OBJECTIVES: This study aimed to investigate the association and population-attributable fraction (PAF) of maternal smoking and secondhand smoke (SHS) exposure during pregnancy with placental abruption. DESIGN: Prospective cohort study. SETTING: 15 regional centres in Japan. PARTICIPANTS: Pregnant women registered between January 2011 and March 2014 from the Japan Environment and Children's Study. OUTCOME MEASURES: Data were transcribed from medical records and two self-administered questionnaires. The outcome measure was the incidence of placental abruption. Maternal smoking exposure during pregnancy was categorised based on the number of cigarettes smoked (≤10 or ≥11 cigarettes per day). SHS exposure during pregnancy was evaluated by frequency and duration (almost never or never, 1-3 days/week and/or <1 hour/day and 4-7 days/week and ≥1 hour/day). A modified Poisson regression model, adjusted for known placental abruption risk factors, calculated the risk ratio (RR) and PAF for placental abruption with a 95% Cl. RESULTS: Of the 81 974 eligible pregnant women, pregnant women smoking ≥11 cigarettes/day during pregnancy had a significantly higher risk of placental abruption. The adjusted RR (aRR) was 2.21 (95% CI 1.21 to 4.06), and the adjusted PAF (aPAF) was 1.90% (95% CI 0.09 to 3.71%). Pregnant women among never-smokers with SHS exposure of 4-7 days/week and ≥1 hour/day had a significantly higher risk (aRR: 2.34, 95% CI 1.29 to 4.28), and the aPAF was 1.89% (95% CI -0.05 to 3.83). Additionally, pregnant women among those who smoked during pregnancy with similar SHS exposure had a significantly higher risk (aRR: 2.21, 95% CI 1.30 to 3.76), with the aPAF of 2.29% (95% CI 0.11 to 4.48). CONCLUSIONS: Maternal smoking and SHS exposure during pregnancy significantly contribute to the risk of placental abruption in Japan. Therefore, preventive interventions and measures to reduce exposure are required to prevent placental abruption.

Abstract Background The association of maternal hyperglycemia with childhood developmental delay has been examined; however, only 2 studies used maternal blood glucose level as a continuous variable as an exposure. A present study aimed to investigate the influence of maternal fasting plasma glucose (mFPG) level in early gestation on developmental delay in children. Methods This cohort study included 1541 mother–child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. mFPG level before 24 gestational weeks was obtained as a continuous and categorical variable. Developmental delay in 2-year-old children was assessed by mothers using the Ages and Stages Questionnaire (third edition). Associations between mFPG level and developmental delay in children were evaluated using multiple logistic regression analyses. Results The prevalence of mFPG level ≥95 mg/dL was 5.2%. At 2 years old, 15.1% of the children had developmental delays. mFPG level as a continuous variable was not associated with an increased risk of developmental delay across the 5 domains in children [adjusted odds ratio (aOR), 95% confidence interval (CI): 1.004, 0.990-1.018]. mFPG level ≤70 mg/dL was associated with developmental delay across 5 domains (aOR, 95% CI: 0.464, 0.229-0.943) in children than that with a mFPG level 71 to 94 mg/dL. No association was found between mFPG level ≤70 mg/dL and ≥95 mg/dL and developmental delay in any domains among children. Conclusion mFPG level in early gestation was not associated with an increased risk of any developmental delays in 2-year-old children.

BACKGROUND: The primary prevention of atrial fibrillation (AF), which increases mortality through complications including stroke and heart failure, is important. Excessive salt intake and low potassium intake are risk factors for cardiovascular disease; however, their association with AF remains inconclusive. This study investigated the association between sodium- and potassium-related urinary markers and AF prevalence. METHODS AND RESULTS: Data from the Tohoku Medical Megabank Project Community-based Cohort Study were used in this cross-sectional study. The urinary sodium-to-potassium (Na/K) ratio and estimated 24-h sodium and potassium excretion were calculated using spot urine samples and categorized into quartiles (Q1-Q4). The prevalence of AF was the primary outcome. Of the 26,506 participants (mean age 64.8 years; 33.2% males) included in this study, 630 (2.4%) had AF. Using Q1 as the reference group, the odds ratios for AF prevalence in Q4 were 1.35 (95% confidence interval [CI] 1.07-1.73) and 1.59 (95% CI 1.20-2.12) for 24-h estimated urinary Na/K ratio and estimated 24-h sodium excretion, respectively. Estimated 24-h potassium excretion was not associated with AF prevalence. CONCLUSIONS: AF prevalence was positively associated with the urinary Na/K ratio and estimated 24-h urinary sodium excretion, but not with estimated 24-h urinary potassium excretion. Although further prospective studies are warranted, the findings of this study suggest that salt intake may be a modifiable risk factor for AF.

AIMS: This study investigated the association between maternal age and early and late gestational diabetes mellitus (GDM). METHODS: In total, 72,270 pregnant women were included in this prospective birth cohort study. Associations between maternal age and early GDM (diagnosed at <24 gestational weeks) and late GDM (diagnosed at ≥24 gestational weeks) were evaluated using a multinomial logistic regression model with possible confounding factors. The reference category was maternal age of 30-34.9 years. RESULTS: Higher maternal age was associated with higher odds of early and late GDM (P-value for trend <0.0001 and <0.0001, respectively). The adjusted odds ratios (aORs) for early GDM with maternal age of 35-39.9 years and ≥40 were 1.399 (95% confidence interval [CI]: 1.134-1.725) and 2.494 (95% CI: 1.828-3.402), respectively. The aORs for late GDM with maternal age of 35-39 years and ≥40 were 1.603 (95% CI: 1.384-1.857) and 2.276 (95% CI: 1.798-2.881), respectively. CONCLUSIONS: Higher maternal age was associated with an increased risk of GDM regardless of when GDM was diagnosed. The association between maternal age and early GDM was similar to that between maternal age and late GDM.

OBJECTIVES: Previous studies have assessed the impact of active smoking on mortality using the population-attributable fraction (PAF). However, these studies have not included second-hand smoking (SHS), potentially underestimating smoking's impact. We compared the PAF from active smoking alone with the PAF, including SHS exposure. DESIGN: Prospective cohort study. SETTING: A community-based cohort study in Japan. PARTICIPANTS: 40 796 participants aged ≥20 years. MAIN OUTCOME MEASURES: SHS was defined as inhaling someone else's cigarette smoke at the workplace or home in the past year. We classified smoking status and SHS into ten categories: never-smoker without SHS, never-smoker with SHS, past smoker without SHS, past smoker with SHS, current smoker 1-9 cigarettes/day without SHS, current smoker 1-9 cigarettes/day with SHS, 10-19 cigarettes/day without SHS, 10-19 cigarettes/day with SHS, ≥20 cigarettes/day without SHS and ≥20 cigarettes/day with SHS. The main outcome was all-cause mortality. RESULTS: During the median follow-up period of 6.5 (5.7-7.5) years, 788 men and 328 women died. For men, compared with never-smokers without SHS, past smokers without SHS (HR, 1.39 [95% CI, 1.11 to 1.73]) and past smokers with SHS (HR, 1.48 (95% CI, 1.10 to 2.00)) were associated with all-cause mortality. For women, never-smokers with SHS had a significantly higher risk of all-cause mortality (HR, 1.36 (95% CI, 1.00 to 1.84)). Without considering SHS, 28.0% and 2.3% of all-cause mortality in men and women, respectively, were attributable to past and current smoking. Including SHS, PAF increased to 31.3% in men and 8.4% in women. CONCLUSIONS: We clarified that smoking's impact was underestimated by not accounting for SHS, especially in women. Information on SHS is crucial for understanding smoking's health impact. This study supports the importance of avoiding smoking and preventing SHS.

In this study, we aimed to reveal the trends of self-measured blood pressure (SMBP) and SMBP-derived indices during pregnancy and the postpartum period. The Babies and Their Parents Longitudinal Observation in Suzuki Memorial Hospital in the Intrauterine Period (BOSHI) Study is a prospective cohort study in Japan. Participants were instructed to measure SMBP daily during pregnancy and for 1 month after delivery. Among 237 participants with normotensive blood pressure (BP) during pregnancy and the postpartum period who were analyzed using mixed-effects models for repeated measures, the SMBP was measured, on average, 14.3 times from the day before delivery to 28 days postpartum. The systolic blood pressure (SBP) and diastolic blood pressure (DBP) on the day before delivery were 110.6 ± 1.0 and 68.1 ± 0.8 mmHg (estimate ± standard error). Postpartum BP increased from postpartum Days 3-8 in SBP and from Days 3-22 in DBP, compared to that on the day before delivery. The SBP and DBP were 4.9 and 4.7 mmHg higher on postpartum Days 8 and 7 than the day before pregnancy, respectively. During pregnancy, the pulse rate (PR) showed an inverted U-shaped trend and then sharply increased rapidly until the first postpartum day after delivery. The Shock Index showed a similar trend to that of the PR, decreased from labor until postpartum Day 8, and plateaued thereafter. The double product peaked during labor, remained higher than the prelabor levels for approximately 10 days, and then decreased in the postpartum period.

BACKGROUND: The Tohoku Medical Megabank Project has initiated the Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study) including genomic and omics investigations, and conducted a self-administered food frequency questionnaire with the response option "constitutionally unable to eat or drink it" for individual food items (TMM-FFQ) for pregnant women. This study evaluated the validity of the TMM-FFQ among pregnant women. METHODS: Participants comprised 122 pregnant women aged ≥20 years residing in Miyagi Prefecture who completed weighed food records (WFRs) for 3 days as reference intake and the TMM-FFQ during mid-pregnancy. Correlations between nutrient or food group intakes based on the WFR and the TMM-FFQ were calculated using Spearman's rank correlation coefficients (CCs), adjusting for energy intake and correcting for random within-individual variation of WFR. Cross-classification was also conducted according to quintiles using the WFR and TMM-FFQ data. RESULTS: The percentages of participants who chose the "constitutionally unable to eat or drink it" option were >3% for seven food and drink items. CCs were >0.30 for 31 nutrients; the median across energy and 44 nutrients was 0.41. CCs were >0.30 for 14 food groups; the median across 20 food groups was 0.35. The median percentages of cross-classification into exact plus adjacent quintiles and extreme quintiles were 63.1% and 3.3% for energy and nutrients and 61.9% and 4.1% for food groups, respectively. CONCLUSIONS: The validity of the TMM-FFQ compared with the WFR was reasonable for certain nutrients and food groups among pregnant women in the TMM BirThree Cohort Study.

AIM: The aim of this study was to evaluate depression at 6 and 12 months postpartum, using the Edinburgh Postpartum Depression Scale (EPDS) total score and its subitem regarding self-harm ideation (SHI) at 1 month postpartum. METHODS: A sample of 12,358 postpartum women answered the EPDS and questionaries at 1, 6, and 12 months postpartum longitudinally. RESULTS: For participants with postpartum depression (PPD; EPDS total score ≥9) and SHI (SHI sub-score ≥1) at 1 month postpartum, the risk of depression at 6 and 12 months postpartum (odds ratio [95% confidence interval] at 6 and 12 months postpartum: 20.03 [16.8-23.8] and 14.55 [12.3-17.2], respectively) was higher than for those with PPD but without SHI at 1 month postpartum (OR: 8.57 [7.36-10.0], and 6.24 [5.38-7.24], respectively). Additionally, SHI even without depressive symptoms at 1 month postpartum is also a risk for depression at 6 and 12 months postpartum. To support our longitudinal evaluation of depression at 6 and 12 months postpartum, these related factors were examined: traumatic events or relocations after the Great East Japan Earthquake, employment status, household income, personality traits, sleep status, psychological distress, and social networks. The result showed employment status, low household income and poor social networks were significantly associated with depression at 12 months postpartum but not at 6 months postpartum. CONCLUSION: This study showed a high risk of depression at 6 and 12 months postpartum for those who had depressive symptoms with SHI at 1 month postpartum. Our findings may contribute to the precise evaluation of depression at 6 and 12 months postpartum while considering sleep status, psychological distress and social network during pregnancy.

Recently, web-based dietary assessment tools for the targeted population have been developed and used to estimate the dietary intake level in several epidemiological studies. This study aimed to examine the validity of estimating energy and nutrient intake by the web-based 24 h dietary recall (Web24HR), which we developed for the Japanese population. Overall, 228 adults aged ≥20 years who agreed to participate were included. Web24HR was administered three times per person: twice within 3 weeks and once 3 months later. The data on 3-day weighed food records (WFR) at 3-month intervals in the four seasons were collected using the reference method. The intake of energy and nutrients between Web24HR and WFR were compared using Pearson's correlation coefficients and the Bland-Altman analysis. As results, the correlations were moderate for both men (median r = 0.51) and women (median r = 0.38) except for iodine, retinol, retinol equivalents, and β-tocopherol. The Bland-Altman method revealed that the bias in intake was within ±10% for most nutrients, except for cholesterol, iodine, vitamin C, and the water content, in both sexes. Additionally, monounsaturated fatty acids in men and β-cryptoxanthin in women exhibited an underestimation of more than 10%. In conclusion, the Web24HR intake assessment showed moderate correlations for most nutrients in both sexes. The bias in intake was within ±10% for most nutrients, but there were discrepancies for some nutrients. This tool's performance is comparable to Japan's standard dietary exposure assessment methods and will be helpful for future applications in epidemiological studies, though caution is needed for certain nutrient assessments.

BACKGROUND: Various disease prediction models have been developed, capitalizing on the wide use of electronic health records, but environmental factors that are important in the development of noncommunicable diseases are rarely included in the prediction models. Hypertensive disorders of pregnancy are leading causes of maternal morbidity and mortality and are known to cause several serious complications later in life. OBJECTIVE: This study aims to develop early hypertensive disorders of pregnancy prediction models using comprehensive environmental factors based on self-report questionnaires in early pregnancy. STUDY DESIGN: We developed machine learning and artificial intelligence models for the early prediction of hypertensive disorders of pregnancy using early pregnancy data from approximately 23,000 pregnancies in the Tohoku Medical Megabank Birth and Three Generation Cohort Study. We clarified the important features for prediction based on regression coefficients or Gini coefficients of the interpretable artificial intelligence models (i.e., logistic regression, random forest and XGBoost models) among our developed models. RESULTS: The performance of the early hypertensive disorders of pregnancy prediction models reached an area under the receiver operating characteristic curve of 0.93, demonstrating that the early hypertensive disorders of pregnancy prediction models developed in this study retain sufficient performance in hypertensive disorders of pregnancy prediction. Among the early prediction models, the best performing model was based on self-reported questionnaire data in early pregnancy (mean of 20.2 gestational weeks at filling) which consist of comprehensive lifestyles. The interpretation of the models reveals that both eating habits were dominantly important for prediction. CONCLUSION: We have developed high-performance models for early hypertensive disorders of pregnancy prediction using large-scale cohort data from the Tohoku Medical Megabank project. Our study clearly revealed that the use of comprehensive lifestyles from self-report questionnaires led us to predict hypertensive disorders of pregnancy risk at the early stages of pregnancy, which will aid early intervention to reduce the risk of hypertensive disorders of pregnancy.

Hypertensive disorders of pregnancy can cause hypertension in the future. Understanding how the blood pressure values of women with and without hypertensive disorders of pregnancy differ will facilitate follow-up blood pressure monitoring in clinical settings. This study investigated the association between hypertensive disorders of pregnancy and subsequent high blood pressure and hypertension. This study used Japanese data from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Follow-up systolic and diastolic blood pressures in normotensive women during pregnancy and those with hypertensive disorders of pregnancy were estimated using analysis of covariance adjusted for women with low birthweight, history of gestational diabetes mellitus, age, body mass index, pulse rate, smoking and drinking at the follow-up assessment, paternal hypertension history, and maternal hypertension or hypertensive disorders of pregnancy history. Finally, we performed a multiple logistic regression analysis. In total, 7343 women were included in the analysis. Women with a history of hypertensive disorders of pregnancy had higher blood pressure approximately three years postpartum compared with normotensive women. Hypertensive disorders of pregnancy in the most recent pregnancy in different subgroups, such as nulliparous women, multiparous women without a history of hypertensive disorders of pregnancy, and multiparous women with a history of hypertensive disorders of pregnancy, were associated with an increased risk of subsequent hypertension. Women's birthweight was also weakly associated with hypertension. Even one experience of hypertensive disorders of pregnancy may contribute to elevated blood pressure and hypertension approximately three years postpartum. In addition, women's birthweights may have a weak relationship with increasing blood pressure.

PURPOSE: Japanese traditional (Kampo) medicines are often used for pregnant women in Japan. However, no comprehensive studies have been conducted regarding the self-reported use of these medicines during pregnancy. This study investigated the use of Kampo medicines during pregnancy in Japan using the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). METHODS: Questionnaires were distributed to pregnant women participating in the TMM BirThree Cohort Study (July 2013 to March 2017) at approximately 12 weeks (early pregnancy) and 26 weeks (middle pregnancy). We analysed Kampo medicines use over three periods: (1) 12 months before pregnancy diagnosis, (2) the period between pregnancy diagnosis and around Week 12 of pregnancy and (3) from around Week 12 of pregnancy. RESULTS: In total, 19 220 women were included in the analysis. The proportions using prescribed Kampo medicines were 4.1% before pregnancy diagnosis, 4.5% from diagnosis to Week 12% and 4.5% after Week 12 of pregnancy. The most frequently prescribed Kampo medicines were tokishakuyakusan (1.0%) before pregnancy diagnosis, shoseiryuto (1.3%) from diagnosis to Week 12 and shoseiryuto (1.5%) Post-week 12. Sixty of the pregnant women used Kampo medicines containing crude drugs, which should be administered cautiously during pregnancy. CONCLUSION: The proportion of Kampo medicines use before and during pregnancy was 4%-5%. Some pregnant women used Kampo medicines containing crude drugs that should be administered cautiously during pregnancy. Further research is required to determine the safety of Kampo medicines during pregnancy.

AIM: Genome-wide association studies (GWAS) of postpartum depression (PPD) based on accumulated cohorts with multiple ethnic backgrounds have failed to identify significantly associated loci. Herein, we conducted a GWAS of Japanese perinatal women along with detailed confounding information to uncover PPD-associated loci. METHODS: The first and second cohorts (n = 9260 and n = 8582 perinatal women enrolled in the Tohoku Medical Megabank Project) and the third cohort (n = 997), recruited at Nagoya University, underwent genotyping. Of them, 1421, 1264, and 225 were classified as PPD based on the Edinburgh Postnatal Depression Scale 1 month after delivery. The most influential confounding factors of genetic liability to PPD were selected, and logistic regression analyses were performed to evaluate genetic associations with PPD after adjusting for confounders. RESULTS: A meta-analysis of GWAS results from the three cohorts identified significant associations between PPD and the following loci (P < 5 × 10-8) by integrating the number of deliveries and the number of family members living together as the most influential confounders: rs377546683 at DAB1, rs11940752 near UGT8, rs141172317, rs117928019, rs76631412, rs118131805 at DOCK2, rs188907279 near ZNF572, rs504378, rs690150, rs491868, rs689917, rs474978, rs690118, rs690253 near DIRAS2, rs1435984417 at ZNF618, rs57705782 near PTPRM, and rs185293917 near PDGFB. Pathway analyses indicated that SNPs suggestively associated with PPD were mostly over-represented in categories including long-term depression, GnRH signaling, glutamatergic synapse, oxytocin signaling, and Rap1 signaling. CONCLUSION: The current GWAS study identified eight loci significantly associated with PPD, which may clarify the genetic structure underlying its pathogenesis.

Abstract Objective To investigate the inter-relationships among genetic risk, healthy lifestyle adherence, and hyperuricaemia susceptibility. Methods This prospective cohort study was conducted with 7,241 hyperuricaemia-free individuals aged ≥ 20 years from the Tohoku Medical Megabank Community-based cohort study. A comprehensive lifestyle score included body mass index, smoking, drinking, and physical activity, and a polygenic risk score (PRS) was constructed based on uric acid loci from a previous genome-wide association study meta-analysis. A multiple logistic regression model was used to estimate the association between genetic risk, healthy lifestyle, and hyperuricaemia incidence and calculate the area under the receiver operating characteristic curve (AUROC). Hyperuricaemia was defined as a uric acid level ≥7.0 mg/dl or a self-reported history of hyperuricaemia. Results Of the 7,241 adults (80.7% females; mean [SD] age: 57.7 [12.6] years), 217 (3.0%) developed hyperuricaemia during 3.5 years of follow-up. Genetic risk correlated with hyperuricaemia development (P for interaction = 0.287), and lifestyle risks were independently associated. Those with a high genetic risk and poor lifestyle had the highest risk (odds ratio: 5.34; 95% confidence interval [CI]: 2.61–12.10). Although not statistically significant, incorporating the PRS in the model with lifestyle information improved predictive ability (AUROC = 0.771, 95% CI: 0.736–0.806 for lifestyle; AUROC = 0.785, 95% CI: 0.751–0.819 for lifestyle and PRS; p = 0.07). Conclusion : A healthy lifestyle to prevent hyperuricaemia, irrespective of genetic risk, may mitigate the genetic risk. Genetic risk may complement lifestyle factors in identifying individuals at a heightened hyperuricaemia risk.

BACKGROUND: We aim to discover which, if any, of the subscales of internalizing and externalizing behavioral problems at age 3 are still associated with screen time (ST) at age 2 after adjusting for behavioral problems scores at age 2. METHODS: This study was conducted under the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Information was gathered prospectively, with 7207 mother-child pairs included in the analysis. Children's ST was categorized in hours a day at age 2 (<1, 1-<2, 2-<4, ≥4). We assessed children's behavioral problems using the Child Behavior Checklist for Ages 1½-5 (CBCL) at ages 2 and 3. 'Having behavioral problems' was defined by them being within a clinical range for internalizing behaviors (withdrawn, somatic complaints, anxious/depressed and emotionally reactive) and externalizing behaviors (attention problems and aggressive behaviors) at age 3. Continuous scores on each of the behavioral problem scales at age 2 were used as covariates. RESULTS: Greater ST for children at age 2 was associated with specific subscales for emotionally reactive and aggressive behaviors at age 3. CONCLUSIONS: This study found that ST is prospectively associated with some behavioral scales but not others.

