Maternal diabetes and risk of offspring congenital heart diseases: the Japan Environment and Children's Study.

BACKGROUND: Few prospective cohort studies have examined the association between maternal diabetes, including pre-pregnancy and gestational diabetes, and the risk of congenital heart disease (CHD) in Asian offspring. METHODS: We examined the association between maternal diabetes and offspring CHD among 97,094 mother-singleton infant pairs in the Japan Environment and Children's Study (JECS) between January 2011 and March 2014. Odds ratios (OR) and 95% confidence intervals (CI) of offspring CHD based on maternal diabetes (pre-pregnancy diabetes and gestational diabetes) were estimated using logistic regression after adjusting for maternal age at delivery, pre-pregnancy body mass index (BMI), maternal smoking habits, alcohol consumption, annual household income, and maternal education. The diagnosis of CHD in the offspring was ascertained from the transcript of medical records. RESULTS: The incidence of CHD in the offspring was 1,132. Maternal diabetes, including both pre-pregnancy diabetes and gestational diabetes, was associated with a higher risk of offspring CHD: multivariable OR (95%CI) = 1.81 (1.40-2.33) for maternal diabetes, 2.39 (1.05-5.42) for pre-pregnancy diabetes and 1.77 (1.36-2.30) for gestational diabetes. A higher risk of offspring CHD was observed in pre-pregnancy BMI ≥25.0 kg/m2 (OR = 2.55, 95% CI: 1.74-3.75) than in pre-pregnancy BMI <25.0 kg/m2 (OR = 1.49, 95% CI: 1.05-2.10, p for interaction = 0.04). CONCLUSIONS: Maternal diabetes, including both pre-pregnancy and gestational, was associated with an increased risk of CHD in offspring.

Maternal Autistic Traits and Adverse Birth Outcomes.

Importance: Women with a high level of autistic traits in the general population may experience larger health disparities during pregnancy, particularly women diagnosed with autism spectrum disorder (ASD), which in turn may be associated with increased risk of adverse birth outcomes. Objective: To investigate the association between maternal autistic traits and the risk of adverse birth outcomes in the general population. Design, Setting, and Participants: This cohort study included mothers of singletons from a nationwide, multicenter prospective birth cohort, the Japan Environmental Children's Study. Expecting mothers were recruited between January 2011 and March 2014. Data were analyzed between June 2021 and November 2023. Exposures: Autistic traits were self-reported during the second and third trimesters using the short form of the Autism-Spectrum Quotient Japanese version (AQ-J10) (score range, 0-10; clinical range, ≥7). Main Outcomes and Measures: Data on preterm birth (<37 weeks' gestation) and neonates born small for gestational age (SGA) were transcribed from medical records. Additional analysis of gestational age groups (very preterm birth, <32 weeks' gestation; moderate-to-late preterm birth, 32-36 weeks' gestation) was also performed. Results: Among 87 687 women (mean [SD] age, 31.2 [5.0] years) included in the study, 2350 (2.7%) had AQ-J10 scores within the clinical range yet only 18 (0.02%) were diagnosed with ASD. A higher AQ-J10 score was associated with an increased risk of all birth outcomes, including preterm births (relative risk [RR] per 1-SD increase, 1.06; 95% CI, 1.03-1.09), moderate-to-late preterm births (RR per 1-SD increase, 1.05; 95% CI, 1.01-1.08), very preterm births (RR per 1-SD increase, 1.16; 95% CI, 1.06-1.26), and child born SGA (RR per 1-SD increase, 1.04; 95% CI, 1.01-1.06) after adjusting for maternal and pregnancy-related factors. The risks of all outcomes increased with higher AQ-J10 scores; compared with women below the clinical range, women within the clinical range had greater risk of preterm births (RR, 1.16; 95% CI, 1.07-1.26), moderate-to-late preterm births (RR, 1.12; 95% CI, 1.03-1.22), very preterm births (RR, 1.49; 95% CI, 1.18-1.89), and a child born SGA (RR, 1.11; 95% CI, 1.04-1.19). Conclusions and Relevance: In this cohort study, higher level of maternal autistic traits was associated with increased risk of adverse birth outcomes, particularly very preterm birth. Acknowledging the risks and providing tailored and timely antenatal care support to women with a high level of autistic traits in the general population, particularly women with autistic traits within the clinical range, regardless of formal diagnosis, is warranted.

Neurodevelopmental outcomes at age 3 years after moderate preterm, late preterm and early term birth: the Japan Environment and Children's Study.

