Early growth characteristics and the risk of reduced lung function and asthma: A meta-analysis of 25,000 children.

BACKGROUND: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma. OBJECTIVE: We sought to assess the hypothesis that these associations are explained by reduced airway patency. METHODS: We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma. RESULTS: Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma. CONCLUSIONS: Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent.

Breastfeeding and asthma outcomes at the age of 6 years: The Generation R Study.

BACKGROUND: Breastfeeding is associated with a lower risk of asthma symptoms in early childhood, but its effect at older ages remains unclear. We examined the associations of duration and exclusiveness of breastfeeding with asthma outcomes in children aged 6 years, and whether these associations were explained by atopic or infectious mechanisms. METHODS: We performed a population-based prospective cohort study among 5675 children. Information about breastfeeding was collected by questionnaires. At age 6 years, we measured interrupter resistance (Rint) and fractional exhaled nitric oxide (FeNO). Information about wheezing patterns (early (≤3 years only), late (>3 years only), persistent (≤3 and >3 years)), and current asthma at 6 years was derived from repeated questionnaires. RESULTS: Compared to children who were ever breastfed, those who were never breastfed had lower FeNO levels (sympercent (95% CI): -16.0 (-24.5, -7.5)) and increased risks of late and persistent wheezing (OR(95% CI): 1.69 (1.06, 2.69) and 1.44 (1.00, 2.07), respectively). Shorter duration of breastfeeding was associated with early wheezing and current asthma (1.40 (1.14, 1.73) and 2.19 (1.29, 3.71), respectively). Less exclusive breastfeeding was associated with early wheezing (1.28 (1.08, 1.53)). Breastfeeding duration and exclusiveness were not associated with FeNO or Rint. The associations were not explained by inhalant allergies, partly by lower respiratory tract infections in early life, and to a lesser extent by lower respiratory tract infections in later life. CONCLUSIONS: Breastfeeding patterns may influence wheezing and asthma in childhood, which seems to be partly explained by infectious mechanisms.

Role of environmental exposures and filaggrin mutations on associations of ethnic origin with risk of childhood eczema. The Generation R Study.

BACKGROUND: The prevalence of childhood eczema varies considerably between ethnic groups. However, data from longitudinal studies remain scarce. METHODS: We examined the associations of ethnic origin with the development of eczema from birth until the age of 4 years, and whether known environmental and genetic risk factors explain these associations. This study was performed in a multiethnic population-based prospective cohort among 5,082 children. Ethnic origin was based on the parents' country of birth. Data on physician-diagnosed eczema were obtained by annual questionnaires. Information on environmental risk factors was mostly obtained by questionnaires. Filaggrin (FLG) mutations (2282del4, R2447X, R501X, and S3247X) were genotyped for 3,096 children. We used generalized estimating equation models to examine the associations of ethnic origin with the longitudinal odds of eczema at 6 months and 1, 2, 3, and 4 years of age overall and independently. RESULTS: Compared with Dutch children, Cape Verdean, Dutch Antillean, Surinamese-Creole, and Surinamese-Hindustani children had overall increased risks of eczema (OR (95%-CI): 1.53 (1.15, 2.03), 1.60 (1.21, 2.12), 1.95 (1.56, 2.44), and 2.06 (1.65, 2.57), respectively). Effect estimates for the associations of Cape Verdean and Dutch Antillean origin with eczema became non-significant after adjustment for genetic risk factors or both environmental and genetic risk factors, respectively. Surinamese-Creole and Surinamese-Hindustani children remained to have increased risks of eczema. CONCLUSIONS: Cape Verdean, Dutch Antillean, Surinamese-Creole, and Surinamese-Hindustani children had increased risks of eczema in the first 4 years of life. Environmental and genetic risk factors partly weakened these associations.

Foetal and infant growth patterns, airway resistance and school-age asthma.

BACKGROUND AND OBJECTIVE: Preterm birth, low birth weight and rapid infant weight gain are associated with increased risks of asthma symptoms in childhood. The underlying mechanism may include persistently higher airway resistance (Rint). The aim of our study was to examine the associations of longitudinally measured foetal and infant growth characteristics with Rint and asthma outcomes in school-age children. METHODS: This study was embedded in a population-based prospective cohort study in Rotterdam, The Netherlands. Foetal growth was estimated by ultrasound in the second and third trimesters. Infant growth was measured at birth, 3, 6 and 12 months. At age 6 years, Rint was measured, and information about wheezing and asthma was obtained by questionnaires. The number of subjects per analysis differed per available outcome (3954-5066 subjects). RESULTS: Longitudinal growth analyses showed that school-age children with increased Rint had lower foetal length growth and weight gain, and lower infant length growth. Children with persistent wheezing until age 6 years and physician-diagnosed asthma had a higher Rint compared with children who never wheezed or without asthma (difference z-scores Rint: 0.58 (0.19, 0.97) and 0.55 (0.15, 0.95), respectively). CONCLUSION: Rint in school-age children is influenced by foetal growth restriction and is associated with asthma outcomes. See article, page 574.