OBJECTIVE: To evaluate the association between exposure to atypical antipsychotics during pregnancy and risk of miscarriage. MATERIAL AND METHODS: This nested case-control study used a large Japanese administrative database. Pregnancy onset and outcomes were estimated using previously reported algorithms, classifying cases as women becoming pregnant between 2013 and 2022 and ending in a miscarriage. Controls were randomly selected from the entire pregnancy cohort by risk-set sampling with replacement and were individually matched to the cases (3:1). The association between exposure to atypical antipsychotics and risk of miscarriage was assessed using conditional logistic regression adjusted for confounders. The association between benzodiazepine exposure and the risk of miscarriage was assessed as a positive control. RESULTS: In the cohort, 44,118 patients were matched with 132,317 controls. The mean ages (standard deviations) of the case and control groups were 33.3 (5.7) and 33.2 (5.5) years, respectively. The prevalence of atypical antipsychotics was 0.5% in both groups. Aripiprazole is an individual antipsychotic with the highest prescription prevalence. The adjusted odds ratios (aOR) for miscarriage were 0.966 (95% confidence interval [CI], 0.796-1.173) for atypical antipsychotics and 0.998 (0.784-1.269) for aripiprazole. A higher aOR (1.431, 95% CI 1.303-1.573) suggested an association with benzodiazepines. A sensitivity analysis that limited the population to women diagnosed with schizophrenia alone did not suggest an association between atypical antipsychotics and the risk of miscarriage. CONCLUSIONS: The results of this study do not suggest an association between exposure to atypical antipsychotics during pregnancy and the risk of miscarriage.

AIM: To examine the association of the combination of taking neuropsychiatric medications from the onset of pregnancy to mid-pregnancy and maternal psychological distress at mid-pregnancy, with children's behavioral problems. METHODS: Neuropsychiatric medication use from the onset of pregnancy to mid-pregnancy was defined by the self-reported name of the neuropsychiatric medication in the questionnaire in early and mid-pregnancy. Maternal psychological distress was defined by the Kessler Psychological Distress Scale (K6) ≥13 on the questionnaire in mid-pregnancy. We classified the participants into four categories based on the combination of taking neuropsychiatric medications and psychological distress: "None," "Medications only," "K6 ≥ 13 only," and "Both." Children's behavioral problems were assessed using the Child Behavior Checklist for Ages 1½-5 (CBCL) at 2 years of age. The clinical ranges of the internalizing and externalizing scales of the CBCL were defined as behavioral problems. We conducted a multivariable logistic regression analysis to examine the associations between the four categories of maternal exposure and children's behavioral problems. RESULTS: Compared with the "None" category (n = 9873), the "K6 ≥ 13 only" category (n = 308) was statistically significantly associated with internalizing and externalizing problems. In contrast, the "Medications only" (n = 93) and "Both" (n = 22) categories were not statistically significantly associated with internalizing and externalizing problems, although the point estimates of the odds ratio in the "Both" category were relatively high (1.58 for the internalizing problem and 2.50 for the externalizing problem). CONCLUSION: The category of mothers taking neuropsychiatric medications and having no psychological distress during pregnancy was not associated with children's behavioral problems in the present population.

Whether all obesity-related variants contribute to the onset of obesity or one or a few variants cause obesity in genetically heterogeneous populations remains obscure. Here, we investigated the genetic architecture of obesity by clustering the Japanese and British populations with obesity using obesity-related factors. In Step-1, we conducted a genome-wide association study (GWAS) with body mass index (BMI) as the outcome for eligible participants. In Step-2, we assigned participants with obesity (BMI ≥25 kg/m2) to five clusters based on obesity-related factors. Subsequently, participants from each cluster and those with a BMI <25 kg/m2 were combined. A GWAS was conducted for each cluster. Several previously identified obesity-related genes were verified in Step-1. Of the genes detected in Step-1, unique obesity-related genes were detected separately for each cluster in Step-2. Our novel findings suggest that a smaller sample size with increased homogeneity may provide insights into the genetic architecture of obesity.

To examine child-parent associations of HCT among Japanese adults and their parents. Factors associated with hematocrit (HCT) were analyzed in 3,574 sons and 7,203 daughters using Pearson's correlation coefficient and Student's t-test. Multiple linear regression analysis, adjusted by the factors identified by univariate analyses and by living with parents, was performed on 242 son-parent trios and 587 daughter-parent trios. When a child-parent association was observed in the multiple linear regression analysis, it was validated using the random family method (RFM). In univariate analyses, the son's HCT was associated with age (correlation coefficient = -0.072), white blood cell (WBC) (0.19), alanine aminotransferase (ALT) (0.20), triglyceride (0.11), and estimated glomerular filtration rate (eGFR) (- 0.087). The daughter's HCT was associated with WBC (0.014), ALT (0.18), and eGFR (- 0.17). In multiple linear regression analysis, the son's HCT was associated with the son's WBC (coefficient = 3.48 × 10-4), the son's eGFR (0.031), the father's HCT (0.11), and the mother's HCT (0.17). RFM confirmed the association between the son's and father's HCT (p = 0.0070) and between the son's and mother's HCT (p = 0.0011). The daughter's HCT was associated with WBC (2.6 × 10-4), ALT (0.037), and the mother's HCT (0.14). RFM confirmed the association between the daughter's and mother's HCT (p = 0.00043). Child-parent association of HCT was confirmed between son-father, son-mother, and daughter-mother relationships, and differed depending on the sex of the child and the parents.

This study aimed to investigate the association of combination of birth weight and current body mass index (BMI) with the risk of hypertension in adulthood. This cross-sectional study used data from the Tohoku Medical Megabank Community-based Cohort Study conducted in Japan. A total of 10,688 subjects aged ≥20 years were eligible. We calculated the least square (LS) means of systolic blood pressure (SBP) and trend tests were performed to evaluate the linear relationships between birth weight categories and SBP. We also used a multivariate logistic regression analysis to assess the risk of hypertension associated with the combination of birth weight and current BMI. There was a statistically inverse association between birth weight and SBP in the 20-64 age group, but no significant association in the ≥65 age group. Low birth weight (LBW) with normal BMI group had a higher risk of hypertension than the normal or high birth weight groups with normal BMI. Furthermore, the group with LBW and BMI ≥25.0 kg/m2 was the highest risk for hypertension (adjusted odds ratio: 2.73; 95% CI, 2.04-3.65) compared to the reference group (birth weight 2500-3499 g and BMI 18.5-24.9 kg/m2). There was a significant association between LBW and subsequent risk of hypertension. In addition, participants with lower birth weights had a higher risk of hypertension than those with higher birth weights. However, even in participants with a lower birth weight, the risk of hypertension could be reduced when they maintained an optimal BMI.

BACKGROUND: The Tohoku Medical Megabank Project (TMM) was established to realize personalized healthcare and medicine using genomic and omics data. This study evaluated the validity and reproducibility of food group intakes derived from a self-administered food frequency questionnaire (TMM-FFQ) that included the response option "constitutionally unable to eat/drink it" among community-dwelling Japanese adults. METHODS: Participants comprised 89 men and 124 women aged ≥20 years from Miyagi Prefecture. Participants completed weighed food records (WFRs) for 3 consecutive days per season as reference intake and FFQs in 2019 (FFQ1) and 2021 (FFQ3). Spearman's rank correlation coefficients (CCs) were calculated for correlations between food group intakes estimated from the 12-day WFR and FFQ3 (validity), and for correlations between those estimated from the FFQ1 and FFQ3 (reproducibility). Cross-classification according to quintiles using FFQ and WFR data was also performed. RESULTS: The percentage of participants who chose the "constitutionally unable to eat/drink it" option was non-negligible for some food groups. In the validity analysis, CCs were >0.40 for many food groups; the median across 21 food groups was 0.49 in men and 0.45 in women. The median percentages of cross-classification into exact plus adjacent quintiles were 73.0% in men and 66.9% in women. In the reproducibility analysis, CCs were >0.50 for many food groups; the median across 21 food groups was 0.60 in men and 0.51 in women. CONCLUSIONS: The validity of the TMM-FFQ compared with 12-day WFR and the reproducibility of the TMM-FFQ were reasonable for food groups in the TMM cohort studies.

No study, to our knowledge, has constructed a polygenic risk score based on clinical blood pressure and investigated the association of genetic and lifestyle risks with home hypertension. We examined the associations of combined genetic and lifestyle risks with hypertension and home hypertension. In a cross-sectional study of 7027 Japanese individuals aged ≥20 years, we developed a lifestyle score based on body mass index, alcohol consumption, physical activity, and sodium-to-potassium ratio, categorized into ideal, intermediate, and poor lifestyles. A polygenic risk score was constructed with the target data (n = 1405) using publicly available genome-wide association study summary statistics from BioBank Japan. Using the test data (n = 5622), we evaluated polygenic risk score performance and examined the associations of combined genetic and lifestyle risks with hypertension and home hypertension. Hypertension and home hypertension were defined as blood pressure measured at a community-support center ≥140/90 mmHg or at home ≥135/85 mmHg, respectively, or self-reported treatment for hypertension. In the test data, 2294 and 2322 participants had hypertension and home hypertension, respectively. Both polygenic risk and lifestyle scores were independently associated with hypertension and home hypertension. Compared with those of participants with low genetic risk and an ideal lifestyle, the odds ratios for hypertension and home hypertension in the low genetic risk and poor lifestyle group were 1.94 (95% confidence interval, 1.34-2.80) and 2.15 (1.60-2.90), respectively. In summary, lifestyle is important to prevent hypertension; nevertheless, participants with high genetic risk should carefully monitor their blood pressure despite a healthy lifestyle.

This study aimed to evaluate the associations of fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) levels at <24 weeks of gestation with hypertensive disorders of pregnancy (HDP) and compare the strengths of the associations of HDP with FPG and HbA1c levels. Totally, 1,178 participants were included in this prospective cohort study. HDP, FPG, HbA1c, and potential confounding factors were included in multiple logistic regression models. The number of HDP cases was 136 (11.5%). When FPG and HbA1c were included in the model separately, quartile 4 (Q4) of FPG (87-125 mg/dL) and HbA1c (5.2-6.3% [33-45 mmol/mol]) levels had higher odds of HDP than quartile 1. The odds ratios (ORs) were 1.334 (95% confidence interval [CI]: 1.002-1.775) for Q4 of FPG and 1.405 (95% CI: 1.051-1.878) for Q4 of HbA1c. When the participants were divided into two categories based on the cut-off value with the maximum Youden Index of FPG or HbA1c, the ORs for high FPG (≥84 mg/dL) or high HbA1c (≥5.2% [33 mmol/mol]) were 1.223 (95% CI: 1.000-1.496) and 1.392 (95% CI: 1.122-1.728), respectively. When both FPG and HbA1c were included in the model simultaneously, the statistical significance of Q4 of FPG disappeared, whereas that of HbA1c remained. In two-category models, the same results were obtained. High FPG and HbA1c levels at <24 weeks of gestation were risk factors for HDP in pregnant Japanese women. In addition, high HbA1c levels were more strongly associated with HDP than high FPG levels.

INTRODUCTION: To examine the interaction between lifestyle habits and the COVID-19 vaccinations for preventing SARS-CoV-2 infection, we analyzed 11,016 adult participants registered in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. METHODS: Lifestyle variables, including regular exercise, smoking and drinking habits, sleep status, body mass index, and daily breakfast consumption, were assessed from 2014 to 2019 using baseline questionnaires. Information on SARS-CoV-2 infection and the COVID-19 vaccination were also collected from March 2020 to May 2023. The study period was divided into two in the postvaccination phase: the first period (the beginning of the vaccination program) and the second period (the fourth shot onward). RESULTS: In the Cox proportional-hazards model analysis, the five-time vaccinations group showed a significantly lower risk of SARS-CoV-2 infection adjusted age, sex, underlying health condition, and lifestyle variables (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.76-0.86). Logistic regression analysis revealed that a higher number of vaccinations was significantly associated with a low risk of SARS-CoV-2 infection regardless of lifestyle habits (three times in the first period: odds ratio [OR] 0.19, 95% CI 0.15-0.24; five times in the second period: OR 0.07, 95% CI 0.05-0.11 vs. none). Regarding lifestyle habits, the risk reduction in those who had sleep satisfaction (OR 0.12, 95% CI 0.08-0.18) was slightly larger than in those who had sleep dissatisfaction (OR 0.23, 95% CI 0.17-0.32) in the group with the highest number of vaccinations in the first period; however, this interaction was hardly confirmed in the second period when the number of infected cases significantly increased. CONCLUSIONS: Our findings indicated that a higher number of COVID-19 vaccinations was associated with reduced risk of SARS-CoV-2 infection; otherwise, we may need to understand the advantages and limitations of a healthy lifestyle for preventing infection depending on the situation with vaccinations and infection spreading.

Depression is comorbid with somatic diseases; however, the relationship between depressive symptoms and hypertension (HT), a risk factor for cardiovascular events, remains unclear. Home blood pressure (BP) is more reproducible and accurately predictive of cardiovascular diseases than office BP. Therefore, we focused on home BP and investigated whether depressive symptoms contributed to the future onset of home HT. This prospective cohort study used data from the Tohoku Medical Megabank Community-Cohort Study (conducted in the Miyagi Prefecture, Japan) and included participants with home normotension (systolic blood pressure (SBP) < 135 mmHg and diastolic blood pressure (DBP) < 85 mmHg). Depressive symptoms were evaluated using the Center for Epidemiologic Studies Depression Scale-Japanese version at the baseline survey. In the secondary survey, approximately 4 years later, the onset of home HT was evaluated (SBP ≥ 135 mmHg or DBP ≥ 85 mmHg) and was compared in participants with and without depressive symptoms. Of the 3 082 (mean age: 54.2 years; females: 80.9%) participants, 729 (23.7%) had depressive symptoms at the baseline survey. During the 3.5-year follow-up, 124 (17.0%) and 388 (16.5%) participants with and without depressive symptoms, respectively, developed home HT. Multivariable adjusted odds ratios were 1.37 (95% confidence interval (CI): 1.02-1.84), 1.18 (95% CI: 0.86-1.61), and 1.66 (95% CI: 1.17-2.36) for home, morning, and evening HT, respectively. This relationship was consistent in the subgroup analyses according to age, sex, BP pattern, and drinking habit. Depressive symptoms increased the risk of new-onset home HT, particularly evening HT, among individuals with home normotension. This prospective cohort study revealed that depressive symptoms are risk factors for new-onset home hypertension, particularly evening hypertension among individuals with home normotension. Assessing home blood pressure in individuals with depressive symptoms is important for the prevention of hypertension and concomitant cardiovascular diseases.

Understanding the physiological changes associated with aging and the associated disease risks is essential to establish biomarkers as indicators of biological aging. This study used the NMR-measured plasma metabolome to calculate age-specific metabolite indices. In doing so, the scope of the study was deliberately simplified to capture general trends and insights into age-related changes in metabolic patterns. In addition, changes in metabolite concentrations with age were examined in detail, with the period from 55-59 to 60-64 years being a period of significant metabolic change, particularly in men, and from 45-49 to 50-54 years in females. These results illustrate the different variations in metabolite concentrations by sex and provide new insights into the relationship between age and metabolic diseases.

AIM: This study examined the relationship between genetic risk, healthy lifestyle, and risk of developing diabetes. METHODS: This prospective cohort study included 11,014 diabetes-free individuals ≥ 20 years old from the Tohoku Medical Megabank Community-based cohort study. Lifestyle scores, including the body mass index, smoking, physical activity, and gamma-glutamyl transferase (marker of alcohol consumption), were assigned, and participants were categorized into ideal, intermediate, and poor lifestyles. A polygenic risk score (PRS) was constructed based on the type 2 diabetes loci from the BioBank Japan study. A multiple logistic regression model was used to estimate the association between genetic risk, healthy lifestyle, and diabetes incidence and to calculate the area under the receiver operating characteristic curve (AUROC). RESULT: Of the 11,014 adults included (67.8% women; mean age [standard deviation], 59.1 [11.3] years old), 297 (2.7%) developed diabetes during a mean 4.3 (0.8) years of follow-up. Genetic and lifestyle score is independently associated with the development of diabetes. Compared with the low genetic risk and ideal lifestyle groups, the odds ratio was 3.31 for the low genetic risk and poor lifestyle group. When the PRS was integrated into a model including the lifestyle and family history, the AUROC significantly improved to 0.719 (95% confidence interval [95% CI]: 0.692-0.747) compared to a model including only the lifestyle and family history (0.703 [95% CI, 0.674-0.732]). CONCLUSION: Our findings indicate that adherence to a healthy lifestyle is important for preventing diabetes, regardless of genetic risk. In addition, genetic risk might provide information beyond lifestyle and family history to stratify individuals at high risk of developing diabetes.

OBJECTIVES: To evaluate the performance of the multimodal model, termed variable Vision Transformer (vViT), in the task of predicting isocitrate dehydrogenase (IDH) status among adult patients with diffuse glioma. MATERIALS AND METHODS: vViT was designed to predict IDH status using patient characteristics (sex and age), radiomic features, and contrast-enhanced T1-weighted images (CE-T1WI). Radiomic features were extracted from each enhancing tumor (ET), necrotic tumor core (NCR), and peritumoral edematous/infiltrated tissue (ED). CE-T1WI were split into four images and input to vViT. In the training, internal test, and external test, 271 patients with 1070 images (535 IDH wildtype, 535 IDH mutant), 35 patients with 194 images (97 IDH wildtype, 97 IDH mutant), and 291 patients with 872 images (436 IDH wildtype, 436 IDH mutant) were analyzed, respectively. Metrics including accuracy and AUC-ROC were calculated for the internal and external test datasets. Permutation importance analysis combined with the Mann-Whitney U test was performed to compare inputs. RESULTS: For the internal test dataset, vViT correctly predicted IDH status for all patients. For the external test dataset, an accuracy of 0.935 (95% confidence interval; 0.913-0.945) and AUC-ROC of 0.887 (0.798-0.956) were obtained. For both internal and external test datasets, CE-T1WI ET radiomic features and patient characteristics had higher importance than other inputs (p < 0.05). CONCLUSIONS: The vViT has the potential to be a competent model in predicting IDH status among adult patients with diffuse glioma. Our results indicate that age, sex, and CE-T1WI ET radiomic features have key information in estimating IDH status.

Genetic maps are fundamental resources for linkage and association studies. A fine-scale genetic map can be constructed by inferring historical recombination events from the genome-wide structure of linkage disequilibrium-a non-random association of alleles among loci-by using population-scale sequencing data. We constructed a fine-scale genetic map and identified recombination hotspots from 10 092 551 bi-allelic high-quality autosomal markers segregating among 150 unrelated Japanese individuals whose genotypes were determined by high-coverage (30×) whole-genome sequencing, and the genotype quality was carefully controlled by using their parents' and offspring's genotypes. The pedigree information was also utilized for haplotype phasing. The resulting genome-wide recombination rate profiles were concordant with those of the worldwide population on a broad scale, and the resolution was much improved. We identified 9487 recombination hotspots and confirmed the enrichment of previously known motifs in the hotspots. Moreover, we demonstrated that the Japanese genetic map improved the haplotype phasing and genotype imputation accuracy for the Japanese population. The construction of a population-specific genetic map will help make genetics research more accurate.

Blood pressure (BP) control in pregnancy is essential to prevent adverse outcomes. However, BP levels for hypertension treatment are inconsistent among various guidelines. This study investigated the association between BP control and adverse perinatal outcomes. A total of 18,155 mother-offspring pairs were classified into four groups according to BP after 20 gestational weeks: normal BP (<140/90 mmHg without antihypertensive drugs), high BP (≥140/90 mmHg without antihypertensive drugs), controlled BP (<140/90 mmHg with antihypertensive drugs), and uncontrolled BP (≥140/90 mmHg with antihypertensive drugs). The prevalence of small for gestational age was 1,087/17,476 offspring in normal BP, 78/604 in high BP, 5/42 in controlled BP, and 7/33 in uncontrolled BP. Compared to normal BP, adjusted odds ratios (ORs) (95% confidence intervals (CIs)) were 1.76 (1.32-2.35) for high BP, 2.08 (0.79-5.50) for controlled BP, and 2.34 (0.94-5.85) for uncontrolled BP (multiple logistic regression analysis). Similarly, the adjusted ORs (95% CIs) were 1.80 (1.35-2.41), 3.42 (1.35-8.63), and 5.10 (1.93-13.45) for high, controlled, and uncontrolled BPs for low birth weight, respectively; 1.99 (1.48-2.68), 2.70 (1.12-6.50), and 6.53 (3.09-13.82) for high, controlled, and uncontrolled BPs for preterm birth, respectively; 1.64 (1.19-2.24), 2.17 (0.88-5.38), and 2.12 (0.80-5.65) for high, controlled, and uncontrolled BPs for admission to the Neonatal Intensive Care Unit or Growing Care Unit, respectively; and 1.17 (0.70-1.95), 2.23 (0.65-7.68), and 0.91 (0.20-4.16) for high, controlled, and uncontrolled BPs for 1-min Apgar score < 7, respectively. BP ≥ 140/90 mmHg might be taken care for preventing various adverse perinatal outcomes.

PURPOSE: To elucidate the status of medication use among pregnant women in Japan, by means of a multigenerational genome and birth cohort study: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). METHODS: Questionnaires were distributed to pregnant women participating in the TMM BirThree Cohort Study (from July 2013 to March 2017) around 12 weeks (early pregnancy) and 26 weeks (middle pregnancy). We analysed medication use over three periods: (1) 12 months prior to pregnancy diagnosis, (2) the period between pregnancy diagnosis and around week 12 of pregnancy, and (3) post around week 12 of pregnancy. RESULTS: In total, 19,297 women were included in the analysis. The proportion of pregnant women using medications was 49.0% prior to pregnancy diagnosis, 52.1% from diagnosis to week 12, and 58.4% post week 12 of pregnancy. The most frequently prescribed medications were loxoprofen sodium hydrate (5.5%) prior to pregnancy diagnosis, magnesium oxide (5.9%) from diagnosis to week 12, and ritodrine hydrochloride (10.5%) post week 12 of pregnancy. The number of women who used suspected teratogenic medications during early pregnancy was 96 prior to pregnancy diagnosis, 48 from diagnosis to week 12, and 54 post week 12 of pregnancy. CONCLUSION: We found that ~ 50% of the pregnant women used medications before and during pregnancy and some took potential teratogenic medications during pregnancy. In birth genomic cohort study, it is expected that investigations into the safety and effectiveness of medications used during pregnancy will advance.

