Associations between maternal pre-pregnancy BMI and infant striatal mean diffusivity.

BACKGROUND: It is well-established that parental obesity is a strong risk factor for offspring obesity. Further, a converging body of evidence now suggests that maternal weight profiles may affect the developing offspring's brain in a manner that confers future obesity risk. Here, we investigated how pre-pregnancy maternal weight status influences the reward-related striatal areas of the offspring's brain during in utero development. METHODS: We used diffusion tensor imaging to quantify the microstructure of the striatal brain regions of interest in neonates (N = 116 [66 males, 50 females], mean gestational weeks at birth [39.88], SD = 1.14; at scan [43.56], SD = 1.05). Linear regression was used to test the associations between maternal pre-pregnancy body mass index (BMI) and infant striatal mean diffusivity. RESULTS: High maternal pre-pregnancy BMI was associated with higher mean MD values in the infant's left caudate nucleus. Results remained unchanged after the adjustment for covariates. CONCLUSIONS: In utero exposure to maternal adiposity might have a growth-impairing impact on the mean diffusivity of the infant's left caudate nucleus. Considering the involvement of the caudate nucleus in regulating eating behavior and food-related reward processing later in life, this finding calls for further investigations to define the prognostic relevance of early-life caudate nucleus development and weight trajectories of the offspring.

Hair cortisol, cortisone and DHEA concentrations and the composition of microbiota in toddlers.

Animal research suggests that the gut microbiota and the HPA axis communicate in a bidirectional manner. However, human data, especially on early childhood, remain limited. In this exploratory design, we investigated the connections between long-term HPA axis functioning, measured as cortisol, cortisone or dehydroepiandrosterone concentrations and their ratios from hair segments of three centimeters, and gut microbiota profiles, (measured as diversity and bacterial composition by 16 S rRNA sequencing) in healthy 2.5-year-old toddlers (n = 135) recruited from the FinnBrain Birth Cohort Study. The alpha diversity of the microbiota was studied by linear regression. Beta diversity analyses with weighted UniFrac or Bray-Curtis distances were performed using PERMANOVA. The bacterial core genus level analyses were conducted using DESeq2 and ALDEx2. These analyses suggested that hair sample concentrations of separate hormones, cortisol/cortisone and cortisol/dehydroepiandrosterone ratios were associated with various gut bacterial genera such as the Veillonella, the [Ruminococcus] torques group and [Eubacterium] hallii group, although multiple testing correction attenuated the p-values. Alpha or beta diversity was not linked with either steroid concentrations or ratios. These findings in toddlers suggest that long-term HPA axis activity may be related to genera abundancies but not to ecosystem-level measures in gut microbiota. The influence of these observed interrelations on later child health and development warrants further research.

Investigating the role of relationship satisfaction and paternal psychological distress during pregnancy on offspring health in early life.

BACKGROUND: The research on the role of father in the foetal programming of health and behaviour has received increasing attention. However, the influences of paternal depressive symptoms and couple relationship satisfaction during pregnancy - potentially mediated via maternal well-being - on the offspring's risk of infections in early life is still seldom assessed. AIMS: The aim was to investigate if paternal psychological distress during pregnancy is associated with elevated risk of recurrent respiratory infections (RRIs) for offspring at 12 months of age, and whether maternal distress mediates the association between paternal distress and offspring RRIs. METHOD: The study population was drawn from the nested case-control cohort of the FinnBrain Birth Cohort Study. Children with RRIs (n = 50) were identified by maternal reports at the age of 12 months, whereas mothers did not report RRIs for the comparison group (n = 716). Parental depressive symptoms were measured with the Edinburgh Postnatal Depression Scale and couple relationship satisfaction was measured with the Revised Dyadic Adjustment Scale. RESULTS: The association between paternal depressive symptoms during pregnancy and offspring RRIs was mediated by maternal prenatal depressive symptoms. Additionally, paternal poorer relationship satisfaction was associated with child RRIs independently of maternal distress. CONCLUSIONS: The results suggest different pathways through which paternal distress during pregnancy may contribute to elevated risk of offspring RRIs, and more research is needed to study their underlying mechanisms. Paternal distress and couple relationship satisfaction during pregnancy should be assessed and screened as a contributor to offspring health.

Early-life environment and the risk of eczema at 2 years-Meta-analyses of six Finnish birth cohorts.

