Liver, renal, genitourinary and diabetic ketoacidosis risks among new users of empagliflozin versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: Post-authorization safety study based on multinational cohorts.

AIM: To estimate risks of diabetic ketoacidosis (DKA), acute liver injury (ALI), acute kidney injury (AKI), chronic kidney disease (CKD), severe complications of urinary tract infection (UTI) and genital infection (GI) among patients with type 2 diabetes initiating empagliflozin versus those initiating a dipeptidyl peptidase-4 (DPP-4) inhibitor. MATERIALS AND METHODS: In this large multinational, observational, new-user cohort study in UK, Danish and US healthcare data sources, patients initiated empagliflozin or a DPP-4 inhibitor between August 2014 and August 2019, were aged ≥18 years, and had ≥12 months' continuous health plan enrolment. Incidence rates by exposure and incidence rate ratios, adjusted for propensity-score deciles, were calculated. RESULTS: In total, 64 599 empagliflozin initiators and 203 315 DPP-4 inhibitor initiators were included. There was an increased risk [pooled adjusted incidence rate ratios (95% confidence interval)] of DKA [2.19 (1.74-2.76)] and decreased risks of ALI [0.77 (0.50-1.19) in patients without predisposing conditions of liver disease; 0.70 (0.56-0.88) in all patients] and AKI [0.54 (0.41-0.73)]. In the UK data, there was an increased risk of GI [males: 4.04 (3.46-4.71); females: 3.24 (2.81-3.74)] and decreased risks of CKD [0.53 (0.43-0.65)] and severe complications of UTI [0.51 (0.37-0.72)]. The results were generally consistent in subgroup and sensitivity analyses. CONCLUSIONS: Compared with DDP-4 inhibitor use, empagliflozin use was associated with increased risks of DKA and GI and decreased risks of ALI, AKI, CKD and severe complications of UTI. These associations are consistent with previous studies and known class effects of sodium-glucose cotransporter 2 inhibitors, including renoprotective effects and beneficial effects on alanine aminotransferase levels.

Prenatal and child vitamin D levels and allergy and asthma in childhood.

BACKGROUND: Early-life vitamin D deficiency may impair immune system development contributing to allergy and asthma onset. Findings from prospective studies are inconsistent. OBJECTIVE: To examine whether maternal and child vitamin D levels are associated with allergic and asthma-related symptoms throughout childhood in a Spanish birth cohort. METHODS: 25-Hydroxyvitamin D3 (25(OH)D3) levels were measured in the serum of pregnant women (N = 2525) and children (N = 803). Information on allergic and asthma-related symptoms was obtained from repeated questionnaires from 1 to 9 years. RESULTS: A total of 19% of mothers and 24% of children had deficient 25(OH)D3 levels (<20 ng/ml). Higher child 25(OH)D3 levels at 4 years were associated with lower odds of atopic eczema from 4 to 9 years (adjusted odds ratio = 0.90; 95% CI = 0.84-0.97 per 5 ng/ml). Higher maternal and child 25(OH)D3 levels were associated with a lower prevalence of late-onset wheezing at the limit of statistical significance (adjusted relative risk ratio (RRRadj) = 0.86; 95% CI = 0.74-1.00 and RRRadj = 0.76; 95% CI = 0.58-1.02 per 5 ng/ml, respectively). All the remaining associations were null. CONCLUSION: Child 25(OH)D3 levels at pre-school age are associated with a reduced odds of atopic eczema in later childhood and both maternal and child levels may reduce the prevalence of late-onset wheezing. IMPACT: In this Spanish birth cohort, with a total of 19% of mothers and 24% of children with deficient levels of vitamin D, higher child vitamin D at 4 years of age was associated with reduced odds of atopic eczema up to 9 years. There was also some evidence that higher maternal and child vitamin D levels reduced the prevalence of late-onset wheezing. Although these findings need replication, they may imply optimal vitamin D levels at pre-school age to prevent atopic eczema.

Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood: Meta-analysis in six European population-based cohorts.