BACKGROUND: Nausea and vomiting during pregnancy (NVP) and hyperemesis gravidarum (HG), common conditions affecting most pregnant women, are highly heritable and associated with maternal and fetal morbidity. However, the pathologies underlying NVP and HG and their associated loci are scarce. METHODS: We performed genome-wide association studies (GWAS) of NVP in pregnant women (n = 23,040) who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Japan from July 2013 to March 2017. Participants were divided into discovery (n = 9,464) and replication (n = 10,051) stages based on the platform used for their genotyping. Loci that achieved the genome-wide significance level (p < 5.0 × 10- 8) in the discovery stage were selected for genotyping in the replication stage. A meta-analysis integrating the discovery and replication stage results (n = 19,515) was conducted. NVP-related variables were identified as categorical or continuous. RESULTS: GWAS analysis in the discovery phase revealed loci linked to NVP in two gene regions, 11q22.1 (rs77775955) and 19p13.11 (rs749451 and rs28568614). Loci in these two gene regions have also been shown to be associated with HG in a White European population, indicating the generalizability of the GWAS analyses conducted in this study. Of these, only rs749451 and rs28568614 at 19p13.11 reached the genome-wide suggestive level (p < 1.0 × 10- 5) in the replication stage; however, both loci were significant in the meta-analysis. CONCLUSIONS: NVP-related loci were identified in the Japanese population at 11q22.1 and 19p13.11, as reported in previous GWAS. This study contributes new evidence on the generalizability of previous GWAS on the association between genetic background and NVP.

This study is aimed at revealing the risk factors, prognosis, influence on offspring, and genetic architecture of perinatal depression (PD) classified based on the depressive symptom trajectory. Pregnant women with no history of major depressive disorder (MDD) were recruited and followed up with their offspring from 1 to 5 years postpartum. Using four self-report questionnaires in the perinatal period, PD was classified into four subtypes: pregnancy, early postpartum, late postpartum, and chronic PD. Risk factors, depressive symptom trajectory from 1 to 5 years postpartum, and child behavior problems were compared among the four PD subtypes. Genome-wide association studies (GWASs) were conducted for each subtype. The relationships between the PD subtypes and polygenic risk scores (PRS) for MDD, a psychiatric disorder, and premenstrual syndrome (PMS), a hormonal disorder, were examined. Among 12,338 participants, 1,145 (9.3%) developed pregnancy PD, 856 (6.9%) developed early postpartum PD, 382 (3.1%) developed late postpartum PD, and 1,048 (8.5%) developed chronic PD. Depressive symptoms decreased to 61.0%–73.3% in the 5 years postpartum. The relationship between risk factors and PD varied based on the PD subtype. Additionally, chronic PD increased the risk of child behavior problems by 2- to 3-fold. The GWASs uncovered five significant variants in different loci depending on PD subtypes, suggesting a subtype-specific genetic architecture. The PRS for MDD was related to pregnancy, early postpartum, and chronic PD, while that for PMS was related to late postpartum PD. It was concluded that PD is heterogeneous depending on the depressive symptom trajectory. Thus, specific prevention and treatment strategies are needed.

Recently, many phenotyping algorithms for high-throughput cohort identification have been developed. Prospective genome cohort studies are critical resources for precision medicine, but there are many hurdles in the precise cohort identification. Consequently, it is important to develop phenotyping algorithms for cohort data collection. Hypertensive disorders of pregnancy (HDP) is a leading cause of maternal morbidity and mortality. In this study, we developed, applied, and validated rule-based phenotyping algorithms of HDP. Two phenotyping algorithms, algorithms 1 and 2, were developed according to American and Japanese guidelines, and applied into 22,452 pregnant women in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank project. To precise cohort identification, we analyzed both structured data (e.g., laboratory and physiological tests) and unstructured clinical notes. The identified subtypes of HDP were validated against reference standards. Algorithms 1 and 2 identified 7.93% and 8.08% of the subjects as having HDP, respectively, along with their HDP subtypes. Our algorithms were high performing with high positive predictive values (0.96 and 0.90 for algorithms 1 and 2, respectively). Overcoming the hurdle of precise cohort identification from large-scale cohort data collection, we achieved both developed and implemented phenotyping algorithms, and precisely identified HDP patients and their subtypes from large-scale cohort data collection.

PURPOSE: This study aimed to perform multimodal analysis by vision transformer (vViT) in predicting O6-methylguanine-DNA methyl transferase (MGMT) promoter status among adult patients with diffuse glioma using demographics (sex and age), radiomic features, and MRI. METHODS: The training and test datasets contained 122 patients with 1,570 images and 30 patients with 484 images, respectively. The radiomic features were extracted from enhancing tumors (ET), necrotic tumor cores (NCR), and the peritumoral edematous/infiltrated tissues (ED) using contrast-enhanced T1-weighted images (CE-T1WI) and T2-weighted images (T2WI). The vViT had 9 sectors; 1 demographic sector, 6 radiomic sectors (CE-T1WI ET, CE-T1WI NCR, CE-T1WI ED, T2WI ET, T2WI NCR, and T2WI ED), 2 image sectors (CE-T1WI, and T2WI). Accuracy and area under the curve of receiver-operating characteristics (AUC-ROC) were calculated for the test dataset. The performance of vViT was compared with AlexNet, GoogleNet, VGG16, and ResNet by McNemar and Delong test. Permutation importance (PI) analysis with the Mann-Whitney U test was performed. RESULTS: The accuracy was 0.833 (95% confidence interval [95%CI]: 0.714-0.877) and the area under the curve of receiver-operating characteristics was 0.840 (0.650-0.995) in the patient-based analysis. The vViT had higher accuracy than VGG16 and ResNet, and had higher AUC-ROC than GoogleNet (p<0.05). The ED radiomic features extracted from the T2-weighted image demonstrated the highest importance (PI=0.239, 95%CI: 0.237-0.240) among all other sectors (p<0.0001). CONCLUSION: The vViT is a competent deep learning model in predicting MGMT status. The ED radiomic features of the T2-weighted image demonstrated the most dominant contribution.

INTRODUCTION: Developmental delay at an early age indicates the probability of continued problems after school age. Hypertensive disorders of pregnancy (HDP) are associated with developmental delays in offspring, with inconsistent outcomes. Neonatal outcomes vary according to HDP exposure and are relevant to development in later years. Here we aimed to clarify the relationship between HDP and developmental delay in offspring and whether neonatal outcomes mediate this association. MATERIAL AND METHODS: We used data from 5934 mother-child pairs from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, a prospective cohort study conducted in Japan between July 2013 and March 2017. The Ages and Stages Questionnaires, third edition, at 24 and 42 months of age, measured developmental delay in five areas. We performed multivariate quasi-Poisson regression and causal mediation analysis by neonatal outcomes. RESULTS: At 24 months of age, compared to offspring born from normotensive mothers, offspring born from HDP-affected mothers were more likely to experience developmental delay (risk ratio [RR] 1.29, 95% confidence interval [CI]: 1.09-1.52) in the areas of communication (RR 1.21, 95% CI: 1.00-1.45) and personal-social (RR 1.15, 95% CI: 1.03-1.28). This association was mediated by neonatal outcomes: preterm birth, neonatal asphyxia, NICU admission, and neonatal small head circumference. No association was observed between HDP and developmental delay at 42 months of age. CONCLUSIONS: Exposure to HDP during fetal life is associated with offspring developmental delay. This association is partly mediated by neonatal outcomes.

BACKGROUND: The purpose of this study was to report the basic profile of the Miyagi Prefecture part of a repeated center-based survey during the second period (2nd period survey) of the Tohoku Medical Megabank Community-Based Cohort Study (TMM CommCohort Study), as well as the participants' characteristics based on their participation type in the baseline survey. METHODS: The 2nd period survey, conducted from June 2017 to March 2021, included participants of the TMM CommCohort Study (May 2013 to March 2016). In addition to the questionnaire, blood, urine, and physiological function tests were performed during the 2nd period survey. There were three main ways of participation in the baseline survey: Type 1, Type 1 additional, or Type 2 survey. The 2nd period survey was conducted in the same manner as the Type 2 survey, which was based on the community support center (CSC). RESULTS: In Miyagi Prefecture, 29,383 (57.7%) of 50,967 participants participated in the 2nd period survey. The participation rate among individuals who had visited the CSC was approximately 80%. Although some factors differed depending on the participation type in the baseline survey, the 2nd period survey respondents in the Type 1 and Type 2 survey groups at baseline had similar traits. CONCLUSIONS: The 2nd period survey of the TMM CommCohort Study provided detailed follow-up information. Following up on the health conditions of the participants will clarify the long-term effects of disasters and contribute to personalized prevention.

AIMS: This study aimed to investigate the association of maternal birth weight (MBW) with early and late gestational diabetes mellitus (GDM). METHODS: A total of 69318 pregnant Japanese women were included in this birth cohort study. The associations between maternal birth weight and early gestational diabetes mellitus (diagnosed at <24 gestational weeks) and late GDM (diagnosed at ≥24 gestational weeks) were investigated using a multinomial logistic regression model, with an maternal birth weight of 3000-3499 g as the reference category. RESULTS: Lower maternal birth weight was associated with higher odds of developing early and late gestational diabetes mellitus (P < 0.0001 and P < 0.0001, respectively). The adjusted odds ratios (aORs) for early gestational diabetes mellitus in participants with a MBW of <2500 g and 2500-2999 g were 1.345 (95% confidence interval [CI]: 0.912-1.984) and 1.338 (95% CI: 1.098-1.629), respectively. The aORs for late gestational diabetes mellitus in participants with a MBW of <2500 g and 2500-2999 g were, 1.657 (95% CI: 1.298-2.115) and 1.218 (95% CI: 1.058-1.402), respectively. CONCLUSIONS: Regardless of the gestational age when gestational diabetes mellitus was diagnosed, a lower maternal birth weight was associated with an increased risk of gestational diabetes mellitus. Furthermore, the association of a MBW <2500 g with late gestational diabetes mellitus tended to be stronger than that with early gestational diabetes mellitus.

AIMS: Although fat mass (FM) and fat-free mass (FFM) have an impact on lipid metabolism, the relationship between different body composition phenotypes and lipid profiles is still unclear. By dividing the FM and FFM by the square of the height, respectively, the f at mass index (FMI) and fat-free mass index (FFMI) can be used to determine the variations in body composition. This study aimed to investigate the relationship of combined FMI and FFMI with low-density lipoprotein cholesterol (LDL-C) levels. METHODS: This cross-sectional study comprised 5,116 men and 13,630 women without cardiovascular disease and without treatment for hypertension, and diabetes. Following sex-specific quartile classification, FMI and FFMI were combined into 16 groups. Elevated LDL-C levels were defined as LDL-C ≥ 140 mg/dL and/or dyslipidemia treatment. Multivariable logistic regression models were used to examine the relationships between combined FMI and FFMI and elevated LDL-C levels. RESULTS: Overall, elevated LDL-C levels were found in 1,538 (30.1%) men and 5,434 (39.9%) women. In all FFMI subgroups, a higher FMI was associated with elevated LDL-C levels. Conversely, FFMI was inversely associated with elevated LDL-C levels in most FMI subgroups. Furthermore, the groups with the highest FMI and lowest FFMI had higher odds ratios for elevated LDL-C levels than those with the lowest FMI and highest FFMI. CONCLUSIONS: Regardless of FFMI, FMI was positively associated with elevated LDL-C levels. Conversely, in the majority of FMI subgroups, FFMI was inversely associated with elevated LDL-C levels.

This study aimed to evaluate the association between parental and infant birth weights in Japan. In total, 37,504 pregnant Japanese women and their partners were included in this birth cohort study. A multinomial logistic regression model was used to evaluate the associations of parental birth weights with small-for-gestational-age (SGA) or large-for-gestational-age (LGA) infants. Associations between parental birth weight and low birth weight (LBW) infants or macrosomia were also examined, and linear associations between parental birth weight and SGA or LGA were found. The adjusted odds ratios (aORs) for SGA infants per 500 g decrease in maternal and paternal birth weights were 1.50 (95% confidence interval [CI],1.43-1.58) and 1.31 (95% CI, 1.25-1.38), respectively. The aORs for LGA infants per 500 g increase in maternal and paternal birth weights were 1.53 (95% CI, 1.47-1.60) and 1.41 (95% CI, 1.35-1.47), respectively. The association between parental birth weight and LBW infants or macrosomia was also linear. The aORs for LBW infants per 500 g decrease in maternal and paternal birth weights were 1.47 (95% CI, 1.40-1.55) and 1.25 (95% CI, 1.19-1.31), respectively. The aORs for macrosomia per 500 g increase in maternal and paternal birth weights were 1.59 (95% CI, 1.41-1.79) and 1.40 (95% CI, 1.23-1.60), respectively. Parental birth weight was found to be associated with infant birth weight even after adjusting for various parental factors. Furthermore, maternal birth weight was more strongly associated with infant birth weight than with paternal birth weight.

BACKGROUND: Japanese traditional (Kampo) medicines containing ephedra may be used to treat colds during pregnancy. There are reports that ephedrine, a component of ephedra, has a risk of teratogenicity; however, the evidence remains equivocal. OBJECTIVE: This study aimed to evaluate the risk of major congenital malformations (MCMs) associated with exposure to Kampo medicines containing ephedra during the first trimester of pregnancy using the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). METHODS: To 23,730 mother-infant pairs who participated in the TMM BirThree Cohort Study from July 2013 to March 2017, questionnaires in early and middle pregnancy were distributed approximately at weeks 12 and 26 of pregnancy, respectively. Infants' risk of MCMs in women who used Kampo medicines containing ephedra or acetaminophen during the first trimester was assessed, and the odds ratios (ORs) were estimated with unadjusted and adjusted analyses. RESULTS: Among 20,879 women, acetaminophen and Kampo medicines containing ephedra were used in 665 (3.19%) and 376 (1.80%) women, respectively, in the first trimester. Among the infants born to the mothers who used acetaminophen or Kampo medicine containing ephedra during the first trimester, 11 (1.65%) and 8 (2.13%), respectively, had overall MCMs. OR of overall MCMs was higher in women who used Kampo medicines containing ephedra than in those who used acetaminophen in the first trimester (adjusted OR, 1.45; 95% confidence interval (CIs), 0.57-3.71); however, the difference was not statistically significant. CONCLUSIONS: In this study, there was no statistically significant association between the use of Kampo medicines containing ephedra during the first trimester of pregnancy and the risk of MCMs. Although some point estimates of ORs exceeded 1.00, the absolute magnitude of any increased risks would be low.

A fetal growth restriction is related to adverse child outcomes. We investigated risk ratios and population-attributable fractions (PAF) of small-for-gestational-age (SGA) infants in the Japanese population. Among 28,838 infants from five ongoing prospective birth cohort studies under the Japan Birth Cohort Consortium, two-stage individual-participant data meta-analyses were conducted to calculate risk ratios and PAFs for SGA in advanced maternal age, pre-pregnancy underweight, and smoking and alcohol consumption during pregnancy. Risk ratio was calculated using modified Poisson analyses with robust variance and PAF was calculated in each cohort, following common analyses protocols. Then, results from each cohort study were combined by meta-analyses using random-effects models to obtain the overall estimate for the Japanese population. In this meta-analysis, an increased risk (risk ratio, [95% confidence interval of SGA]) was significantly associated with pre-pregnancy underweight (1.72 [1.42-2.09]), gestational weight gain (1.95 [1.61-2.38]), and continued smoking during pregnancy (1.59 [1.01-2.50]). PAF of underweight, inadequate gestational weight gain, and continued smoking during pregnancy was 10.0% [4.6-15.1%], 31.4% [22.1-39.6%], and 3.2% [-4.8-10.5%], respectively. In conclusion, maternal weight status was a major contributor to SGA births in Japan. Improving maternal weight status should be prioritized to prevent fetal growth restriction.

BACKGROUND: Although an association between maternal nutritional intake and developmental delays in children has been demonstrated, the association of the timing of meal intake and development delays remains unclear. We examined the association between breakfast intake frequency before and during pregnancy and developmental delay in children. METHODS: Of the pregnant women who participated in the Tohoku Medical Megabank Project Three-Generation Cohort Study, 7491 answered the required questions and were analyzed. The frequency of breakfast intake from pre- to early pregnancy and from early to mid-pregnancy was classified into four groups: daily, and 5-6, 3-4, and 0-2 times/week. Child developmental delays at age 2 and 3.5 years were assessed using the Ages & Stages Questionnaire, Third Edition. Logistic regression models were constructed to examine the association between breakfast intake frequency in pregnant women and developmental delays in children aged 2 and 3.5 years. RESULTS: The proportion of pregnant women who had breakfast daily was 78.1% in pre- to early pregnancy, and 82.2% in early to mid-pregnancy. The proportion of children with developmental delays was 14.7% and 13.4% at age 2 and 3.5 years, respectively. Compared with the risk in children of women who had breakfast daily from pre- to early pregnancy, children of women who had breakfast 0-2 times/week had a higher risk of developmental delays at 2 years of age: odds ratio (OR) 1.30, (95% confidence interval [CI], 1.02-1.66). The risk of developmental delays at age 2 years increased in the children of women who had breakfast 0-2 times/week in early to mid- pregnancy: OR 1.75 (95% CI, 1.32-2.32). The risk of developmental delays at age 3.5 years did not increase in the children of women who had breakfast 0-2 times/week from pre- to early and early to mid-pregnancy: OR 1.06 (95% CI, 0.81-1.39 and OR 1.15 (95% CI 0.84-1.57), respectively. CONCLUSION: For women with a low frequency of breakfast intake from pre- to mid-pregnancy there was an association with developmental delays in their children at age 2, but not at 3.5 years.

OBJECTIVES: This study aimed to investigate the association between maternal birth weight (MBW) and hypertensive disorders of pregnancy (HDP) according to the gestational age when HDP develops. STUDY DESIGN: A total of 77,345 subjects were included in this prospective birth cohort study. The association between MBW and HDP was investigated by a multinomial logistic regression model. MAIN OUTCOME MEASURES: Early-onset HDP (EO-HDP), preterm late-onset HDP (preterm LO-HDP), and term late-onset HDP (term LO-HDP). RESULTS: Lower MBW was associated with higher odds of preterm and term LO-HDP (p-values for trend < 0.0001 and = 0.0005, respectively). A linear association between MBW and EO-HDP was observed (p-values for trend = 0.0496). The shape of the association between MBW and preterm LO-HDP was a combination of the associations between MBW with EO-HDP or LO-HDP. The effect size of the association between MBW < 2,500 g and EO-HDP was lower than that of MBW < 2,500 g with preterm or term LO-HDP. The adjusted odds ratios for EO-HDP, preterm LO-HDP, and term LO-HDP in subjects with MBW < 2,500 g were 1.052 (95 % confidence interval [CI]: 0.665-1.664), 1.745 (95 % CI: 1.220-2.496), and 1.496 (95 % CI: 1.154-1.939), respectively. CONCLUSIONS: MBW was associated with HDP, regardless of gestational age when HDP developed. Furthermore, the association of MBW < 2,500 g with preterm or term LO-HDP was stronger than that with EO-HDP.

Masked hypertension is a risk factor for cardiovascular diseases. However, masked hypertension is sometimes overlooked owing to the requirement for home blood pressure measurements for diagnosing. Mental status influences blood pressure. To reduce undiagnosed masked hypertension, this study assessed the association between depressive symptoms and masked hypertension. This cross-sectional study used data from the Tohoku Medical Megabank Project Community-Based Cohort Study (conducted in Miyagi Prefecture, Japan, from 2013) and included participants with normotension measured at the research center (systolic blood pressure<140 mmHg and diastolic blood pressure <90 mmHg). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (Japanese version). Masked hypertension was defined as normotension measured at the research center and home hypertension (home systolic blood pressure ≥135 mmHg or home diastolic blood pressure ≥85 mmHg). The study comprised 6705 participants (mean age: 55.7 ± 13.7 years). Of these participants, 1106 (22.1%) without depressive symptoms and 393 (23.2%) with depressive symptoms were categorized to have masked hypertension. Sex-specific and age-adjusted least mean squares for home blood pressure, not for research blood pressure were significantly higher in the group with depressive symptoms in both sex categories. The multivariate odds ratio for masked hypertension in the patients with depressive symptoms was 1.72 (95% confidence interval: 1.26-2.34) in male participants and 1.30 (95% confidence interval: 1.06-1.59) in female ones. Depressive symptoms were associated with masked hypertension in individuals with normotension measured at the research center. Depressive symptoms may be one of the risk factors for masked hypertension. Depressive symptoms were associated with masked hypertension in individuals with normotension measured at research center.