BACKGROUND: Urban-related nature exposures are suggested to contribute to the rising prevalence of allergic diseases despite little supporting evidence. Our aim was to evaluate the impact of 12 land cover classes and two greenness indices around homes at birth on the development of doctor-diagnosed eczema by the age of 2 years, and the influence of birth season. METHODS: Data from 5085 children were obtained from six Finnish birth cohorts. Exposures were provided by the Coordination of Information on the Environment in three predefined grid sizes. Adjusted logistic regression was run in each cohort, and pooled effects across cohorts were estimated using fixed or random effect meta-analyses. RESULTS: In meta-analyses, neither greenness indices (NDVI or VCDI, 250 m × 250 m grid size) nor residential or industrial/commercial areas were associated with eczema by age of 2 years. Coniferous forest (adjusted odds ratio 1.19; 95% confidence interval 1.01-1.39 for the middle and 1.16; 0.98-1.28 for the highest vs. lowest tertile) and mixed forest (1.21; 1.02-1.42 middle vs. lowest tertile) were associated with elevated eczema risk. Higher coverage with agricultural areas tended to associate with elevated eczema risk (1.20; 0.98-1.48 vs. none). In contrast, transport infrastructure was inversely associated with eczema (0.77; 0.65-0.91 highest vs. lowest tertile). CONCLUSION: Greenness around the home during early childhood does not seem to protect from eczema. In contrast, nearby coniferous and mixed forests may increase eczema risk, as well as being born in spring close to forest or high-green areas.

Test-retest reliability of diffusion tensor imaging scalars in 5-year-olds.

Diffusion tensor imaging (DTI) has provided great insights into the microstructural features of the developing brain. However, DTI images are prone to several artifacts and the reliability of DTI scalars is of paramount importance for interpreting and generalizing the findings of DTI studies, especially in the younger population. In this study, we investigated the intrascan test-retest repeatability of four DTI scalars: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in 5-year-old children (N = 67) with two different data preprocessing approaches: a volume censoring pipeline and an outlier replacement pipeline. We applied a region of interest (ROI) and a voxelwise analysis after careful quality control, tensor fitting and tract-based spatial statistics. The data had three subsets and each subset included 31, 32, or 33 directions thus a total of 96 unique uniformly distributed diffusion encoding directions per subject. The repeatability of DTI scalars was evaluated with intraclass correlation coefficient (ICC(3,1)) and the variability between test and retest subsets. The results of both pipelines yielded good to excellent (ICC(3,1) > 0.75) reliability for most of the ROIs and an overall low variability (<10%). In the voxelwise analysis, FA and RD had higher ICC(3,1) values compared to AD and MD and the variability remained low (<12%) across all scalars. Our results suggest high intrascan repeatability in pediatric DTI and lend confidence to the use of the data in future cross-sectional and longitudinal studies.

Maternal prenatal psychological distress associates with offspring early-life wheezing - FinnBrain Birth Cohort.

BACKGROUND: Exposure to prenatal maternal psychological distress may contribute to the development of childhood atopic disorders. Little is known about the importance of distress severity and its duration for the risk. Our aim was to investigate how chronic maternal depressive and anxiety symptoms across gestation influence the risk of wheezing and eczema at child age 24 months. METHODS: The study population was drawn from the FinnBrain Birth Cohort Study, including 1305 mother-infant dyads followed across gestation until the child age of 24 months when the outcomes were mother-reported wheezing ever and doctor-diagnosed eczema. To investigate the risk of wheezing phenotypes, wheezing with and without eczema was separated. Maternal distress was assessed with the Edinburgh Postnatal Depression Scale for depressive and the Symptom Checklist-90 for anxiety symptoms three times during pregnancy, and the chronicity was demonstrated using symptom trajectories composed by latent growth mixture modeling. RESULTS: Of the children, 219/1305 (17%) had wheezing ever and 285/1276 (22%) had eczema. Risk of wheezing ever was elevated with maternal consistently high depressive symptoms (adjusted odds ratio 2.74; 95% confidence interval 1.37-5.50) or moderate and increasing anxiety symptoms (1.94; 1.06-3.54, respectively). Similarly, wheezing without eczema was associated with consistently high depressive (3.60; 1.63-7.94, respectively) and moderate and increasing anxiety symptoms (2.43; 1.21-4.91, respectively). CONCLUSIONS: Maternal chronic psychological distress across gestation was associated with toddler wheezing and especially wheezing without other atopic features (eczema). This finding supports the theory of intrauterine programming effect by maternal psychological distress on offspring immune system and respiratory morbidity.

Prevalence and evolution of snoring and the associated factors in two-year-old children.