The potential etiological role of early acetaminophen exposure on Autism Spectrum Conditions (ASC) and Attention-Deficit/Hyperactivity Disorder (ADHD) is inconclusive. We aimed to study this association in a collaborative study of six European population-based birth/child cohorts. A total of 73,881 mother-child pairs were included in the study. Prenatal and postnatal (up to 18 months) acetaminophen exposure was assessed through maternal questionnaires or interviews. ASC and ADHD symptoms were assessed at 4-12 years of age using validated instruments. Children were classified as having borderline/clinical symptoms using recommended cutoffs for each instrument. Hospital diagnoses were also available in one cohort. Analyses were adjusted for child and maternal characteristics along with indications for acetaminophen use. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. The proportion of children having borderline/clinical symptoms ranged between 0.9 and 12.9% for ASC and between 1.2 and 12.2% for ADHD. Results indicated that children prenatally exposed to acetaminophen were 19% and 21% more likely to subsequently have borderline or clinical ASC (OR = 1.19, 95% CI 1.07-1.33) and ADHD symptoms (OR = 1.21, 95% CI 1.07-1.36) compared to non-exposed children. Boys and girls showed higher odds for ASC and ADHD symptoms after prenatal exposure, though these associations were slightly stronger among boys. Postnatal exposure to acetaminophen was not associated with ASC or ADHD symptoms. These results replicate previous work and support providing clear information to pregnant women and their partners about potential long-term risks of acetaminophen use.

Prenatal Omega-6:Omega-3 Ratio and Attention Deficit and Hyperactivity Disorder Symptoms.

OBJECTIVE: To evaluate whether higher omega-6:omega-3 (n-6:n-3) long-chain polyunsaturated fatty acid ratio in cord plasma is associated with more symptoms of attention deficit and hyperactivity disorder (ADHD) at 4 and 7 years of age. STUDY DESIGN: This study was based on a population-based birth cohort in Spain. N-6 arachidonic acid and n-3 eicosapentaenoic and docosahexaenoic acid concentrations were measured in cord plasma. At 4 years old, ADHD symptoms were reported by teachers through the ADHD Diagnostic and Statistical Manual of Mental Disorders, 4th ed checklist (n = 580). At 7 years old, ADHD symptoms were reported by parents through the Conners' Rating Scale-Revised (short form; n = 642). The ADHD variable was treated as continuous (score) and as dichotomous (symptom diagnostic criteria). Child and family general characteristics were prospectively collected through questionnaires. We applied pooled zero-inflated negative binomial and logistic regressions adjusted for covariates. RESULTS: A higher omega-6:omega-3 long-chain polyunsaturated fatty acid ratio in cord plasma was associated with a higher ADHD index (incidence rate ratio, 1.13; 95% CI, 1.03, 1.23) at 7 years old. The association was not observed at 4 years old (incidence rate ratio, 1.04; 95% CI, 0.92-1.18). No associations were found using ADHD symptom diagnostic criteria. CONCLUSIONS: High prenatal omega-6:omega-3 long-chain polyunsaturated fatty acid ratio preceded the appearance of subclinical ADHD symptoms during mid-childhood. Our findings suggest that maternal diet during pregnancy may modulate the risk to develop long-term ADHD symptoms in the offspring.

Maternal nut intake in pregnancy and child neuropsychological development up to 8 years old: a population-based cohort study in Spain.

There is scientific evidence on the protective effects of nut intake against cognitive decline in the elderly; however, this effect has been less explored in child neurodevelopment and no studies have explored the potential longitudinal association with nut intake during pregnancy. We aimed to analyze the association of maternal nut intake during pregnancy with child neuropsychological outcomes. We included 2208 mother-child pairs from a population-based birth cohort in four regions of Spain. The follow up settings were during pregnancy (first and third trimesters), birth, 1.5, 5 and 8 years. Neuropsychological examinations were based on Bayley Scales of Infant Development (1.5 years), McCarthy scales of Children's Abilities (5 year), Attention Network Test (ANT, 8 year) and N-Back test (8 year). Nut intake in pregnancy was reported through a validated food frequency questionnaire during the first and the third trimester. Multivariable regressions analyzed associations after controlling for priori selected confounders notably maternal education, social class, body mass index, energy intake, fish intake, omega-3 supplements, alcohol consumption and smoking habits during pregnancy. Children within the highest tertile of maternal nut consumption during first pregnancy trimester (> 32 g/week) had a decrease of 13.82 ms [95% confidence interval (CI) - 23.40, - 4.23] in the ANT-hit reaction time standard error, compared to the first tertile (median 0 g/w). A similar protective association pattern was observed with the other cognitive scores at the different child ages. After correcting for multiple testing using Bonferroni familywise error rate (FWER), Hochberg FWER and Simes false discovery rate, ANT-hit reaction time standard error remained significant. Final model estimates by inverse probability weighting did not change results. Third pregnancy trimester nut intake showed weaker associations. These data indicate that nut intake during early pregnancy is associated with long-term child neuropsychological development. Future cohort studies and randomized clinical trials are needed to confirm this association pattern in order to further extend nutrition guidelines among pregnant women.

