Fetal and infant growth patterns, sleep, and 24-h activity rhythms: a population-based prospective cohort study in school-age children.

The study objective was to explore associations of fetal and infant weight patterns and preterm birth with sleep and 24-h activity rhythm parameters at school-age. In our prospective population-based study, 1327 children were followed from birth to age 10-15 years. Fetal weight was estimated using ultrasound in the second and third trimester of pregnancy. Birth weight and gestational age were available from midwife registries. Infant weight was measured at 6, 12 and 24 months. Fetal and infant weight acceleration or deceleration were defined as a change of >0.67 standard deviation between the corresponding age intervals. At school-age, sleep duration, sleep efficiency, wake after sleep onset, social jetlag, inter-daily stability, and intra-daily variability were assessed using tri-axial wrist actigraphy for 9 consecutive nights. We observed that low birth weight (<2500 g) was associated with 0.24 standard deviation (95% confidence interval [CI] 0.04; 0.43) longer sleep duration compared to normal weight. Compared to normal growth, growth deceleration in fetal life and infancy was associated with 0.40 standard deviation (95% CI 0.07; 0.73) longer sleep duration, 0.44 standard deviation (95% CI 0.14; 0.73) higher sleep efficiency, and -0.41 standard deviation (95% CI -0.76; -0.07) shorter wake after sleep onset. A pattern of normal fetal growth followed by infant growth acceleration was associated with -0.40 standard deviation (95% CI -0.61; -0.19) lower inter-daily stability. Preterm birth was not associated with any sleep or 24-h rhythm parameters. Our findings showed that children with fetal and infant growth restriction had longer and more efficient sleep at school-age, which may be indicative of an increased need for sleep for maturational processes and development after a difficult start in life.

Body fat, cardiovascular risk factors and brain structure in school-age children.

BACKGROUND: In adults, cardiovascular risk factors are known to be associated with brain health. We hypothesized that these associations are already present at school-age. We examined the associations of adverse body fat measures and cardiovascular risk factors with brain structure, including volumetric measures and white matter microstructure, in 10-year-old children. METHODS: We performed a cross-sectional analysis in a population-based prospective cohort study in Rotterdam, the Netherlands. Analyses were based on 3098 children aged 10 years with neuroimaging data and at least one measurement of body fat and cardiovascular risk factors. Body fat measures included body mass index (BMI), fat mass index and android fat mass percentage obtained by Dual-energy X-ray absorptiometry. Cardiovascular risk factors included blood pressure, and serum glucose, insulin and lipids blood concentrations. Structural neuroimaging, including global and regional brain volumes, was quantified by magnetic resonance imaging. DTI was used to assess white matter microstructure, including global fractional anisotropy (FA) and mean diffusivity (MD). RESULTS: As compared to children with a normal weight, those with underweight had a smaller total brain and white matter volumes (differences -18.10 (95% Confidence Interval (CI) -30.97,-5.22) cm3, -10.64 (95% CI -16.82,-4.47) cm3, respectively). In contrast, one SDS (Standard Deviation Score) increase in fat mass index was associated with a smaller gray matter volume (differences -3.48 (95% CI -16.82, -4.47) cm3). Also, one SDS increase in android fat mass percentage was associated with lower white matter diffusivity (difference -0.06 (95% CI -0.10, -0.02) SDS). None of the other cardiovascular risk factors were associated with any of the brain outcomes. CONCLUSIONS: Body fat measures, but not other cardiovascular risk factors, were associated with structural neuroimaging outcomes in school-aged children. Prospective studies are needed to assess causality, direction and long-term consequences of the associations.

Associations of Arterial Thickness, Stiffness, and Blood Pressure With Brain Morphology in Early Adolescence: A Prospective Population-Based Study.

BACKGROUND: Arterial wall thickness and stiffness, and high blood pressure have been repeatedly associated with poorer brain health. However, previous studies largely focused on mid- or late-life stages. It is unknown whether any arterial health-related brain changes may be observable already in adolescence. METHODS: We examined whether (1) carotid intima-media thickness, (2) carotid distensibility, and (3) systolic blood pressure and diastolic blood pressure, measured at the age of 10 years, were associated with brain volumes and white matter microstructure (ie, fractional anisotropy and mean diffusivity) at the age of 14 years. In addition to cross-sectional analyses, we explored associations with longitudinal change in each brain outcome from 10 to 14 years. Analyses were based on 5341 children from the Generation R Study. RESULTS: Higher diastolic blood pressure was associated with lower total brain volume (ß, -0.04 [95% CI, -0.07 to -0.01]) and gray matter volume (ß, -0.04 [95% CI, -0.07 to -0.01]) at the age of 14 years, with stronger associations in higher diastolic blood pressure ranges. Similar associations emerged between systolic blood pressure and brain volumes, but these were no longer significant after adjusting for birth weight. No associations were observed between blood pressure and white matter microstructure or between carotid intima-media thickness or distensibility and brain morphology. CONCLUSIONS: Arterial blood pressure, but not intima-media thickness and distensibility, is associated with structural neuroimaging markers in early adolescence. Volumetric measures may be more sensitive to these early arterial health differences compared with microstructural properties of the white matter, but further studies are needed to confirm these results and assess potential causal mechanisms.