OBJECTIVE: To assess the association between gestational age classification at birth and the risk of neurodevelopmental impairments at age 3 years. DESIGN: Cohort study using the Japan Environment and Children's Study database. PATIENTS: A total of 86 138 singleton children born without physical abnormalities at 32-41 weeks of gestation enrolled between January 2011 and March 2014. MAIN OUTCOME MEASURES: Neurodevelopmental impairment, evaluated using the Ages and Stages Questionnaire (third edition). METHODS: Logistic regression analysis was used to evaluate the risk of neurodevelopmental impairment in moderate preterm, late preterm and early term children compared with term children after adjusting for socioeconomic and perinatal factors. RESULTS: The respective adjusted ORs (95% CIs) of incidence of scores below the cut-off value (<-2.0 SD) at age 3 years for moderate preterm, late preterm and early term births, compared with full-term births, were as follows: communication, 2.40 (1.54 to 3.73), 1.43 (1.19 to 1.72) and 1.11 (1.01 to 1.21); gross motor, 2.55 (1.69 to 3.85), 1.62 (1.36 to 1.93) and 1.20 (1.10 to 1.30); fine motor, 1.93 (1.34 to 2.78), 1.55 (1.35 to 1.77) and 1.08 (1.01 to 1.15); problem solving, 1.80 (1.22 to 2.68), 1.36 (1.19 to 1.56) and 1.07 (1.00 to 1.14) and personal-social, 2.09 (1.29 to 3.40), 1.32 (1.07 to 1.63) and 1.00 (0.91 to 1.11). CONCLUSION: Moderate preterm, late preterm and early term births were associated with developmental impairment at age 3 years compared with full-term births, with increasing prematurity. Careful follow-up of non-full-term children by paediatricians and other healthcare providers is necessary for early detection of neurodevelopmental impairment and implementation of available intervention.

The association between constipation and subsequent risk of atopic dermatitis in children: the Japan Environment and Children's Study.

BACKGROUND: No study has examined the association between constipation and atopic dermatitis (AD) in infants and toddlers. We aimed to explore that association in toddlers using the data from a nationwide birth cohort study. METHODS: From the Japan Environment and Children's Study, a nationwide prospective birth cohort study that began in 2011, children born in a singleton live birth were analyzed. Participants completed questionnaires containing questions related to bowel movements and AD, during 1.5 to 3 years after birth. Constipation at 1 year of age was defined as having ≤2 bowel movements per week. AD was defined based on participant's responses to the modified ISAAC questionnaire and/or self-reported physician's diagnosis. Outcome was defined as the cumulative number of AD cases that occurred until 3 years of age. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for development of AD were calculated by a multivariable logistic regression. RESULTS: From a total of 62,777 participants who met the study inclusion criteria, 14,188 children (22.6%) were affected by AD between the ages of 1.5 and 3 years. The adjusted OR of developing AD for the presence versus absence of constipation at 1 year of age was 1.18 (95% CI, 1.01-1.38). CONCLUSION: Constipation at 1 year of age was associated with a slightly higher risk of AD until 3 years of age.

Prenatal exposure to selenium, mercury, and manganese during pregnancy and allergic diseases in early childhood: The Japan Environment and Children's study.

BACKGROUND: Prenatal exposure to metallic elements may adversely affect early childhood health. However, more evidence is needed as population-based cohort studies are currently limited. OBJECTIVES: We aimed to examine the associations between prenatal metallic (mercury, selenium, and manganese) exposure and the risk of allergic diseases in early childhood until three years of age. METHODS: The data from 94,794 mother-infant pairs, who participated in the Japan Environment and Children's study, were used in this study. Prenatal metallic element exposure was measured in maternal blood collected during mid-pregnancy. The incidence of atopic dermatitis, food allergies, asthma, and allergic rhinitis during the first three years of life was prospectively investigated using self-reports of physician-diagnosed allergies. A multivariable modified Poisson regression model was used to estimate the cumulative incidence ratio and their 95% confidence intervals of allergic diseases associated with prenatal exposure to mercury, selenium, and manganese. We further evaluated the interaction between mercury and selenium exposures in this association. RESULTS: We confirmed 26,238 cases of childhood allergic diseases: atopic dermatitis, food allergies, asthma, and allergic rhinitis in 9,715 (10.3%), 10,897 (11.5%), and 9,857 (10.4%), 4,630 (4.9%), respectively. No association was found between prenatal mercury or manganese exposure and the risk of allergic diseases. Prenatal selenium exposure was inversely associated with atopic dermatitis, food allergies, allergic rhinitis, and any allergic diseases, but not with asthma. These inverse associations were more pronounced for lower mercury exposures than for higher exposures. CONCLUSIONS: Our findings suggest that prenatal exposure to selenium may be beneficial for reducing the risk of atopic dermatitis, food allergies, allergic rhinitis, and any allergic diseases in early childhood, especially with lower prenatal mercury exposure.