Head circumference and child ADHD symptoms and cognitive functioning: results from a large population-based cohort study.

The aim of this study is to understand the association between prenatal, newborn and postnatal head circumference (HC) and preschool neurodevelopment in a large population-based birth cohort. The INMA project followed 1795 children from 12 weeks of pregnancy to preschool years. HC measurements were carried out prospectively, and following a standardized protocol during pregnancy (12, 20 and 34 weeks), birth, and child ages of 1-1.5 and 4 years old; and z-scores were further estimated. Prenatal head growth was assessed using conditional z-scores between weeks 12-20 and 20-34. Several neuropsychological tests [MSCA (cognition), CPT (attention)] and behavioral rating scales [DSM-IV-ADHD, CAST (autism), CPSCS (social competence)] were carried out during the last follow-up (5 years old). Multivariable models adjusted for family and child characteristics were applied to analyze associations between HC and neurodevelopment. In fully adjusted models, prenatal HC and head growth showed little or no associations with the neurodevelopment outcomes. Independent associations were observed between HC z-scores at birth, 1-1.5 years and 4 years and MSCA global cognitive scores and DSM-IV inattention symptoms. Specifically, z-score at birth was positively associated with general cognitive scores [ß 1.22, 95% confidence interval (CI) 0.59, 1.85], and we observed a protective association with ADHD-DSM-IV total symptoms, mean ratio (MR) 0.85 (0.75, 0.96). Prenatal HC and head growth measurements gave little information about child cognitive abilities and behavior at preschool years. However, HC at birth and early childhood was positively associated with a range of neuropsychological outcomes, including protective associations with ADHD symptoms.

Air Pollution Exposure During Pregnancy and Symptoms of Attention Deficit and Hyperactivity Disorder in Children in Europe.

BACKGROUND: Exposure to air pollution during pregnancy may increase attention-deficit/hyperactivity disorder (ADHD) symptoms in children, but findings have been inconsistent. We aimed to study this association in a collaborative study of eight European population-based birth/child cohorts, including 29,127 mother-child pairs. METHODS: Air pollution concentrations (nitrogen dioxide [NO2] and particulate matter [PM]) were estimated at the birth address by land-use regression models based on monitoring campaigns performed between 2008 and 2011. We extrapolated concentrations back in time to exact pregnancy periods. Teachers or parents assessed ADHD symptoms at 3-10 years of age. We classified children as having ADHD symptoms within the borderline/clinical range and within the clinical range using validated cutoffs. We combined all adjusted area-specific effect estimates using random-effects meta-analysis and multiple imputations and applied inverse probability-weighting methods to correct for loss to follow-up. RESULTS: We classified a total of 2,801 children as having ADHD symptoms within the borderline/clinical range, and 1,590 within the clinical range. Exposure to air pollution during pregnancy was not associated with a higher odds of ADHD symptoms within the borderline/clinical range (e.g., adjusted odds ratio [OR] for ADHD symptoms of 0.95, 95% confidence interval [CI] = 0.89, 1.01 per 10 µg/m increase in NO2 and 0.98, 95% CI = 0.80, 1.19 per 5 µg/m increase in PM2.5). We observed similar associations for ADHD within the clinical range. CONCLUSIONS: There was no evidence for an increase in risk of ADHD symptoms with increasing prenatal air pollution levels in children aged 3-10 years. See video abstract at, http://links.lww.com/EDE/B379.

Traffic-related Air Pollution and Attention in Primary School Children: Short-term Association.

