial stiffness.

Association of arterial stiffness with silent cerebrovascular lesions: the Ohasama study.

BACKGROUND: Arterial stiffness is a risk factor for symptomatic stroke, and is associated with symptomatic cerebral infarction and cognitive impairment. Hence, we hypothesized that arterial stiffness would be a significant determinant of silent cerebrovascular lesions. METHODS: The subjects were 363 individuals without symptomatic cerebrovascular lesions who had their arterial stiffness assessed by brachial-ankle pulse wave velocity (baPWV) measurement. The subjects were classified into two groups by the presence or absence of lacunar infarcts, as well as into three groups by grade of white matter hyperintensity (WMH). baPWV was compared among these groups. RESULTS: Eighty-six subjects had lacunar infarcts. Of 138 subjects with WMHs, 102 were classified as having grade 1 and 36 as having grade 2 or 3 WMHs. baPWV was significantly higher in subjects with lacunar infarcts than in those without (17.3 ± 0.3 vs. 16.4 ± 0.2 m/s). baPWV tended to increase with higher WMH grade (16.2 ± 0.2, 16.9 ± 0.3, and 17.8 ± 0.5 m/s in grade 0, 1, and 2 or 3, respectively) after adjustments for confounding factors. The adjusted odds ratio (OR) for lacunar infarcts in subjects with middle-tertile baPWV was significantly higher (OR, 2.37; 95% confidence interval, CI, 1.10-5.11) and the OR in subjects with the highest-tertile baPWV tended to be higher (OR 2.26; 95% CI 0.99-5.45) compared with the lowest-tertile baPWV. The adjusted OR for WMH tended to increase with increased baPWV. CONCLUSIONS: Arterial stiffness appeared to be associated with the presence of a lacunar infarct and WMH, independently of the risks for other cerebrovascular diseases.

Rhodium-catalyzed substitution reaction of aryl fluorides with disulfides: p-orientation in the polyarylthiolation of polyfluorobenzenes.

In the presence of a catalytic amount of RhH(PPh3)4 and 1,2-bis(diphenylphosphino)benzene, an aromatic fluoride, an organic disulfide (0.5 equiv), and triphenylphosphine (0.5 equiv) reacted in refluxing chlorobenzene to give an aryl sulfide in high yield. Since triphenylphosphine trapped fluoride atoms forming phosphine difluoride, both organothio groups of the disulfide reacted effectively, and the fluoride substituent reacted more readily than the chloride and bromide. The reaction of hexafluorobenzene and a diaryl disulfide gave 1,4-diarylthio-2,3,5,6-tetrafluorobenzene, 1,2,4,5-tetraarylthio-3,6-difluorobenzene, and hexaarylthiobenzene in a stepwise manner; pentafluorobenzene gave 1-arylthio-2,3,5,6-tetrafluorobenzene; 1,2,3,4-tetrafluorobenzene gave 1,2-diarylthio-3,6-difluorobenzene; and 1,2,4,5-tetrafluorobenzene gave 1,4-diarylthio-2-5-difluorobenzene. The polyarylthiolation reaction of polyfluorobenzenes exhibited a strong tendency to form 1,4-difluorobenzenes.