Compatibility of Commonly Used Active Pharmaceutical Ingredients in a Ready-to-Use Oral Suspending Vehicle.

The present study aimed to evaluate the stability of active pharmaceutical ingredients (APIs) from different pharmacological classes in a compounded oral suspending vehicle. Oral suspensions of amoxicillin trihydrate (50 mg/mL), clozapine (25 mg/mL), indomethacin (5.0 mg/mL), levodopa/carbidopa (10.0/2.5 mg/mL), levothyroxine sodium (T4, 25 µg/mL), lomustine (4.0 and 10.0 mg/mL), methyldopa (25 mg/mL) and procarbazine (10.0 mg/mL) were formulated in SyrSpend® SF PH4 and the stability was monitored for up to 90 days, except for amoxicillin trihydrate, which was evaluated for 30 days only. The APIs' stability was determined by measuring percent recovery using stability-indicating high-performance liquid chromatography (HPLC or UHPLC) or titration (amoxicillin trihydrate only). The stability of amoxicillin trihydrate, clozapine, indomethacin and levodopa/carbidopa were studied at both refrigerated (2-8 °C) and room temperature (20-25 °C). Lomustine, procarbazine, and methyldopa were studied at refrigerated temperature only. Our data demonstrated promising stability for the compounded suspensions containing various APIs, investigated in SyrSpend® SF PH4, as all APIs exhibited stability throughout the study duration and met content uniformity criteria. These findings lead to the conclusion that the tested compounded oral suspensions present a viable approach for creating personalized, age-appropriate formulations. The capacity to ensure dose consistency and stability using APIs from diverse pharmacological classes renders them suitable choices for both pediatric and geriatric patients.

Body fat, pericardial fat, liver fat and arterial health at age 10 years.

BACKGROUND: Body mass index is associated with carotid intima-media thickness and distensibility in adults and children. OBJECTIVE: To examine whether general and specific fat depots are associated with these markers of arterial health at school age. METHODS: This cross-sectional analysis was embedded in a population-based prospective cohort study among 4708 children aged 10 years. Body, lean and fat mass index were estimated by dual-energy X-ray absorptiometry. Pericardial, visceral and liver fat were estimated by magnetic resonance imaging. Carotid intima-media thickness and distensibility were measured by ultrasound. RESULTS: A 1-standard-deviation-score (SDS) higher body mass index was associated with higher carotid intima-media thickness (0.06 SDS, 95% confidence interval [CI]: 0.03-0.08) and lower distensibility (-0.17 SDS, 95% CI: -0.20 to -0.14). These associations tended to be similar for lean mass index. A 1-SDS higher fat mass index was associated with lower carotid intima-media thickness (-0.08 SDS, 95% CI: -0.11 to -0.05) and lower distensibility (-0.10 SDS, 95% CI: -0.14 to -0.07). A 1-SDS higher liver fat fraction was associated with lower carotid intima-media thickness (-0.04 SDS, 95% CI: -0.08 to -0.00) and lower distensibility (-0.06 SDS, 95% CI: -0.10 to -0.03). We observed similar associations for visceral fat. CONCLUSIONS: At school age, lean and fat mass seem to be differentially related to carotid intima-media thickness but not distensibility. Arterial development might be affected by lean mass, general and specific fat mass.

Infant weight growth patterns, childhood BMI, and arterial health at age 10 years.

OBJECTIVE: Associations of obesity with cardiovascular disease may originate in childhood. This study examined critical periods for BMI in relation to arterial health at school age. METHODS: Among 4,731 children from a prospective cohort study, associations of infant peak weight velocity, both age and BMI at adiposity peak, and BMI trajectories with carotid artery intima-media thickness and carotid artery distensibility at 10 years were examined. RESULTS: A 1-standard deviation score (SDS) higher peak weight velocity and BMI at adiposity peak were associated with higher intima-media thickness (0.10 SDS; 95% CI: 0.06 to 0.13 and 0.08 SDS; 95% CI: 0.05 to 0.12) and lower distensibility (-0.07 SDS; 95% CI: -0.10 to -0.03 and -0.07 SDS; 95% CI: -0.11 to -0.03) at 10 years. For distensibility, current BMI explained these associations. Children within the highest BMI tertile at ages 2 and 10 years had the lowest distensibility (p < 0.05), but similar intima-media thickness, compared with children constantly within the middle tertile. CONCLUSIONS: Infant weight growth patterns and childhood BMI are associated with subtle differences in carotid intima-media thickness and carotid distensibility at school age. For distensibility, current BMI seems critical. Follow-up is needed to determine whether these associations lead to adult cardiovascular disease.