BACKGROUND: Although air pollution's short-term effects are well understood to be marked and preventable, its acute neuropsychological effects have, to our knowledge, not yet been studied. We aim to examine the association between daily variation in traffic-related air pollution and attention. METHODS: We conducted a follow-up study from January 2012 to March 2013 in 2,687 school children from 265 classrooms in 39 schools in Barcelona (Catalonia, Spain). We assessed four domains of children's attention processes every 3 months over four repeated visits providing a total of 10,002 computerized tests on 177 different days using the child Attention Network test (ANT). Ambient daily levels of nitrogen dioxide (NO2) and elemental carbon (EC) in particulate matter <2.5 µm (PM2.5) filters were measured at a fixed air quality background monitoring station and in schools. RESULTS: Daily ambient levels of both NO2 and EC were negatively associated with all attention processes (e.g., children in the bottom quartile of daily exposure to ambient NO2 levels had a 14.8 msecond [95% confidence interval, 11.2, 18.4] faster response time than those in the top quartile, which was equivalent to a 1.1-month [0.84, 1.37] retardation in the natural developmental improvement in response speed with age). Similar findings were observed after adjusting for the average indoor (classroom) levels of pollutants. Associations for EC were similar to those for NO2 and robust to several sensitivity analyses. CONCLUSIONS: The short-term association of traffic-related air pollutants with fluctuations in attention adds to the evidence that air pollution may have potential harmful effects on neurodevelopment. See video abstract at, http://links.lww.com/EDE/B158.

Association between breastfeeding duration and cognitive development, autistic traits and ADHD symptoms: a multicenter study in Spain.

BACKGROUND: Several studies have related longer breastfeeding duration to better intellectual performance in children. By contrast, few studies have investigated the potential protective effects of breastfeeding against behavioral problems such as attention deficit hyperactivity disorder (ADHD) symptoms, and even fewer on autism spectrum disorders (ASD) traits. METHODS: We examined the association between breastfeeding duration and cognitive development, attention, ADHD symptoms, and autistic traits using data from the INMA Project, a Spanish multicenter birth-cohort study, and taking into account the intensity of breastfeeding. Duration of any, predominant, and exclusive breastfeeding was documented during infancy through maternal questionnaires. Children (N = 1,346; mean age = 4.9 y) were assessed using the McCarthy Scales of Children's Abilities, Conners' Kiddie Continuous Performance Test, criteria of the DSM-ADHD symptoms form list, and the Childhood Autism Spectrum Test. RESULTS: After adjustment for several confounders, longer duration of breastfeeding was independently associated with better cognitive development and with fewer autistic traits. CONCLUSION: This study provides further evidence of a positive association of breastfeeding with cognitive function apart from socio-environmental factors, and also suggests a protective role against autistic traits. Results are in agreement with recommendations for prolonged breastfeeding duration to promote child development.

Longitudinal association between air pollution exposure at school and cognitive development in school children over a period of 3.5 years.

INTRODUCTION: Recently, we showed that exposure to traffic-related air pollutants (TRAPs) at school was negatively associated with cognitive development, specifically working memory and inattentiveness, in primary schoolchildren during a course of 12 months. The persistence of such associations over longer periods remains as an open question. OBJECTIVE: To study the longitudinal association between TRAPs at school and cognitive development over a period of 3.5 years. METHODS: Indoor and outdoor levels of TRAPs (elemental carbon (EC), dioxide nitrogen (NO2), particulate matter (PM2.5) from traffic sources and ultrafine particles (UFP)) were measured at 39 schools across Barcelona during 2012/2013. Working memory, as a measure of cognitive development, was evaluated 4 times in 2012/2013 assessment and was re-evaluated one more time in 2015 using computerized n-back test (3-back d' as main outcome). Linear mixed effects models were used to test the association between TRAPs and 3-back d', adding child and school as random effects to account for the multilevel nature of the data, and school air pollutants levels (one at a time) as predictor. RESULTS: We found detrimental associations between all TRAPs and annual change in 3-back d' (working memory) (i.e. slower development of working memory in children attending schools with higher levels of air pollution). The associations (per one interquartile range increase in exposure) were strongest for outdoor NO2 (Coefficient (Coef) = - 4.22, 95% confidence interval (CI), - 6.22, - 2.22) and indoor UFP (Coef = - 4.12, 95%CI, - 5.68, - 1.83). These reductions were equivalent to - 20% (95%CI, - 30.1, - 10.7) and - 19.9% (95%CI, - 31.5, - 8.4) change in annual working memory development associated with one interquartile range increase in outdoor NO2 and indoor UFP, respectively. CONCLUSION: Our findings suggest the persistence of the negative association between TRAPs exposure at school and cognitive trajectory measured by n-back test over a period of 3.5 years.