Association between neonatal phototherapy and sleep: The Japan Environment and Children's Study.

This observational cohort study aimed to evaluate the association between the duration of neonatal phototherapy and sleep-and-wakefulness states at 1 month, 1.5 years, and 3 years of age. We analysed data from 77,876 infants using the Japan Environment and Children's Study, a nationwide birth cohort study. The participants were divided into three groups: no phototherapy, short phototherapy (1-24 h), and long phototherapy (>24 h). Multiple regression analysis was performed to assess the effect of phototherapy duration on infant sleep at each age after adjusting for potential risk factors. A longer duration of phototherapy was associated with a shorter sleep time over 24 h at 1 month of age (ß, -0.62; SE, -0.77 to -0.47) when compared with a shorter duration of, or no, phototherapy, following the adjustment of confounding factors. Contrastingly, the short duration group, when compared with the no phototherapy group, was associated with later sleep onset (ß, 0.04; SE, 0.00-0.08) and later sleep offset (ß, 0.05; SE, 0.01-0.09) at 1.5 years of age. We concluded that the duration of phototherapy may be transiently associated with sleep duration in infants, as emphasised by the shortening of the total sleep time per 24 h at 1 month of age.

Phototherapy and risk of developmental delay: the Japan Environment and Children's Study.

This observational cohort study aimed to examine the association between the duration of phototherapy for neonatal jaundice and the risk of developmental delay at 3 years of age using nationwide birth cohort data. Data from 76,897 infants were analyzed. We divided participants into four groups: no phototherapy, short phototherapy (1-24 h), long phototherapy (25-48 h), and very long phototherapy (> 48 h). The Japanese version of the Ages and Stages Questionnaire-3 was used to evaluate the risk of developmental delay at 3 years of age. Logistic regression analysis was performed to assess the impact of phototherapy duration on the prevalence of developmental delay. After adjustment for potential risk factors, a dose-response relationship was identified between the duration of phototherapy and Ages and Stages Questionnaire-3, and the differences were significant in four domains; odds ratio for communication delay was associated with short, long, and very long phototherapy = 1.10 (95% confidence interval 0.97-1.26), 1.32 (1.04-2.66), and 1.48 (1.11-1.98), respectively; for gross motor delay = 1.01 (0.89-1.15), 1.28 (1.03-2.58), and 1.26 (0.96-1.67); for problem solving delay = 1.13 (1.03-1.25), 1.19 (0.99-1.43), and 1.41 (1.11-1.79); and for personal social delay = 1.15 (0.99-1.32), 1.10 (0.84-1.44), and 1.84 (1.38-2.45). CONCLUSION: Longer duration of phototherapy is a predictive factor for developmental delay, making it important to avoid extended periods of phototherapy. However, whether it increases the prevalence of developmental delay remains unclear. WHAT IS KNOWN: • Phototherapy is a common treatment for neonatal jaundice, associated with both short-term and long-term complications. • However, an association between phototherapy and the prevalence of developmental delay has not been revealed in a large cohort study. WHAT IS NEW: • We identified that a long duration of phototherapy was a predictive factor for developmental delay at 3 years of age. • However, whether a long duration of phototherapy increases the prevalence of developmental delay remains unclear.

Association between gestational weight gain and risk of overweight at 3 years old: The Japan Environment and Children's Study.

BACKGROUND: It is unclear if gestational weight gain (GWG) increases the risk of children with overweight. OBJECTIVES: We examined the association between GWG and the risk of overweight in 3-year-old children in the Japanese nationwide birth cohort study. METHODS: Among 64 336 singleton births, we calculated the risk ratios (RRs) and 95% confidence intervals (95% CIs) of the association between GWG categories and children with overweight, following an adjustment of the confounding variables. RESULTS: GWG was positively associated with the risk of overweight among 3-year-old children. The multivariable RR (95% CI) was 1.21 (1.17-1.25) per 5 kg increase of the GWG. The multivariable RR (95% CI) for excessive GWG was 1.20 (1.12-1.28) and 1.27 (1.16-1.39) based on the modified Japanese and IOM criteria, respectively, compared to adequate GWG. The multivariable RR (95% CI) of overweight with children for inadequate versus adequate GWG was 0.83 (0.78-0.88) and 0.84 (0.79-0.89) based on the modified Japanese and IOM criteria, respectively. CONCLUSIONS: GWG was positively associated with a high risk of overweight at 3 years of age. The risk of offspring overweight was 20%-27% higher and 16%-17% lower with excessive GWG and inadequate GWG, respectively, compared to adequate GWG, based on the aforementioned criteria.

