Telomere length in early childhood and its association with attention: a study in 4-6 year old children.

Telomere length (TL), a marker of cellular aging, has been studied in adults with regard to its connection to cognitive function. However, little is known about the association between TL and cognitive development in children. This study investigated the interplay between TL and cognitive functioning in 283 Belgian children aged four to six years of the Environmental Influence on Aging in Early Life (ENVIRONAGE) birth cohort. Child leukocyte TL was measured using qPCR, while cognitive functioning, including attention and memory, was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Linear regression models were employed to examine the association between TL and cognitive outcomes, adjusting for potential confounders. We found an inverse association between TL and the spatial errors made during the Motor Screening task (p = 0.017), indicating a higher motor accuracy in children with longer telomeres. No significant associations were found between TL and other cognitive outcomes. Our results suggest a specific link between TL and motor accuracy but not with the other cognitive domains.

Cord Blood Proteomic Profiles, Birth Weight, and Early Life Growth Trajectories.

Importance: The cord blood proteome, a repository of proteins derived from both mother and fetus, might offer valuable insights into the physiological and pathological state of the fetus. However, its association with birth weight and growth trajectories early in life remains unexplored. Objective: To identify cord blood proteins associated with birth weight and the birth weight ratio (BWR) and to evaluate the associations of these cord blood proteins with early growth trajectories. Design, Setting, and Participants: This cohort study included 288 mother-child pairs from the ongoing prospective Environmental Influence on Early Aging birth cohort study. Newborns were recruited from East-Limburg Hospital in Genk, Belgium, between February 2010 and November 2017 and followed up until ages 4 to 6 years. Data were analyzed from February 2022 to September 2023. Main Outcomes and Measures: The outcome of interest was the associations of 368 inflammatory-related cord blood proteins with birth weight or BWR and with early life growth trajectories (ie, rapid growth at age 12 months and weight, body mass index [BMI] z score, waist circumference, and overweight at age 4-6 years) using multiple linear regression models. The BWR was calculated by dividing the birth weight by the median birth weight of the population-specific reference growth curve, considering parity, sex, and gestational age. Results are presented as estimates or odds ratios (ORs) for each doubling in proteins. Results: The sample included 288 infants (125 [43.4%] male; mean [SD] gestation age, 277.2 [11.6] days). The mean (SD) age of the child at the follow-up examination was 4.6 (0.4) years old. After multiple testing correction, there were significant associations of birth weight and BWR with 7 proteins: 2 positive associations: afamin (birth weight: coefficient, 341.16 [95% CI, 192.76 to 489.50]) and secreted frizzled-related protein 4 (SFRP4; birth weight: coefficient, 242.60 [95% CI, 142.77 to 342.43]; BWR: coefficient, 0.07 [95% CI, 0.04 to 0.10]) and 5 negative associations: cadherin EGF LAG 7-pass G-type receptor 2 (CELSR2; birth weight: coefficient, -237.52 [95% CI, -343.15 to -131.89]), ephrin type-A receptor 4 (EPHA4; birth weight: coefficient, -342.78 [95% CI, -463.10 to -222.47]; BWR: coefficient, -0.11 [95% CI, -0.14 to -0.07]), SLIT and NTRK-like protein 1 (SLITRK1; birth weight: coefficient, -366.32 [95% CI, -476.66 to -255.97]; BWR: coefficient, -0.11 [95% CI, -0.15 to -0.08]), transcobalamin-1 (TCN1; birth weight: coefficient, -208.75 [95% CI, -305.23 to -112.26]), and unc-5 netrin receptor D (UNC5D; birth weight: coefficient, -209.27 [95% CI, -295.14 to -123.40]; BWR: coefficient, -0.07 [95% CI, -0.09 to -0.04]). Further evaluation showed that 2 proteins were still associated with rapid growth at age 12 months (afamin: OR, 0.32 [95% CI, 0.11-0.88]; TCN1: OR, 2.44 [95% CI, 1.26-4.80]). At age 4 to 6 years, CELSR2, EPHA4, SLITRK1, and UNC5D were negatively associated with weight (coefficients, -1.33 to -0.68 kg) and body mass index z score (coefficients, -0.41 to -0.23), and EPHA4, SLITRK1, and UNC5D were negatively associated with waist circumference (coefficients, -1.98 to -0.87 cm). At ages 4 to 6 years, afamin (OR, 0.19 [95% CI, 0.05-0.70]) and SLITRK1 (OR, 0.32 [95% CI, 0.10-0.99]) were associated with lower odds for overweight. Conclusions and Relevance: This cohort study found 7 cord blood proteins associated with birth weight and growth trajectories early in life. Overall, these findings suggest that stressors that could affect the cord blood proteome during pregnancy might have long-lasting associations with weight and body anthropometrics.