Association between traffic-related air pollution in schools and cognitive development in primary school children: a prospective cohort study.

BACKGROUND: Air pollution is a suspected developmental neurotoxicant. Many schools are located in close proximity to busy roads, and traffic air pollution peaks when children are at school. We aimed to assess whether exposure of children in primary school to traffic-related air pollutants is associated with impaired cognitive development. METHODS AND FINDINGS: We conducted a prospective study of children (n = 2,715, aged 7 to 10 y) from 39 schools in Barcelona (Catalonia, Spain) exposed to high and low traffic-related air pollution, paired by school socioeconomic index; children were tested four times (i.e., to assess the 12-mo developmental trajectories) via computerized tests (n = 10,112). Chronic traffic air pollution (elemental carbon [EC], nitrogen dioxide [NO2], and ultrafine particle number [UFP; 10-700 nm]) was measured twice during 1-wk campaigns both in the courtyard (outdoor) and inside the classroom (indoor) simultaneously in each school pair. Cognitive development was assessed with the n-back and the attentional network tests, in particular, working memory (two-back detectability), superior working memory (three-back detectability), and inattentiveness (hit reaction time standard error). Linear mixed effects models were adjusted for age, sex, maternal education, socioeconomic status, and air pollution exposure at home. Children from highly polluted schools had a smaller growth in cognitive development than children from the paired lowly polluted schools, both in crude and adjusted models (e.g., 7.4% [95% CI 5.6%-8.8%] versus 11.5% [95% CI 8.9%-12.5%] improvement in working memory, p = 0.0024). Cogently, children attending schools with higher levels of EC, NO2, and UFP both indoors and outdoors experienced substantially smaller growth in all the cognitive measurements; for example, a change from the first to the fourth quartile in indoor EC reduced the gain in working memory by 13.0% (95% CI 4.2%-23.1%). Residual confounding for social class could not be discarded completely; however, the associations remained in stratified analyses (e.g., for type of school or high-/low-polluted area) and after additional adjustments (e.g., for commuting, educational quality, or smoking at home), contradicting a potential residual confounding explanation. CONCLUSIONS: Children attending schools with higher traffic-related air pollution had a smaller improvement in cognitive development.

Intrauterine and early postnatal exposure to outdoor air pollution and lung function at preschool age.

BACKGROUND: Effects of prenatal and postnatal exposure to air pollution on lung function at preschool age remain unexplored. We examined the association of exposure to air pollution during specific trimesters of pregnancy and postnatal life with lung function in preschoolers. METHODS: Lung function was assessed with spirometry in preschoolers aged 4.5 years (n=620) participating in the INfancia y Medio Ambiente (INMA) cohort. Temporally adjusted land use regression (LUR) models were applied to estimate individual residential exposures to benzene and nitrogen dioxide (NO2) during specific trimesters of pregnancy and early postnatal life (the first year of life). Recent and current (1 year and 1 week before lung function testing, respectively) exposures to NO2 and nitrogen oxides (NOx) were also assessed. RESULTS: Exposure to higher levels of benzene and NO2 during pregnancy was associated with reduced lung function. FEV1 estimates for an IQR increase in exposures during the second trimester of pregnancy were -18.4 mL, 95% CI -34.8 to -2.1 for benzene and -28.0 mL, 95% CI -52.9 to -3.2 for NO2. Relative risk (RR) of low lung function (<80% of predicted FEV1) for an IQR increase in benzene and NO2 during the second trimester of pregnancy were 1.22, 95% CI 1.02 to 1.46 and 1.30, 95% CI 0.97 to 1.76, respectively. Associations for early postnatal, recent and current exposures were not statistically significant. Stronger associations appeared among allergic children and those of lower social class. CONCLUSIONS: Prenatal exposure to residential traffic-related air pollution may result in long-term lung function deficits at preschool age.