Association Between Interpregnancy Interval and Risk of Preterm Birth and Its Modification by Folate Intake: The Japan Environment and Children's Study.

BACKGROUND: Both short and long interpregnancy intervals (IPIs) have been associated with risk of preterm birth, but the evidence is limited in Asians. It is also uncertain whether the association is modified by dietary folate intake or folic acid supplementation during pregnancy. Thus, we examined associations between IPI and risk of preterm birth and effect modification of those associations by dietary intake of folate and supplementation with folic acid on the basis of a nationwide birth cohort study. METHODS: Among 103,062 pregnancies registered in the Japan Environment and Children's Study, 55,203 singleton live-birth pregnancies were included in the analysis. We calculated IPI using birth date, gestational age at birth of offspring, and birth data of the latest offspring. Odds ratios (ORs) and 95% confidence intervals (CIs) of the risk of preterm birth were estimated according to IPI categories. RESULTS: Both <6-month and ≥120-month IPIs were associated with an increased risk of preterm birth, compared with an 18-23-month IPI. The multivariable ORs were 1.63 (95% CI, 1.30-2.04) for <6-month and 1.41 (95% CI, 1.11-1.79) for ≥120-month IPIs. These associations were confined to women with inadequate intake of dietary folate and folic acid supplementation during pregnancy. Multivariable ORs were 1.76 (95% CI, 1.35-2.29) for <6-month IPI and 1.65 (95% CI, 1.24-2.19) for ≥120-month IPI. CONCLUSION: Both <6-month and ≥120-month IPIs were associated with an increased risk of preterm birth. These higher risks were confined to women with inadequate intake of dietary folate and folic acid supplementation during pregnancy.

The Duration of Neonatal Phototherapy and Allergic Disorders: The Japan Environment and Children's Study.

INTRODUCTION: Currently, the association between the duration of neonatal phototherapy and the risk of allergic disorders has not been reported. This observational cohort study aimed to examine the association between allergic disorders, including food allergies, that are present before 3 years of age and the duration of phototherapy using the nationwide birth cohort data. METHODS: The Japan Environment and Children's Study was a nationwide birth cohort study. Data of 77,064 infants aged 1 year, 1.5 years, 2 years, and 3 years were analyzed. We divided the participants into three groups: no phototherapy, short phototherapy (1-24 h), and long phototherapy (>24 h) and evaluated the cumulative incidence of allergic disorders before 3 years of age, including asthma, atopic dermatitis, and food allergies. Logistic regression analysis was performed to assess the impact of phototherapy duration on the cumulative incidence of allergic disorders. RESULTS: After adjustment for potential risk factors, long phototherapy was found to be positively associated with food allergies at age 2 years (OR: 1.16; 95% CI: 1.01-1.33) and all allergic disorders at age 3 years (OR: 1.12; 95% CI: 1.01-1.24), including food allergies (OR 1.18; 95% CI: 1.04-1.35). CONCLUSION: A long duration of neonatal phototherapy was positively associated with the risk of allergic disorders, especially food allergies.

Pregnancy outcomes after preterm premature rupture of membranes: The Japan Environment and Children's Study.

AIM: To evaluate the pregnancy outcomes of preterm premature rupture of membranes (preterm PROM; PPROM) by gestational age. METHODS: This cohort study analyzed data from the Japan Environment and Children's Study. Pregnancy outcomes were documented using descriptive statistics. Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of complications. RESULTS: Data were collected for 104 062 fetuses, and 99 776 were eligible for inclusion. The incidences of early (18-23 weeks) and late (24-36 weeks) PPROM were 0.1% (n = 102) and 1.2% (n = 1205), respectively. Of the 1307 cases, 66 (5.0%) resulted in miscarriage or stillbirth. Overall, 85.6% (1119/1307) resulted in preterm births, and 9.3% (122/1307) in term births. There was a higher incidence of oligohydramnios (OR 6.82, 95% CI 4.07, 11.4; OR 2.42, 95% CI 1.72, 3.40), intrauterine infection (OR 11.9, 95% CI 7.06, 19.9; OR 4.39, 95% CI 3.01, 6.41), cesarean delivery (OR 3.31, 95% CI 2.32, 4.71; OR 1.34, 95% CI 0.97, 1.85), placental abruption (OR 5.57, 95% CI 2.30, 13.5; OR 5.40, 95% CI 3.58, 8.14), and 5-min Apgar score <7 (OR 35.3, 95% CI 21.5, 57.9; OR 2.66, 95% CI 1.75, 4.05) for early and late, compared to no, PPROM, respectively. Miscarriage or stillbirth was higher in early (OR 5.84, 95% CI 3.72, 9.15) and lower in late (OR 0.21, 95% CI 0.06, 0.68) compared to those without PPROM. CONCLUSIONS: This study described the epidemiology of pregnancy outcomes of early (occurring at the limit of viability) and late PPROM.