Exploring mitochondrial heteroplasmy in neonates: implications for growth patterns and overweight in the first years of life.

BACKGROUND: Mitochondrial heteroplasmy reflects genetic diversity within individuals due to the presence of varying mitochondrial DNA (mtDNA) sequences, possibly affecting mitochondrial function and energy production in cells. Rapid growth during early childhood is a critical development with long-term implications for health and well-being. In this study, we investigated if cord blood mtDNA heteroplasmy is associated with rapid growth at 6 and 12 months and overweight in childhood at 4-6 years. METHODS: This study included 200 mother-child pairs of the ENVIRONAGE birth cohort. Whole mitochondrial genome sequencing was performed to determine mtDNA heteroplasmy levels (in variant allele frequency; VAF) in cord blood. Rapid growth was defined for each child as the difference between WHO-SD scores of predicted weight at either 6 or 12 months and birth weight. Logistic regression models were used to determine the association of mitochondrial heteroplasmy with rapid growth and childhood overweight. Determinants of relevant cord blood mitochondrial heteroplasmies were identified using multiple linear regression models. RESULTS: One % increase in VAF of cord blood MT-D-Loop16362T > C heteroplasmy was associated with rapid growth at 6 months (OR = 1.03; 95% CI: 1.01-1.05; p = 0.001) and 12 months (OR = 1.02; 95% CI: 1.00-1.03; p = 0.02). Furthermore, this variant was associated with childhood overweight at 4-6 years (OR = 1.01; 95% CI 1.00-1.02; p = 0.05). Additionally, rapid growth at 6 months (OR = 3.00; 95% CI: 1.49-6.14; p = 0.002) and 12 months (OR = 4.05; 95% CI: 2.06-8.49; p < 0.001) was also associated with childhood overweight at 4-6 years. Furthermore, we identified maternal age, pre-pregnancy BMI, maternal education, parity, and gestational age as determinants of cord blood MT-D-Loop16362T > C heteroplasmy. CONCLUSIONS: Our findings, based on mitochondrial DNA genotyping, offer insights into the molecular machinery leading to rapid growth in early life, potentially explaining a working mechanism of the development toward childhood overweight.

Prenatal particulate matter exposure is linked with neurobehavioural development in early life.

BACKGROUND: Early life exposure to ambient particulate matter (PM) may negatively affect neurobehavioral development in children, influencing their cognitive, emotional, and social functioning. Here, we report a study on prenatal PM2.5 exposure and neurobehavioral development focusing on different time points in the first years of life. METHODS: This study was part of the ENVIRONAGE birth cohort that follows mother-child pairs longitudinally. First, the Neonatal Behavioral Assessment Scale (NBAS) was employed on 88 newborns aged one to two months to assess their autonomic/physiological regulation, motor organisation, state organisation/regulation, and attention/social interaction. Second, our study included 393 children between the ages of four and six years, for which the Strengths and Difficulties Questionnaire (SDQ) was used to assess the children's emotional problems, hyperactivity, conduct problems, peer relationship, and prosocial behaviour. Prenatal PM2.5 exposure was determined using a high-resolution spatial-temporal method based on the maternal address. Multiple linear and multinomial logistic regression models were used to analyse the relationship between prenatal PM2.5 exposure and neurobehavioral development in newborns and children, respectively. RESULTS: A 5 µg/m³ increase in first-trimester PM2.5 concentration was associated with lower NBAS range of state cluster scores (-6.11%; 95%CI: -12.00 to -0.23%; p = 0.04) in one-to-two-month-old newborns. No other behavioural clusters nor the reflexes cluster were found to be associated with prenatal PM2.5 exposure. Furthermore, a 5 µg/m³ increment in first-trimester PM2.5 levels was linked with higher odds of a child experiencing peer problems (Odds Ratio (OR) = 3.89; 95%CI: 1.39 to 10.87; p = 0.01) at ages four to six. Additionally, a 5 µg/m³ increase in second-trimester PM2.5 concentration was linked to abnormal prosocial behaviour (OR = 0.49; 95%CI: 0.25 to 0.98; p = 0.04) at four to six years old. No associations were found between in utero PM2.5 exposure and hyperactivity or conduct problems. CONCLUSIONS: Our findings suggest that prenatal exposure to PM may impact neurobehavioural development in newborns and preschool children. We identified sensitive time windows during early-to-mid pregnancy, possibly impacting stage changes in newborns and peer problems and prosocial behaviour in children.

Exposure to Residential Green Space and Bone Mineral Density in Young Children.

Importance: Bone mass accrual is influenced by environmental and lifestyle factors. Targeted interventions at the early stages of life might decrease fracture and/or osteoporosis risk later in life. Objective: To investigate whether early-life exposure to residential surrounding green space is associated with a change in bone mineral density in young children. Design, Setting, and Participants: In this prospective birth cohort study (ENVIRONAGE [Environmental Influence on Aging in Early Life]), mother-child pairs from Flanders, Belgium, were recruited at birth and followed up for 4 to 6 years, between October 1, 2014, and July 31, 2021. Data analysis was conducted between January and February 2022. Exposures: Green space was estimated for high green (>3 m vegetation height), low green (≤3 m vegetation height ), and total green (sum of high and low) within several radii (100-3000 m) around the residence after geocoding of the addresses. Main Outcomes and Measures: Radial bone mineral density was assessed using quantitative ultrasound measurement at follow-up, measured as the mean of the axially transmitted speed of sound in meters per second. Multiple linear and logistic regression models were used while accounting for relevant covariates and potential confounders. Results: The study population comprised 327 children (180 [55.0%] female; mean [SD] age, 4.6 [0.4] years at the follow-up evaluation). Early-life exposure to residential green space was associated with increased childhood bone health. An IQR increment in total green (21.2%) and high green (19.9%) space within 500 m was associated with an increase of 27.38 m/s (95% CI, 9.63-45.13 m/s) and 25.30 m/s (95% CI, 7.93-42.68 m/s) in bone mineral density, respectively. Additionally, an IQR increase in total (25.2%) and high (23.2%) green space within 1000 m was associated with a 67% (odds ratio, 0.33; 95% CI, 0.17-0.61) and 61% (odds ratio, 0.39; 95% CI, 0.18-0.75) lower risk of having a bone density lower than the sex-specific 10th percentile (3567.6 m/s for girls and 3522.8 m/s for boys). Conclusions and Relevance: In this study of children aged 4 to 6 years, higher bone mineral density and a lower risk of having low bone density were associated with higher residential green space exposure during childhood. These findings highlight the importance of early-life exposure to residential green space on bone health during critical periods of growth and development, with long-term implications.

Exposure to endocrine disrupters and cardiometabolic health effects in preschool children: Urinary parabens are associated with wider retinal venular vessels.

BACKGROUND AND AIM: Parabens are widely used as antimicrobial preservatives in personal care products. Studies investigating obesogenic or cardiovascular effects of parabens show discordant results, while data on preschool children are lacking. Paraben exposure during early childhood could have profound cardiometabolic effects later in life. METHODS: In this cross-sectional study paraben concentrations [methyl (MeP), ethyl (EtP), propyl (PrP), butyl (BuP)] were measured by ultra-performance liquid chromatography/tandem mass spectrometry in 300 urinary samples of 4-6-year-old children of the ENVIRONAGE birth cohort. Paraben values below the limit of quantitation (LOQ) were imputed by censored likelihood multiple imputation. The associations between log-transformed paraben values and cardiometabolic measurements (BMI z-scores, waist circumference, blood pressure and retinal microvasculature) were analyzed in multiple linear regression models with a priori selected covariates. Effect modification by sex was investigated by including interaction terms. RESULTS: Geometric means (geometric SD) of urinary MeP, EtP, and PrP levels above the LOQ were 32.60 (6.64), 1.26 (3.45), and 4.82 (4.11) µg/L, respectively. For BuP more than 96% of all measurements were below the LOQ. Regarding the microvasculature, we found direct associations between MeP and central retinal venular equivalent (ß = 1.23, p = 0.039) and PrP with the retinal tortuosity index (x103)(ß = 1.75, p = 0.0044). Furthermore, we identified inverse associations between MeP and ∑parabens with BMI z-scores (ß = -0.067, p = 0.015 and ß = -0.070, p = 0.014 respectively), and EtP with mean arterial pressure (ß = -0.69, p = 0.048). The direction of association between EtP and BMI z-scores showed evidence for sex-specific differences with a direct trend in boys (ß = 0.10, p = 0.060). CONCLUSIONS: Already at young age paraben exposure is associated with potentially adverse changes in the retinal microvasculature.

Association of indoor dust microbiota with cognitive function and behavior in preschool-aged children.

BACKGROUND: Childhood cognitive development depends on neuroimmune interactions. Immunomodulation by early-life microbial exposure may influence neuropsychological function. In this study, we investigate the association between residential indoor microbiota and cognition and behavior among preschoolers. RESULTS: Indoor-settled dust bacterial and fungal characteristics were assessed using 16S and ITS amplicon sequencing (microbial diversity) and qPCR measurements (microbial loads). Child behavior was assessed using four scales: peer relationship, emotional, conduct, and hyperactivity was assessed by the Strengths and Difficulties Questionnaire (SDQ). Cognitive function was assessed using four tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB) software. The first two tasks were designed to assess attention and psychomotor speed (Motor Screening (MOT) and Big/Little Circle (BLC)) and the last two to evaluate the child's visual recognition/working memory (Spatial Span (SSP) and Delayed Matching to Sample (DMS)). Among the 172 included children (age 4-6 years), we observed a 51% (95%CI;75%;9%) lower odds of children scoring not normal for hyperactivity and a decrease of 3.20% (95%CI, -6.01%; -0.30%) in BLC response time, for every IQR increase in fungal Shannon diversity. Contrarily, microbial loads were directly associated with SDQ scales and response time. For example, a 2-fold increase in Gram-positive bacterial load was associated with 70% (95%CI 18%; 156%) higher odds of scoring not normal for hyperactivity and an increase of 5.17% (95%CI 0.87%; 9.65%) in DMS response time. CONCLUSIONS: Our findings show that early-life exposure to diverse indoor fungal communities is associated with better behavioral and cognitive outcomes, whereas higher indoor microbial load was associated with worse outcomes. Video Abstract.

In utero particulate matter exposure in association with newborn mitochondrial ND4L10550A>G heteroplasmy and its role in overweight during early childhood.

BACKGROUND: Mitochondria play an important role in the energy metabolism and are susceptible to environmental pollution. Prenatal air pollution exposure has been linked with childhood obesity. Placental mtDNA mutations have been associated with prenatal particulate matter exposure and MT-ND4L10550A>G heteroplasmy has been associated with BMI in adults. Therefore, we hypothesized that in utero PM2.5 exposure is associated with cord blood MT-ND4L10550A>G heteroplasmy and early life growth. In addition, the role of cord blood MT-ND4L10550A>G heteroplasmy in overweight during early childhood is investigated. METHODS: This study included 386 mother-newborn pairs. Outdoor PM2.5 concentrations were determined at the maternal residential address. Cord blood MT-ND4L10550A>G heteroplasmy was determined using Droplet Digital PCR. Associations were explored using logistic regression models and distributed lag linear models. Mediation analysis was performed to quantify the effects of prenatal PM2.5 exposure on childhood overweight mediated by cord blood MT-ND4L10550A>G heteroplasmy. RESULTS: Prenatal PM2.5 exposure was positively associated with childhood overweight during the whole pregnancy (OR = 2.33; 95% CI: 1.20 to 4.51; p = 0.01), which was mainly driven by the second trimester. In addition, prenatal PM2.5 exposure was associated with cord blood MT-ND4L10550A>G heteroplasmy from gestational week 9 - 13. The largest effect was observed in week 10, where a 5 µg/m3 increment in PM2.5 was linked with cord blood MT-ND4L10550A>G heteroplasmy (OR = 0.93; 95% CI: 0.87 to 0.99). Cord blood MT-ND4L10550A>G heteroplasmy was also linked with childhood overweight (OR = 3.04; 95% CI: 1.15 to 7.50; p = 0.02). The effect of prenatal PM2.5 exposure on childhood overweight was mainly direct (total effect OR = 1.18; 95% CI: 0.99 to 1.36; natural direct effect OR = 1.20; 95% CI: 1.01 to 1.36)) and was not mediated by cord blood MT-ND4L10550A>G heteroplasmy. CONCLUSIONS: Cord blood MT-ND4L10550A>G heteroplasmy was linked with childhood overweight. In addition, in utero exposure to PM2.5 during the first trimester of pregnancy was associated with cord blood MT-ND4L10550A>G heteroplasmy in newborns. Our analysis did not reveal any mediation of cord blood MT-ND4L10550A>G heteroplasmy in the association between PM2.5 exposure and childhood overweight.

Association of Newborn Telomere Length With Blood Pressure in Childhood.

Importance: Adult telomere length (TL) is a biological marker of aging associated with vascular health. TL at birth is associated with later life TL and may contain early biological information of later life cardiovascular health and disease. Objective: To evaluate whether newborn TL is associated with early life blood pressure differences in childhood. Design, Setting, and Participants: This cohort study was part of the ENVIRONAGE (Environmental Influence on Aging in Early Life) study, a birth cohort of Belgian mother-child pairs with recruitment at birth and a median follow-up of 4.5 years conducted between October 2014 and July 2021. Participants included for analysis provided full data for evaluation at follow-up visit. Data analysis was conducted between August and September 2021. Main Outcomes and Measures: Cord blood and placental average relative TL were measured at birth using quantitative polymerase chain reaction (qPCR). Systolic, diastolic, and mean arterial pressure (MAP) were evaluated at follow-up. High childhood blood pressure (standardized for child age, sex, and height) was defined following the 2017 American Academy of Pediatrics guidelines. Multivariable adjusted linear and logistic regression models were used to associate newborn TL and blood pressure indicators in childhood. Results: This study included 485 newborn children (52.8% girls) with a mean (SD) age of 4.6 (0.4) years at the follow-up visit. Newborn TL was associated with lower blood pressure in childhood. A 1-IQR increase in cord blood TL was associated with a -1.54 mm Hg (95% CI, -2.36 to -0.72 mm Hg) lower diastolic blood pressure and -1.18 mm Hg (95% CI, -1.89 to -0.46 mm Hg) lower MAP. No association was observed with systolic blood pressure. Furthermore, a 1-IQR increase in cord blood TL was associated with lower odds of having high blood pressure at the age of 4 to 6 years (adjusted OR, 0.72; 95% CI, 0.53 to 0.98). In placenta, a 1-IQR increase in TL was associated with a -0.96 mm Hg (95% CI, -1.72 to -0.21 mm Hg) lower diastolic, -0.88 mm Hg (95% CI, -1.54 to -0.22 mm Hg) lower MAP, and a lower adjusted OR of 0.69 (95% CI, 0.52 to 0.92) for having a high blood pressure in childhood. Conclusions and Relevance: In this prospective birth cohort study, variation in early life blood pressure at school-age was associated with TL at birth. Cardiovascular health may to some extent be programmed at birth, and these results suggest that TL entails a biological mechanism in this programming.

Early life exposure to residential green space impacts cognitive functioning in children aged 4 to 6 years.

INTRODUCTION: During early childhood, neuronal networks are highly susceptible to environmental factors. Previous research suggests that green space exposure is beneficial for cognitive functioning. Here, we investigate the associations between residential green space exposure and behavioral problems and cognitive development in children aged four to six years. METHOD: We included children participating in the ENVIRONAGE birth cohort. Residential green spaces were calculated based on high-resolution land cover data within several buffers (50-1,000 m) around the residence. The children's behavior was assessed with the Strengths and Difficulties Questionnaire (SDQ) among 411 children. In addition, to evaluate cognitive function, 456 children completed four tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB). We used multivariate logistic and linear regression models while accounting for potential confounders and covariables. RESULTS: An interquartile (IQR) increase of residential green space within 50 m was associated with a 38% (95% CI: 56;14) lower odds of a child having hyperactivity problems. Additionally, we found a beneficial influence of residential green space in close proximity (50-100 m) on the attention and psychomotor speed, represented by the Motor Screening Task. For example, we found a decrease of 0.45 (95% CI: -0.82;-0.09) pixel units from target center with an IQR increase of residential green space in a 50 m buffer. In addition, we observed an improved visual recognition/working memory, represented by the Delayed Matching to Sample Task within all included buffers (50-1000 m). For example, we observed a decrease of 4.91% (95 %CI: -7.46;-2.36) probability of an error occurring if the previous trial was correct and a 2.02% (95 %CI: 0.08; 3.97) increase of correct trials with an IQR increase of green space within a 100 m buffer. CONCLUSION: This study provides additional indications for a beneficial influence of green space exposure on the development of behavioral problems and cognitive function as young as four years of age.

