Medication use before and during pregnancy in Japan: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

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.

Genome-wide association study of nausea and vomiting during pregnancy in Japan: the TMM BirThree Cohort Study.

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.

Identifying key factors for predicting O6-Methylguanine-DNA methyltransferase status in adult patients with diffuse glioma: a multimodal analysis of demographics, radiomics, and MRI by variable Vision Transformer.

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

Development of phenotyping algorithms for hypertensive disorders of pregnancy (HDP) and their application in more than 22,000 pregnant women.

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

Hypertensive disorders of pregnancy, neonatal outcomes and offspring developmental delay in Japan: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

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.

Association between Maternal Birth Weight and Prevalence of Congenital Malformations in Offspring: The Japanese Environment and Children's Study.

Congenital malformations are functional and structural alterations in embryonic or foetal development resulting from a variety of factors including maternal health status. This study aimed to investigate the association between maternal birth weight (MBW) and the prevalence of congenital malformations in offspring using data from a nationwide birth cohort study in Japan including 103,060 pregnancies. A binary logistic regression model with adjustment for various covariates revealed that an MBW of <2500 g (low MBW) was associated with an increased risk of congenital heart disease (adjusted odds ratio: 1.388, [95% confidence interval: 1.075-1.792]), angioma (1.491 [1.079-2.059]), and inguinal hernia (1.746, [1.189-2.565]), while those with an MBW of ≥4000 g (high MBW) were associated with congenital anomalies of the urinary tract (2.194, [1.261-3.819]) and arrhythmia (1.775, [1.157-2.725]) compared with those with an MBW of 3000-3499 g. Low MBW was associated with cleft lip and/or palate (1.473, [1.052-2.064]), congenital heart disease (1.615, [1.119-2.332]), genital organs (1.648, [1.130-2.405]), hypospadias (1.804, [1.130-2.881]), and inguinal hernia (1.484, [1.189-1.851]) in male infants and CAKUT (1.619, [1.154-2.273]) in female infants, whereas high MBW was associated with congenital heart disease (1.745, [1.058-2.877]) and CAKUT (2.470, [1.350-4.517]) in male infants. The present study is the first to demonstrate a link between MBW and congenital malformations in Japanese children. While these results must be interpreted with caution, MBW should be considered a major predictor of congenital malformation risk.

Progress report of the Tohoku Medical Megabank Community-Based Cohort Study: Study profile of the repeated center-based survey during second period in Miyagi Prefecture.

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

Relationships of Fat Mass Index and Fat-Free Mass Index with Low-Density Lipoprotein Cholesterol Levels in the Tohoku Medical Megabank Community-Based Cohort Study.

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

Maternal birth weight as an indicator of early and late gestational diabetes mellitus: The Japan Environment and Children's Study.

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

Relationship between traditional risk factors for hypertension and systolic blood pressure in the Tohoku Medical Megabank Community-based Cohort Study.

Risk factors for hypertension have been emphasized in the Japanese Society of Hypertension Guidelines for the Management of Hypertension. However, large-scale studies on the association of smoking, potassium excretion, and gamma-glutamyl transferase level with BP in the Japanese population are limited. We conducted a cross-sectional study to examine the association between hypertension risk factors and systolic blood pressure in the Tohoku Medical Megabank Community-based Cohort Study (23,446 men and 38,921 women aged ≥20 years). A model adjusted for age, body mass index, smoking status, drinking status, estimated daily salt intake, potassium excretion, (or urinary sodium-to-potassium ratio), gamma-glutamyl transferase, physical activity, education level, status of damage to homes during the Great East Japan Earthquake, and residential areas was used. The average age and systolic blood pressure were 62.5 (10.3) years for men and 59.6 (11.3) years for women, 128.9 (16.7) mmHg for men and 124.7 (17.5) mmHg for women, respectively. Body mass index estimated daily salt intake, urinary sodium-to-potassium ratio and gamma-glutamyl transferase levels were positively associated with systolic blood pressure. Compared with never-drinkers, current drinkers who consumed 23-45 g/day and ≥46.0 g/day had significantly increased systolic blood pressure. Conversely, current smokers (1-10 cigarettes/day and 11-20 cigarettes/day) were inversely associated with systolic blood pressure compared to never-smokers. Overall, systolic blood pressure was associated with gamma-glutamyl transferase and hypertension risk factors, including body mass index, alcohol consumption, estimated daily salt intake, urinary sodium-to-potassium ratio, and potassium excretion. Our findings support the notion that lifestyle modifications should be attempted to prevent hypertension.

The association between blood pressure control in women during pregnancy and adverse perinatal outcomes: the TMM BirThree Cohort Study.

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.

Risk of Major Congenital Malformations Associated with the Use of Japanese Traditional (Kampo) Medicine Containing Ephedra During the First Trimester of Pregnancy.

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.

The Population-Attributable Fractions of Small-for-Gestational-Age Births: Results from the Japan Birth Cohort Consortium.

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

Maternal social isolation and behavioral problems in preschool children: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

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.

The association between depressive symptoms and masked hypertension in participants with normotension measured at research center.

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

Association between frequency of breakfast intake before and during pregnancy and developmental delays in children: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

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.

Maternal birth weight as an indicator of early-onset and late-onset hypertensive disorders of pregnancy: The Japan Environment and Children's study.

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

Influence of Diabetes Family History on the Associations of Combined Genetic and Lifestyle Risks with Diabetes in the Tohoku Medical Megabank Community-Based Cohort Study.

AIM: The influence of family history of diabetes, probably reflecting genetic and lifestyle factors, on the association of combined genetic and lifestyle risks with diabetes is unknown. We examined these associations. METHODS: This cross-sectional study included 9,681 participants in the Tohoku Medical Megabank Community-based Cohort Study. A lifestyle score, which was categorized into ideal, intermediate, and poor lifestyles, was given. Family history was obtained through a self-reported questionnaire. A polygenic risk score (PRS) was constructed in the target data (n=1,936) using publicly available genome-wide association study summary statistics from BioBank Japan. For test data (n=7,745), we evaluated PRS performance and examined the associations of combined family history and genetic and lifestyle risks with diabetes. Diabetes was defined as non-fasting blood glucose ≥ 200 mmHg, HbA1c ≥ 6.5%, and/or self-reported diabetes treatment. RESULTS: In test data, 467 (6.0%) participants had diabetes. Compared with a low genetic risk and an ideal lifestyle without a family history, the odds ratio (OR) was 3.73 (95% confidence interval [CI], 1.92-7.00) for a lower genetic risk and a poor lifestyle without a family history. Family history was significantly associated with diabetes (OR, 3.58 [95% CI, 1.73-6.98]), even in those with a low genetic risk and an ideal lifestyle. Even among participants who had an ideal lifestyle without a family history, a high genetic risk was associated with diabetes (OR, 2.49 [95% CI, 1.65-3.85]). Adding PRS to family history and conventional lifestyle risk factors improved the prediction ability for diabetes. CONCLUSIONS: Our findings support the notion that a healthy lifestyle is important to prevent diabetes regardless of genetic risk.

Screen Time at Age 1 Year and Communication and Problem-Solving Developmental Delay at 2 and 4 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.