BACKGROUND: Low birth weight (LBW) is a leading cause of neonatal morbidity and mortality, and increases various disease risks across life stages. Prediction models of LBW have been developed before, but have limitations including small sample sizes, absence of genetic factors and no stratification of neonate into preterm and term birth groups. In this study, we challenged the development of early prediction models of LBW based on environmental and genetic factors in preterm and term birth groups, and clarified influential variables for LBW prediction. METHODS: We selected 22,711 neonates, their 21,581 mothers and 8,593 fathers from the Tohoku Medical Megabank Project Birth and Three-Generation cohort study. To establish early prediction models of LBW for preterm birth and term birth groups, we trained AI-based models using genetic and environmental factors of lifestyles. We then clarified influential environmental and genetic factors for predicting LBW in the term and preterm groups. RESULTS: We identified 2,327 (10.22%) LBW neonates consisting of 1,077 preterm births and 1,248 term births. Our early prediction models archived the area under curve 0.96 and 0.95 for term LBW and preterm LBW models, respectively. We revealed that environmental factors regarding eating habits and genetic features related to fetal growth were influential for predicting LBW in the term LBW model. On the other hand, we identified that genomic features related to toll-like receptor regulations and infection reactions are influential genetic factors for prediction in the preterm LBW model. CONCLUSIONS: We developed precise early prediction models of LBW based on lifestyle factors in the term birth group and genetic factors in the preterm birth group. Because of its accuracy and generalisability, our prediction model could contribute to risk assessment of LBW in the early stage of pregnancy and control LBW risk in the term birth group. Our prediction model could also contribute to precise prediction of LBW based on genetic factors in the preterm birth group. We then identified parental genetic and maternal environmental factors during pregnancy influencing LBW prediction, which are major targets for understanding the LBW to address serious burdens on newborns' health throughout life.

IMPORTANCE: Whether some domains of child development are specifically associated with screen time and whether the association continues with age remain unknown. OBJECTIVE: To examine the association between screen time exposure among children aged 1 year and 5 domains of developmental delay (communication, gross motor, fine motor, problem-solving, and personal and social skills) at age 2 and 4 years. DESIGN, PARTICIPANTS, AND SETTING: This cohort study was conducted under the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Pregnant women at 50 obstetric clinics and hospitals in the Miyagi and Iwate prefectures in Japan were recruited into the study between July 2013 and March 2017. The information was collected prospectively, and 7097 mother-child pairs were included in the analysis. Data analysis was performed on March 20, 2023. EXPOSURE: Four categories of screen time exposure were identified for children aged 1 year (<1, 1 to <2, 2 to <4, or ≥4 h/d). MAIN OUTCOMES AND MEASURES: Developmental delays in the 5 domains for children aged 2 and 4 years were assessed using the Japanese version of the Ages & Stages Questionnaires, Third Edition. Each domain ranged from 0 to 60 points. Developmental delay was defined if the total score for each domain was less than 2 SDs from its mean score. RESULTS: Of the 7097 children in this study, 3674 were boys (51.8%) and 3423 were girls (48.2%). With regard to screen time exposure per day, 3440 children (48.5%) had less than 1 hour, 2095 (29.5%) had 1 to less than 2 hours, 1272 (17.9%) had 2 to less than 4 hours, and 290 (4.1%) had 4 or more hours. Children's screen time was associated with a higher risk of developmental delay at age 2 years in the communication (odds ratio [OR], 1.61 [95% CI, 1.23-2.10] for 1 to <2 h/d; 2.04 [1.52-2.74] for 2 to <4 h/d; 4.78 [3.24-7.06] for ≥4 vs <1 h/d), fine motor (1.74 [1.09-2.79] for ≥4 vs <1 h/d), problem-solving (1.40 [1.02-1.92] for 2 to <4 h/d; 2.67 [1.72-4.14] for ≥4 vs <1 h/d), and personal and social skills (2.10 [1.39-3.18] for ≥4 vs <1 h/d) domains. Regarding risk of developmental delay at age 4 years, associations were identified in the communication (OR, 1.64 [95% CI, 1.20-2.25] for 2 to <4 h/d; 2.68 [1.68-4.27] for ≥4 vs <1 h/d) and problem-solving (1.91 [1.17-3.14] for ≥4 vs <1 h/d) domains. CONCLUSIONS AND RELEVANCE: In this study, greater screen time for children aged 1 year was associated with developmental delays in communication and problem-solving at ages 2 and 4 years. These findings suggest that domains of developmental delay should be considered separately in future discussions on screen time and child development.

Introduction Perinatal women tend to have difficulties with sleep along with autonomic characteristics. This study aimed to identify a machine learning algorithm capable of achieving high accuracy in predicting sleep–wake conditions and differentiating between the wake conditions before and after sleep during pregnancy based on heart rate variability (HRV). Methods Nine HRV indicators (features) and sleep–wake conditions of 154 pregnant women were measured for 1 week, from the 23rd to the 32nd weeks of pregnancy. Ten machine learning and three deep learning methods were applied to predict three types of sleep–wake conditions (wake, shallow sleep, and deep sleep). In addition, the prediction of four conditions, in which the wake conditions before and after sleep were differentiated—shallow sleep, deep sleep, and the two types of wake conditions—was also tested. Results and Discussion In the test for predicting three types of sleep–wake conditions, most of the algorithms, except for Naïve Bayes, showed higher areas under the curve (AUCs; 0.82–0.88) and accuracy (0.78–0.81). The test using four types of sleep–wake conditions with differentiation between the wake conditions before and after sleep also resulted in successful prediction by the gated recurrent unit with the highest AUC (0.86) and accuracy (0.79). Among the nine features, seven made major contributions to predicting sleep–wake conditions. Among the seven features, “the number of interval differences of successive RR intervals greater than 50 ms (NN50)” and “the proportion dividing NN50 by the total number of RR intervals (pNN50)” were useful to predict sleep–wake conditions unique to pregnancy. These findings suggest alterations in the vagal tone system specific to pregnancy.

PURPOSE: This study aimed to determine the factors associated with new onset father-to-infant (paternal) bonding failure from 1 to 6 months postpartum. METHODS: This was a prospective birth-cohort study. Paternal bonding failure was evaluated using the Japanese version of the Mother-to-Infant Bonding Scale (MIBS-J) at 1 and 6 months postpartum. For cut-off scores, overall bonding failure, MIBS-J total scores ≥ 5; subscale for lack of affection, MIBS-J_LA scores ≥ 3; and subscale for anger/rejection, MIBS-J_AR scores ≥ 3 were used in this study. Multivariate regression analysis was performed to analyze relative variables. RESULTS: We analyzed 872 fathers. The frequency of new-onset overall bonding failure, lack of affection, and anger/rejection was 5.6%, 4.9%, and 6.3%, respectively. For new-onset overall bonding failure, significant associated factors were paternal childcare leave (adjusted odds ratio [AOR] 3.192; 95% confidence interval [CI] 1.203-8.469), paternal new-onset depression symptoms (AOR 3.181; 95% Cl 1.311-7.716), and maternal new-onset overall bonding failure (AOR 4.595; 95% Cl 1.119-18.866). For new-onset lack of affection, significant associated factors were preterm birth (AOR 4.189; 95% Cl 1.473-11.913) and paternal new-onset depression symptoms (AOR 3.290; 95% Cl 1.294-8.362). For new-onset anger and rejection, significant associated factors were paternal childcare leave (AOR 3.142; 95% Cl 1.138-8.676), paternal new-onset depression symptoms (AOR 2.829; 95% Cl 1.133-7.068), and maternal new-onset anger/rejection (AOR 7.064; 95% Cl 2.300-21.700). CONCLUSIONS: The factors associated with new-onset paternal bonding failure from 1 to 6 months postpartum were paternal childcare leave, preterm birth, paternal postpartum depression symptoms, and maternal bonding failure.

PURPOSE: Studies examining the associations between maternal social relationships and early childhood development have mainly focused on social relationships after childbirth. We aimed to prospectively examine the associations between the transition of maternal social isolation from the prenatal to postnatal period and early childhood development. METHODS: We analyzed data for 6692 mother-child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Social isolation in the prenatal and postnatal periods was assessed by the Lubben Social Network Scale-abbreviated version and categorized into four groups: none, prenatal only, postnatal only, and both. The Ages and Stages Questionnaire, Third Edition, which consists of five developmental areas, was used to assess developmental delays in children at 2 and 3.5 years of age. Multiple logistic regression analyses were conducted to examine the associations between maternal social isolation and developmental delays. RESULTS: The prevalence of social isolation in both the prenatal and postnatal periods was 13.1%. Social isolation in both the prenatal and postnatal periods was associated with developmental delays in children at 2 and 3.5 years of age: the multivariate-adjusted odds ratios (95% confidence intervals) were 1.68 (1.39-2.04) and 1.43 (1.17-1.76), respectively. Social isolation in the prenatal period only and social isolation in the postnatal period only were not associated with developmental delays in children at 2 and 3.5 years of age. CONCLUSION: Maternal social isolation in both the prenatal and postnatal periods was associated with an increased risk of developmental delays in early childhood.

OBJECTIVE: The association between high sugar-sweetened beverages (SSB) intake during pregnancy and offspring overweight/obesity has been reported only from Western countries. The objective of this study was to examine the association between SSB intake before and during pregnancy and offspring overweight/obesity among Japanese women. DESIGN: Japanese prospective birth cohort study. SETTING: We analysed mother-offspring pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study from 2013 to 2017. SSB intake during pregnancy was evaluated using the FFQ and classified into three groups: none (0 g/d), medium (<195 g/d) and high (>195 g/d). Overweight or obesity at 1 year of age in offspring was defined as having a BMI Z-score greater than 2 sd, calculated based on the BMI reference data for Japanese children. Multiple logistic regression analyses were performed to examine the associations between SSB intake before and during pregnancy and offspring overweight/obesity, after adjusting for covariates. PARTICIPANTS: Japanese mother-offspring pairs (n 7114). RESULTS: The overweight/obesity rate of the offspring was 8·8 %. Pregnant women with a high intake of SSB in early to mid-pregnancy had a higher risk of overweight/obesity in their offspring compared with those who did not; the OR was 1·52 (95 % CI (1·09, 2·12)). CONCLUSIONS: High SSB intake in early to mid-pregnancy was associated with an increased risk of offspring overweight/obesity at 1 year of age.

To examine whether body type at birth, body weight, and obesity in early childhood are associated with overweight/obesity during school age and puberty. Data from maternal and child health handbooks, baby health checkup information, and school physical examination information of participants at birth and three-generation cohort studies were linked. Association between body type and body weight at different time intervals (at birth and at 1.5, 3.5, 6, 11, and 14 years of age) were comprehensively analyzed using a multivariate regression model adjusted for gender, maternal age at childbirth, maternal parity, and maternal body mass index, and drinking and smoking statuses at pregnancy confirmation. Children who are overweight in young childhood had a greater risk of being overweight. Particularly, overweight at one year of age during checkup was associated with overweight at 3.5 years (adjusted odds ratio (aOR), 13.42; 95% confidence interval (CI), 4.46-45.42), 6 years (aOR, 6.94; 95% CI, 1.64-33.46), and 11 years (aOR, 5.22; 95% CI, 1.25-24.79) of age. Therefore, being overweight in young childhood could increase the risk of being overweight and obese during school age and puberty. Early intervention in young childhood may be warranted to prevent obesity during school age and puberty.

AIM: Previous studies based on a relatively limited number of subjects have indicated potential associations between plasma cytokine concentrations in perinatal women and postpartum depression (PPD). This report aimed to examine alterations in cytokine levels during pregnancy and after delivery by measuring nine cytokines in prenatal and postnatal plasma samples in a large cohort. METHODS: A nested, case-control study was conducted using plasma samples from 247 women with PPD (Edinburgh Postnatal Depression Scale: EPDS ≥9) and 243 age-matched control (EPDS ≤2) women from among perinatal women who participated in the Tohoku Medical Megabank three-generation cohort. Concentrations of nine plasma cytokines (IFN-γ, IL-1β, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, and TNF-α) in plasma collected at the time of enrollment during pregnancy and one month after delivery were determined using an immunoassay kit. RESULTS: Cross-sectional comparisons of cytokine levels during pregnancy and after delivery indicated that the PPD group maintained significantly lower plasma IL-4 levels during pregnancy and after delivery than the control group, and that plasma IL-4 levels decreased significantly during pregnancy regardless of PPD status. Plasma IL-10 levels were significantly higher during pregnancy than after delivery only among healthy controls, and plasma IL-10 levels were significantly higher in the control group than in the PPD group. Moreover, IFN-γ, IL-6, IL-12p40, and TNF-α levels were significantly lower during pregnancy compared with after delivery regardless of PPD status. CONCLUSIONS AND RELEVANCE: These results suggest a potential protective effect of the anti-inflammatory cytokines IL-4 and IL-10 during pregnancy against the development of PPD. This article is protected by copyright. All rights reserved.

AIM: An association between maternal psychological distress and children's development has been reported, but  reports from Japan are limited. This study aimed to examine the association of maternal psychological distress with children's neurodevelopment in Japan. METHODS: The study assessed data of 7646 mother-infant pairs in the Japanese population. We used Kessler Psychological Distress Scale, a screening tool for psychological distress, to assess maternal psychological distress in early pregnancy and 2 years postpartum and divided it into four categories: none in both the pre-natal and post-natal periods, only the pre-natal period, only the post-natal period and both the pre-natal and post-natal periods. Children's neurodevelopment was assessed using the Ages & Stages Questionnaires Third Edition (ASQ-3) at 4 years of age. ASQ-3 comprises five domains (communication, gross motor, fine motor, problem solving and personal-social), and the score of less than -2 standard deviation relative to the mean in reference was defined as having developmental delay. We conducted multivariate logistic regression analysis to examine the association between maternal psychological distress and children's neurodevelopment. RESULTS: The prevalence of developmental delay of communication, gross motor, fine motor, problem solving and personal-social were 4.0%, 4.3%, 4.9%, 3.8% and 4.6%, respectively. Maternal psychological distress in only the postpartum period and both pre-natal and postpartum periods were associated with risks of developmental delay in all domains. Maternal psychological distress in only the pre-natal period was associated with developmental delay in communication. CONCLUSIONS: Maternal psychological distress is associated with risks of children's developmental delay.

BACKGROUND: Low birth weight is associated with an increased risk of developing chronic diseases in adulthood, with a particularly high incidence in Japan among developed countries. Maternal undernutrition is a risk factor for low birth weight, but the association between the timing of food intake and infant birth weight has not been investigated. This study aimed to examine the association between breakfast intake frequency among Japanese pregnant women and infant birth weight. METHODS: Of all pregnant women who participated in the Tohoku Medical Megabank Project Three Generation Cohort Study, 16,820 who answered the required questions were included in the analysis. The frequency of breakfast intake from pre- to early pregnancy and from early to mid-pregnancy was classified into four groups: every day and 5-6, 3-4, and 0-2 times/week. Multivariate linear regression models were constructed to examine the association between breakfast intake frequency among pregnant women and infant birth weight. RESULTS: The percentage of pregnant women who consumed breakfast daily was 74% in the pre- to early pregnancy period and 79% in the early to mid-pregnancy period. The average infant birth weight was 3,071 g. Compared to women who had breakfast daily from pre- to early pregnancy, those who had breakfast 0-2 times/week had lower infant birth weight (β = -38.2, 95% confidence interval [CI]: -56.5, -20.0). Similarly, compared to women who had breakfast daily from early to mid-pregnancy, those who had breakfast 0-2 times/week had lower infant birth weight (β = -41.5, 95% CI: -63.3, -19.6). CONCLUSIONS: Less frequent breakfast intake before and mid-pregnancy was associated with lower infant birth weight.

OBJECTIVE: In a large-scale disaster, medical professionals need to access medication records and provide medicines to people who cannot return home to take their daily medicines. We investigated the proportion of carrying the paper notebook or availability of the smartphone application of the medication record among people who are assumed to have difficulty in taking their medicines during large-scale disasters. METHODS: In Japan, a web-based survey was conducted in 2018 by randomly selecting adults ≥ 20 years of age. RESULTS: There were 2286 medication record owners in 3082 participants. Of the medication record owners, 784 (34.3%) took medicines that could not be missed for even a day. Among them, 724 used paper notebooks alone, 26 used smartphone applications alone, and 34 used both. Among the 724, 208 (28.8%) always carried a paper notebook. Among the 26, 16 (61.5%) could use their applications anytime. Therefore, among the 784, at least 560 (71.4%) could not always access their medication information. CONCLUSIONS: An awareness campaign to carry paper notebooks and install applications for medication records should be held, since only a limited number of people carry their medication records and always have access to their medication information.

Although there is some evidence regarding an association between maternal bonding disorder and child development, studies have mainly focused on development during the period of infancy. We aimed to examine the associations between maternal postnatal bonding disorder and developmental delays in children beyond 2 years of age. We analyzed data from 8380 mother-child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Maternal bonding disorder was defined as Mother-to-Infant Bonding Scale score of ≥5 at 1 month after delivery. The Ages & Stages Questionnaires, Third Edition, which consists of five developmental areas, was used to assess developmental delays in children at 2 and 3.5 years of age. Multiple logistic regression analyses were conducted to examine the associations between postnatal bonding disorder and developmental delays after adjustment for age, education, income, parity, feelings toward pregnancy, postnatal depressive symptoms, child's sex, preterm birth, and birth defects. Bonding disorder was associated with developmental delays in children at 2 and 3.5 years of age: the odds ratios (95% confidence intervals) were 1.55 (1.32-1.83) and 1.60 (1.34-1.90), respectively. Bonding disorder was associated with delay in communication only at 3.5 years of age. Bonding disorder was associated with delay in gross motor, fine motor, and problem solving, but not delay in the personal-social domain, at 2 and 3.5 years of age. In conclusion, maternal bonding disorder 1 month after delivery was associated with an increased risk of developmental delays in children beyond 2 years of age.

Hypertensive disorders of pregnancy (HDP) are associated with poor maternal and neonatal prognoses. Although several studies have indicated an effect of secondhand smoke (SHS) exposure on HDP, such evidence is lacking in Japan. Therefore, we analyzed data from the Japan Environment and Children's Study, a large-scale epidemiological investigation, to elucidate a possible link between SHS exposure and HDP risk. Data were obtained from the all-birth fixed datasets and included information on 104,062 fetuses and their parents. SHS exposure was assessed in terms of the frequency (rarely, 1-3, or 4-7 days/week) and the daily duration of exposure (<1, 1-2, or ≥2 h(s)/day). Modified Poisson regression model analyses were performed with adjustment for known risk factors for HDP. Additionally, the population attributable fractions (PAFs) of SHS exposure and maternal smoking to HDP prevalence were estimated. The relative risks of developing HDP among individuals with SHS exposures of 4-7 days/week and ≥2 h/day were 1.18 and 1.27 (95% confidence interval: 1.02-1.36 and 0.96-1.67), respectively, compared to the reference groups (rare exposure and <1 h/day). The PAFs for the risk of HDP due to SHS exposure and perinatal smoking were 3.8% and 1.8%, respectively. Japanese women with greater exposure to SHS have a higher risk of HDP after adjustment for possible confounding factors; thus, relevant measures are required to reduce SHS exposure to alleviate HDP risk. The association between second-hand smoking exposure and hypertensive disorders of pregnancy risk was analyzed using the JECS data. The relative risks in 4-7 days/week and ≥2 h/day of SHS exposures were 1.18 and 1.27, respectively. The PAFs due to SHS exposure and maternal smoking were 3.80% and 1.81%, respectively.

It is essential to clarify factors associated with mental health and behavioral problems in early childhood, because children are critical stages of life for mental health. We aimed to prospectively examine the associations between maternal social isolation and behavioral problems in preschool children. We analyzed data from 5842 mother-child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. The Lubben Social Network Scale-abbreviated version was used to assess social isolation (defined as scores < 12) one year after delivery. The Child Behavior Checklist 1½-5 was used to assess behavioral problems, and its subscales were used to assess internalizing and externalizing problems in children at 4 years of age. Multiple logistic regression analyses were conducted to examine the associations between social isolation and behavioral problems, after adjustment for age, education, income, work status, marital status, extraversion, neuroticism, depressive symptoms, child sex, and number of siblings. Multiple logistic regression analyses were also conducted for internalizing problems and externalizing problems. The prevalence of maternal social isolation was 25.4%. Maternal social isolation was associated with an increased risk of behavioral problems in children: the odds ratio (OR) was 1.37 (95% confidence interval [CI] 1.14-1.64). Maternal social isolation was also associated with increased risks of internalizing problems and externalizing problems in children: the ORs were 1.33 (95% CI, 1.12-1.59) and 1.40 (95% CI, 1.18-1.66), respectively. In conclusion, maternal social isolation one year after delivery was associated with behavioral problems in children at 4 years of age.

BACKGROUND: Although there is some evidence that maternal perinatal mental disorders are associated with emotional/behavioral problems in children, the long-term impacts of postnatal bonding disorder remain unclear. We aimed to examine the associations between maternal postnatal bonding disorder and emotional/behavioral problems in preschool children. METHODS: We analyzed data from 7220 mother-child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Maternal bonding disorder was defined as Mother-to-Infant Bonding Scale score ≥5 at 1 month after delivery. The Child Behavior Checklist 1½-5 was used to assess emotional/behavioral problems, and its subscales were used to assess internalizing and externalizing problems in children at 4 years of age. Multiple logistic regression analyses were conducted to examine the associations of postnatal bonding disorder with emotional/behavioral, internalizing, and externalizing problems after adjustment for age, education, income, parity, prenatal psychological distress, postnatal depressive symptoms, child's sex, preterm birth, and birth defects. RESULTS: The prevalence of postnatal bonding disorder was 14.8 %. Postnatal bonding disorder was associated with an increased risk of emotional/behavioral problems in children: the odds ratio (OR) was 2.06 (95 % confidence interval [CI], 1.72-2.46). Postnatal bonding disorder was also associated with increased risks of internalizing problems and externalizing problems in children: the ORs were 1.69 (95 % CI, 1.42-2.02) and 1.90 (95 % CI, 1.59-2.26), respectively. LIMITATIONS: Bonding and problems were self-reported. CONCLUSIONS: Bonding disorder at 1 month after delivery was associated with an increased risk of emotional/behavioral problems in children at 4 years of age.