Early exposure to bio-contaminants and asthma up to 10 years of age: results of the HITEA study.

Inverse associations have been found between exposure to bio-contaminants and asthma and allergies. The aim of this study was to prospectively assess whether early exposure to bio-contaminants in dust is associated with asthma and allergy later in childhood among children from (sub)-urban areas. In subsets of three European birth cohorts (PIAMA: n=553; INMA: n=481; and LISAplus: n=395), endotoxin, (1,3,)-ß-d-glucan and extracellular polysaccharide were measured in dust from living rooms shortly after birth. Current asthma at 6 years and 10 years of age and ever asthma up to 10 years of age were assessed by parental questionnaires. Specific IgE levels at 8 years (PIAMA) and 10 years (LISAplus) were available. Adjusted, cohort-specific logistic regression analyses were performed. Higher endotoxin concentrations were positively associated with current asthma at 6 years of age in PIAMA (adjusted OR 1.96, 95% CI 1.07-3.58), but were inversely related with ever asthma up to 10 years of age in INMA (adjusted OR 0.39, 95% CI 0.16-0.94). No associations with asthma were found for LISAplus. No associations were observed with atopic sensitisation in all cohorts. All associations with (1,3)-ß-d-glucan and extracellular polysaccharide were statistically nonsignificant. The suggested immunological mechanisms of early exposure to bio-contaminants with regards to asthma and allergy might be different for children growing up in (sub)-urban environments.

Prenatal head growth and child neuropsychological development at age 14 months.

OBJECTIVE: We sought to assess the association between prenatal head growth and child neuropsychological development in the general population. STUDY DESIGN: We evaluated 2104 children at the age of 14 months from a population-based birth cohort in Spain. Head circumference (HC) was measured by ultrasound examinations at weeks 12, 20, and 34 of gestation and by a nurse at birth. Head growth was assessed using conditional SD scores between weeks 12-20 and 20-34. Trained psychologists assessed neuropsychological functioning using the Bayley Scales of Infant Development. Head size measurements at birth were transformed into a 3-category variable: microcephalic (<10th percentile), normocephalic (≥10th and <90th percentile), and macrocephalic (≥90th percentile) based on the cohort distribution. P values<.05 were considered statistically significant. RESULTS: No overall associations were observed between HC or head growth and mental and psychomotor scores. In particular, no associations were found between HC at birth and mental scores (coefficient, 0.04; 95% confidence interval, -0.02 to 0.09) and between interval head growth (20-34 weeks) and mental scores (0.31; 95% confidence interval, -0.36 to 0.99). Upon stratification by microcephalic, normocephalic, or macrocephalic head size, results were imprecise, although there were some significant associations in the microcephalic and macrocephalic groups. Adjustment by various child and maternal cofactors did not affect results. The minimum sample size required for present study was 883 patients (ß=2, α=0.05, power=0.80). CONCLUSION: Overall prenatal and perinatal HC was not associated with 14-month-old neuropsychological development. Findings suggest HC growth during uterine life among healthy infants may not be an important marker of early-life neurodevelopment but may be marginally useful with specific populations.

Air pollution during pregnancy and childhood cognitive and psychomotor development: six European birth cohorts.

BACKGROUND: Accumulating evidence from laboratory animal and human studies suggests that air pollution exposure during pregnancy affects cognitive and psychomotor development in childhood. METHODS: We analyzed data from 6 European population-based birth cohorts-GENERATION R (The Netherlands), DUISBURG (Germany), EDEN (France), GASPII (Italy), RHEA (Greece), and INMA (Spain)-that recruited mother-infant pairs from 1997 to 2008. Air pollution levels-nitrogen oxides (NO2, NOx) in all regions and particulate matter (PM) with diameters of <2.5, <10, and 2.5-10 µm (PM2.5, PM10, and PMcoarse, respectively) and PM2.5 absorbance in a subgroup-at birth addresses were estimated by land-use regression models, based on monitoring campaigns performed primarily between 2008 and 2011. Levels were back-extrapolated to exact pregnancy periods using background monitoring sites. Cognitive and psychomotor development was assessed between 1 and 6 years of age. Adjusted region-specific effect estimates were combined using random-effects meta-analysis. RESULTS: A total of 9482 children were included. Air pollution exposure during pregnancy, particularly NO2, was associated with reduced psychomotor development (global psychomotor development score decreased by 0.68 points [95% confidence interval = -1.25 to -0.11] per increase of 10 µg/m in NO2). Similar trends were observed in most regions. No associations were found between any air pollutant and cognitive development. CONCLUSIONS: Air pollution exposure during pregnancy, particularly NO2 (for which motorized traffic is a major source), was associated with delayed psychomotor development during childhood. Due to the widespread nature of air pollution exposure, the public health impact of the small changes observed at an individual level could be considerable.

Thyroxine levels during pregnancy in healthy women and early child neurodevelopment.

BACKGROUND: The fetus depends on maternal thyroid hormones during pregnancy for normal brain development. Little is known about the effects of subclinical hypothyroidism and mild hypothyroxinemia during pregnancy on neurodevelopment of the child. METHODS: We evaluated a population-based birth cohort in Spain. A total of 1761 children and their mothers were included in the main analyses. Serum levels of free thyroxine and thyrotropin were measured in pregnant women. Mental and psychomotor development of their children was assessed using the Bayley Scales of Infant Development during the second year of life. RESULTS: Low free thyroxine levels (<5th percentile) and self-reported prepregnancy thyroid disorder without medical treatment were associated with a decrease of mental scores (Beta = -3.4 [95% confidence interval= -6.7 to -0.2]) and -5.5 [-8.9 to -2.0], respectively). No association between thyrotropin levels and mental scores or psychomotor scores was observed. CONCLUSIONS: Low free thyroxine levels in healthy pregnant women are related to a moderate delay in child neurodevelopment. The impairment is similar in magnitude to that observed in mothers with untreated prepregnancy thyroid disorder. The value of screening pregnant women for thyroid function requires further assessment, particularly in mildly iodine-deficient areas.

Early life microbial exposure and fractional exhaled nitric oxide in school-age children: a prospective birth cohort study.

BACKGROUND: Inflammation is a key factor in the pathogenesis of respiratory diseases. Early life exposure to microbial agents may have an effect on the development of the immune system and on respiratory health later in life.In the present work we aimed to evaluate the associations between early life microbial exposures, and fractional exhaled nitric oxide (FeNO) at school age. METHODS: Endotoxin, extracellular polysaccharides (EPS) and ß(1,3)-D-glucan were measured in living room dust collected at 2-3 months of age in homes of participants of three prospective European birth cohorts (LISA, n = 182; PIAMA, n = 244; and INMA, n = 355). Home dampness and pet ownership were periodically reported by the parents through questionnaires. FeNO was measured at age 8 for PIAMA and at age 10/11 for LISA and INMA. Cohort-specific associations between the indoor microbial exposures and FeNO were evaluated using multivariable regression analyses. Estimates were combined using random-effects meta-analyses. RESULTS: FeNO at school age was lower in children exposed to endotoxin at age 2-3 months (ß -0.05, 95% confidence interval (CI) -0.10;-0.01) and in children with reported dog ownership during the first two years of life (GM ratio 0.82, CI 0.70-0.96). FeNO was not significantly associated with early life exposure to EPS, ß(1,3)-D-glucan, indoor dampness and cat ownership. CONCLUSION: Early life exposure to bacterial endotoxin and early life dog ownership are associated with lower FeNO at school age. Further studies are needed to confirm our results and to unravel the underlying mechanisms and possible clinical relevance of this finding.

DNA hypomethylation at ALOX12 is associated with persistent wheezing in childhood.

RATIONALE: Epigenetic changes may play a role in the occurrence of asthma-related phenotypes. OBJECTIVES: To identify epigenetic marks in terms of DNA methylation of asthma-related phenotypes in childhood, and to assess the effect of prenatal exposures and genetic variation on these epigenetic marks. METHODS: Data came from two cohorts embedded in the Infancia y Medio Ambiente (INMA) PROJECT: Menorca (n = 122) and Sabadell (n = 236). Wheezing phenotypes were defined at age 4-6 years. Cytosine-guanine (CpG) dinucleotide site DNA methylation differences associated with wheezing phenotypes were screened in children of the Menorca study using the Illumina GoldenGate Panel I. Findings were validated and replicated using pyrosequencing. Information on maternal smoking and folate supplement use was obtained through questionnaires. Dichlorodiphenyldichloroethylene was measured in cord blood or maternal serum. Genotypes were extracted from genome-wide data. MEASUREMENT AND MAIN RESULTS: Screening identified lower DNA methylation at a CpG site in the arachidonate 12-lipoxygenase (ALOX12) gene in children having persistent wheezing compared with those never wheezed (P = 0.003). DNA hypomethylation at ALOX12 loci was associated with higher risk of persistent wheezing in the Menorca study (odds ratio per 1% methylation decrease, 1.13; 95% confidence interval, 0.99-1.29; P = 0.077) and in the Sabadell study (odds ratio, 1.16; 95% confidence interval, 1.03-1.37; P = 0.017). Higher levels of prenatal dichlorodiphenyldichloroethylene were associated with DNA hypomethylation of ALOX12 in the Menorca study (P = 0.033), but not in the Sabadell study (P = 0.377). ALOX12 DNA methylation was strongly determined by underlying genetic polymorphisms. CONCLUSIONS: DNA methylation of ALOX12 may be an epigenetic biomarker for the risk of asthma-related phenotypes.

Association of ADHD symptoms and social competence with cognitive status in preschoolers.

We aimed to investigate the association of attention-deficit hyperactivity disorder (ADHD) symptoms and social competence outcomes with cognitive status in preschool children. The study population was drawn from three birth cohorts belonging to the Spanish INMA (Infancia y Medio Ambiente) project: Menorca (n = 289), Ribera d'Ebre (n = 60), and Granada (n = 108). Children were assessed at the age of 4 years for cognitive functions (McCarthy Scales of Children's Abilities, MSCA) by psychologists and for inattention and hyperactivity symptoms (ADHD Criteria of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, ADHD-DSM-IV) and social competence (California Preschool Social Competence Scale) by their teachers. Multiple regression analyses were conducted to examine potential associations between behavioral outcomes (ADHD symptoms and social competence) and MSCA cognitive outcomes, adjusting for confounders. The presence of general ADHD symptoms (inattention, hyperactivity, or both) and poorer social competence both showed negative associations with cognitive outcomes. When we compared children according to ADHD subtypes, those with inattention symptoms alone and those with both inattention and hyperactivity symptoms showed significantly lower cognitive function scores in comparison to children with no ADHD symptoms. Behavioral dysfunctions in preschoolers may be associated with impairment of cognitive functions.

Gender differences in prevalence, diagnosis and incidence of allergic and non-allergic asthma: a population-based cohort.

BACKGROUND: Although women with severe non-allergic asthma may represent a substantial proportion of adults with asthma in clinical practice, gender differences in the incidence of allergic and non-allergic asthma have been little investigated in the general population. METHODS: Gender differences in asthma prevalence, reported diagnosis and incidence were investigated in 9091 men and women randomly selected from the general population and followed up after 8-10 years as part of the European Community Respiratory Health Survey. The protocol included assessment of bronchial responsiveness, IgE specific to four common allergens and skin tests to nine allergens. RESULTS: Asthma was 20% more frequent in women than in men over the age of 35 years. Possible under-diagnosis of asthma appeared to be particularly frequent among non-atopic individuals, but was as frequent in women as in men. The follow-up of subjects without asthma at baseline showed a higher incidence of asthma in women than in men (HR 1.94; 95% CI 1.40 to 2.68), which was not explained by differences in smoking, obesity or lung function. More than 60% of women and 30% of men with new-onset asthma were non-atopic. The incidence of non-allergic asthma was higher in women than in men throughout all the reproductive years (HR 3.51; 95% CI 2.21 to 5.58), whereas no gender difference was observed for the incidence of allergic asthma. CONCLUSIONS: This study shows that female sex is an independent risk factor for non-allergic asthma, and stresses the need for more careful assessment of possible non-allergic asthma in clinical practice, in men and women.