Early-life respiratory tract infections and the risk of school-age lower lung function and asthma: a meta-analysis of 150 000 European children.

BACKGROUND: Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking. Our objective was to examine if children with early-life respiratory tract infections had increased risks of lower lung function and asthma at school age. METHODS: We used individual participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow at 75% of FVC (FEF75%) and asthma at a median (range) age of 7 (4-15) years. RESULTS: Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV1, FEV1/FVC and FEF75% (z-score range: -0.09 (95% CI -0.14- -0.04) to -0.30 (95% CI -0.36- -0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR range: 2.10 (95% CI 1.98-2.22) to 6.30 (95% CI 5.64-7.04) and 1.25 (95% CI 1.18-1.32) to 1.55 (95% CI 1.47-1.65), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as a proxy for early-life asthma. CONCLUSIONS: Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower respiratory tract infections.

Correction: Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritization.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritisation.

A systematic review of pharmacogenomic studies capturing adverse drug reactions (ADRs) related to asthma medications was undertaken, and a survey of Pharmacogenomics in Childhood Asthma (PiCA) consortia members was conducted. Studies were eligible if genetic polymorphisms were compared with suspected ADR(s) in a patient with asthma, as either a primary or secondary outcome. Five studies met the inclusion criteria. The ADRs and polymorphisms identified were change in lung function tests (rs1042713), adrenal suppression (rs591118), and decreased bone mineral density (rs6461639) and accretion (rs9896933, rs2074439). Two of these polymorphisms were replicated within the paper, but none had external replication. Priorities from PiCA consortia members (representing 15 institution in eight countries) for future studies were tachycardia (SABA/LABA), adrenal suppression/crisis and growth suppression (corticosteroids), sleep/behaviour disturbances (leukotriene receptor antagonists), and nausea and vomiting (theophylline). Future pharmacogenomic studies in asthma should collect relevant ADR data as well as markers of efficacy.

Prenatal Particulate Air Pollution and DNA Methylation in Newborns: An Epigenome-Wide Meta-Analysis.

BACKGROUND: Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes. OBJECTIVES: We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter [Formula: see text] ([Formula: see text]) or [Formula: see text] ([Formula: see text]) and DNA methylation in newborns and children. METHODS: We meta-analyzed associations between exposure to [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression. RESULTS: Six CpGs were significantly associated [false discovery rate (FDR) [Formula: see text]] with prenatal [Formula: see text] and 14 with [Formula: see text] exposure. Two of the [Formula: see text] CpGs mapped to FAM13A (cg00905156) and NOTCH4 (cg06849931) previously associated with lung function and asthma. Although these associations did not replicate in the smaller newborn sample, both CpGs were significant ([Formula: see text]) in 7- to 9-y-olds. For cg06849931, however, the direction of the association was inconsistent. Concurrent [Formula: see text] exposure was associated with a significantly higher NOTCH4 expression at age 16 y. We also identified several DMRs associated with either prenatal [Formula: see text] and or [Formula: see text] exposure, of which two [Formula: see text] DMRs, including H19 and MARCH11, replicated in newborns. CONCLUSIONS: Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes. https://doi.org/10.1289/EHP4522.

Epigenome-wide association studies in asthma: A systematic review.

OBJECTIVE: Asthma is a common chronic respiratory airway disease influenced by environmental factors and possibly their interaction with the human genome causing epigenetic changes. Epigenome-wide association studies (EWAS) have mainly investigated DNA methylation and its association with disease or traits, exposure factors or gene expression. This systematic review aimed to identify all EWAS assessing differentially methylated sites associated with asthma in humans. DESIGN: Structured systematic literature search following PRISMA guidelines, Newcastle-Ottawa Scale (NOS) for cohort studies was used for bias assessment. DATA SOURCES: We searched PubMed and Embase databases from 2005 to 2019. ELIGIBILITY CRITERIA: Epigenome-wide association studies testing association between differential methylation and asthma in humans. RESULTS: Overall, we identified 16 EWAS studies complying with our search criteria. Twelve studies were conducted on children, and 10 were conducted on sample sizes <150 subjects. Four hundred and nineteen CpGs were reported in children studies after correction for multiple testing. In the adult studies, thousands of differentially methylated sites were identified. Differential methylation in inflammatory-related genes correlated with higher levels of gene expressions of inflammatory modulators in asthma. Differentially methylated genes associated with asthma included SMAD3, SERPINC1, PROK1, IL13, RUNX3 and TIGIT. Forty-one CpGs were replicated at least once in blood samples, and 28 CpGs were replicated in nasal samples. CONCLUSION: Although many differentially methylated CpGs in genes known to be involved in asthma have been identified in EWAS to date, we conclude that further studies of larger sample sizes and analyses of differential methylation between different phenotypes are needed in order to comprehensively evaluate the role of epigenetic factors in the pathophysiology and heterogeneity of asthma, and the potential clinical utility to predict or classify patients with asthma.

Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course.

RATIONALE: We aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course. METHODS: We meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7-13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes. RESULTS: We identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways. INTERPRETATION: Our findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.

Epigenome-wide meta-analysis of DNA methylation and childhood asthma.

BACKGROUND: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. OBJECTIVE: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. METHODS: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. CONCLUSION: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

Maternal blood pressure and hypertensive disorders during pregnancy and childhood respiratory morbidity: the Generation R Study.

Pre-eclampsia is associated with an increased risk of bronchopulmonary dysplasia, wheezing and asthma in later childhood. Currently, there are no studies available investigating maternal blood pressure measurements during multiple time-points in pregnancy and respiratory outcome measures in the child.We examined the associations of maternal blood pressure and hypertensive disorders with the risk of lower lung function, wheezing and asthma in children aged 10 years. This study among 4894 children was embedded in a population-based prospective cohort study. We used multivariate analyses, taking lifestyle and socioeconomic factors into account.We observed consistent associations per 5 mmHg higher maternal blood pressure in early pregnancy with a lower forced expiratory volume in 1 s/forced vital capacity ratio (z-score -0.03 (95% CI -0.05- -0.01)) and per 5 mmHg higher blood pressure in late pregnancy with a higher risk for current wheezing and current asthma (OR 1.07 (95% CI 1.02-1.12) and 1.06 (95% CI 1.00-1.11), respectively). We found no associations of maternal hypertensive disorders during pregnancy with child lung function, current wheezing or current asthma.Our results suggest that higher blood pressure in pregnant women is associated with lower lung function and increased risks of current wheezing and current asthma in children. The associations may be trimester specific.

Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.

The effect of early growth patterns and lung function on the development of childhood asthma: a population based study.

BACKGROUND: Infant weight gain is associated with lower lung function and a higher risk of childhood asthma. Detailed individual childhood growth patterns might be better predictors of childhood respiratory morbidity than the difference between two weight and height measurements. We assessed the associations of early childhood growth patterns with lung function and asthma at the age of 10 years and whether the child's current body mass index (BMI) influenced any association. METHODS: We derived peak height and weight growth velocity, BMI at adiposity peak, and age at adiposity peak from longitudinally measured weight and height data in the first 3 years of life of 4435 children enrolled in a population-based prospective cohort study. At 10 years of age, spirometry was performed and current asthma was assessed by questionnaire. Spirometry outcomes included forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, and forced expiratory flow after exhaling 75% of vital capacity (FEF75). RESULTS: Greater peak weight velocity was associated with higher FVC but lower FEV1/FVC and FEF75. Greater BMI at adiposity peak was associated with higher FVC and FEV1 but lower FEV1/FVC and FEF75. Greater age at adiposity peak was associated with higher FVC, FEV1, FEV1/FVC and FEF75, particularly in children with a small size at birth, and lower odds of current asthma in boys. The child's current BMI only explained the associations of peak weight velocity and BMI at adiposity peak with FVC and FEV1. Peak height velocity was not consistently associated with impaired lung function or asthma. CONCLUSION: Peak weight velocity and BMI at adiposity peak were associated with reduced airway patency in relation to lung volume, whereas age at adiposity peak was associated with higher lung function parameters and lower risk of asthma at 10 years, particularly in boys.

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

Influence of genetic variants on childhood lung function - The Generation R Study.