Influence of childhood growth on asthma and lung function in adolescence.

BACKGROUND: Low birth weight and rapid infant growth in early infancy are associated with increased risk of childhood asthma, but little is known about the role of postinfancy growth in asthmatic children. OBJECTIVES: We sought to examine the associations of children's growth patterns with asthma, bronchial responsiveness, and lung function until adolescence. METHODS: Individual growth trajectories from birth until 10 years of age were estimated by using linear spline multilevel models for 9723 children participating in a population-based prospective cohort study. Current asthma at 8, 14, and 17 years of age was based on questionnaires. Lung function and bronchial responsiveness or reversibility were measured during clinic visits at 8 and 15 years of age. RESULTS: Rapid weight growth between 0 and 3 months of age was most consistently associated with increased risks of current asthma at the ages of 8 and 17 years, bronchial responsiveness at age 8 years, and bronchial reversibility at age 15 years. Rapid weight growth was associated with lung function values, with the strongest associations for weight gain between 3 and 7 years of age and higher forced vital capacity (FVC) and FEV1 values at age 15 years (0.12 [95% CI, 0.08 to 0.17] and 0.11 [95% CI, 0.07 to 0.15], z score per SD, respectively) and weight growth between 0 and 3 months of age and lower FEV1/FVC ratios at age 8 and 15 years (-0.13 [95% CI, -0.16 to -0.10] and -0.04 [95% CI, -0.07 to -0.01], z score per SD, respectively). Rapid length growth was associated with lower FVC and FVC1 values at age 15 years. CONCLUSION: Faster weight growth in early childhood is associated with asthma and bronchial hyperresponsiveness, and faster weight growth across childhood is associated with higher FVC and FEV1 values.

Is parent-child bed-sharing a risk for wheezing and asthma in early childhood?

Household crowding can place young children at risk for respiratory infections which subsequently provoke asthma symptoms. However, crowding might also protect against asthma, in accordance with the hygiene hypothesis. We tested if parent-infant bed-sharing, an important dimension of household crowding, increases or decreases the risk for asthma. In a population-based prospective cohort (N = 6160) we assessed bed-sharing at 2 and 24 months; wheezing between 1 and 6 years of age; and asthma at 6 years of age. Generalised estimating equation models were used to assess repeated measures of wheezing and asthma. We found no association between bed-sharing in early infancy and wheezing or diagnosis of asthma. By contrast, we found a positive association between bed-sharing in toddlerhood and both wheezing (OR 1.42, 95% CI 1.15-1.74) and asthma (OR 1.57, 95% CI 1.03-2.38). Wheezing was not associated with bed-sharing when using cross-lagged modelling. This study suggests that bed-sharing in toddlerhood is associated with an increased risk of asthma at later ages, and not vice versa. Further studies are needed to explore the underlying causal mechanisms.

Parental psychological distress during pregnancy and wheezing in preschool children: the Generation R Study.

BACKGROUND: Maternal psychological distress during pregnancy might affect fetal lung development and subsequently predispose children to childhood asthma. OBJECTIVE: We sought to assess the associations of maternal psychological distress during pregnancy with early childhood wheezing. METHODS: We performed a population-based prospective cohort study among 4848 children. We assessed maternal and paternal psychological distress at the second trimester of gestation and 3 years after delivery and maternal psychological distress at 2 and 6 months after delivery by using the Brief Symptom Inventory questionnaire. Wheezing in the children was annually examined by using questionnaires from 1 to 4 years. Physician-diagnosed ever asthma was reported at 6 years. RESULTS: Mothers with psychological distress during pregnancy had increased odds of wheezing in their children from 1 to 4 years of life (overall distress: odds ratio [OR], 1.60 [95% CI, 1.32-1.93]; depression: OR, 1.46 [95% CI, 1.20-1.77]; and anxiety: OR, 1.39 [95% CI, 1.15-1.67]). We observed similar positive associations with the number of wheezing episodes, wheezing patterns, and physician-diagnosed asthma at 6 years. Paternal distress during pregnancy and maternal and paternal distress after delivery did not affect these results and were not associated with childhood wheezing. CONCLUSION: Maternal psychological distress during pregnancy is associated with increased odds of wheezing in their children during the first 6 years of life independent of paternal psychological distress during pregnancy and maternal and paternal psychological distress after delivery. These results suggest a possible intrauterine programming effect of maternal psychological distress leading to respiratory morbidity.

