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.

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.

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 'Having behavioral problems' was defined by them being within a clinical range for internalizing behaviors (withdrawn, somatic complaints, anxious/depressed and emotionally reactive) and externalizing behaviors (attention problems and aggressive behaviors) at age 3.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

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

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

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

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

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.

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.

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.

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.

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

BACKGROUND: To investigate the use of calcineurin inhibitors (CNIs) in pregnant Japanese women and to evaluate their safety in infants. METHODS: Data were extracted from the claims database of the Japan Medical Data Center. The prevalence of CNIs was evaluated 180 days before pregnancy onset, during pregnancy, and within180-days post partum. We investigated the characteristics of the infants, including the presence of major malformations and their diagnoses, for 1 year after birth. RESULTS: A total of 91,865 pregnancies in 80,049 women were included. Fifty-three women were prescribed CNIs between 180-day before pregnancy onset and 180-day postpartum; 35 of the 53 women were prescribed the drugs during pregnancy, and 10 of their infants were born preterm. Three were diagnosed with major congenital malformations, such as patent ductus arteriosus. Six preterm infants presented with infant respiratory distress syndrome. CONCLUSIONS: No congenital anomalies were clearly attributable to the use of CNIs during pregnancy.

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

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.

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.

OBJECTIVE: When using administrative data, validation is essential since these data are not collected for research purposes and misclassification can occur. Thus, this study aimed to develop algorithms identifying pregnancy and to evaluate the validity of administrative claims data in Japan. METHODS: All females who visited the Tohoku University Hospital Department of Obstetrics in 2018 were included. The diagnosis, medical procedure, medication, and medical service addition fee data were utilized to identify pregnancy, with the electronic medical records set as the gold standard. Combination algorithms were developed using predefined pregnancy-related claims data with a positive predictive value (PPV) ≥80%. Sensitivity (SE), specificity (SP), PPV, and negative predictive value (NPV) with their corresponding 95% confidence intervals (CIs) were calculated for these combination algorithms. RESULTS: This study included 1,757 females with a mean age of 32.8 (standard deviation: 5.9) years. In general, the individual claims data were able to identify pregnancy with a PPV ≥80%; however, the number of pregnancies identified using a single claims data was limited. Based on the combination algorithm with all of the categories, including diagnosis, medical procedure, medication, and medical service addition, the calculated SE, SP, PPV, and NPV were 73.4% (95% CI: 71.2%-75.4%), 96.9% (95% CI: 89.3%-99.6%), 99.8%,(95% CI: 99.4%-100.0%), and 12.3% (95% CI: 9.6%-15.4%), respectively. CONCLUSIONS: The combination algorithm to identify pregnancy demonstrated a high PPV and moderate SE. The algorithm validated in this study is expected to accelerate future studies that aim to identify pregnancies and evaluate pregnancy outcome.

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.

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

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.

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

BACKGROUND 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.

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

<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>

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.

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

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.

Introduction: Evaluation of the safety of taking lamotrigine (LTG) during lactation in breastfed infants varies according to the information sources. As it is possible that prescribers may avoid prescribing LTG despite of it being one of the essential drugs, more information needs to be accumulated to facilitate its use. Materials and Methods: We retrospectively compared the safety of LTG during the lactation period in 20 pairs of mothers and infants with 20 pairs as the control group. Results: The mean dose of LTG in 20 mothers was 161.1 mg/day (range: 50-400 mg/day). None of the infants showed a neonatal withdrawal syndrome score of 2 or more up to 1 month after delivery. Although drowsiness (n = 3), skin rash (n = 11), jaundice (n = 8), heart murmur (n = 1), poor suckling (n = 1), and retractive breathing (n = 1) were observed in infants, none of these adverse events were serious and the infants recovered. Nineteen of 20 pairs could continue lactation until 1 month after delivery. One pair discontinued breastfeeding because of pain in the mother's nipples. All pairs could continue maternal medication. We then compared the results with those of the control group. There were no significant differences in the presence of adverse events between the LTG and control groups. Conclusion: These data suggest that taking low to moderate doses of LTG during the lactation period might be relatively safe, at least for a period of 1 month after delivery.

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.