BACKGROUND: The study analyzed the relation between disaster exposure prior to pregnancy, maternal characteristics, and obstetric outcomes. METHODS: The participants were 13,148 pregnant women recruited from 2013 to 2017. The women were classified into three groups by the severity of housing damage caused by the Great East Japan Earthquake of 2011: group A, house was not destroyed/did not live in the disaster area; group B, half/part of the house was destroyed; and group C, house was totally/mostly destroyed. Maternal characteristics, hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), and gestational weeks were obtained by questionnaires and medical records. Multiple logistic regression analyses were performed to investigate the relation between disaster exposure and maternal characteristics, HDP, and GDM. A structural equation model was applied to investigate the relation between disaster exposure, and HDP and gestational weeks. RESULTS: The homes of about 11% of the women were totally/mostly destroyed. For groups B and C compared with those in group A, the adjusted ORs for HDP were 1.04 and 1.26 (P for trend = 0.01), and for GDM were 0.89 and 1.14 (P for trend = 0.9), respectively. Pre-pregnancy body mass index (BMI) mediated 23.2% of the relation between disaster exposure and HDP. Disaster exposure was associated with gestational weeks. CONCLUSION: Disaster exposure at least 2.5 years before pregnancy was found to be associated with maternal characteristics and the prevalence of HDP. Pre-pregnancy BMI mediated the relation between disaster exposure and the prevalence of HDP, and gestational weeks were reduced through HDP.

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.

The Tohoku Medical Megabank Project (TMM) has been conducting a birth and three-generation cohort study (the BirThree Cohort Study). We recruited 73,529 pregnant women and their family members for this cohort study, which included 23,143 newborns and 9,459 of their siblings. We designed and are in the process of conducting three-step health assessments for each newborn at approximately ages of 5, 10 and 16. These health assessments are administered at seven community support centers. Trained genome medical research coordinators conduct physical examinations of and collect biological specimens from each participant. The Sendai Children's Health Square has been established as the headquarters for these child health assessments and is utilized to accumulate knowledge that can facilitate the proper practice of child health assessments. We designed all the relevant health assessments facilities to allow parents and their children to participate in the health assessments concomitantly. Our centers serve as places where child participants and their parents can feel at ease as a result of the implementation of safety measures and child hospitality measures. The TMM BirThree Cohort Study is in the process of conducting strategically detailed health assessments and genome analysis, which can facilitate studies concerning the gene-environment interactions relevant to noncommunicable diseases. Through these operations, our study allows for a significant depth of data to be collected in terms of the number of biospecimens under study and the comprehensiveness of both basic and clinical data alongside relevant family information.

BACKGROUND: While a wide range of predictors of postpartum smoking relapse have been suggested, population-based studies have rarely examined these factors exclusively among women who quit in early pregnancy. Furthermore, workplace secondhand smoke (SHS) exposure has never been examined. METHODS: We analyzed data from 10,466 pregnant women who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Age, education, parity, breastfeeding, postpartum depression, SHS exposure at home, and SHS exposure at work (not working, working without SHS exposure, working with SHS exposure) were evaluated as possible predictors. Multiple logistic regression analyses were conducted to examine the associations between these factors and smoking relapse by 1 year postpartum among women who quit in early pregnancy. Analyses stratified by SHS exposure at home were also conducted. RESULTS: About one-fourth of early-pregnancy quitters had relapsed into smoking by 1 year postpartum. Lower education, multiparity, not breastfeeding, postpartum depression, and SHS exposure at home were associated with increased risks of smoking relapse. Working with SHS exposure was associated with an increased risk of smoking relapse; the multivariate-adjusted odds ratios (95% confidence intervals) of working without SHS exposure and working with SHS exposure compared with not working were 1.14 (0.82-1.59) and 2.18 (1.37-3.46), respectively. The significant association of workplace SHS exposure was observed only among women without SHS exposure at home. CONCLUSIONS: SHS exposure at work, as well as education, multiparity, breastfeeding, postpartum depression, and SHS exposure at home were associated with postpartum smoking relapse among early-pregnancy quitters.

A system for inputting and storing family information, named “BirThree Enrollment,” was developed to promote a birth and three-generation cohort study (BirThree Cohort Study). In this cohort study, it was necessary to satisfy many operational demands while constantly overwriting and changing input information. Complex kinship information must be quickly and accurately inputed and corrected, and information on those families not yet recruited must be retrieved. For these purposes, many devices are needed, from an input interface to the internal data structure. In the field of genetic statistics, a simple standard expressive form (describe father-child relation and mother-child relation) is used for describing family structure. However, this form doesn't have sufficient information. So we developed a new form in conducting the BirThree Cohort Study. Hence, we expanded the data structure, and constructed the Input control system. Family pedigree information is stored along with initial clinical information, and this enabled the input of all self-reported information to the data base. Operators are able to input this family information before the day is out. As a result, when recruitment is completed, family information will be completed concurrently. Therefore, operators can immediately know certain person's family structure. In this model data correction was improved dramatically, and the system was operated successfully. This study is the first report of the method for storing three generations of family data.

This study aimed to explore the relationship between dietary electrolyte intake and the prevalence of hypertensive disorders of pregnancy (HDP) subtypes. Our analysis included 19 914 pregnant women from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. A food frequency questionnaire was used to estimate dietary calcium, potassium, sodium, and magnesium intakes. HDP was determined based on the medical records during regular antenatal care. Logistic regression analysis assessed the relationship between dietary electrolytes intake quintiles, and HDP subtypes with adjustment for basic characteristics. Dietary electrolyte intakes were applied for the prediction model. Of the cohort, 547 participants delivered with pre-eclampsia (PE), 278 with superimposed PE (SP), and 896 with gestational hypertension (GH). PE was associated with low crude calcium intake (odds ratio of the first quintile [<251 mg/day] to the fifth quintile [>623 mg/day] and 95% confidence interval, 1.31 [1.00-1.70]) and P for trend was .02. SP was not associated with any nutritional intake; however, the combined outcome of PE and SP was related to low crude calcium and potassium and energy-adjusted calcium, potassium, and magnesium intakes (P for trend, .01, .048, .02, .04, and .02, respectively). The same tendency was observed for GH. A prediction model that included crude calcium and potassium intakes performed better than a model without them. In conclusion, low dietary calcium, potassium, and magnesium were associated with higher HDP subtypes prevalence. The prediction model implied that crude calcium and potassium intakes might play a critical role in PE and SP pathogenesis.

OBJECTIVE: We evaluated the relationship between prenatal folic acid supplementation and autism spectrum disorder (ASD) in 3-year-old offspring. METHODS: We used data from the Japan Environment and Children's Study, a nationwide prospective birth cohort study. We analyzed the data to determine the association between folic acid supplement use and the incidence of ASD in offspring, and classified participants into three groups based on the time of initiation of folic acid supplementation, as follows: (1) preconception users of folic acid supplements and (2) post-conception users, and (3) non-users. The dietary folate intake of study participants was also classified into three groups (<200 µg, 200 µg to <400 µg, ≥400 µg). RESULTS: Overall, 361 offspring of 96,931 participants with single pregnancies were diagnosed with ASD (0.37%). A total of 7,046 participants (7.3%) used folic acid supplements before conception, 29,984 (30.9%) took them after detection of pregnancy, and 59,901 (61.8%) never received them. Multivariate logistic regression analyses demonstrated no association between prenatal folic acid supplementation and ASD in offspring (preconception use: adjusted odds ratio [AOR], 1.189; 95% confidence interval [CI], 0.819-1.727 and post-conception use: AOR, 1.072; 95% CI, 0.840-1.368); additionally, no association was observed with the use of folic acid supplements and/or multivitamin supplements (preconception use: AOR, 1.273; 95% CI, 0.921-1.760 and post-conception use: AOR, 1.132; 95% CI, 0.885-1.449). Moreover, no significant association was observed in participants with combined prenatal supplement use and dietary folate intake. CONCLUSIONS: Maternal use of folic acid supplements from the pre- or post-conception period was not significantly associated with ASD in 3-year-old offspring in Japan. Evaluation of the dietary folate intake from preconception also showed no significant association.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) adversely affect the prognosis of mother and child, and the prognosis depends on the subtype of HDP. Skipping breakfast may be associated with increased blood pressure due to disruption of the circadian clock, but the association with the development of HDP has not been studied. The purpose of this study was to examine the association between skipping breakfast and the development of HDP and HDP subtypes in Japanese pregnant women. METHODS: Of the pregnant women who participated in the Tohoku Medical Megabank Project Three-Generation Cohort Study, 18,839 who answered the required questions were included in the analysis. This study had a cross-sectional design. The breakfast intake frequency from pre-pregnancy to early pregnancy was classified into four groups: daily, 5-6 times per week, 3-4 times per week, and 0-2 times per week. HDP was classified into gestational hypertension (GH), chronic hypertension (CH), preeclampsia (PE), and severe preeclampsia (SuPE). Multiple logistic regression analysis and multinomial logistic analysis were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for breakfast intake frequency and development of HDP or HDP subtypes. We performed a stratified analysis based on energy intake. RESULTS: Of the participants, 74.3% consumed breakfast daily, and 11.1% developed HDP. Women who consumed breakfast 0-2 times per week had a higher risk of HDP (OR: 1.33, 95% CI: 1.14-1.56), CH (OR: 1.63, 95% CI: 1.21-2.19), and PE (OR: 1.68, 95% CI: 1.27-2.21) than those who consumed breakfast daily. No association was found between skipping breakfast and the risk of developing GH (OR: 1.26, 95% CI: 0.99-1.61) and SuPE (OR: 0.91, 95% CI: 0.55-1.49). Stratified analysis showed that the risk of developing HDP due to skipping breakfast was highest in the group with the highest daily energy intake. CONCLUSIONS: Skipping breakfast during pre-to early pregnancy is associated with the development of HDP. Further longitudinal studies are required to clarify the causal association between skipping breakfast and HDP.

BACKGROUND: Childcare facilities are a factor that lowers the established association of mother's postnatal psychiatric symptoms with children's behavioral problems. However, no studies have considered the prenatal psychiatric symptoms yet. This study examined whether the use of childcare facilities moderates the association of maternal psychological distress in early pregnancy and at two years postpartum with behavioral problems in children aged four years. METHODS: The present study was based on the data from 23,130 mother-child pairs participating in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. K6 was used to classify maternal psychological distress in early pregnancy and at two years postpartum into four categories: none in both prenatal and postnatal periods (none), only the prenatal period (prenatal only); only the postnatal period (postnatal only); both prenatal and postnatal periods (both). The children's behavioral problems were assessed using the Child Behavior Checklist for Ages 1½-5 (CBCL) aged four years. The clinical range of the externalizing, internalizing, and total problem scales of the CBCL was defined as having behavioral problems. To examine whether availing childcare facilities moderates the association between maternal psychological distress and children's behavioral problems, we conducted a stratified analysis based on the use of childcare facilities or not, at two years of age. The interaction term between maternal psychological distress and use of childcare facilities was included as a covariate in the multivariate logistic regression analysis to confirm the p-value for the interaction. RESULTS: The prevalence of the clinical ranges of externalizing problems, internalizing problems, and clinical range of total problems were 13.7%, 15.4%, and 5.8%, respectively. The association of maternal psychological distress with a high risk of children's behavioral problems was significant; however, the association between prenatal only psychological distress and externalizing problems in the group that did not use childcare facilities was not significant. Interactions between the use of childcare facilities and maternal psychological distress on behavioral problems in children were not significant. CONCLUSIONS: Use of childcare facilities did not moderate the association of maternal psychological distress in early pregnancy and at two years postpartum with behavioral problems in children aged four years.

BACKGROUND: Previous observational studies have shown similarities in cardiometabolic risk factors between spouses. It is still possible that this result reflects the age similarity of spouses rather than environmental factors of spouses (e.g. cohabitation effect). To clarify the importance of mate cardiometabolic risk factors for similarity of environmental factors, it is necessary to examine whether they are observed in random male-female pairs while maintaining the age of the spousal pairs. This study aimed to determine whether the similarities found between spousal pairs for cardiometabolic risks were also observed between random male-female pairs. METHODS: This cross-sectional study included 5,391 spouse pairs from Japan; data were obtained from a large biobank study. For pairings, women of the same age were randomly shuffled to create new male-female pairs of the same age as that of the original spouse pairs. Similarities in cardiometabolic risk factors between the random male-female pairs were analysed using Pearson's correlation or age-adjusted logistic regression analyses. RESULTS: The mean ages of the men and women were 63.2 and 60.4 years, respectively. Almost all cardiometabolic risk factors similarities were not noted in cardiometabolic risk factors, including the continuous risk factors (anthropometric traits, blood pressure, glycated haemoglobin level, and lipid traits); lifestyle habits (smoking, drinking, and physical activity); or diseases (hypertension, type 2 diabetes mellitus, and metabolic syndrome) between the random male-female pairs. The age-adjusted correlation coefficients ranged from - 0.007 for body mass index to 0.071 for total cholesterol. The age-adjusted odds ratio (95% confidence interval) for current drinkers was 0.94 (0.81 - 1.09); hypertension, 1.07 (0.93 - 1.23); and type 2 diabetes mellitus, 1.08 (0.77 - 1.50). CONCLUSION: In this study, few similarities in cardiometabolic risk factors were noted among the random male-female pairs. As spouse pairs may share environmental factors, intervention strategies targeting lifestyle habits and preventing lifestyle-related diseases may be effective.

OBJECTIVES: To estimate the prevalence of insomnia and examine the association between social isolation and insomnia among pregnant women. METHODS: This cross-sectional study was part of the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study from 2013 to 2017. Pregnant women were recruited at obstetric clinics and hospitals in Miyagi Prefecture, Japan. We analyzed 17,586 women who completed the questionnaires and were allowed to transcribe medical records. Insomnia was defined as the Athens Insomnia Scale score of ≥6. The Lubben Social Network Scale-abbreviated version was used to assess social isolation (defined as scores <12), and its subscales were used to assess marginal family ties and marginal friendship ties. Multiple logistic regression analyses were conducted to examine the association between social isolation and insomnia during pregnancy, adjusting for age, parity, prepregnancy body mass index, feelings toward pregnancy, education, income, work status, morning sickness, and psychological distress. Multiple logistic regression analyses were also conducted for marginal family ties and marginal friendship ties. RESULTS: The prevalence of insomnia in the second trimester was 37.3%. Women who were socially isolated were more likely to have insomnia than women who were socially integrated: the multivariate-adjusted odds ratio (OR) was 1.26 (95% confidence interval [CI], 1.16-1.36). Marginal family ties and marginal friendship ties were also associated with increased risks of insomnia: the multivariate-adjusted ORs were 1.40 (95% CI, 1.25-1.56) and 1.15 (95% CI, 1.07-1.24), respectively. CONCLUSIONS: Social isolation from family and friends was associated with increased risks of insomnia among pregnant women.

BACKGROUND: Natural disasters can have serious mental health consequences. We aimed to examine the long-term effects of the 2011 Great East Japan Earthquake (GEJE) on postpartum depressive symptoms (PDS). METHODS: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study recruited pregnant women in Miyagi Prefecture from 2013 to 2016. Data from 11,403 participants were used in this study. Women were asked about their traumatic experiences of the GEJE with questions addressing threat, witness, and loss. PDS were defined as Edinburgh Postnatal Depression Scale score ≥9 at 1 month after delivery. Multiple logistic regression analyses were conducted to examine the associations of different traumatic experiences of the GEJE and number of traumatic experiences with PDS, after adjustment for age, parity, feelings toward pregnancy, education, income, social isolation, house damage caused by the GEJE, and survey year. RESULTS: About two-fifths of women had at least one traumatic experience of the GEJE. The prevalence of PDS at 1 month after delivery was 13.3 %. Life-threatening experience and witnessing another person's actual or threatened death were associated with PDS: the odds ratios (ORs) were 1.40 (95 % confidence interval [CI], 1.24-1.59) and 1.28 (95 % CI, 1.08-1.53), respectively. Loss of close person was not associated with PDS: the OR was 1.13 (95 % CI, 0.99-1.30). Larger number of traumatic experiences of the GEJE was associated with increased risk of PDS (p for trend <0.001). LIMITATIONS: PDS was self-reported. CONCLUSIONS: Traumatic experiences of the GEJE prior to pregnancy were associated with increased risks of PDS.

INTRODUCTION AND OBJECTIVES: Patients with non-alcoholic fatty liver disease (NAFLD) are at risk for cardiovascular and chronic kidney diseases. Liver steatosis and fibrosis were assessed using the fatty liver index and fibrosis-4 index, respectively. This study aimed to examine the association between these two parameters in patients with atherosclerosis and chronic kidney disease. METHODS: The two parameters were calculated for 11,867 adults who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Intima-media thickness and estimated glomerular filtration rate were also measured. Logistic regression models were used to estimate the odds ratios (OR). RESULTS: Overall, 4,257 (35.9%) and 4,733 (39.9%) participants had a higher probability of liver steatosis and fibrosis, respectively. The adjusted OR of higher fatty liver index compared to lower fatty liver index for atherosclerosis and chronic kidney disease were 0.98 (95% confidence interval [CI], 0.77-1.24) and 1.79 (95% CI, 1.19-2.69), and those of higher FIB-4 compared to lower FIB-4 were 1.03 (95% CI, 0.82-1.30) and 0.79 (95% CI, 0.52-1.19) for atherosclerosis and chronic kidney disease, respectively. CONCLUSIONS: A higher FLI was associated with CKD independent of other risk factors. Further research is required to identify the causal relationship between liver fat accumulation and CKD.

Abstract Background Although small for gestational age (SGA) is a serious problem worldwide, the association of dietary patterns before and during pregnancy with SGA risk is unclear. We evaluated this association among Japanese pregnant women using three methods: reduced rank regression (RRR) and partial least squares (PLS), methods for extracting dietary patterns that can explain the variation of response variables, and principal component analysis (PCA), a method for extracting dietary patterns of the population. Methods Between July 2013 and March 2017, 22,493 pregnant women were recruited to the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, a population-based prospective birth cohort study in Japan. Information on dietary intake was obtained using food frequency questionnaires, and dietary patterns were extracted using RRR, PLS, and PCA. Information on birth weight was obtained from obstetric records, and the birth weight SD score and SGA were defined by the method of the Japan Pediatric Society. The associations of dietary patterns with birth weight SD score and SGA risk were investigated using multiple linear regression and multiple logistic regression, respectively. Results A total of 17,728 mother-child pairs were included. The birth weight SD score was 0.15 ± 0.96, and the prevalence of SGA was 6.3%. The dietary patterns extracted by RRR and PLS were similar and characterized by a high intake of cereals and fruits and a low intake of alcoholic and non-alcoholic beverages in both pre- to early pregnancy and from early to mid-pregnancy. Higher adoption of the RRR and PLS patterns in both periods was associated with an increased birth weight SD score and lower risk of SGA. In contrast, the PCA1 pattern was not associated with birth weight SD score or SGA risk in either period. Although the PCA2 pattern was associated with increased birth weight SD score from early to mid-pregnancy, no other associations with birth weight SD score or SGA risk were observed. Conclusions The dietary pattern with a high intake of cereals and fruits and a low intake of alcoholic and non-alcoholic beverages before and during pregnancy was associated with a decreased SGA risk in Japan.

Hypertensive disorders of pregnancy increase the risk of adverse maternal and fetal outcomes. In 2018, the Japanese classification of hypertensive disorders of pregnancy was standardized with those of other countries, and a hypertensive disorder of pregnancy was considered to be present if hypertension existed during pregnancy and up to 12 weeks after delivery. Strategies for the prevention of hypertensive disorders of pregnancy have become much clearer, but further research is needed on appropriate subjects and methods of administration, and these have not been clarified in Japan. Although guidelines for the use of antihypertensive drugs are also being studied and standardized with those of other countries, the use of calcium antagonists before 20 weeks of gestation is still contraindicated in Japan because of the safety concerns that were raised regarding possible fetal anomalies associated with their use at the time of their market launch. Chronic hypertension is now included in the definition of hypertensive disorders of pregnancy, and blood pressure measurement is a fundamental component of the diagnosis of hypertensive disorders of pregnancy. Out-of-office blood pressure measurements, including ambulatory and home blood pressure measurements, are important for pregnant and nonpregnant women. Although conditions such as white-coat hypertension and masked hypertension have been reported, determining their occurrence in pregnancy is complicated by the gestational week. This narrative review focused on recent reports on hypertensive disorders of pregnancy, including those related to blood pressure measurement and classification.

OBJECTIVES: This study aimed to examine the association between infertility treatment and neurodevelopment in children at 2 and 3.5 years of age. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: The study population consisted of mother-child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Miyagi and Iwate Prefectures, Japan. Pregnant women were recruited in obstetric clinics or hospitals and their children were followed up by the questionnaire. OUTCOME MEASURES: The children's neurodevelopmental outcomes were assessed at 2 and 3.5 years of age using the Ages and Stages Questionnaire, third edition (ASQ-3), which consists of questions on five developmental domains. We performed a multivariate logistic regression analysis of the association between infertility treatment (including ovulation induction (OI), artificial insemination with husband's sperm (AIH) and assisted reproductive technology (ART)) and the clinical range of ASQ-3. RESULTS: Of 9655 mother-child pairs, 273 (2.8%) and 487 (5.0%) were conceived through OI/AIH and ART, respectively. The odds of having developmental delays at 2 years of age were higher in children conceived through OI/AIH (OR, 1.36; 95% CI 1.00 to 1.85) and ART (OR, 1.36; 95% CI 1.07 to 1.72) than in those conceived naturally. Additionally, OI/AIH and ART were significantly associated with communication (OR, 1.93; 95% CI 1.25 to 2.98) and gross motor (OR, 1.50; 95% CI 1.08 to 2.09) delays, respectively. There were no statistically significant differences in the odds of having developmental delays at 3.5 years of age in children conceived through OI/AIH (OR, 1.13; 95% CI 0.79 to 1.61) and ART (OR, 1.03; 95% CI 0.78 to 1.37). CONCLUSION: In this study, we found a significant association between infertility treatment and children's neurodevelopment at 2 years of age, whereas no statistically significant differences were found at 3.5 years of age.

This study aimed to construct a prediction model for small-for-gestational-age (SGA) infants in Japan by creating a risk score during pregnancy. A total of 17,073 subjects were included in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, a prospective cohort study. A multiple logistic regression model was used to construct risk scores during early and mid-gestational periods (11-17 and 18-21 weeks of gestation, respectively). The risk score during early gestation comprised the maternal age, height, body mass index (BMI) during early gestation, parity, assisted reproductive technology (ART) with frozen-thawed embryo transfer (FET), smoking status, blood pressure (BP) during early gestation, and maternal birth weight. The risk score during mid-gestation also consisted of the maternal age, height, BMI during mid-gestation, weight gain, parity, ART with FET, smoking status, BP level during mid-gestation, maternal birth weight, and estimated fetal weight during mid-gestation. The C-statistics of the risk scores during early- and mid-gestation were 0.658 (95% confidence interval [CI]: 0.642-0.675) and 0.725 (95% CI: 0.710-0.740), respectively. In conclusion, the predictive ability of the risk scores during mid-gestation for SGA infants was acceptable and better than that of the risk score during early gestation.

The association between fruit and vegetable consumption before and during pregnancy and offspring's physical growth has been well reported, but no study has focused on offspring's neurological development. We aimed to explore the association between maternal fruit and vegetable consumption before and during pregnancy and developmental delays in their offspring aged 2 years. Between July 2013 and March 2017, 23 406 women were recruited for the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Fruit and vegetable consumption was calculated using FFQ, and offspring's developmental delays were evaluated by the Ages & Stages Questionnaires, Third Edition (ASQ-3) for infants aged 2 years. Finally, 10 420 women and 10 543 infants were included in the analysis. Totally, 14·9 % of children had developmental delay when screened using the ASQ-3. Women in the highest quartile of vegetable consumption from pre-pregnancy to early pregnancy and from early to mid-pregnancy had lower odds of offspring's developmental delays (OR 0·74; 95 % CI 0·63, 0·89 and OR 0·70; 95 % CI 0·59, 0·84, respectively) than women in the lowest quartile. Women in the highest quartile of fruit consumption from early to mid-pregnancy had lower odds of offspring's developmental delays (OR 0·78; 95 % CI 0·66, 0·92) than women in the lowest quartile. In conclusion, high fruit and vegetable consumption before and during pregnancy was associated with a lower risk of developmental delays in offspring aged 2 years.

Personality has been shown to predict postpartum depressive symptoms (PDS) assessed by the Edinburgh Postnatal Depression Scale (EPDS). However, existing studies have not considered the underlying symptom dimensions in the EPDS. We analyzed data from 15,012 women who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Personality was assessed in middle pregnancy using the short-form Eysenck Personality Questionnaire-Revised. PDS were defined as EPDS score ≥ 9 at 1 month after delivery. The EPDS items were further divided into three dimensions: depressed mood, anxiety, and anhedonia. Multiple analyses were conducted to examine the associations of each personality scale with PDS and three dimensions in the EPDS, adjusting for age, parity, mode of delivery, education, income, and social isolation. The prevalence of PDS assessed by the EPDS at 1 month after delivery was 13.1%. Higher neuroticism scores were associated with PDS (odds ratio [OR], 2.63; 95% confidence interval [CI], 2.48 to 2.79) and all three dimensions (all p < 0.001). Lower extraversion scores were associated with PDS (OR, 0.74; 95% CI, 0.70 to 0.78) and all three dimensions (all p < 0.001). Lower psychoticism scores were associated with PDS (OR, 0.89; 95% CI, 0.85 to 0.94) and anxiety (p < 0.001), but not with depressed mood (p = 0.20) or anhedonia (p = 0.92). In conclusion, higher neuroticism and lower extraversion were associated with PDS and the three underlying dimensions in the EPDS, while lower psychoticism was associated with anxiety, but not with depressed mood or anhedonia.

BACKGROUND: Maternal mental health problems in each of the prenatal period and postnatal period have been demonstrated as possible risk factors for atopic dermatitis (AD) in children. However, the cumulative impacts of maternal psychological distress in the prenatal and postnatal periods on AD in children remain unclear. This study examined the association between cumulative exposure to maternal psychological distress in the prenatal and postnatal periods and the development of AD in children. METHODS: Data were derived from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Japan. In total, 8377 mother-child pairs in which the child had no AD at the age of 1 year were analyzed. Maternal psychological distress in early pregnancy and 1 year after delivery was defined as a K6 score ≥ 5, and the participants were categorized into four groups: no psychological distress in both the prenatal and postnatal periods; only the prenatal period; only the postnatal period; and both periods. The development of AD was defined as the presence of AD in a 2-year-old child without AD reported at the age of 1 year using the International Study of Asthma and Allergies in Childhood questionnaire. Generalized linear model analyses were conducted to examine the association between maternal psychological distress and the development of AD in children adjusted for age at delivery, educational attainment, smoking status in pregnancy, maternal history of AD, paternal history of AD, parity, maternal body mass index, and child sex. RESULTS: Between the ages of 1 and 2 years, 14.0% of children developed AD. Maternal psychological distress in both prenatal and postnatal periods was associated with an increased risk of AD in children compared to no psychological distress in both periods (relative risk (RR), 95% confidence interval (CI): 1.34, 1.20-1.47). Maternal psychological distress in only the postnatal period was associated with an increased risk of AD in children (RR, 95% CI: 1.23, 1.07-1.39), but not in only the prenatal period (RR, 95% CI: 1.14, 0.98-1.30). CONCLUSIONS: Cumulative exposure to maternal psychological distress in the prenatal and postnatal periods was associated with the development of AD in children.

Objective: In Japan, supplementation with 400 µg of folic acid per day is recommended for women who are planning to get pregnant to decrease the risk of their babies getting neural tube defects (NTD). However, the proportion of women who have taken folic acid supplements before conception is low among Japanese pregnant women. In addition, the dietary intake of folic acid has not yet reached the government recommended dietary intake levels (480 µg per day). This study aimed to clarify the prevalence and determinants of adequate folic acid supplements among Japanese pregnant women with dietary folic acid intake lower than 480 µg per day.Methods: This cross-sectional study was a part of the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. We collected information on folic acid supplements before conception, sociological/lifestyle characteristics, and food consumption. The primary outcome was the use of folic acid supplements (adequate or inadequate, based on the timing of initiation of folic acid supplements). Multiple logistic regression analysis was used to examine the association between sociological/lifestyle characteristics and the adequate intake of folic acid supplements.Results: Among the 11,562 pregnant women who took lower than 480 µg per day of folic acid from food, the prevalence of adequate users was 18.0%. Pregnant women who reported adequate use of folic acid supplements were more likely to be older and educated; and reported higher household income, and history of fertility treatment. Conversely, they were less likely to be ever or current smokers and multipara.Conclusion: This study found that the prevalence of folic acid supplements use for the prevention of NTD among Japanese pregnant women was still low.

Widespread coordination and sharing of information regarding adverse drug reactions (ADRs) are important for drug safety assessment. However, the actual status of coordination and sharing of information on ADRs in community pharmacies remains unclear. Therefore, a survey was conducted at community pharmacies to analyze the status. In this cross-sectional study conducted from 31 March 2021 to 9 April 2021, a request letter with the uniform resource locator of the questionnaire form was sent to 302 community pharmacies affiliated with Tsuruha Holdings Inc., and the responses were obtained online. The response rate for the questionnaires was 80.8% (n = 244). In total, 20.9% of the community pharmacies provided information on patients’ ADRs to hospitals or clinics prescribing drugs. None of the community pharmacies provided patient ADR information to other community pharmacies. Of the community pharmacies, 98.8% felt that insufficient information was available to monitor ADRs from hospitals or clinics prescribing drugs. For example, the name of the disease (67.6%), considered to be the most common information, was insufficiently provided. Overall, the existing system for providing information on ADRs between community pharmacies and other medical institutions is insufficient and needs to be developed further.

BACKGROUND: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study was launched in 2013 to evaluate the complex interactions of genetic and environmental factors in multifactorial diseases. The present study describes the maternal baseline profile and perinatal data of participating mothers and infants. METHODS: Expectant mothers living in Miyagi prefecture were recruited from obstetric facilities or affiliated centers between 2013 and 2017. Three sets of self-administered questionnaires were collected, and the medical records were reviewed to obtain precise information about each antenatal visit and each delivery. Biospecimens, including blood, urine, umbilical cord blood, and breast milk, were collected for the study biobank. The baseline maternal sociodemographic characteristics, results of screening tests, and obstetric outcomes were analyzed according to the maternal age group. RESULTS: A total of 23 406 pregnancies involving 23 730 fetuses resulted in 23 143 live births. Younger maternal participants had a tendency toward a higher incidence of threatened abortion and threatened premature labor, while older age groups exhibited a significantly higher rate of low lying placenta, placenta previa, gestational diabetes and hypertensive disorders of pregnancy. CONCLUSIONS: The present study clearly shows the distribution of maternal baseline characteristics and the range of perinatal outcomes according to maternal age group. This cohort study can provide strategic information for creating breakthroughs in the pathophysiology of perinatal, developmental, and noncommunicable diseases by collaborative data visiting or sharing.

Infectious diseases, chronic diseases, and mental disorders in both adults and children are reported after disasters occur. The correlation between chronic diseases and mental disorders has also been reported. Moreover, disasters may affect perinatal outcomes. Thus, both adult and child health should be carefully monitored in disaster aftermath. A prospective cohort study of pregnant women and their families, the Tohoku Medical Megabank Project (TMM) Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study), has been conducted since 2013. A total of 73,529 family members participated in the TMM BirThree Cohort Study. Among siblings, the proportion of "small for gestational age" was the same in the pre- and post-disaster periods. Among parents and grandparents who answered the baseline questionnaire, 5.6% in the inland area and 19.8% in the coastal area had their houses totally/mostly destroyed by the Great East Japan Earthquake. Although a depression trend due to house damage was not observed in mothers, the proportion of psychological distress was high according to house damage (P for trend = 0.04). Among parents, there was an increase in overweight persons (P for trend = 0.004 in mothers and < 0.0001 in fathers) and in the number of smokers based on the severity of house damage (P for trend = 0.002 in mothers and < 0.0001 in fathers), whereas no such trend was observed in grandparents. Continuous monitoring and support for those who need are essential. Moreover, utilizing existing cohort studies to investigate health status when we face a new disaster is desirable.

BACKGROUND/OBJECTIVES: Studies have reported the effects of grain consumption on human health, but the association between maternal grain consumption before and during pregnancy and birth weight remains unclear. We evaluated the association between maternal grain consumption before and during pregnancy and birth weight/low birth weight (LBW). SUBJECTS/METHODS: Grain consumption was calculated using two semi-quantitative food frequency questionnaires (FFQs). The two FFQs evaluated consumption from pre- to early pregnancy and then from early to mid-pregnancy, respectively. Information concerning birth weight was obtained from birth records, and multivariable analyses for birth weight and LBW risk were conducted after adjusting for potential confounders. RESULTS: In total, 17,610 pregnant women (age, 31.8 ± 4.9 years; smoked during pregnancy, 16.1%; gestation period, 38.5 ± 2.5 weeks; first childbirth, 45.5%) and their singleton and term new-borns (birth weight, 3061.8 ± 354.1 g; LBW, 5.4%) were included in the analysis. Women in the highest quartile of grain consumption from pre- to early pregnancy had heavier new-borns (β = 22.3; 95% confidence interval (CI): 5.8-38.9) but did not have a significantly lower LBW risk (odds ratio [OR]: 0.87; 95% CI: 0.71-1.07) than women in the lowest quartile. Women in the highest quartile of grain consumption from early to mid-pregnancy also had heavier new-borns (β = 24.1; 95% CI: 7.1-41.1) but did not have a significantly lower LBW risk (OR: 0.85; 95% CI: 0.69-1.05) than women in the lowest quartile. CONCLUSIONS: Grain consumption before and during pregnancy was positively associated with birth weight.

In this study, the extent to which different emotions of pregnant women can be predicted based on heart rate-relevant information as indicators of autonomic nervous system functioning was explored using various machine learning algorithms. Nine heart rate-relevant autonomic system indicators, including the coefficient of variation R-R interval (CVRR), standard deviation of all NN intervals (SDNN), and square root of the mean squared differences of successive NN intervals (RMSSD), were measured using a heart rate monitor (MyBeat) and four different emotions including "happy," as a positive emotion and "anxiety," "sad," "frustrated," as negative emotions were self-recorded on a smartphone application, during 1 week starting from 23rd to 32nd weeks of pregnancy from 85 pregnant women. The k-nearest neighbor (k-NN), support vector machine (SVM), logistic regression (LR), random forest (RF), naïve bayes (NB), decision tree (DT), gradient boosting trees (GBT), stochastic gradient descent (SGD), extreme gradient boosting (XGBoost), and artificial neural network (ANN) machine learning methods were applied to predict the four different emotions based on the heart rate-relevant information. To predict four different emotions, RF also showed a modest area under the receiver operating characteristic curve (AUC-ROC) of 0.70. CVRR, RMSSD, SDNN, high frequency (HF), and low frequency (LF) mostly contributed to the predictions. GBT displayed the second highest AUC (0.69). Comprehensive analyses revealed the benefits of the prediction accuracy of the RF and GBT methods and were beneficial to establish models to predict emotions based on autonomic nervous system indicators. The results implicated SDNN, RMSSD, CVRR, LF, and HF as important parameters for the predictions.

To reveal gene-environment interactions underlying common diseases and estimate the risk for common diseases, the Tohoku Medical Megabank (TMM) project has conducted prospective cohort studies and genomic and multiomics analyses. To establish an integrated biobank, we developed an integrated database called "dbTMM" that incorporates both the individual cohort/clinical data and the genome/multiomics data of 157,191 participants in the Tohoku Medical Megabank project. To our knowledge, dbTMM is the first database to store individual whole-genome data on a variant-by-variant basis as well as cohort/clinical data for over one hundred thousand participants in a prospective cohort study. dbTMM enables us to stratify our cohort by both genome-wide genetic factors and environmental factors, and it provides a research and development platform that enables prospective analysis of large-scale data from genome cohorts.

BACKGROUND: Secondhand smoke (SHS) from partners is a major source of exposure for non-smoking women. However, epidemiological studies have rarely examined social factors associated with continued and indoor smoking among pregnant women's partners. METHODS: We analyzed data on 6091 partners of non-smoking pregnant women in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Partners' age, education, income, workplace SHS exposure (almost never or sometimes, almost every day), and pregnant women's smoking history (never, quit before pregnancy awareness, quit after pregnancy awareness) were used as social factors. Multivariate logistic regression analyses were conducted to examine the associations of social factors with partners' continued smoking and indoor smoking. RESULTS: Among 2432 smoking partners, 2237 continued to smoke after pregnancy awareness. Workplace SHS exposure was associated with increased risk of partners' continued smoking: the odds ratio of workplace SHS exposure almost every day compared with almost never or sometimes was 2.08 (95% confidence interval, 1.52-2.83). Women's quitting smoking after-but not before-pregnancy awareness was associated with decreased risk of partners' continued smoking: the odds ratio of women's quitting after pregnancy awareness compared with never smoking was 0.57 (95% confidence interval, 0.40-0.80). About one-third of partners who continued to smoke did so indoors. Older age, lower education, workplace SHS exposure, and women's quitting smoking after pregnancy awareness were associated with increased risk of partners' indoor smoking. CONCLUSIONS: Workplace SHS exposure and pregnant women's smoking history were associated with continued smoking and indoor smoking among partners of non-smoking pregnant women.

BACKGROUND AND OBJECTIVES: Although large-scale natural disasters and the resultant changes in living environments worsen dietary habits among adults immediately after the disasters, whether this association remains for a long period is unclear. This is particularly important for recent mothers because lactating women require additional nutrition for milk production. Thus, we investigated the association of living environments with dietary habits and nutritional intake of recent mothers between four and seven years after the Great East Japan Earthquake (11th March, 2011). METHODS AND STUDY DESIGN: We analyzed 8,551 mothers who participated to the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Living environments were characterized into four categories: "same home before the earthquake", "rental housing", "reconstructed home", and "acquaintance's home". Dietary habits and nutritional intake were evaluated using a food frequency questionnaire answered 12 months after their deliveries (the questionnaire was answered between March 2015 and July 2018). RESULTS: Multiple linear regression analyses demonstrated that mothers in 'rental housing' or 'reconstructed home' had a significantly lower intake of almost all nutrients or certain nutrients, respectively, compared with those residing in 'same home before the earthquake'. However, fewer significant differences were detected between the nutritional intake of the mothers lodging in an 'acquaintance's home' and that of those living in 'same home before the earthquake'. CONCLUSIONS: Our findings indicate that living environments long-term after largescale disasters are associated with dietary habits and nutritional intake among recent mothers.

BACKGROUND: Trajectories of postpartum depressive symptoms up to 1 year after childbirth and the related risk factors remain unclear. Accordingly, this study aimed to examine the 1-year trajectories of postpartum depressive symptoms and their associated risk factors. METHODS: A total of 22,493 pregnant women were recruited between July 2013 and September 2016 in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Japan. Among them, 11,668 women with no missing data were included in the analyses. Depressive symptoms were assessed at 1 month and 1 year postpartum using the Edinburgh Postnatal Depression Scale. Multinominal logistic regression analysis was conducted after adjusting for covariates. RESULTS: The prevalence of depression was 13.9% at 1 month and 12.9% at 1 year postpartum. We identified four depression trajectories, i.e., "persistent (depressed throughout the 1 year postpartum)" (6.0%), "recovered (depressed at 1 month postpartum and recovered within a year)" (7.9%), "late-onset (became depressed after 1 month postpartum)" (6.8%), and "resilient (not depressed throughout 1 year postpartum)" (79.2%). Psychological distress during pregnancy was significantly associated with all trajectories (persistent: odds ratio [OR]=10.24, 95% confidence interval (CI)=8.40-12.48; recovered: OR=3.78, 95%CI=3.28-4.36; and late-onset: OR=3.96, 95%CI=3.40-4.62). LIMITATIONS: Postpartum depression was evaluated only by a self-administered questionnaire and the dropout rate was not neglectable. CONCLUSIONS: This study highlighted the high prevalence of depressive symptoms at 1 year postpartum and found that half of the depressive symptoms at 1 year were late-onset. The findings suggest the necessity of long-term follow-up (up to 1 year) for perinatal mental health.

BACKGROUND: Studies on associations between maternal personality and alcohol use have examined only one time point during pregnancy in Western countries. We aimed to examine the association between maternal personality and alcohol use in early and middle pregnancy in Japan. METHODS: We analyzed data from 17,144 pregnant women in Japan who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study from 2013 to 2017. Personality was assessed using the short-form Eysenck Personality Questionnaire-Revised. Women were dichotomized as current drinkers or non-drinkers in both early and middle pregnancy. Odds ratios (ORs) and 95% confidence intervals (CIs) for alcohol use in early and middle pregnancy and continued alcohol use between early and middle pregnancy were calculated for 1 standard deviation increase in each personality scale, adjusted for age, as well as education, work status, fertility treatment, and parity. RESULTS: Higher extraversion scores were associated with alcohol use in early (OR, 1.16; 95% CI, 1.12-1.20) and middle pregnancy (OR, 1.17; 95% CI, 1.10-1.25). Higher psychoticism scores were associated with continued alcohol use into middle pregnancy (OR, 1.07; 95% CI, 1.01-1.14) and alcohol use in middle pregnancy (OR, 1.07; 95% CI, 1.02-1.13). Neuroticism was not associated with alcohol use in early or middle pregnancy. Lower lie was associated with alcohol use in early (OR, 0.95; 95% CI, 0.91-0.98), but not in middle pregnancy. CONCLUSIONS: Different personality scales are associated with alcohol use at different points during pregnancy.

This study aimed to clarify the interannual changes in intimate partner violence against pregnant women after the March 11, 2011 Great East Japan Earthquake in target areas of Miyagi Prefecture that were damaged by the earthquake and tsunami. Because of this disaster, in Miyagi Prefecture, approximately 12,000 people died or went missing, and approximately 238,000 buildings were destroyed. According to the U.S. Geological Survey, the Great East Japan Earthquake is the fourth largest earthquake in the world and the largest in Japan since 1900. The present study was part of the Japan Environment and Children's Study. Data from June 2011 to May 2014 of 79,222 pregnant women were analyzed, calculating the prevalence of physical and mental intimate partner violence in the inland, north coastal, and south coastal areas of Miyagi. These prevalence rates were compared with nationwide rates of intimate partner violence in 2011 using univariate and logistic regression analyses. After the disaster, the incidence of mental intimate partner violence increased in the south coastal area and then improved later (19.4%, 13.1%, and 13.3% for south coastal area, and 13.8%, 13.8%, and 13.1% for nationwide in 2011, 2012, and 2013, respectively). However, in the north coastal area, the incidence of physical intimate partner violence increased after the disaster and then improved later (2.7%, 1.5%, and 1.3% for north coastal area, and 1.4%, 1.3%, and 1.1% for nationwide in 2011, 2012, and 2013, respectively). In the inland area, however, the prevalence of both mental and physical intimate partner violence was consistently higher than nationwide rates after the disaster.

BACKGROUND AND AIMS: Few studies have examined and compared spousal concordance in different populations. This study aimed to quantify and compare spousal similarities in cardiometabolic risk factors and diseases between Dutch and Japanese populations. METHODS: This cross-sectional study included 28,265 Dutch Lifelines Cohort Study spouse pairs (2006-2013) and 5,391 Japanese Tohoku Medical Megabank Organization (ToMMo) Cohort Study pairs (2013-2016). Spousal similarities in cardiometabolic risk factors were evaluated using Pearson's correlation or logistic regression analyses adjusted for spousal age. RESULTS: The husbands' and wives' average ages in the Lifelines and ToMMo cohorts were 50.0 and 47.7 years and 63.2 and 60.4 years, respectively. Significant spousal similarities occurred with all cardiometabolic risk factors and diseases of interest in both cohorts. The age-adjusted correlation coefficients ranged from 0.032 to 0.263, with the strongest correlations observed in anthropometric traits. Spousal odds ratios [95% confidence interval] for the Lifelines vs. ToMMo cohort ranged from 1.45 (1.36-1.55) vs. 1.20 (1.05-1.38) for hypertension to 6.86 (6.30-7.48) vs. 4.60 (3.52-6.02) for current smoking. An increasing trend in spousal concordance with age was observed for sufficient physical activity in both cohorts. For current smoking, those aged 20-39 years showed the strongest concordance between pairs in both cohorts. The Dutch pairs showed stronger similarities in anthropometric traits and lifestyle habits (smoking and drinking) than their Japanese counterparts. CONCLUSIONS: Spouses showed similarities in several cardiometabolic risk factors among Dutch and Japanese populations, with regional and cultural influences on spousal similarities.