Preterm birth, infant weight gain, and childhood asthma risk: a meta-analysis of 147,000 European children.

BACKGROUND: Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results. OBJECTIVES: We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years). METHODS: First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes. RESULTS: Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27). CONCLUSION: Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth.

Maternal weight, gestational weight gain and preschool wheezing: the Generation R Study.

We studied the associations of maternal pre-pregnancy body mass index and gestational weight gain with risks of preschool wheezing in offspring and explored the role of growth, infectious and atopic mechanisms. This substudy of 4656 children was embedded in a population-based birth cohort. Information about maternal pre-pregnancy weight, gestational weight gain and wheezing at the ages of 1-4 years was obtained by either physical measurements or questionnaires. Among mothers with a history of asthma or atopy, maternal pre-pregnancy obesity was associated with an overall increased risk of preschool wheezing (odds ratio 1.47, 95% confidence interval 1.12-1.95). Also, each standard deviation increase of gestational weight gain was associated with an increased overall risk of preschool wheezing (1.09, 1.04-1.14), was independent of pre-pregnancy body mass index and was not different between mothers with and without a history of asthma or atopy. Child's growth, respiratory tract infections or eczema did not alter the results. Mothers with pre-pregnancy obesity and a history of asthma or atopy, and mothers with higher gestational weight gain showed higher risks of wheezing in their offspring. These associations could not be explained by growth, infectious or atopic mechanisms. Further research is needed to identify underlying mechanisms and long-term consequences.

Influence of maternal and cord blood C-reactive protein on childhood respiratory symptoms and eczema.

BACKGROUND: Inflammatory processes during pregnancy might affect fetal lung development and immune responses. We examined the associations of maternal and cord blood C-reactive protein levels with respiratory symptoms and eczema in preschool children. METHODS: This study was embedded in a population-based prospective cohort study of 4984 children. Generalized estimating equations were used to assess the effect of C-reactive protein levels on respiratory symptoms or eczema. C-reactive protein levels were measured during early pregnancy and at birth. Wheezing, lower respiratory tract infections, and eczema until the age of 4 yr were annually obtained by questionnaires. RESULTS: Maternal C-reactive protein was not associated with the risks of wheezing and lower respiratory tract infections. Compared to children with maternal C-reactive protein in the lowest quarter, children in the highest quarter had increased risks of eczema OR 1.20 (1.03, 1.40). Compared to children with cord blood C-reactive protein lower than 0.20 mg/l, those with levels higher than 0.20 mg/l had increased risks of wheezing, OR 1.21 (1.07, 1.36), and lower respiratory tract infections, OR 1.21 (1.05, 1.39), but not of eczema. CONCLUSIONS: Our results suggest that elevated maternal C-reactive protein in pregnancy is associated with a higher risk of eczema, and C-reactive protein in cord blood with a higher risk of wheezing and lower respiratory tract infections in the first 4 yrs.

Fetal and infant growth and asthma symptoms in preschool children: the Generation R Study.

RATIONALE: Low birth weight is associated with an increased risk of wheezing in childhood. OBJECTIVES: We examined the associations of longitudinally measured fetal and infant growth patterns with the risks of asthma symptoms in preschool children. METHODS: This study was embedded in a population-based prospective cohort study among 5,125 children. Second- and third-trimester fetal growth characteristics (head circumference, femur length, abdominal circumference, and weight) were estimated by repeated ultrasounds. Infant growth (head circumference, length, and weight) was measured at birth and at the ages of 3, 6, and 12 months. Parental report of asthma symptoms until the age of 4 years was yearly obtained by questionnaires. MEASUREMENTS AND MAIN RESULTS: Both fetal restricted and accelerated growth, defined as a negative or positive change of more than 0.67 standard deviation score, were not associated with asthma symptoms until the age of 4 years. Accelerated weight gain from birth to 3 months following normal fetal growth was associated with increased risks of asthma symptoms (overall odds ratio for wheezing: 1.44 [95% confidence interval: 1.22, 1.70]; shortness of breath: 1.32 [1.12, 1.56]; dry cough: 1.16 [1.01, 1.34]; persistent phlegm: 1.30 [1.07, 1.58]), but not with eczema (0.95 [0.80, 1.14]). These associations were independent of other fetal growth patterns and tended to be stronger for children of atopic mothers than for children of nonatopic mothers. CONCLUSIONS: Weight-gain acceleration in early infancy was associated with increased risks of asthma symptoms in preschool children, independent of fetal growth. Early infancy might be a critical period for the development of asthma.

Air pollution, fetal and infant tobacco smoke exposure, and wheezing in preschool children: a population-based prospective birth cohort.