Purpose: Spontaneous adverse drug reaction reporting is the foundation of postmarketing drug safety monitoring. The present study aimed to analyze and clarify the quality and characteristics of the Japanese Adverse Drug Event Report database (JADER) using the World Health Organization (WHO) documentation grading scheme and the vigiGrade completeness score. The characteristics of reports were described using both schemes simultaneously. The way of proper use of these two schemes was explored. Methods: The WHO documentation grading scheme and the vigiGrade completeness score were applied to the same dataset (JADER202001 dataset). Reports classified as high-quality under both assessment criteria were extracted, and the characteristics of these reports were analyzed. Results: Of the 607,361 adverse drug reaction reports analyzed, 52.8% were ‘well-documented reports’ with a vigiGrade completeness score &gt;0.8. Under the WHO documentation grading scheme, 328,702 reports (54.1%) were Grade 2 and 5,178 (0.9%) were Grade 3 (including rechallenge information). Among well-documented Grade 3 reports, classified as the highest quality, a high proportion of the adverse drug reaction reports were related to disorders of hematopoietic function resulting from anticancer drugs. Because a high proportion of the reports with rechallenge information were for anticancer drugs as suspect drugs, the WHO documentation grading scheme tended to extract reports regarding anticancer drugs as high quality. Conclusions: We conclude that the two schemes need to be used appropriately, depending on the purpose of analysis, the target adverse drug reactions, and suspect drugs.

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.

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

OBJECTIVE: Safety information regarding the use of medication, over-the-counter drugs, and supplements for Japanese children is scarce. The aim of this study was to clarify adverse drug reaction (ADR) experiences in children and consider the method to collect ADRs efficiently. METHODS: We conducted a questionnaire survey regarding the ADR experiences of 20,412 children who were attending a preschool or kindergarten in the cities of Warabi and Toda, Saitama Prefecture, in May 2013. RESULTS: Responses were received from the guardians of 15,076 children (49.5% girls; 8.2 ± 3.5 yr). A total of 196 guardians (1.3%) responded that their children had experienced ADRs. Among them, a total of 243 suspected drugs and 284 ADRs were reported. Of the 243 suspected drugs, 2.5% were associated with a vaccine. The most frequently reported medication, reaction, and "medication-reaction pair" were antibacterials for systemic use, rash, and "antibacterials for systemic use and rash," respectively. CONCLUSIONS: In this study, we clarified that there were many potential ADRs among children, but all "medication-reaction pairs" reported were consistent with adverse events reported in the clinical trials available in the prescribing information of each medication. This study provides data respective to the frequency of these adverse events in the general pediatric population. Additional education is needed to enlighten guardians of the importance to report ADRs through the Direct Patient Reporting System.

Purpose: The purpose of this study was to assess the differences between consumer (patient) and healthcare professional submissions of adverse drug reaction (ADR) reports associated with certain antiviral treatments in children. Material and Methods: We extracted ADR reports for children aged <20 years who received oseltamivir or similar drugs (zanamivir and amantadine) between April 2004 and May 2020 from the Japanese Adverse Drug Event Report database. Abnormal behavior after oseltamivir administration was reported frequently in the news in November 2005, and a Dear Healthcare Professional letter about abnormal behavior after oseltamivir use was issued on March 20, 2007. We compared the number of ADR reports by three periods: (1) before the news, (2) between the news and the letter, and (3) after the letter. These reports were tabulated and analyzed after stratification according to the reporter (healthcare professionals only, patients and healthcare professionals, patients only), patient age (<10 years, 10-19 years), and ADR (abnormal behavior, other ADRs). Results: For the reports from healthcare professionals only, the number of reports per quarter associated with oseltamivir was largest during the period between the news about abnormal behavior after oseltamivir use and publication of the Dear Healthcare Professional letter. The reports from patients only about abnormal behavior after oseltamivir use were first reported after publication of the letter. The proportions of reports from patients only about abnormal behavior with oseltamivir were 81.0% and 92.2% for ages <10 and 10-19 years, respectively. A ripple effect of increasing reports was observed with zanamivir or amantadine. Conclusion: Reports from patients only might increase in response to the media more than reports from healthcare professionals only or patients and healthcare professionals do. The ADR reports from patients must be carefully assessed from the perspective of when they were reported.

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.

The present study aimed to describe the trends and characteristics of adverse events following immunization (AEFI) reporting for children in the Japanese Adverse Drug Event Report database (JADER). We used 6280 AEFI reports for children aged <19 years among 504,407 ADR reports included in the JADER from 2004 to 2017. The number of AEFI reports gradually increased among children aged <10 years and was the highest in 2011 among children aged 10-19 years. The number of suspected vaccines per AEFI report increased after 2011 among children aged <10 years. The percentage of "death" and "did not recover" as AEFI outcomes reported were 4.3% and 3.7% among children aged <10 years and 0.2% and 21.1% among children aged 10-19 years, respectively. The most frequently reported vaccine-reaction pair was Haemophilus influenzae type b conjugate vaccine and pyrexia among children aged <10 years and recombinant adsorbed bivalent human papillomavirus-like particle vaccine and a loss of consciousness among children aged 10-19 years. It is necessary to consider the Weber effects to understand the trend and characteristics of AEFI reporting because pharmacovigilance activity regarding vaccination is not sufficient in Japan.