OBJECTIVES: To evaluate the prevalence and persistence of snoring during the first two years of life in two Finnish birth cohorts and to assess the associated factors. STUDY DESIGN: The study population comprised 947 children from the CHILD-SLEEP (CS) and 1393 children from the FinnBrain (FB) birth cohorts. Questionnaires were provided to both parents when the child was 24 months of age. The questionnaire consisted of parts concerning the child's sleep and environmental factors. RESULTS: The combined prevalence of habitual snoring in the two birth cohorts at the age of 24 months was 2.3% (95% CI 1.5-3.1), which is markedly lower than reported previously. Children suffering from recurrent infections (CS odds ratio (OR) 3.9, 95% CI 1.2-12.5) or asthma (FB OR 4.3, 1.4-13.5) snored habitually more often. Both the mother's (CS OR 3.2, 1.2-9.0) and father's (CS OR 3.4, 1.4-8.0) snoring every night added to the risk of the child snoring. In the multivariate models, parental snoring (CS adjusted odds ratio (ORa) 2.8, 1.1-6.8), the mother's lower level of education (CS ORa 2.9, 1.2-7.5, FB ORa 2.1, 1.0-4.5), and the mother's lower monthly income (FB ORa 2.9, 1.3-6.3) associated with the child's habitual snoring. CONCLUSIONS: The prevalence of habitual snoring in two Finnish birth cohorts is lower than reported previously. The independent risk factors for habitual snoring at the age of two years were the parents' snoring and the mother's low income and low education.

Interactions of genetic variants and prenatal stress in relation to the risk for recurrent respiratory infections in children.

Genetic variants may predispose children to recurrent respiratory infections (RRIs) but studies on genotype-environment interaction are rare. We hypothesized that the risk for RRIs is elevated in children with innate immune gene variants, and that prenatal exposure to maternal psychological distress further increases the risk. In a birth cohort, children with RRIs (n = 96) were identified by the age of 24 months and compared with the remaining cohort children (n = 894). The risk for RRIs in children with preselected genetic variants and the interaction between maternal distress during pregnancy and child genotype were assessed with logistic regression. The IL6 minor allele G was associated with elevated risk for RRIs (OR 1.55; 95% CI 1.14-2.12). Overall, there was no interaction between maternal psychological distress and child genotype. Exploratory analyses showed that, the association between the variant type of IL6 and the risk for RRIs was dependent on prenatal exposure to maternal psychological distress in males (OR 1.96; 95% CI 1.04-3.67). Our study didn't find genotype-environment interaction between prenatal maternal distress and child genotype. Exploratory analyses suggest sex differences in gene-environment interaction related to susceptibility to RRIs.

Gut microbiota diversity but not composition is related to saliva cortisol stress response at the age of 2.5 months.

Human brain and intestinal microbes reportedly maintain a constant bidirectional connection through diverse neural, endocrine, immune, and metabolic pathways. Increasing evidence indicates that this communication system, referred to as microbiota-gut-brain axis, enables the gut microbes to influence several aspects of brain function and behavior, including hypothalamic-pituitary-adrenal (HPA) axis stress responses, and on the other hand, stress can affect gut microbiota. However, the role of gut microbiota in the HPA axis functioning in humans remains to be specified especially in early life. This study aimed at identifying the potential link between the cortisol stress response and the gut microbiota at the age of 2.5 months. Fecal microbiota profiles were acquired by 16S rRNA gene sequencing, while salivary cortisol responses after an exposure to a mild acute stressor represented the HPA axis reactivity. We observed that a blunted cortisol stress response was weakly associated with a diverse gut microbiota diversity at the age of 2.5 months. Gut microbiota composition was not associated with cortisol stress responsiveness, but rather with covariates, i.e. factors that influence gut microbiota composition and colonization.LAY SUMMARYThis exploratory study aimed at identifying possible links between cortisol stress responses and fecal microbiota composition in early infancy. In a well-characterized study population of 2.5-month-old infants, we observed that an attenuated cortisol stress responsiveness after a mild stressor was weakly associated with a diverse fecal microbiota. Our results suggest that the gut microbiota composition is associated with environmental factors, such as delivery mode and number of siblings, rather than with cortisol stress responsiveness, in this age group.

Prenatal maternal distress associates with a blunted cortisol response in rhinovirus-positive infants.