BACKGROUND: Air pollution is associated with asthma exacerbations. We examined the associations of exposure to ambient particulate matter (PM10) and nitrogen dioxide (NO2) with the risk of wheezing in preschool children, and assessed whether these associations were modified by tobacco smoke exposure. METHODS: This study was embedded in the Generation R Study, a population-based prospective cohort study among 4,634 children. PM10 and NO2 levels were estimated for the home addresses using dispersion modeling. Annual parental reports of wheezing until the age of 3 years and fetal and infant tobacco smoke exposure was obtained by questionnaires. RESULTS: Average annual PM10 or NO2 exposure levels per year were not associated with wheezing in the same year. Longitudinal analyses revealed non-significant tendencies towards positive associations of PM10 or NO2 exposure levels with wheezing during the first 3 years of life (overall odds ratios (95% confidence interval): 1.21 (0.79, 1.87) and 1.06 (0.92, 1.22)) per 10 µg/m3 increase PM10 and NO2, respectively). Stratified analyses showed that the associations were stronger and only significant among children who were exposed to both fetal and infant tobacco smoke (overall odds ratios 4.54 (1.17, 17.65) and 1.85 (1.15, 2.96)) per 10 µg/m3 increase PM10 and NO2, respectively (p-value for interactions <0.05). CONCLUSIONS: Our results suggest that long term exposure to traffic-related air pollutants is associated with increased risks of wheezing in children exposed to tobacco smoke in fetal life and infancy. Smoke exposure in early life might lead to increased vulnerability of the lungs to air pollution.

Prevalence of Asthma Characteristics in COPD Patients in a Dutch Well-Established Asthma/COPD Service for Primary Care.

Purpose: Primary care COPD guidelines indicate that COPD patients with asthma characteristics should be treated as having asthma. This study aims to describe the prevalence of asthma characteristics in patients with a pulmonologist-confirmed working diagnosis of COPD or ACO. Patients and Methods: This retrospective cross-sectional study used real-life data (collected between 2007 and 2017) from a Dutch asthma/COPD-service, a structured web-based system in which pulmonologists support general practitioners in their diagnosis of patients with suspicion of obstructive lung disease. The prevalence of asthma characteristics (history of asthma, atopy, symptoms, and reversibility) and blood eosinophil (Eos) counts were assessed in patients with a working diagnosis of COPD or ACO. Results: Of the 14,141 patients, ≥40 years in the dataset, 4475 (31.6%) were diagnosed with asthma, 3532 (25.0%) with COPD, and 1276 (9.0%) with ACO. Asthma characteristics were present in 65.6% (n=1956) of the COPD and 90.9% (n=1059) of the ACO patients. Eos counts of ≥ 300 cells per µL were found in 35.7% (n=924) of the COPD patients and 35.3% (n=341) of the ACO patients. Conclusion: In this group of COPD and ACO patients remotely diagnosed by pulmonologists, a substantial proportion would be considered to have asthma characteristics according to the guidelines. This may explain the high number of inhaled corticosteroid (ICS) prescriptions found in primary care COPD patients. Prospective studies are necessary to identify patients who may or may not benefit from ICS containing treatment. Hence, personalized care in primary care can be optimized.

Socioeconomic and sociodemographic factors associated with asthma related outcomes in early childhood: the Generation R Study.

RATIONALE: Few studies have analyzed the association of socioeconomic and sociodemographic factors with asthma related outcomes in early childhood, including Fraction of exhaled Nitric Oxide (FeNO) and airway resistance (Rint). We examined the association of socioeconomic and sociodemographic factors with wheezing, asthma, FeNO and Rint at age 6 years. Additionally, the role of potential mediating factors was studied. METHODS: The study included 6717 children participating in The Generation R Study, a prospective population-based cohort study. Data on socioeconomic and sociodemographic factors, wheezing and asthma were obtained by questionnaires. FeNO and Rint were measured at the research center. Statistical analyses were performed using logistic and linear regression models. RESULTS: At age 6 years, 9% (456/5084) of the children had wheezing symptoms and 7% (328/4953) had asthma. Children from parents with financial difficulties had an increased risk of wheezing (adjusted Odds Ratio (aOR) = 1.63, 95% Confidence Interval (CI):1.18-2.24). Parental low education, paternal unemployment and child's male sex were associated with asthma, independent of other socioeconomic or sociodemographic factors (aOR = 1.63, 95% CI:1.24-2.15, aOR = 1.85, 95% CI:1.11-3.09, aOR = 1.58, 95% CI:1.24-2.01, respectively). No socioeconomic or gender differences in FeNO were found. The risks of wheezing, asthma, FeNO and Rint measurements differed between ethnic groups (p<0.05). