Social isolation, characterized by a lack of social connections with family, friends, and others, is associated with adverse health outcomes. However, the genetic contribution to the susceptibility to social isolation remains unclear. This study aimed to identify genetic loci associated with social isolation using the Lubben Social Network Scale (LSNS-6) in a Japanese population. The Tohoku Medical Megabank Community-Based Cohort Study was conducted between 2013 and 2016. The participants were genotyped using the Affymetrix Axiom Japonica Array. The LSNS-6 was used to assess familial and friend ties through six questions and social isolation statuses were defined using the total scale, family subscale, and friend subscale. Genome-wide association studies (GWASs) were conducted using a generalized linear mixed model, adjusting for age, sex, 10 genetic principal components and batch effects. In total, 63,497 participants who completed genotyping and the LSNS-6 were included. The mean age was 59.4 ± 11.9 years, and 41,126 (64.8%) were female. Significant genetic loci were identified in GWASs for the total scale (rs10736933 near ACADSB and HMX3) and friend subscale of LSNS-6 (rs1778366 near LINC02315 and LRFN5). This study provides the first genome-wide evidence of social isolation in the Japanese population, suggesting associations with ACADSB, HMX3, LINC02315, and LRFN5. These findings could enable personalized prevention and intervention for social isolation and related psychiatric disorders.

Abstract <p> Subcortical brain volumes have been extensively mapped by genome-wide association studies (GWASs) in Europeans, but their genetic architecture in East Asians remains unclear. We conducted GWASs on magnetic resonance imaging derived volumes of eight subcortical structures in 9,225 Japanese participants aged 21.6–88.0 years (mean 54.0 ± 15.5 years) from the Tohoku Medical Megabank Brain MRI Study. Genotyping used Japonica Array and volumes were estimated with FreeSurfer. GWASs were performed separately in the discovery ( n  = 7,328) and replication ( n  = 1,897) studies, followed by a meta-analysis. We identified nine significant genome-wide loci in the discovery study, three of which were replicated. Meta-analysis revealed four additional significant loci. We identified three novel variants associated with the volumes of subcortical structures. Previously reported loci in European ancestry studies, including ALPL , SMIM19 , CHRNB3 , DSCAML1 , KTN1 , RPL13AP3 , and DCC , were replicated, leading to the identification of ancestry-specific signals. Functional mapping and expression analyses revealed brain-specific enrichment of genes associated with the caudate and putamen. This first GWAS of subcortical volumes in a Japanese population refines the genetic architecture of these structures and provides insight into mechanisms of brain aging and neuropsychiatric disease. </p>

Small-for-gestational age (SGA) is an important global public health issue because of its increasing prevalence and long-term effects. Maternal smoking is a known risk factor for SGA; however, the effect of grandmaternal smoking on the risk of SGA in grandchildren SGA remains unclear. In this study, we examined whether grandmaternal smoking during pregnancy was associated with small birth weight, length, and head circumference for gestational age. Data were obtained from 23,730 pregnant women and their offspring from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Studies. A total of 1,130 grandmaternal-maternal-child triads were identified. Grandmaternal smoking during pregnancy was defined by the Maternal and Child Health Handbook owned by the mothers at birth mothers when they were born. Birth outcomes of grandchildren were obtained from medical records and converted to SGA using the 10th percentile for weight, length, and head circumference. A multivariate logistic regression and propensity scores were used for the analysis. Prevalence of <10th percentile for birth weight, length, and head circumference in grandmaternal smokers were 10.2%, 2.0%, and 10.2%, respectively. Grandmaternal smoking during pregnancy was associated with the lower grandchild's birth weight (odds ratio (OR) [95% (CI)]: 2.86 [1.05-7.82]) and remained consistent when adjusted by propensity score (OR [95% CI]: 2.87 [1.04-7.92]). Grandmaternal smoking should not be ignored when assessing the SGA risk. Future work should consider the complex mediating relationship between smoking and growth restriction across generations.

The placenta plays a crucial role in preeclampsia (PE) pathogenesis, with early onset (EOPE) and late onset (LOPE) presenting with unique manifestations. In this prospective study of 17,709 pregnant Japanese women, the relationship between the PE subtype and birth weight to placental weight ratio (BW/PW ratio) was examined. EOPE was not associated with BW/PW ratio, which was consistent with reduced birth and placental weights. LOPE showed lower BW/PW ratios, indicating potential adaptive hypertrophy of the placenta. These results emphasize the consideration of PE subtypes when utilizing the BW/PW ratio as an index of placental function and to elucidate PE mechanisms.

PURPOSE: Japanese traditional (Kampo) medicines containing ephedra are used to relieve symptoms of the common cold during pregnancy. The risks associated with perinatal outcomes, however, remain unclear. Thus, we evaluated the risk of adverse perinatal outcomes associated with the use of Kampo medicines containing ephedra during pregnancy using data from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). METHODS: Questionnaires were distributed to pregnant women who participated in the TMM BirThree Cohort Study at approximately weeks 12 and 26 of pregnancy. Adverse perinatal outcomes in women who used Kampo medicines containing ephedra or acetaminophen during pregnancy were assessed. Odds ratios (ORs) were estimated using weighted logistic regression analyses. RESULTS: Among 20 083 pregnant women, acetaminophen and Kampo medicines containing ephedra were used by 5.3% and 3.5% of women, respectively. The OR for caesarean section was 0.95 (95% confidence interval [CI], 0.75-1.20), for preterm birth (PTB) was0.99 (95% CI, 0.63-1.55), for low birth weight (LBW) was 1.04 (95% CI, 0.72-1.49), for small for gestational age (SGA) was 0.98 (95% CI, 0.58-1.65), and for low Apgar scores at 5 min was 0.85 (95% CI, 0.25-2.93) in the women who used Kampo medicines containing ephedra during pregnancy. CONCLUSIONS: No statistically significant association was seen between the use of Kampo medicines containing ephedra during pregnancy and an increased risk of needing a caesarean section, PTB, LBW, SGA, or low Apgar scores. Although further research is needed, this study may assist in clinical decision-making.

BACKGROUND: Associations have been suggested between prenatal exposure and allergic diseases in children as well as between respiratory allergies and maternal sleep disorders during pregnancy. PURPOSE: This study aimed to examine the association between maternal sleep disorders during pregnancy and allergic diseases, including respiratory, skin, and ocular allergies, in their children. METHODS: This study was based on the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Sleep disorders during pregnancy were defined as an Athens Insomnia Scale score of ≥6. Allergic diseases in children up to 5 years of age were assessed by maternal selfreport on "bronchial asthma," "atopic dermatitis," "food allergy," and "allergic conjunctivitis/allergic rhinitis/hay fever." Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a Cox proportional hazards model. RESULTS: A total of 11,123 mother-child pairs were included. The mean gestational age at registration was 19.6±7.6 weeks. During pregnancy, 4,115 women (37.0%) experienced sleep disorders. Additionally, 53.7% of the participants had a history of parity, 8.8% worked night shifts, and 0.4% used sleep medications. In the crude models, maternal sleep disorders during pregnancy were associated with all examined allergic diseases in children. After the adjustment for all confounders, the associations remained significant for atopic dermatitis and allergic conjunctivitis/ allergic rhinitis/hay fever (HR [95% CI], 1.09 [0.97-1.23] for bronchial asthma, 1.17 [1.05-1.31] for atopic dermatitis, 1.11 [0.98-1.26] for food allergy, and 1.25 [1.13-1.39] for allergic conjunctivitis/allergic rhinitis/hay fever). CONCLUSION: Maternal sleep disorders during pregnancy were associated with atopic dermatitis as well as allergic conjunctivitis/allergic rhinitis/hay fever in children.

Heritability of cognitive function is estimated to be 50%-80%. Genome-wide association studies (GWASs) have identified multiple cognitive function-associated loci, primarily in the European population. However, those in Asian populations, particularly in individuals of Japanese ancestry, remain limited. Hence, this GWAS aimed to identify cognitive function-associated genetic loci in elderly individuals of Japanese ancestry. Herein, 2571 elderly participants from the Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study were included. Their cognitive function was assessed using the Japanese version of the Mini-Mental State Examination (MMSE), and both binary and continuous MMSE scores were analysed. Genotyping was performed using the Affymetrix Axiom Japonica Array v2, and imputation was conducted with 3.5KJPNv2 and 1KGP3. Statistical analyses were performed using FastGWA-GLMM and FastGWA for binary and continuous MMSE scores, respectively. Although no genome-wide significant loci were identified using binary MMSE values, the following two were detected using continuous MMSE values: rs77877360 (20p12.1) near BANF2 and SNX5 and rs9460729 (6p22.3) near PRL and HDGFL1. Additionally, functional annotation suggested the involvement of these loci in pathways related to cognitive function, including chromatin structure regulation, neuroinflammation, and iron metabolism. Notably, SNX5, identified through chromatin-interaction mapping, has been implicated in neurodegenerative processes, particularly in Parkinson's disease. The findings of this study provide preliminary genome-wide evidence suggesting a genetic predisposition to impaired cognitive function in elderly Japanese individuals.

BACKGROUND: The number of young patients with cardiac disease has recently increased. To describe the electrocardiogram characteristics and identify the possible factors affecting the characteristics in early life might be helpful for the prevention and assessment of abnormal cardiac function. The aim of this study is to analyze the electrocardiogram characteristics of healthy children and investigate the possible associated factors in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Japan. METHODS: Children were recruited between 2013 and 2017 and the ECG parameters for 6,061 children. Student's t-test was conducted to confirm sex-related differences. ECG parameters were also described by age. Multiple regression analysis of 2,285 children, whose body mass index and their parents' ECG parameters were available in addition to sex and age, was used to analyze the possible factors associated with ECG characteristics. In addition, ECG parameters were compared between gestational age < 37 (premature birth) and ≥ 37. RESULTS: Heart rate, QRS duration, QT interval, corrected QT interval, and P-QRS-T axes showed significant sex-related differences (P < 0.05), and the QRS duration varied with age. The ECGs of parents in PR interval and QRS duration were associated with those of children (Boys: β [95% confidence interval] was 0.17[0.12-0.22] and 0.18[0.14-0.23] with mothers, 0.11[0.063-0.16] and 0.11[0.075-0.15] with fathers, Girls: 0.12[0.074-0.16] and 0.16[0.12-0.20] with mothers, 0.090[0.050-0.13] and 0.089[0.056-0.12] with fathers). Maternal QTc and P axes were also associated with child QTc and P axes. Premature birth showed significantly difference only in the QRS axis (P = 0.02). CONCLUSION: This study described the ECG characteristics of Japanese children and found a relation between parents and children. ECG parameters in children aged 4-9 correlate with those in their parents, but not with sex or BMI. In particular, mother's ECG was strongly associated with that of children than father's ECG. The relation might be reflected by both genetic background and uterine environment.

BACKGROUND: More research is needed to clarify the health effects of dietary carotenoid intakes, and this requires the use of high-quality assessments of habitual dietary intake. Cohort studies from the Tohoku Medical Megabank Organization included a self-administered food frequency questionnaire (TMM-FFQ) for community-dwelling adults. This study evaluated the validity of carotenoid intakes derived from the TMM-FFQ using serum carotenoid concentrations as the gold standard. METHODS: In Miyagi Prefecture, 88 men and 124 women aged ≥20 years voluntarily agreed to participate in the study and provided completed TMM-FFQs and blood samples in 2019 and 2021. Carotenoids examined included α-carotene, β-carotene, β-cryptoxanthin, and lycopene. Intraclass correlation coefficients (ICCs) were calculated to assess correlations between serum concentrations in 2019 and 2021. Spearman's rank correlation coefficients were calculated to evaluate the correlations between energy-adjusted dietary carotenoid intakes from the TMM-FFQ in 2021 and the average serum carotenoid concentrations in 2019 and 2021, with correction for the attenuating effect of random within-individual variation. RESULTS: The ICCs between serum concentrations over the 2 years were >0.50 for all carotenoids. Among men, correlation coefficients were 0.33 for α-carotene, 0.42 for β-carotene, 0.50 for β-cryptoxanthin, and -0.09 for lycopene. Among women, the coefficients were lower than those for men, except for lycopene: 0.11 for α-carotene, 0.23 for β-carotene, 0.21 for β-cryptoxanthin, and 0.28 for lycopene. CONCLUSIONS: The TMM-FFQ demonstrated reasonable validity for assessing intakes of α-carotene, β-carotene, and β-cryptoxanthin among men, but not among women, in the TMM cohort studies when using serum concentrations as the gold standard.

ABSTRACT Introduction While social capital can prevent diabetes, these benefits can be heterogeneous with respect to socioeconomic status. We investigated the association between social capital and gestational diabetes mellitus (GDM) while examining effect modification by household income. Materials and Methods We conducted a secondary data analysis using the Tohoku Medical Megabank Project Birth and Three‐Generation Cohort Study carried out between July 2013 and March 2017. Social capital (mutual aid, social trust, informal social control, collective action) and covariates were self‐reported, while GDM diagnosis and other medical and physiological information were obtained from medical records. To assess the association between social capital and GDM, we conducted logistic regression models. We further tested for interactions between social capital and household income as well as stratified the models by income. Results Among 20,339 study participants, 700 (3.4%) were diagnosed with GDM. Multivariable logistic regression models found that social trust and collective action were associated with lower GDM prevalence, even after adjustment of covariates. When stratifying household income, however, social capital was significantly associated with the reduced risks of GDM only among participants with higher household income (OR: 0.90, 95% CI: 0.85–0.97). No significant association was observed among those with lower household income. Conclusions The health benefit of social capital on GDM prevalence was heterogeneous, and the protective effect of social capital on GDM was found only among women with higher household income. The differential impact of social capital on GDM highlights the need for targeted interventions addressing structural health inequities.

BACKGROUND AND OBJECTIVES: Repeating food frequency questionnaires (FFQs) within the same population was reported to improve the validity of correlation coefficient (CC). However, the enhancement of validity in ranking agreement remains underreported. Herein, we assessed the validity of energy and nutrient intake es-timates using single and multiple FFQs and their ability to rank individuals. METHODS AND STUDY DESIGN: 213 men and women aged ≥20 years were recruited from the residents participating in the Tohoku Medical Mega-bank Project (TMM) cohort studies; three FFQs were conducted in November each year from 2019 to 2021, with 12-day weighted food records (WFRs) as the reference method. Spearman's rank CCs were calculated between single or multiple FFQs estimates and those obtained through the 12-day WFR. Additionally, the ranking agreement was compared based on cross-classification. RESULTS: CCs between intake estimated using a single FFQ and 12-day WFR were moderate for several nutrients, with median CCs of 0.52 for men and 0.48 for women. CCs for multiple FFQs were slightly higher than that of single FFQ, with median CCs of 0.59 for men and 0.56 for women. Regardless of the number of FFQs, the proportion of subjects classified into the opposite extreme category was ≤5% for most nutrients. CONCLUSIONS: A single FFQ used for adults in the TMM cohort studies showed moderate validity. Estimates from multiple FFQs improved the accuracy slightly; nevertheless, this indicates that relying on a single FFQ is unlikely to result in a serious misclassifica-tion compared to using intake data from multiple FFQs over a relatively short period.

AIM: Autism spectrum disorder (ASD) is a neurodevelopmental condition clinically characterized by abnormalities in eye contact during social interactions. Eye-tracking systems have been used to screen individuals with ASD by capturing atypical eye gaze patterns of diagnostic significance, such as reduced duration of eye gaze fixation on social information. However, most prior studies have focused on the screening accuracy of eye-tracking systems in children already diagnosed with ASD, with few longitudinal assessments conducted on a large scale. This large-scale, longitudinal, community-based study aimed to analyze the association between specific neurodevelopmental symptoms and the duration of eye gaze fixation on social information within a community-based setting. METHODS: A longitudinal study involving 2101 participants utilized a generalized linear model (GLM) to examine associations between the duration of eye gaze fixation on social information at age 4 years and subscale scores of the Strengths and Difficulties Questionnaire (SDQ) at ages 6-7. RESULTS: GLM analysis revealed that shorter durations of eye gaze fixation on social information at age 4 years were significantly associated with emotional problems and peer problems, and with hyperactivity/inattention attention-deficit hyperactivity disorder (ADHD) at ages 6-7 years. CONCLUSION: These findings demonstrate the ability to detect not only peer problems characteristic of ASD but also hyperactivity/inattention characteristic of ADHD longitudinally, which it might be related to the comorbidity of ASD and ADHD. This preliminary study highlights the potential for neurodevelopmental screening; however, further research is needed to validate the accuracy of these methods.

Adverse pregnancy outcomes (APOs) affect approximately 20% pregnant women, and their incidence is increasing. The aim of this study was to investigate the effect of cardiovascular health (CVH) during pregnancy on APOs. We analyzed data from 14,930 pregnant women in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. CVH status during pregnancy was assessed using the eight components of Life's Essential 8. APOs were defined as composite outcomes encompassing preeclampsia, gestational diabetes mellitus, preterm birth, and small for gestational age. The numbers of participants with high, moderate, and low CVH status were 2891 (19.4%), 11,498 (77.0%), and 541 (3.6%), respectively. Poisson regression analyses with robust error variance, which adjusted for maternal age at conception, alcohol consumption, conception via in vitro fertilization, parity, psychological distress, social isolation, and household income, showed a positive association between moderate and low CVH levels and APOs (risk ratio and 95% confidence interval 1.15 [1.03-1.28] and 2.14 [1.78-2.58], respectively). Among pregnant women with low CVH, those who reported social isolation had a higher prevalence of APOs than did those without social isolation (36.4% vs. 27.4%). This difference was attenuated for pregnant women with high CVH status (13.6% vs. 13.1%). In conclusion, CVH status may be useful for assessing the risk of APOs. Socially isolated pregnant women are more vulnerable to the effects of low CVH status.

Genomic information from pregnant women and the paternal parent of their fetuses may provide effective biomarkers for preeclampsia (PE). This study investigated the association of parental polygenic risk scores (PRSs) for blood pressure (BP) and PE with PE onset and evaluated predictive performances of PRSs using clinical predictive variables. In the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, 19,836 participants were genotyped using either Affymetrix Axiom Japonica Array v2 (further divided into two cohorts-the PRS training cohort and the internal-validation cohort-at a ratio of 1:2) or Japonica Array NEO (external-validation cohort). PRSs were calculated for systolic BP (SBP), diastolic BP (DBP), and PE and hyperparameters for PRS calculation were optimized in the training cohort. PE onset was associated with maternal SBP-, DBP-, and PE-PRSs and paternal SBP- and DBP-PRSs only in the external-validation cohort. Meta-analysis revealed overall associations with maternal PRSs but highlighted significant heterogeneity between cohorts. Maternal DBP-PRS calculated using "LDpred2" presented the most improvement in prediction models and provided additional predictive information on clinical predictive variables. Paternal DBP-PRS improved prediction models in the internal-validation cohort. In conclusion, Parental PRS, along with clinical predictive variables, is potentially useful for predicting PE.

Gestational diabetes mellitus (GDM) is common in Japanese women, posing serious risks to mothers and offspring. This study investigated the influence of maternal genotypes on the risk of GDM and examined how these genotypes modify the effects of psychological and dietary factors during pregnancy. We analyzed data from 20,399 women in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort. Utilizing two customized SNP arrays for the Japanese population (Affymetrix Axiom Japonica Array v2 and NEO), we performed a meta-analysis to combine the datasets. Gene-environment interactions were assessed by modeling interaction terms between genome-wide significant single nucleotide polymorphisms (SNPs) and psychological and dietary factors. Our analysis identified two SNP variants, rs7643571 (p = 9.14 × 10-9) and rs140353742 (p = 1.24 × 10-8), located in an intron of the MDFIC2 gene, as being associated with an increased risk of GDM. Additionally, although there were suggestive patterns for interactions between these SNPs and both dietary factors (e.g., carbohydrate and fruit intake) and psychological distress, none of the interaction terms remained significant after Bonferroni correction (p < 0.05/8). While nominal significance was observed in some models (e.g., psychological distress, p = 0.04), the data did not provide robust evidence of effect modification on GDM risk once adjusted for multiple comparisons. These findings reveal novel genetic associations with GDM in Japanese women and highlight the importance of gene-environment interactions in its etiology. Given that previous genome-wide association studies (GWAS) on GDM have primarily focused on Western populations, our study provides new insights by examining an Asian population using a population-specific array.

OBJECTIVES: Adiposity rebound (AR) corresponds to the start of the second rise in the body mass index curve during infant growth. Early AR (before age 5) confers increased risk of adiposity and metabolic disorders but is less likely to occur in breastfed infants. Although lipids in breast milk are important in child growth, information is limited regarding which lipids are involved in AR. The object of this study was to explore the association between breast milk lipids and AR status in children. METHODS: We designed a case-control study of 184 mother-child pairs (AR cases: n = 93; controls: n = 91) included from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Breast milk was collected 1 month postpartum and comprehensive lipid analysis was performed. Partial least square-discriminant analysis was used to explore candidate lipids, and multivariable logistic regression analysis was used to evaluate associations with the AR status of children. RESULTS: We detected 667 lipid molecules in 12 lipid classes in breast milk. Partial least square-discriminant analysis revealed the association of fatty acid-hydroxy fatty acid (FAHFA) and cholesterol ester (ChE) with AR status. Multivariable logistic regression analysis showed that in pairs with exclusive breastfeeding at 1 month postpartum, FAHFA (odds ratio 1.57 [95% confidence interval, 1.06-2.32]) was positively associated with early AR, and ChE (odds ratio 0.55 [95% confidence interval, 0.36-0.86]) was negatively associated. CONCLUSIONS: Breast milk lipids (FAHFA, ChE) associated with the AR status of children, indicating the potential to regulate a child's adiposity and possible metabolic disorders in adulthood.

BACKGROUND: Adiposity rebound (AR) is the point when the body mass index (BMI) begins to rise again during early childhood. Early AR (before age 5) is associated with a higher risk of lifelong obesity and metabolic disorders and may be influenced by breastfeeding. Although human milk oligosaccharides (HMOs) in breast milk are crucial for child growth, their association with AR status has not been studied. OBJECTIVE: To explore breast milk HMO compositions and molecules associated with AR status in children. METHODS: In this case-control study, we included 184 mother-child pairs from the Tohoku Medical Megabank Project Birth and Three-Generation (TMM BirThree) Cohort Study (93 AR cases, 91 controls). Breast milk was collected 1 month postpartum, and the concentration of 15 HMO molecules and alpha-diversity index (Inverse Simpson index) were quantified. Wilcoxon's rank-sum test and partial least squares-discriminant analysis (PLS-DA) identified candidate HMOs, and multivariable logistic regression analysis evaluated associations between candidate HMOs and AR status. Analyses were stratified by maternal secretor status (secretor or non-secretor). RESULTS: In secretor mothers, multivariable logistic regression showed that the Inverse Simpson index (OR, 0.54 [95% CI, 0.36-0.82]), sum of sialic acid-bound HMOs (0.61 [0.41-0.91]), and 3'-sialyllactose (0.67 [0.46-0.98]) were inversely associated with early AR in a fully adjusted model. A trend of interaction between sialyl-lacto-N-tetraose a (LSTa) and maternal secretor status on AR was observed in a fully adjusted model (P-value for interaction = 0.051). CONCLUSIONS: Alpha diversity, sialic acid-bound HMOs, and 3'SL may be involved in inhibiting AR in children of secretor mothers, and a trend of interactive effect of LSTa among maternal secretor status on AR was indicated. These findings offer novel perspectives on the associations between breastfeeding and a child's adiposity as well as potential metabolic disorders later in life. REGISTRY NUMBER/WEBSITE: https://www.umin.ac.jp/ (trial registration number: UMIN000047160).

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: Studies investigating whether respiratory syncytial virus (RSV) infection, non-RSV respiratory infections, respiratory-related disorders, and non-respiratory-related disorders are associated with subsequent wheezing are limited in Japan. We aimed to elucidate the relationship between hospitalization for RSV infection, non-RSV respiratory infections, respiratory-related disorders, as well as non-respiratory-related disorders and subsequence wheezing in Japanese children. METHODS: This study included 7340 children and was conducted under the TMM BirThree Cohort Study (Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study). Data was collected from birth records and questionnaires. We categorized hospitalization history into five categories: "no hospitalization," hospitalizations for "RSV infection," "non-RSV respiratory infections," "respiratory-related disorders," and "non-respiratory-related disorders." The association of the five categories with later wheezing at 3 years of age was evaluated using multivariable logistic regression analysis. RESULTS: After adjusting for covariates, an association was shown between hospitalization under 2 years of age and later wheezing (odds ratio [OR] = 2.78; 95% confidence interval [CI] = 1.97-3.88 for "RSV infection"; OR = 2.61; 95% CI = 1.44-4.57 for "non-RSV respiratory infections"; and OR = 3.33; 95% CI = 2.43-4.54 for "respiratory-related disorders"). CONCLUSION: Hospitalization of children under 2 years of age for RSV infection as well as non-RSV respiratory infections and respiratory-related disorders were associated with subsequent wheezing.

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.

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.

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.

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.

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.

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.

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: 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.

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.

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: 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.

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.

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.

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.

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: 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.

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.

Examining plasma metabolic profiling during pregnancy and postpartum could help clinicians understand the risk factors for postpartum depression (PPD) development. This analysis targeted paired plasma metabolites in mid-late gestational and 1 month postpartum periods in women with (n = 209) or without (n = 222) PPD. Gas chromatogram-mass spectrometry was used to analyze plasma metabolites at these two time points. Among the 170 objected plasma metabolites, principal component analysis distinguished pregnancy and postpartum metabolites but failed to discriminate women with and without PPD. Compared to women without PPD, those with PPD exhibited 37 metabolites with disparate changes during pregnancy and the 1-month postpartum period and an enriched citrate cycle. Machine learning and multivariate statistical analysis identified two or three compounds that could be potential biomarkers for PPD prediction during pregnancy. Our findings suggest metabolic disturbances in women with depression and may help to elucidate metabolic processes associated with PPD development.

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: 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.

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.

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.

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.

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.

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 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: 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.

<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.

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.

<title>Abstract</title> <sec> <title>Background</title> Secondhand smoke by partners is a major source of exposure for non-smoking women. However, factors associated with smoking continuation and indoor smoking among pregnant women’s partners remain unknown. </sec> <sec> <title>Methods</title> We used data from 6348 partners of non-smoking pregnant women who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Japan from 2013 to 2017. Partners’ age, educational attainment, equivalent household income, and pregnant women’s smoking history (never, quitting before pregnancy awareness, quitting after pregnancy awareness) were used as explanatory variables. Multivariate logistic regression analyses were conducted to examine the associations between these variables and smoking continuation/indoor smoking of partners. </sec> <sec> <title>Results</title> Among 6348 partners, 2506 partners had been smokers at pregnancy awareness. Among them, the prevalence of smoking continuation after pregnancy awareness was 92.0%. Partners whose wives had quitted smoking after pregnancy awareness were less likely to continue smoking than partners whose wives had never smoked; the odds ratio was 0.57 (95% confidence interval, 0.41–0.80). Among partners who continued smoking, the prevalence of indoor smoking was 30.7%. Partners with ≤high school education were more likely to smoke indoors than partners with ≥university education; the odds ratio was 1.60 (95% confidence interval, 1.23–2.07). </sec> <sec> <title>Conclusions</title> Women’s smoking cessation after pregnancy awareness was associated with decreased risk of partners’ smoking continuation, and lower level of partners’ education was associated with increased risk of partners’ indoor smoking. </sec> <sec> <title>Key messages</title> Interventions for both women and their partners may be effective in reducing secondhand smoke exposure during pregnancy. </sec>

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

<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.

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 P < 5.0 × 10-8. Some of these loci were located within or near previously reported candidate genes for ASD: CDH5, CNTN5, CNTNAP5, DNAH17, DPP10, DSCAM, FOXK1, GABBR2, GRIN2A5, ITPR1, NTM, SDK1, SNCA, and SRRM4. Of these 65 significant chromosomal loci, rs11064685 located within the SRRM4 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.

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.

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.