Introducing nature at the work floor: A nature-based intervention to reduce stress and improve cognitive performance.

BACKGROUND: Although a growing body of research has shown that exposure to nature has restorative effects on human health, the potential beneficial effects of nature-based interventions in the working environment are still underexplored. METHODS: We performed a randomized controlled study with a nature-based program during working hours. We enrolled employees, randomized the participants into two groups being an intervention and a control group. Twice a week for three consecutive weeks, the intervention group participated in nature-based activities for 2 h. The primary outcomes were cognitive performance, burnout assessment, salivary cortisol levels, and continuous stress levels. We performed intervention-response analyses using mixed-effects models that included random effects for each participant across the different examinations. RESULTS: Compared to the control group (n = 20), the intervention group (n = 25) participating in the nature-based program had a lower Burnout Assessment Tool score (-14.9% CI-16.2 to -14.3, difference; p < 0.001), lower salivary cortisol levels (-29.3% CI-34.7 to -25.3; p < 0.001) and higher visual information processing speed (7.4% CI6.9-8.0; p < 0.001). Selective attention of the participants that participated in the nature-based program improved during the interventions (-10.6 CI-19.6 to -6.9, p = 0.045), compared to the controls. CONCLUSIONS: This study provides novel evidence that exposure to nature during work hours reduces stress and improves cognitive performance. The trial is registered with ClinicalTrials.gov, number: NCT04111796.

Different epigenetic signatures of newborn telomere length and telomere attrition rate in early life.

Telomere length (TL) and telomere shortening are biological indicators of aging, and epigenetic associates have been found for TL in adults. However, the role of epigenetic signatures in setting newborn TL and early life telomere dynamics is unknown. In the present study, based on 247 participating newborns from the ENVIRONAGE birth cohort, whole-genome DNA methylation, profiled on the Illumina MethylationEPIC BeadChip microarray, and TL were measured in cord blood. In a follow-up visit at a mean age of 4.58 years, leukocyte TL was evaluated. We combined an epigenome-wide association study and a statistical learning method with re-sampling to select CpGs and their two-way interactions to model baseline (cord blood) TL and early-life telomere attrition rate, where distinct epigenetic signatures were identified for the two outcomes. In addition, a stronger epigenetic regulation was suggested in setting newborn TL than that of telomere dynamics in early life: 47 CpGs and 7 between-CpG interactions explained 76% of the variance in baseline TLs, while 72% of the total variance in telomere attrition rate was explained by 31 CpGs and 5 interactions. Functional enrichment analysis based on the selected CpGs in the two models revealed GLUT4 translocation and immune cell signaling pathways, respectively. These CpGs and interactions, as well as the cellular pathways, are potential novel targets of further investigation of telomere biology and aging.

Association of Retinal Microvascular Characteristics With Short-term Memory Performance in Children Aged 4 to 5 Years.