Long-term outcomes of children with neonatal transfer: the Japan Environment and Children's Study.

This study aimed to evaluate the association of neonatal transfer with the risk of neurodevelopmental outcomes at 3 years of age. Data were obtained from the Japan Environment and Children's Study. A general population of 103,060 pregnancies with 104,062 fetuses was enrolled in the study in 15 Regional Centers between January 2011 and March 2014. Live-born singletons at various gestational ages, including term infants, without congenital anomalies who were followed up until 3 years were included. Neurodevelopmental impairment was assessed using the Ages and Stages Questionnaire, third edition (ASQ-3) at 3 years of age. Logistic regression was used to estimate the adjusted risk and 95% confidence interval (CI) for newborns with neonatal transfer. Socioeconomic and perinatal factors were included as potential confounders in the analysis. Among 83,855 live-born singletons without congenital anomalies, 65,710 children were studied. Among them, 2780 (4.2%) were transferred in the neonatal period. After adjustment for potential confounders, the incidence of neurodevelopmental impairment (scores below the cut-off value of all 5 domains in the ASQ-3) was higher in children with neonatal transfer compared with those without neonatal transfer (communication: 6.5% vs 3.5%, OR 1.42, 95% CI 1.19-1.70; gross motor: 7.6% vs 4.0%, OR 1.26, 95% CI 1.07-1.49; fine motor: 11.3% vs 7.1%, OR 1.19, 95% CI 1.03-1.36; problem solving: 10.8% vs 6.8%, OR 1.29, 95% CI 1.12-1.48; and personal-social: 6.2% vs 2.9%, OR 1.52, 95% CI 1.26-1.83).   Conclusion: Neonatal transfer was associated with a higher risk of neurodevelopmental impairment at 3 years of age. What is Known: • Neonatal transfer after birth in preterm infants is associated with adverse short-term outcomes. • Long-term outcomes of outborn infants with neonatal transfer in the general population remain unclear. What is New: • This study suggests that neonatal transfer at birth is associated with an increased risk of neurodevelopmental impairment. • Efforts for referring high-risk pregnant women to higher level centers may reduce the incidence of neonatal transfer, leading to improved neurological outcomes in the general population.

Relationships Between Reproductive History and Mortality From Cardiovascular Diseases Among Japanese Women: The Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC) Study.

BACKGROUND: Reproductive history has been addressed as a risk factor for cardiovascular disease (CVD). We examined the relationship between reproductive history and CVD mortality in Japanese women. METHODS: We followed 53,836 women without previous CVD or cancer history from 1988-1990 to 2009 in a prospective cohort study. Hazard ratios (HRs) and 95% confidence intervals (CIs) of CVD mortality were estimated according to the number of deliveries and maternal age at first delivery. RESULTS: During the follow-up, 2,982 CVD-related deaths were identified. There was U-shaped association between the number of deliveries and risk of CVD mortality with reference to three deliveries, although the excess risk of CVD mortality associated with ≥5 deliveries was of borderline statistical significance. The corresponding multivariable HRs were 1.33 (95% CI, 1.12-1.58) and 1.11 (95% CI, 0.99-1.24). In addition, higher CVD mortality was associated with maternal age ≥28 years at first delivery than maternal age of 24-27 years at first delivery. The multivariable HRs were 1.22 (95% CI, 1.10-1.36) for 28-31 years at first delivery and 1.26 (95% CI, 1.04-1.52) for ≥32 years at first delivery. Moreover, among women with ≥3 deliveries, maternal age ≥28 years at first delivery was associated with 1.2- to 1.5-fold increased CVD mortality. CONCLUSION: The number of deliveries showed a U-shaped association with risk of CVD mortality. Higher maternal age at first delivery was associated with an increased risk of CVD mortality, and excessive risk in women aged ≥28 years at first delivery was noted in those with ≥3 deliveries.