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: Some studies in Western countries have suggested that education and income are differentially associated with different drinking patterns. This study aimed to examine the associations of education and income with heavy drinking and problem drinking among community-dwelling Japanese men. METHODS: A questionnaire survey was conducted in metropolitan areas in Japan from 2010 to 2011 among residents aged 25 to 50 years; valid responses were received from 2004 men. Drinking patterns were categorized as non-to-moderate drinking, non-problematic heavy drinking, and problem drinking. Multiple logistic regression analyses were conducted to determine whether educational attainment or income was associated with drinking patterns, after adjustment for age, marital status, working status, income/education, self-rated health, and psychological distress. RESULTS: The study population included 84.4% non-to-moderate drinkers, 8.9% non-problematic heavy drinkers, and 6.7% problem drinkers. Lower educational attainment (high school or less) was significantly associated with increased risks of both non-problematic heavy drinking (odds ratio [OR], 1.80; 95% confidence interval [CI], 1.21-2.67) and problem drinking (OR, 2.06; 95% CI, 1.34-3.16), compared with university education or higher. Lower income (lowest tertile) was significantly associated with a lower risk of non-problematic heavy drinking (OR, 0.66; 95% CI, 0.43-1.00), but not of problem drinking (OR, 0.80; 95% CI, 0.50-1.30), compared with the highest income tertile. CONCLUSIONS: These findings indicate that education and income are differentially associated with alcohol drinking patterns among community-dwelling Japanese men.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been used for risk stratification in heart failure or acute coronary syndrome, but the beyond 5-year predictive value of NT-proBNP for stroke remains an unsettled issue in Asian patients. The aim of the present study was to clarify this point.Methods and Results:We followed 1,198 participants (33.4% men; mean age, 60.5±11.1 years old) in the Japanese general population for a median of 13.0 years. A first stroke occurred in 93 participants. Referencing previous reports, we stratified participants according to NT-proBNP 30.0, 55.0, and 125.0 pg/mL. Using the NT-proBNP <30.0 pg/mL group as a reference, adjusted HR for stroke (95% CI) in the NT-proBNP 30.0-54.9-pg/mL, 55.0-124.9-pg/mL, and ≥125.0-pg/mL groups were 1.92 (0.94-3.94), 1.77 (0.85-3.66), and 1.99 (0.86-4.61), respectively. With the maximum follow-up period set at 5 years, the hazard ratio of the NT-proBNP≥125.0-pg/mL group compared with the <30.0-pg/mL group increased significantly (HR, 4.51; 95% CI: 1.03-19.85). On extension of the maximum follow-up period, however, the association between NT-proBNP and stroke risk weakened. CONCLUSIONS: NT-proBNP was significantly associated with an elevated stroke risk. Given, however, that the predictive power decreased with the number of years after NT-proBNP measurement, NT-proBNP should be re-evaluated periodically in Asian patients.

AIM: Few studies have addressed stroke risk factors in older populations, particularly among the old-old. We examined differences in traditional risk factors for stroke among the old-old compared with the young-old in community-dwelling Japanese adults. METHODS: We followed 2,065 residents aged ≥ 60 years who had no history of stroke. Traditional risk factors for stroke were obtained from a self-administered questionnaire at baseline. We classified participants into two age categories, 60-74 years (n=1,502) and ≥ 75 years (n=563), and assessed whether traditional risk factors were differentially associated with stroke incidence according to age category. Hazard ratios were calculated by the Cox proportional hazards model, adjusting for confounding factors and competing risk of death. RESULTS: During a median follow-up of 12.8 and 7.9 years, 163 and 111 participants aged 60-74 and ≥ 75 years, respectively, developed a first stroke. Hypertension was consistently associated with increased risk of stroke, regardless of age category. Diabetes mellitus was associated with increased risk of stroke in those aged 60-74 years (hazard ratio, 1.50; 95% confidence interval, 1.00-2.25), but not in those aged ≥ 75 years (hazard ratio, 0.65; 95% confidence interval, 0.33-1.29), with significant interaction by age (P=0.035). No traditional risk factor other than hypertension was associated with stroke among those aged ≥ 75 years. CONCLUSION: Those with hypertension had significantly higher stroke risk among old people, while diabetes mellitus was differentially associated with stroke according to age category. Our findings indicate the importance of different prevention strategies for stroke incidence according to age category.