Genetic variants associated with adult lung function could already exert the effects on childhood lung function. We aimed to examine the associations of adult lung function-related genetic variants with childhood lung function and asthma, and whether these associations were modified by atopic predisposition, tobacco smoke exposure, or early growth characteristics. In a population-based prospective cohort study among 3347 children, we selected 7 and 20 single nucleotide polymorphisms (SNPs) associated with adult forced expiratory volume in 1 second (FEV1 ) and FEV1 /forced vital capacity (FEV1 /FVC), respectively. Weighted genetic risk scores (GRSs) for FEV1 and FEV1 /FVC were constructed. At age 10, FEV1 , FVC, FEV1 /FVC, forced expiratory flow between 25% and 75% (FEF25-75 ), and forced expiratory flow at 75% (FEF75 ) of FVC were measured, and information on asthma was obtained by parental-reported questionnaires. The FEV1 -GRS was associated with lower childhood FEV1 , FEV1 /FVC, and FEF75 (Z-score (95% CI): -0.03 (-0.05, -0.01), -0.03 (-0.05, -0.01), and -0.04 (-0.05, -0.01), respectively, per additional risk allele). The FEV1 /FVC-GRS was associated with lower childhood FEV1 /FVC and FEF75 (Z-score (95% CI): -0.04 (-0.05, -0.03) and -0.03 (-0.05, -0.02), respectively, per additional risk allele). Effect estimates of FEV1 -GRS with FEF25-75 , FEV1 , FEF75 , and FVC, and of FEV1 /FVC-GRS with FEV1 /FVC and FEF25-75 were stronger among children exposed to non-atopic mothers, smoking during pregnancy or in childhood, or those born with a lower birthweight, respectively (P-values for interaction < .05). Genetic risk scores were not associated with asthma. Adult lung function-related genetic variants were associated with childhood lung function. Maternal atopy, smoking during pregnancy or in childhood, and birthweight modified the observed effects.

Fetal and Infant Growth Patterns and Risk of Lower Lung Function and Asthma. The Generation R Study.

RATIONALE: Children with lower birth weight are at increased risk of asthma symptoms. OBJECTIVES: To examine associations of fetal and infant growth with childhood lung function and asthma. METHODS: This study was embedded in a population-based prospective cohort study of 5,635 children. Growth was estimated by repeated ultrasounds in the second and third trimesters, and measured at birth and at 3, 6, and 12 months. At age 10 years, spirometry was performed and asthma was assessed by parental questionnaire. Restricted and accelerated growth were defined as the growth percentile change between time periods less than -0.67 and more than 0.67 SD scores (SDSs), respectively. We applied multiple regression analyses, including conditional regression analyses, to account for correlations between repeated growth measures. MEASUREMENTS AND MAIN RESULTS: Overall greater weight in the second and third trimesters, at birth, and at 12 months was associated with higher FEV1 and FVC (range of z-score difference, 0.04-0.08, per SDS increase in weight). Greater weight at 3 months was associated with lower FEV1/FVC and forced expiratory flow at 75% of the pulmonary volume (FEF75%) (z-score differences [95% confidence interval]: -0.09 [-0.14 to -0.05] and -0.09 [-0.13 to -0.05] per SDS increase in weight, respectively). Restricted fetal weight growth was associated with lower childhood lung-function measures, partly depending on infant weight growth patterns (range of z-score difference, -0.25 to -0.13). Accelerated fetal weight growth was associated with higher FVC and lower FEV1/FVC only if followed by accelerated infant weight growth. Fetal and infant weight growth was not associated with childhood asthma. CONCLUSIONS: Both restricted fetal weight growth, partly depending on infant weight growth, and accelerated fetal and infant weight growth predispose children to lower lung function and a potential risk for respiratory diseases later in life.

Maternal hemoglobin and hematocrit levels during pregnancy and childhood lung function and asthma. The Generation R Study.

OBJECTIVE: To examine the associations of maternal hemoglobin and hematocrit levels during pregnancy with childhood lung function and asthma, and whether adverse pregnancy outcomes and atopic predisposition modify the associations. METHODS: In a population-based prospective cohort study among 3672 subjects, we measured maternal hemoglobin and hematocrit levels in early pregnancy, and lung function by spirometry and current asthma by questionnaire at age 10 years. RESULTS: Higher maternal hematocrit levels, both continuously and categorized into clinical cut-offs, were associated with lower forced expiratory flow at 75% of forced vital capacity (FEF75 ) in children (Z-score (95%CI): -0.04 (-0.07, -0.01), per increase of 1 SDS in hematocrit level; Z-score (95%CI) difference: -0.11 (-0.20, -0.03) compared with normal hematocrit levels, respectively), taking lifestyle and socio-economic factors into account. Adverse pregnancy outcomes and atopic predisposition did not modify the results. No associations of maternal hemoglobin and hematocrit with current asthma were observed. CONCLUSION: Higher maternal hematocrit levels during pregnancy are associated with lower childhood lung function but not with risk of asthma. Adverse pregnancy outcomes and atopic predisposition do not modify these associations. Underlying mechanisms need to be further studied.

A population-based prospective cohort study examining the influence of early-life respiratory tract infections on school-age lung function and asthma.

BACKGROUND: Early-life respiratory tract infections could affect airway obstruction and increase asthma risk in later life. However, results from previous studies are inconsistent. OBJECTIVE: We examined the associations of early-life respiratory tract infections with lung function and asthma in school-aged children. METHODS: This study among 5197 children born between April 2002 and January 2006 was embedded in a population-based prospective cohort study. Information on physician-attended upper and lower respiratory tract infections until age 6 years (categorised into ≤ 3 and >3-6 years) was obtained by annual questionnaires. Spirometry measures and physician-diagnosed asthma were assessed at age 10 years. RESULTS: Upper respiratory tract infections were not associated with adverse respiratory outcomes. Compared with children without lower respiratory tract infections ≤3 years, children with lower respiratory tract infections ≤3 years had a lower FEV1, FVC, FEV1:FVC and forced expiratory flow at 75% of FVC (FEF75) (Z-score (95% CI): ranging from -0.22 (-0.31 to -0.12) to -0.12 (-0.21 to -0.03)) and an increased risk of asthma (OR (95% CI): 1.79 (1.19 to 2.59)). Children with lower respiratory tract infections >3-6 years had an increased risk of asthma (3.53 (2.37 to 5.17)) only. Results were not mediated by antibiotic or paracetamol use and not modified by inhalant allergic sensitisation. Cross-lagged modelling showed that results were not bidirectional and independent of preschool wheezing patterns. CONCLUSION: Early-life lower respiratory tract infections ≤3 years are most consistently associated with lower lung function and increased risk of asthma in school-aged children.

Structural and functional ventilatory impairment in infants with severe bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most frequent serious complication in preterm infants. We aimed to describe lung structure and ventilatory function of preterm infants with severe BPD and explored the association between early postnatal growth and these outcomes. METHODS: We included preterm infants born ≤32 weeks gestational age (GA) with severe BPD. Lung structure was assessed on chest CT with the PRAGMA-BPD scoring system and ventilatory function by polysomnography (PSG) at 6 months corrected age. Postnatal growth was assessed by weight measured at birth, and at 2 and 6 months corrected age. RESULTS: We included 49 infants (median [IQR] GA of 25.7 [24.6-26.3] weeks and mean [SD] birth weight of 760 [210] g). A 95.5% of the chest CT scans showed architectural distortion of the lung, and an oxygen desaturation index (ODI) >5 was found in 74% of the infants. An increase in GA of 1 week was associated with higher total and normal lung volume (ß coefficient [95% CI]: 1.86 [0.15, 3.57] and 2.03 [0.41, 3.65]), less hypoattenuation (-4.3 [-7.70, -0.90]%) and lower ODI (-36.7 [-64.2, -9.10]%). Higher weight at 6 months was independently associated with higher total and normal lung volume, and with less severe desaturations. Increased weight gain between 2 and 6 months of corrected age was associated with less severe desaturations during sleep (ß coefficient [95% CI]: 2.09 [0.49, 3.70]). CONCLUSION: Most preterm infants with severe BPD have structural lung abnormalities and impaired ventilatory function early in life, partly explained by birth characteristics and infant growth.

Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium.

AIM: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium. MATERIALS & METHODS: Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire. RESULTS: A total of 21 studies, including 14,227 children/young persons (58% male), from 12 different countries are currently enrolled in the PiCA consortium. Fifty six percent of the patients are Caucasians. In total, 7619 were inhaled corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center and the results will be meta-analyzed. CONCLUSION: PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population.

Duration and exclusiveness of breastfeeding and school-age lung function and asthma.