Importance: Neurocognitive functions develop rapidly in early childhood and depend on the intrinsic cooperation between cerebral structures and the circulatory system. The retinal microvasculature can be regarded as a mirror image of the cerebrovascular circulation. Objective: To investigate the association between retinal vessel characteristics and neurological functioning in children aged 4 to 5 years. Design, Setting, and Participants: In this cohort study, mother-child pairs were recruited at birth from February 10, 2010, to June 24, 2014, and renewed consent at their follow-up visit from December 10, 2014, to July 13, 2018. Participants were followed up longitudinally within the prospective Environmental Influence on Aging in Early Life birth cohort. A total of 251 children underwent assessment for this study. Data were analyzed from July 17 to October 30, 2019. Main Outcomes and Measures: Retinal vascular diameters, the central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), vessel tortuosity, and fractal dimensions were determined. Attention and psychomotor speed, visuospatial working memory, and short-term visual recognition memory were assessed by the Cambridge Neuropsychological Test Automated Battery, including the following tasks: Motor Screening (MOT), Big/Little Circle (BLC), Spatial Span (SSP), and Delayed Matching to Sample (DMS). Results: Among the 251 children included in the assessment (135 girls [53.8%]; mean [SD] age, 4.5 [0.4] years), for every 1-SD widening in CRVE, the children performed relatively 2.74% (95% CI, -0.12 to 5.49; P = .06) slower on the MOT test, had 1.76% (95% CI, -3.53% to -0.04%; P = .04) fewer correct DMS assessments in total, and made 2.94% (95% CI, 0.39 to 5.29; P = .02) more errors given a previous correct answer in the DMS task on multiple linear regression modeling. For every 1-SD widening in CRAE, the total percentage of errors and errors given previous correct answers in the DMS task increased 1.44% (95% CI, -3.25% to 0.29%; P = .09) and 2.30% (95% CI, -0.14% to 4.61%; P = .07), respectively. A 1-SD higher vessel tortuosity showed a 4.32% relative increase in latency in DMS task performance (95% CI, -0.48% to 9.12%; P = .07). Retinal vessel characteristics were not associated with BLC and SSP test outcomes. Conclusions and Relevance: These findings suggest that children's microvascular phenotypes are associated with short-term memory and that changes in the retinal microvasculature may reflect neurological development during early childhood.

Association Between Maternal Prepregnancy Body Mass Index and Anthropometric Parameters, Blood Pressure, and Retinal Microvasculature in Children Age 4 to 6 Years.

Importance: Maternal prepregnancy body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) has previously been associated with offspring cardiometabolic risk factors, such as fat mass, glucose and insulin levels, and blood pressure, but these associations appear to be largely mediated by offspring BMI. To our knowledge, no studies have assessed alterations in the retinal microvasculature in association with maternal prepregnancy BMI. Objective: To investigate the association between maternal prepregnancy BMI and anthropometric parameters, blood pressure, and retinal vessel parameters in children age 4 to 6 years. Design, Setting, and Participants: Participants included mother-child pairs of the population-based Environmental Influence on Early Aging (ENVIRONAGE) birth cohort study (Flanders, Belgium) who were recruited at birth from February 2010 to June 2014 and followed-up at age 4 to 6 years between October 2014 and July 2018. Data were analyzed from February 2019 to April 2019. Exposures: Maternal prepregnancy BMI based on height and weight measurements at the first antenatal visit (weeks 7-9 of gestation). Main Outcomes and Measures: Children's anthropometric, blood pressure, and retinal microcirculation measurements at age 4 to 6 years. Retinal vessel diameters and the tortuosity index, a measure for the curvature of the retinal vasculature, were obtained by fundus image analysis. Results: This study included 240 mothers and children with a mean (SD) age of 29. 9 (4.2) years and 54.8 (4.7) months, respectively. Of these, 114 children (47.5%) were boys. Maternal prepregnancy BMI was positively associated with the child's birth weight, BMI, waist circumference, blood pressure, and retinal vessel tortuosity. A 1-point increase in maternal prepregnancy BMI was associated with a 0.26-mm Hg (95% CI, 0.08-0.44) higher mean arterial pressure for their children, with similar estimates for systolic and diastolic blood pressure. Independent from the association with blood pressure, a 1-point increase in maternal prepregnancy BMI was associated with a 0.40 (95% CI, 0.01-0.80) higher retinal tortuosity index (× 103). The hypothesis that these associations reflect direct intrauterine mechanisms is supported by the following observations: associations were independent of the current child's BMI and the estimates for paternal BMI at the follow-up visit did not reach significance. Conclusions and Relevance: Considering that blood pressure tracks from childhood into adulthood and microvascular changes may be early markers of cardiometabolic disease development, our results suggest that maternal prepregnancy BMI is an important modifiable risk factor for later-life cardiovascular health of the offspring.