INTRODUCTION: Prenatal exposure to maternal psychological distress (PD) may have programming effects on the fetus/infant hypothalamic-pituitary-adrenal (HPA) axis and subsequently on the development of the fetus' immune function. Therefore, our aim was to study whether prenatal exposure to PD is related to early infant HPA axis reactivity in the context of a subclinical rhinovirus infection that challenges infants HPA axis postnatally. METHODS: This study included 336 10-week-old infants from the nested case control Focus Cohort of the FinnBrain Birth Cohort Study. The outcome was infant HPA axis reactivity in a stress test. The acute stressor comprised of pediatric examination with venipuncture and nasal swabs for virus assessment. Saliva cortisol samples were collected at 5 time points: baseline, 0, 15, 25 and 35 min after the stressor. HPA axis reactivity was defined by the cumulative post-stressor cortisol concentration. RESULTS: HPA axis reactivity was blunted in the PD/rhinovirus + group compared to the average of control/rhinovirus+, PD/rhinovirus-, and control/rhinovirus- groups (difference: 14.7 ln [nmol/L] × min, 95% confidence interval 3.8-25.6, p = .008). HPA axis reactivity was significantly blunted only in boys with rhinovirus detected when separately tested for boys and girls (p = .04). CONCLUSION: Our finding of PD-exposed rhinovirus-positive infants having blunted cortisol secretion gives rise to a hypothesis that maternal PD during pregnancy influences infant HPA axis functioning and the functioning of the immune system. Future studies are needed to test whether this suppression of the HPA axis that co-occurs with rhinovirus infection associates with later disease development (e.g., asthma).

Pulmonary function and bronchial reactivity 4 years after the first virus-induced wheezing.

BACKGROUND: Wheezing illnesses among young children are common and are a risk factor for asthma. However, determinants of childhood bronchial reactivity, a key feature of asthma, are largely unknown. The aim of this study was to determine how patient characteristics during the first severe virus-induced wheezing episode are associated with pulmonary function at preschool age. METHODS: Study consisted of 76 children presenting with their first wheezing episode at the ages of 3 to 23 months. At study entry, viral etiology, rhinovirus genome load, atopic and clinical characteristics, and standardized questionnaire were analyzed. At 4-year follow-up visit, impulse oscillometry with exercise challenge was performed. RESULTS: At study entry, the mean age of the children was 12 months (SD 6.0), 57 (75%) were rhinovirus positive, and 22 (30%) were sensitized. At follow-up visit four years later, the mean age of the children was 60 months (SD 7.9) and 37 (49%) were using asthma medication regularly (discontinued before testing in 25 [68%] children). Bronchial reactivity (≥35% change in mean crude values of resistance) after exercise challenge or bronchodilation was present in nine (12%) children. Children with atopic sensitization at the time of the first wheezing episode were more often likely to develop bronchial reactivity (odds ratio 8.8, P = 0.03) than the children without sensitization. No other significant associations were found. CONCLUSIONS: Atopic sensitization at the time of the first severe wheezing episode is an important early risk factor for increased bronchial reactivity at preschool age.

Prednisolone for the first rhinovirus-induced wheezing and 4-year asthma risk: A randomized trial.

BACKGROUND: Previous findings show that corticosteroid treatment during the first acute wheezing episode may reduce recurrent wheezing in children with high rhinovirus genome load at 12-month follow-up. Longer-term effects have not been investigated prospectively. METHODS: After PCR confirmation of rhinovirus from nasopharyngeal aspirate, 79 children with the first acute wheezing episode were randomized to receive orally prednisolone or placebo for 3 days. The initiation of asthma control medication before the age of 5 years was confirmed from medical record and/or from parental interview. The outcome was the time to initiation of regular asthma control medication. Interaction analysis examined rhinovirus genome load. RESULTS: Fifty-nine (75%) children completed the follow-up. Asthma control medication was initiated in 40 (68%) children at the median age of 20 months. Overall, prednisolone did not affect the time to initiation of asthma control medication when compared to placebo (P=.99). Rhinovirus load modified the effect of prednisolone regarding the time to initiation of asthma control medication (P-value for interaction=.04). In children with high rhinovirus load (>7000 copies/mL; n=23), the risk for initiation of medication was lower in the prednisolone group compared to the placebo group (P=.05). In the placebo group, asthma medication was initiated to all children with high rhinovirus load (n=9) during the 14 months after the first wheezing episode. CONCLUSIONS: Overall, prednisolone did not affect the time to initiation of asthma control medication when compared to placebo. However, prednisolone may be beneficial in first-time wheezing children whose episode was severe and associated with high rhinovirus load. (ClinicalTrials.gov, NCT00731575).

Rhinovirus-induced first wheezing episode predicts atopic but not nonatopic asthma at school age.