BACKGROUND: Breastfeeding reduces the risk of asthma in early childhood, but it is not clear whether its effect on respiratory morbidity is still present in later childhood. OBJECTIVE: To examine the associations of any breastfeeding, breastfeeding duration, and breastfeeding exclusiveness with lung function and asthma in school-aged children and whether associations were influenced by respiratory tract infections and maternal or child's atopic status. METHODS: This study of 4,464 children was embedded in a population-based prospective cohort study. Information on breastfeeding was obtained by multiple questionnaires from birth until 1 year of age. At 10 years of age, lung function was measured by spirometry, and information on asthma was obtained by questionnaire. Adjusted linear and logistic regression models were used to examine the associations. RESULTS: Shorter duration of breastfeeding was associated with a lower forced expiratory volume in 1 second (FEV1) only (z score change, -0.01; 95% confidence interval [CI], -0.02 to -0.00) per month shorter breastfeeding, but not asthma. When categorized, breastfeeding for 2 to 4 months was associated with a lower forced vital capacity (FVC) (z score change, -0.11; 95% CI, -0.20 to -0.03) compared with breastfeeding for 6 months or longer. Nonexclusive breastfeeding for 4 months was associated with a lower FVC (z score change, -0.08; 95% CI, -0.16 to -0.01) compared with exclusive breastfeeding for 4 months. Results did not materially change after additional adjustment for lower respiratory tract infections and were not modified by maternal history of asthma or atopy, child's eczema, or inhalant allergic sensitization. CONCLUSION: Shorter duration and nonexclusivity of breastfeeding were associated with a lower FEV1 and FVC but not asthma at school-age.

Fish and seafood consumption during pregnancy and the risk of asthma and allergic rhinitis in childhood: a pooled analysis of 18 European and US birth cohorts.

Background: It has been suggested that prenatal exposure to n-3 long-chain fatty acids protects against asthma and other allergy-related diseases later in childhood. The extent to which fish intake in pregnancy protects against child asthma and rhinitis symptoms remains unclear. We aimed to assess whether fish and seafood consumption in pregnancy is associated with childhood wheeze, asthma and allergic rhinitis. Methods: We pooled individual data from 60 774 mother-child pairs participating in 18 European and US birth cohort studies. Information on wheeze, asthma and allergic rhinitis prevalence was collected using validated questionnaires. The time periods of interest were: infancy (0-2 years), preschool age (3-4 years), and school age (5-8 years). We used multivariable generalized models to assess associations of fish and seafood (other than fish) consumption during pregnancy with child respiratory outcomes in cohort-specific analyses, with subsequent random-effects meta-analyses. Results: The median fish consumption during pregnancy ranged from 0.44 times/week in The Netherlands to 4.46 times/week in Spain. Maternal fish intake during pregnancy was not associated with offspring wheeze symptoms in any age group nor with the risk of child asthma [adjusted meta-analysis relative risk (RR) per 1-time/week = 1.01, 95% confidence interval 0.97-1.05)] and allergic rhinitis at school age (RR = 1.01, 0.99-1.03). These results were consistently found in further analyses by type of fish and seafood consumption and in sensitivity analyses. Conclusion: We found no evidence supporting a protective association of fish and seafood consumption during pregnancy with offspring symptoms of wheeze, asthma and allergic rhinitis from infancy to mid childhood.

A systematic review of maternal smoking during pregnancy and fetal measurements with meta-analysis.

BACKGROUND: Maternal smoking during pregnancy is linked to reduced birth weight but the gestation at onset of this relationship is not certain. We present a systematic review of the literature describing associations between maternal smoking during pregnancy and ultrasound measurements of fetal size, together with an accompanying meta-analysis. METHODS: Studies were selected from electronic databases (OVID, EMBASE and Google Scholar) that examined associations between maternal smoking or smoke exposure and antenatal fetal ultrasound measurements. Outcome measures were first, second or third trimester fetal measurements. RESULTS: There were 284 abstracts identified, 16 papers were included in the review and the meta-analysis included data from eight populations. Maternal smoking was associated with reduced second trimester head size (mean reduction 0.09 standard deviation (SD) [95% CI 0.01, 0.16]) and femur length (0.06 [0.01, 0.10]) and reduced third trimester head size (0.18 SD [0.13, 0.23]), femur length (0.27 SD [0.21, 0.32]) and estimated fetal weight (0.18 SD [0.11, 0.24]). Higher maternal cigarette consumption was associated with a lower z score for head size in the second (mean difference 0.09 SD [0, 0.19]) and third (0.15 SD [0.03, 0.26]) trimesters compared to lower consumption. Fetal measurements were not reduced for those whose mothers quit before or after becoming pregnant compared to mothers who had never smoked. CONCLUSIONS: Maternal smoking during pregnancy is associated with reduced fetal measurements after the first trimester, particularly reduced head size and femur length. These effects may be attenuated if mothers quit or reduce cigarette consumption during pregnancy.