<title>Abstract</title> ObjectiveThe aim of our study was to develop prediction model for preeclampsia (PE) using routinely examined items in early pregnancy especially dipstick test for proteinuria.MethodThe Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study recruited pregnant women and we included 9,086 of them in analysis. Maternal basic characteristics were obtained by self-report, and blood pressure and dipstick test of proteinuria were obtained by medical record at regular antenatal care. The outcome was defined as PE including superimposed preeclampsia. We developed prediction model without dipstick test of proteinuria (model 1) and model with it (model 2), and we compared them by the mean of area under the receiver operating characteristic curve (mAUROC) using five-fold cross validation.ResultsmAUROC of model 1 was 0.769 (95% CI; 0.741 to 0.797) and that of model 2 was 0.785 (95% CI; 0.758 to 0.812). The difference of two mAUROCs was 0.016 (95% CI; 0.004 to 0.028). In model 2, detection rates at false-positive rate of 5%, 10% and 20% were 40%, 49% and 64%, respectively.ConclusionsWe could develop prediction model for PE using routine antenatal care items and it was improved by including dipstick test for proteinuria.

The elucidation of dynamic metabolomic changes during gestation is particularly important for the development of methods to evaluate pregnancy status or achieve earlier detection of pregnancy-related complications. Some studies have constructed models to evaluate pregnancy status and predict gestational age using omics data from blood biospecimens; however, less invasive methods are desired. Here we propose a model to predict gestational age, using urinary metabolite information. In our prospective cohort study, we collected 2741 urine samples from 187 healthy pregnant women, 23 patients with hypertensive disorders of pregnancy, and 14 patients with spontaneous preterm birth. Using gas chromatography-tandem mass spectrometry, we identified 184 urinary metabolites that showed dynamic systematic changes in healthy pregnant women according to gestational age. A model to predict gestational age during normal pregnancy progression was constructed; the correlation coefficient between actual and predicted weeks of gestation was 0.86. The predicted gestational ages of cases with hypertensive disorders of pregnancy exhibited significant progression, compared with actual gestational ages. This is the first study to predict gestational age in normal and complicated pregnancies by using urinary metabolite information. Minimally invasive urinary metabolomics might facilitate changes in the prediction of gestational age in various clinical settings.

We investigated the association between hypertensive disorders of pregnancy (HDP) subtypes and child autistic behavior to accumulate the evidence. We found the association between superimposed preeclampsia and autistic behavior in children aged two years old by investigating 6794 mother-child pairs in the birth cohort study. Since early intervention for autism-spectrum disorder might be effective, it suggests that early prediction is necessary for children born of mothers who developed particularly superimposed preeclampsia to support their development. Not only for introducing early prediction, but also research for establishing effective intervention is necessary.

BACKGROUND: There is inconsistent evidence on the associations of education and work status with alcohol use during pregnancy. Our aim was to examine the associations of education and work status with alcohol use and alcohol cessation during pregnancy in Japan. METHODS: Data were analyzed from 11,839 pregnant women who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study from 2013 to 2017 in Japan. Women were dichotomized as current drinkers or non-drinkers in both early and middle pregnancy. Alcohol cessation was defined as alcohol use in early pregnancy, but not in middle pregnancy. Multivariable log-binomial regression analyses were conducted to examine associations of education and work status with alcohol use in early and middle pregnancy and alcohol cessation, adjusted for age and income. The prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated by work status and education. RESULTS: The prevalence of alcohol use in early and middle pregnancy was 20.9 and 6.4%, respectively. Higher education was associated with alcohol use in early pregnancy both among working and non-working women; the PRs of university education or higher compared with high school education or lower were 1.62 (95% CI, 1.34-1.96) and 1.29 (95% CI, 1.16-1.45), respectively. Higher education was associated with alcohol cessation during pregnancy among working women; the corresponding PR was 1.09 (95% CI, 1.01-1.17). Working was associated with alcohol use in early and middle pregnancy. Working was associated with a decreased probability of alcohol cessation among women with lower education but with an increased probability of alcohol cessation among women with higher education; the PRs of working compared with not working were 0.91 (95% CI, 0.82-1.00) and 1.10 (95% CI, 1.00-1.20), respectively. CONCLUSIONS: Women with higher education were more likely to consume alcohol in early pregnancy and to cease alcohol use between early and middle pregnancy, especially working women. Working women were more likely to consume alcohol throughout pregnancy. Working women with lower education were less likely to cease alcohol use, whereas working women with higher education were more likely to cease alcohol use between early and middle pregnancy.

Abstract Background There may be a difference in the number of articles about COVID-19 and SARS-CoV-2 between low- and middle-income countries (LMICs) and high-income countries (HICs). Methods We analyzed authors’ affiliations from 36 432 articles related to COVID-19 and SARS-CoV-2. We introduced logarithmic density and compared the number of articles and logarithmic density of LMICs with those of HICs. Results The number of articles and the logarithmic density of LMICs were lower than those of HICs (p&amp;lt;0.0001 for both). Conclusions There was a disparity in the number of articles related to COVID-19 and SARS-CoV-2 between LMICs and HICs.

BACKGROUND: Although the postpartum period is suggested to provide an ideal opportunity for interventions to prevent hazardous drinking, evidence on the associations of education and income with hazardous drinking during this period is limited, including in Japan. METHODS: We analyzed data from 11,031 women who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Japan. Hazardous drinking was defined as ethanol intake of ≥20 g/day 1 year after delivery. We conducted multiple logistic regression analyses to examine whether educational attainment or equivalent household income was associated with hazardous drinking, adjusting for age, parity, drinking status during pregnancy, work status, postpartum depression, breastfeeding, and income/education. We also conducted stratified analyses by income and education groups. RESULTS: The prevalence of hazardous drinking 1 year after delivery was 3.6%. Lower education was associated with hazardous drinking; the odds ratio (95% confidence interval) of high school education or lower compared with university education or higher was 2.17 (1.59-2.98). Lower income was also associated with hazardous drinking, but this association disappeared after further adjustments for education; the odds ratios (95% confidence intervals) of the lowest compared with highest level of income were 1.42 (1.04-1.94) and 1.12 (0.81-1.54), respectively. A significant interaction was detected; lower education and lower income were associated with increased risks of hazardous drinking only in a lower income group and lower education group, respectively. CONCLUSIONS: Postpartum women with lower education and lower income had higher risks of hazardous drinking in Japan.

Japanese toddler and preschool children, ages 1.5-5 years, have lower rates of obesity, ≥95 th percentile body mass index, compared with North American ones. We examined parental reported beverage consumption patterns in 3 Japanese based mother-child cohorts from three different regions of Japan compared with data from cross-sectional and longitudinal studies from North America. Specifically, we used data from the Hamamatsu Birth Cohort for Mothers and Children (HBC Study) in Hamamatsu (Shizuoka Prefecture), the Seiiku Boshi Birth Cohort from Setagaya, Tokyo and the TMM BirThree Cohort Study from Miyagi. We additionally compared cross-sectional data from preschoolers from 24 prefectures in Japan as previously reported from a national study. While Japanese children had lower but comparable rates to North American children for introduction of sugar-sweetened beverages and 100% fruit juices, Japanese children consumed these beverages daily at a much lower level than North American children. Additionally, North American children may get more added sugars from soda and fruit juices as a relative percentage of total added sugar. By contrast, Japanese children consume more sweetened dairy drinks as a relative percentage of total added sugar. Sweetened dairy drinks may have the added benefits of including fats, calcium and probiotics which may be associated with lower risk for obesity compared with consumption of other types of sugar sweetened beverages.

Low gestational weight gain (GWG) is a known risk factor of low birthweight. Although studies have previously examined the associations between GWG and birthweight, the period-specific effects of low GWG in each trimester remain unclear. This study aimed to quantify the trimester-specific direct effects of low GWG in Japanese women on birthweight. Using perinatal data from a cohort study, we analyzed pregnant women delivered at an obstetrics/gynecology hospital between October 2006 and May 2010. We focused on women with a pre-pregnancy body mass index (BMI) below 25 kg/m2. The exposure was low GWG. The gestation period was subdivided into trimesters, and the direct effects of low trimester-specific GWG on birthweight were estimated using marginal structural models. These models were guided by a direct acyclic graph that incorporated potential confounders, including pre-pregnancy BMI, age, smoking during pregnancy, height, and parity. We analyzed 563 women and their families. The mean cumulative GWG by the end of the first, second, and third trimesters was 0.9, 6.2, and 10.7 kg, respectively. Approximately 14.0% of the women gained total weight below the range recommended by Japanese Ministry of Health, Labour and Welfare. The direct effects of low GWG on birthweight were 65.9 g (95% confidence interval: 11.4, 120.5), -195.4 g (-263.4, -127.4), and -188.8 g (-292.0, -85.5) for the first, second, and third trimesters, respectively. Insufficient weight gain in the second and third trimesters had a negative impact on birthweight after adjusting for pre-pregnancy BMI and other covariates.

BACKGROUND: Despite much knowledge of the effects of maternal psychopathology on bonding, the effects of personality have received less attention. We aimed to examine the association between maternal personality and postnatal bonding disorder. METHODS: We analyzed data from 15,654 women who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Personality was assessed in middle pregnancy using the short-form Eysenck Personality Questionnaire-Revised, with the score for each subscale categorized into four levels. Bonding disorder was defined as the Mother-to-Infant Bonding Scale score of ≥5 one month after delivery. Multiple logistic regression analyses were conducted to examine the association between personality and bonding disorder after adjusting for age, education, parity, feelings towards pregnancy, social isolation, as well as the Edinburgh Postpartum Depression Scale (EPDS) score. RESULTS: Higher extraversion was associated with a decreased risk of bonding disorder (p for trend <0.001). Higher neuroticism was associated with an increased risk of bonding disorder (p for trend <0.001), and this association disappeared after further adjustment for EPDS score (p for trend 0.39). No association between psychoticism and bonding disorder was observed (p for trend 0.83), and the association appeared after further adjustment for EPDS score (p for trend 0.0017). Higher lie was associated with a decreased risk of bonding disorder (p for trend <0.001). LIMITATIONS: Maternal personality and bonding were self-reported. CONCLUSIONS: Lower extraversion, higher psychoticism, and lower lie were associated with bonding disorder. The association between higher neuroticism and bonding disorder was explained by postnatal depressive symptoms.

BACKGROUND: To examine changes in psychological distress prevalence among pregnant women in Miyagi Prefecture, which was directly affected by the Great East Japan Earthquake and tsunami, and compare it with the other, less damaged areas of Japan. METHODS: This study was conducted in conjunction with the Japan Environment and Children`s Study. We examined 76,152 pregnant women including 8270 in Miyagi Regional Center and 67,882 in 13 other regional centers from the all-birth fixed data of the Japan Environment and Children's Study. We then compared the prevalence and risk of distress in women in Miyagi Regional Center and women in the 13 regional centers for 3 years after the disaster. RESULTS: Women in the Miyagi Regional Center suffered more psychological distress than those in the 13 regional centers: OR 1.38 (95% CI, 1.03-1.87) to 1.92 (95% CI, 1.42-2.60). Additionally, women in the inland area had a consistently higher prevalence of psychological distress compared to those from the 13 regional centers: OR 1.67 (95% CI, 1.18-2.38) to 2.19 (95% CI, 1.60-2.99). CONCLUSIONS: The lack of pre-disaster data in the Japan Environment and Children's Study made it impossible to compare the incidence of psychological distress before and after the March 2011 Great East Japan Earthquake. However, 3 years after the Great East Japan Earthquake, the prevalence of pregnant women with psychological distress did not improve in Miyagi Regional Center. Further, the prevalence of mental illness in inland areas was consistently higher than that in the 13 regional centers after the disaster.

BackgroundWe established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environmental interactions on the incidence of major diseases such as cancer and cardiovascular diseases.MethodsWe asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria was aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), for example, carotid echography, calcaneal ultrasound bone mineral density, and so on. All participants agreed to measure genome information and to distribute their information widely.ResultsAs a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants with Type 1 survey were more likely to have psychological distress than those of Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents regardless of sex.ConclusionThis cohort comprised large sample size and it contains information on disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.

Blood pressure (BP) measurements of pregnant women have been collected in offices and at home for previous research. However, it remains uncertain whether there is difference between research BP, defined as BP measured for the purpose of epidemiological research and BP measured at home or in an office. Therefore, the present study aimed to compare research BP with home and unstandardized office BP. Research, home, and office BP were measured among pregnant women who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). Research BP was measured twice at our research center while the participant was seated and after resting for 1-2 minutes. Research, home, and office BP were compared and agreement among the values was assessed. Differences among research, home, and office BP values and possible factors affecting differences were analyzed. Among 656 pregnant women, the mean (± standard deviations) research systolic (S), diastolic (D) BP, home SBP, home DBP office SBP, and office DBP were 103.8 ± 8.5, 61.8 ± 7.3, 104.4 ± 9.2, 61.2 ± 6.8, 110.5 ± 10.8, and 63.8 ± 8.7mmHg, respectively. Research SBP value was lower than home value (P = .0072; difference between mean research and home BP: -0.61 ± 7.8 mmHg). Research SBP and DBP values were lower than office values (P < .0001 for both SBP and DBP; means ± standard deviations of differences between research and office BP: 6.7 ± 10.1 and 2.0 ± 8.5 mmHg for SBP and DBP, respectively). In conclusion, when research BP is measured under conditions controlled, research BP can give close values to home BP for pregnant women.

AIMS: To investigate the associations between glycosylated hemoglobin (HbA1c) levels at less than 24 weeks of gestation and adverse pregnancy outcomes in Japan. METHODS: This was a prospective nationwide birth cohort study of 77,526 subjects with an HbA1c level of <6.5% (<48 mmol/mol) at less than 24 weeks of gestation. Associations of HbA1c level with adverse pregnancy outcomes were evaluated using multivariate analyses. RESULTS: The adjusted odds ratios per 1% (11 mmol/mol) increase in HbA1c level were 1.77 (95% confidence interval [CI]: 1.48-2.12) for hypertensive disorders of pregnancy; 1.78 (95% CI: 1.12-2.83) for placental abruption; 1.30 (95% CI: 1.12-1.50) for preterm birth; 2.11 (95% CI: 1.41-3.16) for very preterm birth; 1.49 (95% CI: 1.33-1.68) for low birth weight infants; 1.95 (95% CI: 1.42-2.70) for macrosomia; 1.23 (95% CI: 1.09-1.39) for small for gestational age; 1.15 (95% CI: 1.04-1.28) for large for gestational age; and 1.29 (95% CI: 1.20-1.39) for the composite adverse pregnancy outcome. CONCLUSIONS: The higher the HbA1c level, the higher the risk of adverse pregnancy outcomes in Japan. Further studies will be needed to determine prenatal management based on the HbA1c level in pregnant women with HbA1c <6.5% (<48 mmol/mol) at less than 24 weeks of gestation.

<title>Abstract</title> <bold>Background:</bold> Associations of education and income with secondhand smoke (SHS) exposure have been well documented in the general population. However, evidence among non-smoking pregnant women is limited, including in Japan. The purpose of the study was to examine the associations of education and income with SHS exposure among non-smoking pregnant women in Japan.<bold>Methods:</bold> We analyzed data from 17815 non-smoking pregnant women in Japan who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study from 2013 to 2017. SHS exposure was defined as indoor exposure to someone else’s cigarette smoke ≥1 day/week during pregnancy. Multiple logistic regression analyses were conducted to examine whether pregnant women’s educational attainment or equivalent household income was associated with SHS exposure, adjusting for age, work status, smoking history, partners’ education, and income/education. Stratified analyses by work status were also conducted.<bold>Results:</bold> The prevalence of SHS exposure during pregnancy was 34.0%; 29.4% among non-working women and 37.1% among working women. Lower educational attainment was associated with an increased risk of SHS exposure; the odds ratio of high school education or lower compared with university education or higher was 1.78 (95% confidence interval, 1.59–1.99). Lower equivalent household income was associated with an increased risk of SHS exposure; the odds ratio of the lowest compared with the highest level of income was 1.67 (95% confidence interval, 1.51–1.84). These associations did not differ between non-working women and working women.<bold>Conclusions:</bold> Pregnant women with lower education and/or lower household income had higher risks of SHS exposure in Japan. These findings imply that educational interventions and financial incentives are needed for pregnant women and their household smokers in helping to reduce SHS exposure among non-smoking pregnant women.

A hypertensive disorder of pregnancy (HDP) is defined as hypertension emerging after 20 weeks of gestation and resolving up to 12 weeks post-partum, and occurs in about 5% of all pregnancies. Complications associated with HDP have poor prognoses, and maternal deaths attributable to HDP are predicted to exceed 70 000 per year worldwide. Understanding the pathogenesis and risk factors of hypertensive disorders of pregnancy is important, and they are often investigated in observational studies. Given that therapeutic interventions cannot be controlled in observed studies, it is necessary to interpret which factors correspond to exposure and which factors correspond to confounding and intermediate factors in each study. From the Babies and their parents' longitudinal observation in the Suzuki Memorial Hospital on Intrauterine period study, blood pressure in early pregnancy was not only predictive of a child's birthweight, but the trajectory was also associated with the birthweight. From the larger-scale birth cohort studies currently conducted in Japan will provide the novel potential risk factors of hypertensive disorders of pregnancy and preventive strategies of them. In Japan, observational or intervention studies are just beginning to emerge. The continuation of both a distinctive cohort and a large cohort is needed, and the development of good quality intervention trials based on the results of observational studies is important.

<title>Abstract</title>Autism spectrum disorder (ASD) has phenotypically and genetically heterogeneous characteristics. A simulation study demonstrated that attempts to categorize patients with a complex disease into more homogeneous subgroups could have more power to elucidate hidden heritability. We conducted cluster analyses using the k-means algorithm with a cluster number of 15 based on phenotypic variables from the Simons Simplex Collection (SSC). As a preliminary study, we conducted a conventional genome-wide association study (GWAS) with a data set of 597 ASD cases and 370 controls. In the second step, we divided cases based on the clustering results and conducted GWAS in each of the subgroups vs controls (cluster-based GWAS). We also conducted cluster-based GWAS on another SSC data set of 712 probands and 354 controls in the replication stage. In the preliminary study, which was conducted in conventional GWAS design, we observed no significant associations. In the second step of cluster-based GWASs, we identified 65 chromosomal loci, which included 30 intragenic loci located in 21 genes and 35 intergenic loci that satisfied the threshold of <italic>P</italic> &lt; 5.0 × 10⁻⁸. Some of these loci were located within or near previously reported candidate genes for ASD: <italic>CDH5</italic>, <italic>CNTN5, CNTNAP5, DNAH17, DPP10, DSCAM</italic>, <italic>FOXK1</italic>, <italic>GABBR2, GRIN2A</italic>5, <italic>ITPR1, NTM, SDK1, SNCA</italic>, and <italic>SRRM4</italic>. Of these 65 significant chromosomal loci, rs11064685 located within the <italic>SRRM4</italic> gene had a significantly different distribution in the cases vs controls in the replication cohort. These findings suggest that clustering may successfully identify subgroups with relatively homogeneous disease etiologies. Further cluster validation and replication studies are warranted in larger cohorts.

Low birth weight is known to be associated with hypertension, cardiovascular disease and hypertensive disorders of pregnancy (HDP); however, this association might vary by race/ethnicity. This study aimed to clarify the association between women's own birth weight and their subsequent risk for HDP in a Japanese population, in combination with pre-pregnancy body mass index (BMI). We conducted a cohort study as part of the Tohoku Medical Megabank Birth and Three-Generation Cohort Study in Miyagi, Japan. Our study's population included 4810 women. A multivariate logistic regression analysis was performed to calculate the adjusted odds ratio (aOR) and the 95% confidence interval (CI) of the women's own birth weight for HDP, in the combination categories of birth weight and pre-pregnancy BMI. As a result, the group with a low birth weight of <2500 g had a significant association with HDP (the aOR, 1.50; 95% CI, 1.02-2.21). In the subtype analysis, the odds ratio for only preeclampsia was significantly increased in the low birth weight group (aOR, 3.37; 95% CI, 1.84-6.16). In the group with a low birth weight, the prevalence of HDP was higher in both the underweight and overweight groups. In conclusion, there was a significant association between low birth weight and subsequent HDP in Japanese women. Furthermore, a significant association with HDP was found for women born with a low birth weight who were underweight or overweight as adults. Maintaining a normal weight may be effective for preventing HDP even if a woman was born small.

BACKGROUND: Associations of fruit and vegetable consumption before and during pregnancy with birth weight of new-borns and the risk of low birth weight (LBW) remain unclear. METHODS: Between July 2013 and March 2017, we recruited 23,406 pregnant women in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). Fruit and vegetable consumption before and during pregnancy was calculated using food frequency questionnaires. Information regarding birth weight was obtained from medical records, and LBW was defined as < 2500 g. We used a multivariable linear regression model and a multivariate logistic regression model to assess associations between fruit and vegetable consumption and birth weight/risk of LBW. RESULTS: In total, 17,610 women were included in the analysis. Mean birth weight was 3061.8 ± 354.1 g, and 5.4% of the new-borns had LBW. Compared to women in the lowest quartile of fruit consumption between pre- and early pregnancy, women in the highest quartile had heavier new-borns (β = 49.4; 95% CI: 34.1-64.7) and lower risk of LBW (OR: 0.79; 95% CI: 0.65-0.95). Women in the highest quartile of fruit consumption from early to mid-pregnancy also had heavier new-borns (β = 32.3; 95% CI: 17.1-47.6), and they tended to have lower risk of LBW (OR: 0.83; 95% CI: 0.69-1.01). Results of analysing the association between changes in fruit consumption from pre- to mid-pregnancy and birth outcomes revealed that women with continuous high fruit consumption from pre- to mid-pregnancy had heavier new-borns (β = 37.6; 95% CI: 25.0-50.3), but they did not have lower risk of LBW (OR: 0.90; 95% CI: 0.77-1.06). Associations involving vegetable consumption and birth weight/risk of LBW were not observed. CONCLUSIONS: Fruit consumption before and during pregnancy was positively associated with birth weight of new-borns and negatively associated with risk of LBW.