BACKGROUND: There are no reports on investigations of the characteristics of adverse drug reaction (ADR) reports for pediatric patients in the Japanese Adverse Drug Event Report database (JADER) and the utility of database for drug safety surveillance in these patients. METHOD: We aimed to evaluate ADR reports for pediatric patients in the JADER. We used spontaneous ADR reports included in the JADER since April 1, 2004, to December 31, 2017, which was downloaded in April 2018. In a total of 504,407 ADR reports, the number of spontaneous reports was 386,400 (76.6%), in which 37,534 (7.4%) were unknown age reports. After extraction of 27,800 ADR reports for children aged < 10 and 10-19 years, we excepted for ADR reports associated with a vaccine (n = 6355) and no-suspected drug reports (n = 86). A total of 21,359 (4.2%) reports were finally included in this analysis. RESULTS: More than half of the ADR reports were for children aged < 10 years. Approximately 30% of ADR reports had multiple suspected drugs, which did not differ by age. The percentages of fatal outcomes of ADRs among patients aged < 10 and 10-19 years were 4.7 and 3.9%, respectively. The most frequently reported drug, reaction, and drug-reaction pair were oseltamivir, abnormal behavior, and oseltamivir and abnormal behavior, respectively. CONCLUSION: We clarified the characteristics of ADR reports for Japanese children by using the JADER. ADR report databases, especially those for pediatric patients, are valuable pharmacovigilance tools in Japan and other countries. Therefore, a proper understanding of the characteristics of the ADR reports in the JADER is important. Additionally, potential signals for ADRs in pediatric patients should be monitored continuously and carefully.

Objective: To clarify changes in community pharmacists' knowledge, attitudes, and practice regarding the management of hypertension before and after attending educational interventions based on their self-report on a questionnaire survey.Method: We conducted questionnaire surveys regarding the management of hypertension with a sample of community pharmacists before and after educational interventions.Results: The proportions of pharmacists who knew the 2014 Japanese Society of Hypertension Guidelines, guidelines for home blood pressure measurement, reference values for hypertension based on clinic-measured blood pressure, and reference values for hypertension based on home-measured blood pressure after the educational interventions (59.3%, 41.4%, 75.1%, and 70.8% respectively) were significantly higher relative to those recorded before interventions (31.6%, 13.7%, 47.7%, and 25.4% respectively).Conclusions: These findings suggest that in-house training might increase the knowledge of community pharmacists regarding hypertension management.

Background The quality of adverse drug reaction reports can have a strong influence on the causality assessment or the detection of safety signals. Various methods have been used to evaluate the quality of adverse drug reaction reports. Objective We used the vigiGrade completeness score to evaluate the quality of the Japanese adverse drug event report database (JADER). Methods Among all reports in the JADER (cases received by regulatory authorities from April 2004 to November 2018), 427,797 cases that did not meet the exclusion criteria were analyzed using vigiGrade. An report was considered a 'well-documented' report if the completeness score > 0.8. For each dimension, the proportion of incomplete information was calculated. Main outcome measure Proportion of 'well-documented' reports. Results A total of 211,774 (49.5%) cases were classified as 'well-documented' reports. When classified by sender, 6240 out of 8257 cases (75.6%) from medical institutions were 'well-documented', while 205,534 out of 419,540 cases (49.0%) from pharmaceutical companies were categorized as such. 'Time-to-onset' could not be calculated in 173,027 (41.2%) cases from the pharmaceutical companies and in 1228 (14.9%) cases from medical institutions. Conclusion In the JADER, the proportion of 'well-documented' adverse drug reaction reports from medical institutions was higher than that from pharmaceutical companies, and reports from medical institutions could help to clarify generated safety signals. We also found that more than 40% of the reports from pharmaceutical companies did not include information that is considered essential for the evaluation of any causal relationship between suspected drugs and adverse drug reactions, which could pose challenges to the detection of safety signals.

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.