Maternal Cardiovascular Health in Early Pregnancy and Childhood Brain Structure.

Background Poor cardiovascular health during pregnancy has been associated with adverse neurocognitive outcomes in the offspring. We examined the associations of maternal cardiovascular health factors with brain structure in 10-year-old children. Methods and Results We included 2797 mother-offspring pairs from the Generation R Study. Maternal body mass index, gestational weight gain, blood pressure, insulin, glucose, and lipid blood concentrations were obtained in early pregnancy. Childhood structural brain measures, including global metrics of brain tissue volumes and white matter microstructure, were quantified by magnetic resonance imaging at 10 years. As compared with offspring of mothers with normal weight, those of mothers with underweight had smaller total brain volume (difference, -28.99 [95% CI -56.55 to -1.45] cm3). Similarly, as compared with offspring of mothers with gestational weight gain between the 25th and 75th percentile, those of mothers with gestational weight loss or no gestational weight gain (<25th percentile), had smaller total brain volume (difference, -13.07 [95% CI, -23.82 to -2.32] cm3). Also, higher maternal diastolic blood pressure in early pregnancy was associated with lower offspring white matter mean diffusivity (difference, -0.07 [95% CI, -0.11 to -0.02] SD score). After multiple testing correction, only the association of maternal diastolic blood pressure with lower offspring white matter mean diffusivity remained statistically significant. No associations were observed of maternal insulin, glucose, and lipid concentrations with childhood brain outcomes. Conclusions Our findings suggest that maternal cardiovascular health during pregnancy might be related to offspring brain development in the long term. Future studies are needed to replicate our findings and to explore the causal nature of the associations.

Associations of Fetal and Infant Growth Patterns With Early Markers of Arterial Health in School-Aged Children.

Importance: Fetal life and infancy might be critical periods for predisposing individuals to develop cardiovascular disease in adulthood. Objective: To examine the associations of fetal and infant weight growth patterns with early markers of arterial health. Design, Setting, and Participants: This population-based prospective cohort study was conducted from early fetal life onward among 4484 offspring of women in Rotterdam, the Netherlands, delivering between April 1, 2002, and January 31, 2006. Statistical analysis was performed between January 1 and August 31, 2021. Exposures: Estimated fetal weight was measured in the second and third trimester. Data on weight and gestational age at birth were collected from midwives. Infant weight was measured at 6, 12, and 24 months. Main Outcomes and Measures: The common carotid intima-media thickness (cIMT) and carotid distensibility were measured as early markers of arterial health. Results: Follow-up measurements were available for 4484 children (2260 girls [50.4%]; median age, 9.7 years [95% range, 9.3-10.5 years]; and 2578 [57.5%] of Dutch ethnicity). Gestational age at birth was not associated with markers of arterial health. A 500-g-higher birth weight was associated with increased cIMT (standard deviation score [SDS], 0.08 mm [95% CI, 0.05-0.10 mm]) and a lower carotid distensibility (SDS, -0.05 × 10-3 kPa-1; [95% CI, -0.08 to -0.03 × 10-3 kPa-1]). Compared with children with a birth weight of 2500 to 4500 g, those weighing more than 4500 g had the lowest carotid distensibility (difference in SDS, -0.22 × 10-3 kPa-1 [95% CI, -0.42 to -0.02 × 10-3 kPa-1]). Conditional regression analyses showed that higher third-trimester fetal weight and birth weight were associated with increased cIMT (difference in SDS: third-trimester fetal weight, 0.08 mm [95% CI, 0.04-0.12 mm]; birth weight, 0.05 mm [95% CI, 0.01-0.09 mm]) and that higher weight at 6, 12, and 24 months was associated with increased cIMT (difference in SDS: 6 months, 0.05 mm [95% CI, 0.01-0.10 mm]; 12 months, 0.06 mm [95% CI, 0.02-0.10 mm]; and 24 months, 0.07 mm [95% CI, 0.03-0.11 mm]) and lower carotid distensibility (difference in SDS: 6 months, -0.04 × 10-3 kPa-1 [95% CI, -0.09 to -0.001 × 10-3 kPa-1]; 12 months, -0.05 × 10-3 kPa-1 [95% CI, -0.09 to -0.01 × 10-3 kPa-1]; and 24 months, -0.10 × 10-3 kPa-1 [95% CI, -0.15 to -0.06 × 10-3 kPa-1]). Compared with children with normal fetal and infant growth, children with normal fetal growth that was followed by accelerated infant growth had the highest cIMT (SDS, 0.19 mm [95% CI, 0.07-0.31 mm]) and lowest carotid distensibility (SDS, -0.16 × 10-3 kPa-1 [95% CI, -0.28 to -0.03 × 10-3 kPa-1]). The observed associations were largely explained by childhood body mass index. Conclusions and Relevance: In this cohort study of 4484 children aged approximately 10 years, higher fetal and infant weight growth patterns were associated with early markers of impaired arterial health. Childhood body mass index seemed to be involved in the underlying pathways of the observed associations.