Children's microvascular traits and ambient air pollution exposure during pregnancy and early childhood: prospective evidence to elucidate the developmental origin of particle-induced disease.

BACKGROUND: Particulate matter exposure during in utero life may entail adverse health outcomes later in life. The microvasculature undergoes extensive, organ-specific prenatal maturation. A growing body of evidence shows that cardiovascular disease in adulthood is rooted in a dysfunctional fetal and perinatal development, in particular that of the microcirculation. We investigate whether prenatal or postnatal exposure to PM2.5 (particulate matter with a diameter ≤ 2.5 µm) or NO2 is related to microvascular traits in children between the age of four and six. METHODS: We measured the retinal microvascular diameters, the central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE), and the vessel curvature by means of the tortuosity index (TI) in young children (mean [SD] age 4.6 [0.4] years), followed longitudinally within the ENVIRONAGE birth cohort. We modeled daily prenatal and postnatal PM2.5 and NO2 exposure levels for each participant's home address using a high-resolution spatiotemporal model. RESULTS: An interquartile range (IQR) increase in PM2.5 exposure during the entire pregnancy was associated with a 3.85-µm (95% CI, 0.10 to 7.60; p = 0.04) widening of the CRVE and a 2.87-µm (95% CI, 0.12 to 5.62; p = 0.04) widening of the CRAE. For prenatal NO2 exposure, an IQR increase was found to widen the CRVE with 4.03 µm (95% CI, 0.44 to 7.63; p = 0.03) and the CRAE with 2.92 µm (95% CI, 0.29 to 5.56; p = 0.03). Furthermore, a higher TI score was associated with higher prenatal NO2 exposure. We observed a postnatal effect of short-term PM2.5 exposure on the CRAE and a childhood NO2 exposure effect on both the CRVE and CRAE. CONCLUSIONS: Our results link prenatal and postnatal air pollution exposure with changes in a child's microvascular traits as a fundamental novel mechanism to explain the developmental origin of cardiovascular disease.

Establishing reference values for macro- and microvascular measurements in 4-to-5 year-old children of the ENVIRONAGE prospective birth cohort.

Cardiovascular risk factors are usually better tolerated, and can therefore be perceived as less harmful, at a young age. However, over time the effects of these adverse factors may persist or accumulate and lead to excess morbidity and mortality from cardiovascular diseases later in life. Until now, reference values for the basic cardiovascular health characteristics of 4-to-6 year-old children are lacking. Within a follow-up study of the ENVIRONAGE (ENVIRonmental influence ON early AGE) birth cohort we assessed various cardiovascular measurements in 288 children aged 4-5 years. For the macrovasculature, we measured their blood pressure and examined the intima-media thickness of the carotid artery (CIMT), the arterial elasticity (including the pulse-wave velocity (PWV), carotid distensibility (DC) and compliance (CC) coefficients), the carotid ß stiffness index (SIß) and Young's Elastic Modulus (YEM). Retinal microvascular traits included the Central Retinal Arteriolar Equivalent (CRAE) and Central Retinal Venular Equivalent (CRVE). Age of the study population averaged (±SD) 4.2 (±0.4 years. Mean systolic and diastolic blood pressure were 97.9 (±8.1) mmHg and 54.7(±7.6) mmHg, respectively. CIMT for the total population averaged 487.1 (±68.1) µm. The average stiffness values for DC, CC, SIß, and PWV were 78.7 (±34.2) 10-³/kPa, 1.61 (±0.59) mm2/kPa and 4.4 (±2.4), and 3.7 m/s (±0.9) respectively. The mean determined for YEM was 163.2 kPa (±79.9). Concerning the microvasculature, the average CRAE was 180.9 (±14.2) µm and the corresponding value for CRVE was 251.0 (±19.7) µm. In contrast to the macrovasculature, a significant gender-related difference existed for the microvasculature: in boys, both the CRAE (178.8 µm vs 182.6 µm; p = 0.03) and CRVE (247.9 µm vs 254.0 µm; p = 0.01) were narrower than in girls. We have provided reference values for young children to understand changes in the early cardiovascular health trajectory. Establishing these reference values of cardiovascular phenotypes at this young age is necessary to develop targeted health promotion strategies as well as for better understanding of the life course changes of both small and large blood vessels.