BACKGROUND: Persistent childhood asthma is mainly atopy driven. However, limited data exist on the risk factors for childhood asthma phenotypes. OBJECTIVE: We sought to identify risk factors at the first severe wheezing episode for current asthma 7 years later and separately for atopic and nonatopic asthma. METHODS: One hundred twenty-seven steroid-naive children with the first severe wheezing episode (90% hospitalized/10% emergency department treated) were followed for 7 years. The primary outcome was current asthma at age 8 years, which was also analyzed separately as atopic and nonatopic asthma. Risk factors, including sensitization, viral cause, and other main asthma risk factors, were analyzed. RESULTS: At study entry, median age was 11 months (interquartile range, 6-16 months); 17% were sensitized, and 98% were virus positive. Current asthma (n = 37) at 8 years was divided into atopic (n = 19) and nonatopic (n = 18) asthma. The risk factors for current atopic asthma at study entry were sensitization (adjusted odds ratio [OR], 12; P < .001), eczema (adjusted OR, 4.8; P = .014), and wheezing with rhinovirus (adjusted OR, 5.0; P = .035). The risk factors for nonatopic asthma were the first severe respiratory syncytial virus/rhinovirus-negative wheezing episode (adjusted OR, 8.0; P = .001), first wheezing episode at age less than 12 months (adjusted OR, 7.3; P = .007), and parental smoking (adjusted OR, 3.8; P = .028). CONCLUSIONS: The data suggest diverse asthma phenotypes and mechanisms that can be predicted by using simple clinical markers at the time of the first severe wheezing episode. These findings are important for designing early intervention strategies for secondary prevention of asthma.

Exercise simultaneously increases nasal patency and bronchial obstruction in asthmatic children.

We found that simultaneous post-exercise increase in nasal patency and bronchial obstruction occurs only in children with atopic asthma, but not in sensitized children without asthma. In healthy children, the increase in nasal patency is accompanied by bronchial dilatation.

Physical exercise increases nasal patency in asthmatic and atopic preschool children.

BACKGROUND: Physical exercise causes a decrease in nasal mucosal congestion and hence an increase in nasal patency. This nasal response has been studied only in adults. A correlation between nasal obstruction and asthma or allergic rhinitis has been previously found. This study evaluates the influences of atopy and asthma on nasal patency and the changes in nasal patency induced by physical exercise in preschool children. METHODS: An 8-minute exercise challenge test was conducted in 31 children aged between 4.1 and 6.4 years: 13 children had asthma, 17 were atopic, and 13 had neither asthma nor atopy. Nasal patency was measured with acoustic rhinometry at baseline and 10 minutes after the exercise. RESULTS: At baseline, the total acoustic values were 17-25% larger in nonasthmatic children than in asthmatic children. Accordingly, the acoustic values in nonatopic children were 16-35% larger than in atopic children. After physical exercise, there was an overall increase in mean total nasal volume from 2.973 (SD = 0.647) to 3.405 cm(3) (SD = 0.705), indicating an improvement of 15% in nasal volume (p = 0.025). The increase in nasal patency was similar in asthmatic and nonasthmatic children, as well as in atopic and nonatopic children. CONCLUSION: A significant increase in total nasal volume after physical exercise was found in all preschool children. The minimal cross-sectional areas remained smaller in asthmatic and atopic children after exercise, indicating partly irreversible nasal mucosal congestion in these children.

Prednisolone reduces recurrent wheezing after first rhinovirus wheeze: a 7-year follow-up.

BACKGROUND: To better understand the role of human rhinovirus-associated wheeze as a risk factor for childhood recurrent wheezing, a cohort of young children experiencing their first wheezing episode was followed until school age. METHODS: All 111 hospitalized wheezing children (median age, 12 months) were initially participated in a randomized, double-blind, placebo-controlled, parallel trial on the efficacy of oral prednisolone. In this 7-yr follow-up, risk factors for recurrent wheezing were analysed, and then, the efficacy of prednisolone was evaluated overall and in pre-specified subgroups post-hoc. The main outcome was time to recurrent wheezing. RESULTS: The strongest independent risk factor for recurrent wheezing was rhinovirus detection (hazard ratio 3.54; 95% confidence interval 1.51-8.30) followed by sensitization (3.47; 1.55-8.30, respectively) age <1 yr (2.45; 1.29-4.65) and eczema (2.33; 1.11-4.90). Overall, prednisolone did not prevent recurrent wheezing. In subgroup analysis, prednisolone was associated with less recurrent wheezing in children affected by rhinovirus (0.32; 0.12-0.90, adjusted to sensitization, young age, viral aetiology and parental asthma) and/or with eczema (0.27; 0.08-0.87, adjusted respectively). CONCLUSIONS: Our data strengthen the role of rhinovirus-associated wheeze as an important risk factor for recurrent wheezing and asthma in young first-time wheezing children. Prospective randomized trials on the efficacy of corticosteroids in rhinovirus-associated early wheezing are warranted. (ClinicalTrials.gov number, NCT 00494624).