Patterns of Fetal and Infant Growth and Brain Morphology at Age 10 Years.

Importance: Preterm birth and low birth weight are associated with brain developmental and neurocognitive outcomes in childhood; however, not much is known about the specific critical periods in fetal life and infancy for these outcomes. Objective: To examine the associations of fetal and infant growth patterns with brain morphology in children at school age. Design, Setting, and Participants: This population-based, prospective cohort study was conducted from February 1 to April 16, 2021, as a part of the Generation R Study in Rotterdam, the Netherlands. The study included 3098 singleton children born between April 1, 2002, and January 31, 2006. Exposures: Fetal weight was estimated in the second and third trimesters of pregnancy by ultrasonography. Infant weight was measured at birth and at 6, 12, and 24 months. Fetal and infant weight acceleration or deceleration were defined as a change in SD scores greater than 0.67 between time points. Infant measurements also included peak weight velocity, and age and body mass index reached at adiposity peak. Main Outcomes and Measures: Brain structure, including global and regional brain volumes, was quantified by magnetic resonance imaging at age 10 years. Results: The study evaluated 3098 children (mean [SD] age at follow-up, 10.1 [0.6] years; 1557 girls [50.3%]; and 1753 Dutch [57.8%]). One SD score-higher weight gain until the second and third trimesters, birth, and 6, 12, and 24 months was associated with larger total brain volume independently of growth during any other age windows (second trimester: 5.7 cm3; 95% CI, 1.2-10.2 cm3; third trimester: 15.3 cm3; 95% CI, 11.0-19.6 cm3; birth: 20.8 cm3; 95% CI, 16.4-25.1 cm3; 6 months: 15.6 cm3; 95% CI, 11.2-19.9 cm3; 12 months: 11.3 cm3; 95% CI, 7.0-15.6 cm3; and 24 months: 11.1 cm3; 95% CI, 6.8-15.4 cm3). Compared with children with normal fetal and infant growth, those with fetal and infant growth deceleration had the smallest total brain volume (-32.5 cm3; 95% CI, -53.2 to -11.9 cm3). Children with fetal weight deceleration followed by infant catch-up growth had similar brain volumes as children with normal growth. Higher peak weight velocity and body mass index reached at adiposity peak were associated with larger brain volumes. Similar results were observed for cerebral and cerebellar gray and white matter volumes. Conclusions and Relevance: This cohort study's findings suggest that both fetal and infant weight growth might be critical for cerebral and cerebellar brain volumes during childhood. Whether these associations link to neurocognitive outcomes should be further studied.

Phthalate and Bisphenol Urinary Concentrations, Body Fat Measures, and Cardiovascular Risk Factors in Dutch School-Age Children.

OBJECTIVE: The purpose of this study was to investigate the associations of urinary phthalates and bisphenols at age 6 years old with body fat and cardiovascular risk factors at 6 and 10 years and with the change from 6 to 10 years. METHODS: Among 471 Dutch children, the phthalates and bisphenols urinary concentrations at 6 years and BMI, fat mass index, android fat mass, blood pressure, glucose, insulin, and lipids blood concentrations at 6 and 10 years were measured. RESULTS: An interquartile range increase in di-n-octyl phthalate (DNOP) metabolites concentrations at 6 years was associated with an increased risk of overweight at 6 and 10 years (odds ratio: 1.44; 95% CI: 1.11-1.87, and 1.43; 95% CI: 1.09-1.86, respectively). Also, higher DNOP metabolites concentrations were associated with higher fat mass index at 6 years, higher systolic blood pressure at 10 years, a decrease in high-density lipoprotein cholesterol, and an increase in triglycerides concentrations from 6 to 10 years (P < 0.05). Higher total bisphenols and bisphenol A concentrations were associated with a decrease in BMI from 6 to 10 years (P < 0.01). CONCLUSIONS: DNOP metabolites are associated with overweight and an adverse cardiovascular profile in childhood. Total bisphenols and bisphenol A are associated with a decrease in BMI from 6 to 10 years.