<title>Abstract</title> <bold>Background:</bold> Most studies on social predictors of alcohol use have been conducted at one time point during pregnancy or using postpartum retrospective reports. Furthermore, the studies were mainly conducted in Western countries. We aimed to prospectively examine social predictors of alcohol use and cessation during pregnancy in Japan.<bold>Methods:</bold> This prospective study was part of the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study from 2013 to 2017. Pregnant women were recruited at approximately 50 obstetric clinics and hospitals in Miyagi Prefecture in Japan. We analyzed 11592 pregnant women who completed the questionnaires administered in early pregnancy and middle pregnancy. Women were dichotomized as current drinkers or non-drinkers in both early and middle pregnancy. Age, education, income, work status, and psychological distress were used as social predictors. Multivariate logistic regression analyses were conducted to examine associations between these predictors and alcohol use in early and middle pregnancy. Associations with alcohol cessation between early pregnancy and middle pregnancy were also examined.<bold>Results:</bold> Prevalence of alcohol use in early and middle pregnancy was 20.9% and 6.4%, respectively. Higher education was associated with alcohol use in early pregnancy and alcohol cessation during pregnancy; the odds ratios (ORs) of ≥university education compared with ≤high school education were 1.47 (95% confidence interval [CI], 1.30–1.66) and 1.31 (95% CI, 1.00–1.71), respectively. Work status was associated with alcohol use in both periods and alcohol cessation during pregnancy; for alcohol cessation, the OR of working in early pregnancy only compared with not working in both periods was 1.72 (95% CI, 1.03–2.88).<bold>Conclusions:</bold> Women with higher education were more likely to consume alcohol in early pregnancy and to cease between early pregnancy and middle pregnancy. Working women were more likely to consume alcohol throughout pregnancy in Japan.

This study investigated the association between maternal home blood pressure (HBP) trajectory during pregnancy and infant birth weight. A total of 755 pregnant women were included in this prospective cohort study. A group-based trajectory model identified six trajectory groups for home systolic blood pressure (SBP), diastolic BP (DBP), and mean arterial pressure (MAP). Next, the association of HBP trajectory groups with infant birth weight was evaluated using a general linear model considering potential confounding factors. For home SBP and MAP, the trajectory groups with a low-steep J-curve, moderate J-curve, little high J-curve, and high J-curve were significantly associated with lower infant birth weight than the low-J-curve group. Among the trajectory groups for home DBP, the moderate-steep J-curve, little high J-curve, and high J-curve were significantly associated with lower infant birth weight than the group with low-J-curve. The effect sizes of the trajectory groups varied in infant birth weight from -0.21 standard deviations (SDs) (95% confidence interval (CI): -0.42 to -0.01 SD) to -1.13 SD (95% CI: -1.54 to -0.72 SD). In the analyses of infant birth weight in grams, effect sizes that were significantly associated with infant birth weight varied from -84 g (95% CI: -167 to -1 g) to -567 g (95% CI: -732 to -402 g). Trajectory groups with a moderate-reverse J-curve for home SBP, DBP, and MAP were not significantly associated with infant birth weight. Maternal HBP trajectory during pregnancy was an indicator of infant birth weight. Further studies evaluating the associations between HBP during pregnancy and other perinatal outcomes are needed.

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.

Influenza vaccination is the most effective method for preventing influenza virus infection. The incidence of influenza is higher in schoolchildren than other age groups. This study evaluated the effectiveness of seasonal inactivated influenza vaccination (IIV) in a community population of schoolchildren during two seasons. This study was a cross-sectional survey of public schoolchildren based on data collected in the 2012/2013 and 2014/2015 seasons. The questionnaire was distributed to all public schoolchildren of target grade in a survey area, and 7945 respondents were included in the analysis. The vaccination status and influenza onset were defined based on the self-reported questionnaire by parents or guardians. Generalized linear mixed models were used to adjust clustering within schools and individual covariates and calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between vaccination status and influenza onset. The influenza incidence was higher in the 2015 than the 2013 survey (25% versus 17%), although the vaccination rates were comparable between the two seasons. Receiving one- or two-dose vaccination was more protective against influenza than non-vaccination in both the 2013 (OR, 0.77; 95%CI, 0.65-0.92) and 2015 (OR, 0.88; 95%CI, 0.75-1.02) surveys. Full vaccination was also more protective in both the 2013 (OR, 0.75; 95%CI, 0.62-0.89) and 2015 (OR, 0.86; 95%CI, 0.74-1.00) surveys. Seasonal IIV was protective against influenza for Japanese schoolchildren in a community-based real-world setting. The difference in clinical effectiveness of IIV between the two seasons was likely due to the antigenic mismatch between the circulating and vaccine strains.

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>The average birth weight in Japan has decreased by 200 g in the last 40 years. Only three studies were reported for the association between maternal dietary patterns and birth weight in East Asia, whose results were inconsistent. We examined what maternal dietary patterns were associated with the birth weight in Japan.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Totally 22,493 pregnant women were recruited between July 2013 and September 2016 into the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. We included 17,287 women who had a full-term single healthy baby into the analysis. Consumption of food and beverage items was evaluated based on food frequency questionnaire at the first-trimester. Dietary patterns were analyzed using a machine learning method of k-means clustering algorithm. Birth weight was obtained from the medical record. The association between dietary patterns and birth weight was analyzed using multiple liner regression model adjusted for potential confounders with multiple imputation method for missing values.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Dietary patterns were classified into seven groups by cluster analysis: “high in rice (reference) (n = 8046)”, “middle in vegetables, beans, mushrooms, seaweeds and miso-soup (n = 4842)”, “high in fruits (n = 1176)”, “high in bread, dairy and alcohol (n = 1091)”, “high in meat and fish (n = 1049)”, “high in coffee, black tea, soft drinks and confections (high in coffee) (n = 585)”, and “high in vegetables, beans, mushrooms, seaweeds and miso-soup (n = 498)” groups. In multiple liner regression models, birth weight was 22.6 g (95%CI: 0.1 to 45.2 g) heavier in “high in fruits” group than in reference group and 39.4 g (95%CI: 8.6 to 70.3 g) lighter in “high in coffee” group than in reference group. The other groups were not statistically significant.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>High consumption of fruits and high consumption of coffee, black tea, soft drinks and confections during early pregnancy were associated with increased and decreased birth weight, respectively.</jats:p> </jats:sec> <jats:sec> <jats:title>Key messages</jats:title> <jats:p>We found maternal dietary patterns during early pregnancy using a machine learning method of k-means clustering algorithm. We found maternal dietary patterns which associated with the birth weight in Japan.</jats:p> </jats:sec>

BACKGROUND: Genome cohort studies are used to analyze interactions between genetic and environmental factors, providing valuable information for personalized healthcare. Large-scale and long-term cohort studies require a number of specially trained personnel, of whom those involved in obtaining informed consent play a vital role, especially during the initial phase of such studies. The Japanese Society of Human Genetics (JSHG) previously established a certification system for genome medical research coordinators (GMRCs) responsible for obtaining written consent via face-to-face explanation. Meanwhile, in the Tohoku Medical Megabank Organization (ToMMo), GMRCs are expected to play important roles not only in obtaining informed consent and conducting various assessments, but also in communicating with participants throughout the long-term follow-up. Based on the JSHG program, we therefore developed a specific education and training program for ToMMo GMRCs consisting of 17 lectures, one practical training session on the informed consent procedure, and written and interview examinations. Re-education workshops aimed at self-improvement are also carried out following certification. In this study, we evaluated the education and training program in terms of overall understanding, usefulness, and satisfaction using an anonymous questionnaire. METHODS: An anonymous questionnaire addressing each aspect of the education and training program (understanding, usefulness, and satisfaction) was distributed among 152 qualified ToMMo GMRCs. Responses were received from 94 participants (61.8%). RESULTS: There was a significant association between the level of overall understanding of lectures and medical qualification (nurse or clinical laboratory technologist), but not with age or educational background. The level of understanding and overall usefulness were lower in sessions related to genetics and epidemiology than those dealing with ToMMo practices. In the re-education workshops, GMRCs showed a preference for and hoped to learn more about both background knowledge and research progress in the ToMMo. CONCLUSIONS: The results of our questionnaire suggest that not all ToMMo GMRCs are able to understand everything during the initial education and training program, especially in terms of genomic medicine. Continuous re-education is therefore vital in improving knowledge, skills and motivation, and preparing GMRCs for a specialist role in community-based personalized healthcare.

We evaluated the relationship between preconception folic acid supplementation and the occurrence of neural tube defects (NTDs) in offspring, using data from the Japan Environment and Children's Study (a nationwide prospective birth cohort study) database. Of 92 269 participants with single pregnancies, 74 cases (offspring or fetuses) had NTDs, including 32 cases of spina bifida, 24 cases of anencephaly, and 19 cases of encephalocele. A total of 7634 participants (8.27%) used preconception folic acid supplementation, and of these, 621 (0.67%) also took in dietary folic acid at ≥480 μg/day. Multivariate logistic regression analyses demonstrated no association between preconception folic acid supplementation and NTDs in offspring or fetuses (odds ratio [OR] 0.622; 95% confidence interval [CI]: 0.226-1.713). Moreover, the participants who combined preconception folic acid supplement use with dietary folic acid intake ≥480 μg/day demonstrated no incidence of NTDs in offspring or fetuses. Our analysis is limited by the absence of the data on the daily amount of supplementary folic acid intake, requiring careful attention to the interpretation. Additional surveys are required in Japan to resolve those limitations for further comprehensive assessment.

Smoking during pregnancy is a risk factor for various adverse birth outcomes but lowers the risk of preeclampsia. Cardiovascular adaptations might underlie these associations. We examined the association of maternal smoking with the risk of hypertensive disorders of pregnancy (HDP) in a low-risk population-based cohort of 76,303 pregnant women. This study was a part of the Japan Environment and Children's Study. Smoking status was assessed using questionnaires completed by participants. Information about HDP was assessed using questionnaires completed by doctors. Compared with that for women who did not smoke, women who continued smoking >10 cigarettes per day during pregnancy had a significantly higher risk of developing HDP (odds ratio: 1.58, 95% confidence interval: 1.11-2.25). In multivariate analyses with adjustment for possible confounding factors, the association still remained (odds ratio: 1.51, 95% confidence interval: 1.04-2.19). When we regarded the number of cigarettes as a continuous variable, there was a linear association between the number of cigarettes and risk of HDP, with an odds ratio of 1.02 per cigarette per day (95% confidence interval: 1.00-1.04). Smoking a greater number of cigarettes was associated with a higher risk of HDP after adjustment for possible confounding factors. Cigarette smoking cessation may avoid the complications of HDP. Our findings suggest that, in addition to the risk of small-for-gestational-age children, an increased risk of HDP should be considered in the management of pregnant women who smoke cigarettes.

BACKGROUND: Some studies have suggested that blastocyst transfer is associated with i) imbalance in the secondary sex ratio (SSR) (which favors male offspring), ii) increased incidence of monozygotic twins (MZT). In contrast, others have not found these changes. In this study, we evaluated the association between blastocyst transfer and SSR and MZT, considering potential parental confounders. METHODS: The Japan Environment and Children's Study is a large, nationwide longitudinal birth cohort study funded by the Ministry of the Environment of Japan. We used this large dataset, including 103,099 pregnancies, to further investigate the association between blastocyst transfer, SSR and MZT, using spontaneously conceived pregnancies, non-assisted reproductive technology (non-ART) treatment (intrauterine insemination and ovulation induction with timed intercourse) and cleavage stage embryo transfer for comparison. We evaluated the association with each group, the SSR, and the frequency of MZT, calculating the adjusted odds ratio (AOR) using multivariable logistic regression analyses, adjusting for potential parental confounders such as basic health and socioeconomic status. RESULTS: For each group (spontaneous conception vs. non-ART treatment vs. cleavage stage embryo transfer vs. blastocyst transfer), the percentages of males were 51.3% vs 50.7% vs 48.9% vs 53.4% and the monozygotic twinning rates per pregnancy were 0.27% vs 0.11% vs 0.27% vs 0.99% respectively. Multivariate logistic regression analyses indicated that blastocyst transfer was significantly associated with a higher SSR and higher incidence of MZT than the other three groups (SSR: AOR 1.095, 95% CI1.001-1.198; MZT: AOR 4.229, 95% CI 2.614-6.684). CONCLUSIONS: There are significant relationships between blastocyst transfer and SSR imbalance and a higher occurrence of MZT.

OBJECTIVES: Although a twin pregnancy is a risk factor for hypertensive disorders of pregnancy, studies investigating longitudinal blood pressure changes during twin pregnancies are uncommon. The aims of this study were to evaluate the longitudinal blood pressure changes during twin pregnancies and to compare blood pressure levels between twin and singleton pregnancies. METHODS: Five hundred dichorionic diamniotic twin, 240 monochorionic diamniotic twin, and 80 775 singleton pregnancies were included in this Japanese prospective birth cohort study. A marginal model was applied to evaluate the SBP, DBP, and mean arterial pressure levels during early gestation, mid-gestation, and late gestation. RESULTS: The blood pressure levels fell from early-to-mid-gestation and rose after mid-gestation in the dichorionic and monochorionic diamniotic twin pregnancies. The SBP and mean arterial pressure levels during early gestation and the DBP and mean arterial pressure levels during late gestation were higher in the dichorionic diamniotic twin pregnancies than those in the singleton pregnancies. The blood pressure levels in the monochorionic diamniotic twin pregnancies were higher than those in the singleton pregnancies at each gestational stage, except for the SBP during late gestation. CONCLUSION: Although the longitudinal blood pressure changes during twin pregnancies were similar to those during singleton pregnancies, the blood pressure levels during twin pregnancies were higher. Further studies that examine the associations between the longitudinal blood pressure changes during pregnancy and the perinatal outcomes in twin pregnancies are necessary.

This study examined the association between maternal alcohol consumption during pregnancy and hypertensive disorders of pregnancy in the Japan Environment and Children's Study, a nationwide birth cohort study. A total of 76 940 pregnant women were included in the analysis. Information about alcohol consumption during pregnancy was obtained using two questionnaires: T1 and T2. The mean (standard deviation) gestational age in the T1 and T2 questionnaires were 16.5 (5.8) and 27.9 (3.7) weeks, respectively. Alcohol consumption was considered as an exposure, hypertensive disorders of pregnancy as an outcome, and possible confounding factors were included in a generalized linear mixed-effects model with a logit link function. Among the study subjects, 2 348 (3.1%) women developed hypertensive disorders of pregnancy. Compared with 25 300 women who never drank alcohol, 43 women who drank alcohol according to the T1 questionnaire and continued to drink ≥150 g ethanol/week according to the T2 questionnaire had significantly higher odds of hypertensive disorders of pregnancy. The adjusted odds ratio was 3.98 (95% confidence interval [CI], 1.33-11.9). In conclusion, alcohol consumption of ≥150 g ethanol/week during pregnancy is better avoided because of the high odds of developing hypertensive disorders of pregnancy. It may be meaningful that healthcare providers confirm information about alcohol consumption during pregnancy. Moreover, discontinuation of alcohol consumption is recommended to prevent the onset of hypertensive disorders of pregnancy in Japan.

We investigated whether machine learning methods could potentially identify a subgroup of persons with autism spectrum disorder (ASD) who show vitamin B6 responsiveness by selected phenotype variables. We analyzed the existing data from our intervention study with 17 persons. First, we focused on signs and biomarkers that have been identified as candidates for vitamin B6 responsiveness indicators. Second, we conducted hypothesis testing among these selected variables and their combinations. Finally, we further investigated the results by conducting cluster analyses with two different algorithms, affinity propagation and k-medoids. Statistically significant variables for vitamin B6 responsiveness, including combination of hypersensitivity to sound and clumsiness, and plasma glutamine level, were included. As an a priori variable, the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) scores was also included. The affinity propagation analysis showed good classification of three potential vitamin B6-responsive persons with ASD. The k-medoids analysis also showed good classification. To our knowledge, this is the first study to attempt to identify subgroup of persons with ASD who show specific treatment responsiveness using selected phenotype variables. We applied machine learning methods to further investigate these variables' ability to identify this subgroup of ASD, even when only a small sample size was available.

Involvement of family members, especially grandparents, in genome epidemiological research is important to investigate both genetic and environmental factors of common diseases. The aim of the present study was to establish strategies to obtain enough number of family recruitment, especially focusing on grandparents, for the Tohoku Medical Megabank Birth and Three-Generation Cohort Study. Our main strategies are summarized below. 1) We standardized informed consent process with reference materials to help people understand the consent form, 2) we created an invitation letter to contact family members, and 3) we recruited family members in several settings. To obtain informed consent, we were careful of explaining clearly the complex reasons as well as drawing people's attention. By the end of March 2017, the number of invitation letters distributed to family members through the pregnant women was 23,806, including 18,702 grandparents. Among the grandparents who received invitation letters, 2,935 (15.7%) responded to us. Furthermore, some grandparents were asked to provide informed consent with other family members by staff at maternal clinics or Community Support Centers, and others directly booked Community Support Centers without responding to the invitation letter. Grandparents joined the study anytime during mother's maternal check-ups or delivery. Overall, 8,054 grandparents participated in our birth cohort study. The setting in which most grandparents were recruited was our own facilities. Importantly, both paternal and maternal grandparents more frequently participated in the study if the father also participated. In conclusion, we are able to recruit not only pregnant women but also fathers and grandparents.

OBJECTIVE: Metabolic syndrome and the presence of metabolic syndrome components are risk factors for cardiovascular disease (CVD). However, the association between personality traits and metabolic syndrome remains controversial, and few studies have been conducted in East Asian populations. METHODS: We measured personality traits using the Japanese version of the Eysenck Personality Questionnaire (Revised Short Form) and five metabolic syndrome components-elevated waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting glucose-in 1322 participants aged 51.1±12.7years old from Kakegawa city, Japan. Metabolic syndrome score (MS score) was defined as the number of metabolic syndrome components present, and metabolic syndrome as having the MS score of 3 or higher. We performed multiple logistic regression analyses to examine the relationship between personality traits and metabolic syndrome components and multiple regression analyses to examine the relationship between personality traits and MS scores adjusted for age, sex, education, income, smoking status, alcohol use, and family history of CVD and diabetes mellitus. We also examine the relationship between personality traits and metabolic syndrome presence by multiple logistic regression analyses. RESULTS: "Extraversion" scores were higher in those with metabolic syndrome components (elevated waist circumference: P=0.001; elevated triglycerides: P=0.01; elevated blood pressure: P=0.004; elevated fasting glucose: P=0.002). "Extraversion" was associated with the MS score (coefficient=0.12, P=0.0003). No personality trait was significantly associated with the presence of metabolic syndrome. CONCLUSIONS: Higher "extraversion" scores were related to higher MS scores, but no personality trait was significantly associated with the presence of metabolic syndrome.

Background: Previous studies have reported controversial results for the association between green tea consumption and low-density lipoprotein (LDL)-cholesterol and body weight. Objective: The objective of this trial was to determine the effects of two kinds of green tea on LDL-cholesterol and body weight. Methods: We randomly assigned 151 participants (98 men, 53 women) aged 30-70 years into three groups: Yabukita green tea group, Benifuuki green tea group, or placebo group. Participants consumed 1.8 g/day of green tea extract powder or placebo for 12 weeks. The primary outcomes were LDL-cholesterol level and body weight, and the secondary outcomes were risk factors for cardiovascular disease. Results: Both Yabukita and Benifuuki green tea significantly lowered LDL-cholesterol. The magnitudes of the lipid-lowering effect of both types of tea were significantly larger than that of placebo. No differences with respect to changes in LDL-cholesterol were observed between the Yabukita and Benifuuki green tea groups. Neither Yabukita nor Benifuuki green tea had any effect on body weight and no difference was observed among groups regarding changes in body weight. Conclusion: Both Yabukita and Benifuuki green tea lowered LDL-cholesterol, and the lipid-lowering effects of these two green teas were not different. Neither tea lowered body weight.

Purpose: To elucidate drug use before and during pregnancy in Japan. Methods: The Japan Environment and Children's Study (JECS) is an ongoing nationwide birth cohort study. We analyzed data from JECS involving cases where drugs were used for 12 months before pregnancy was diagnosed, between the time of diagnosis of pregnancy until week 12 of pregnancy, and after week 12 of pregnancy. Results: We analyzed data from 97,464 pregnant women. The percentages of pregnant women who had taken one or more drugs and supplements before diagnosis of pregnancy, between the time of diagnosis of pregnancy until week 12 of pregnancy, and after week 12 of pregnancy, were 78.4%, 57.1%, and 68.8% respectively. Excluding iron supplements, folic acid, and other vitamins and minerals, the percentages of women taking supplements were 75.3%, 36.0%, and 51.7% at each respective time point. The following drugs and supplements were frequently used for 12 months before pregnancy diagnosis: Commercially available antipyretics, analgesics, and/or medicine for treating common cold (34.7%), antipyretics, analgesics, and/or medicine for treating common colds, which were prescribed in hospitals (29.8%), antimicrobial drugs (14.0%), and anti-allergy drugs (12.5%). The following drugs and supplements were frequently used from the time of pregnancy diagnosis until week 12 of pregnancy, and after week 12 of pregnancy: folic acid (28.9% and 26.2%), antipyretics, analgesics and/or medicines for treating common cold, that were prescribed in hospitals (7.8% and 13.3%), Chinese herbal medicines (6.0% and 9.4%, and uterine relaxants (5.1% and 15.2%). Conclusions: The analysis of a nationwide cohort study showed that a high percentage of Japanese pregnant women were taking medicinal drugs. Further research is required to elucidate the relationship between drug use during pregnancy and birth defects in Japan.