Objective: To clarify the present situation of home blood pressure (HBP) measurement among Japanese patients.Methods: A nationwide questionnaire survey regarding HBP measurement was conducted on patients aged 20 years or older who had visited 20 community pharmacies to have their prescriptions filled.Results: In total, 76.7% of 1,103 hypertensives and 40.9% of 1,106 normotensives had their own devices for HBP measurement. Compared with normotensives, a higher proportion of hypertensives recognized the guideline-based reference values for HBP and clinic BP. Compared with hypertensives who did not have a physician's recommendation, those who did more often had their own devices, recognized the guideline-based reference values for HBP, and measured HBP every day (70.4%, 1.5%, and 31.6% vs. 91.1%, 6.9%, and 65.4%, respectively). Among 793 hypertensives who measured HBP, a higher proportion of those with a physician's recommendation measured HBP according to optimal guideline-based procedures compared with those without. Among 560 hypertensives who recorded HBP readings, a higher proportion of those with a physician's recommendation (74.6%) showed all HBP readings to their physicians compared with those without (35.3%).Conclusions: Our findings suggest that physicians should recommend measuring HBP in accordance with the Japanese Society of Hypertension guidelines more aggressively, and provide more detailed explanations to patients regarding how to measure HBP.

<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>

PURPOSE: The dose of mycophenolate mofetil (MMF) used to prevent rejection after lung transplantation is often adjusted based on the 12-hour area under the concentration-time curve (AUC0-12) of mycophenolic acid (MPA). A limited sampling strategy (LSS) is useful to define the pharmacokinetic (PK) profiles of MPA and mycophenolic acid acyl glucuronide (AcMPAG). Therefore, this study aimed to design a LSS based on multiple linear regression for estimating the AUC0-12 of MPA and AcMPAG at the minimum blood sampling points in Japanese lung transplant patients with concomitant tacrolimus. METHODS: Forty-five lung transplantation recipients were enrolled in a PK study of MPA, mycophenolic acid glucuronide (MPAG), and AcMPAG. The plasma MPA, MPAG, and AcMPAG concentrations were determined just before and at 0.5, 1, 2, 4, 8, and 12 hours after dosing. The AUC0-12 of MPA and AcMPAG was calculated using a linear trapezoidal rule from the plasma concentration of each blood sampling time. LSS was used to develop models for estimated AUC in the model group (n = 23) and was evaluated in the validation group (n = 22). RESULTS: The best three time-point equation was 4.04 + 1.64·C1 + 3.08·C4 + 5.17·C8 for MPA, and -0.13 + 3.01·C1 + 3.51·C4 + 5.74·C8 for AcMPAG. The prediction errors (PE) and the absolute prediction errors (APE) were within the clinically acceptable ± 5% and 15% range, respectively (MPA: PE = 2.00%, APE = 11.66%, AcMPAG: PE = 0.98%, APE = 14.69%). The percentage of estimated AUC0-12 within ± 15% of the observed AUC0-12 was 77.27% for MPA and 81.82% for AcMPAG. CONCLUSION: LSS using three time-point (C1, C4, and C8) provides the most reliable and accurate simultaneous estimation of the AUC0-12 of MPA and AcMPAG in Japanese lung transplant patients.

BACKGROUND: The aim was to investigate the relationships between total sunitinib plasma concentrations (sunitinib plus its active metabolite; N-desethyl sunitinib) and clinical outcomes in Japanese patients with metastatic renal cell carcinoma (mRCC). METHODS: Twenty patients with mRCC were enrolled following treatment with sunitinib. To assess safety, the total sunitinib concentration range up to discontinuation of treatment and dosage reduction associated with adverse events within 6 weeks from initiating administration were analyzed. The longest administered sunitinib dosage was defined as the maintenance dose, and the relationship between total sunitinib concentration at the maintenance dosage and sunitinib efficacy was investigated. RESULTS: Total sunitinib concentration was significantly higher in patients who discontinued treatment or had dosage reduction due to adverse events within 6 weeks after initiation of sunitinib than in patients who continued treatment with the initial dosage. The time to treatment failure, progression-free survival, and overall survival were better in patients with total sunitinib concentrations < 50 ng/mL than in those with concentrations ≥ 50 ng/mL. CONCLUSIONS: The present study demonstrated that the effective range of total sunitinib concentration in Japanese patients with mRCC was lower than 50-100 ng/mL which was previously reported. These results indicate that therapeutic drug monitoring could maintain the therapeutic effect of sunitinib while minimizing adverse events by personalizing sunitinib dosages for Japanese patients with mRCC.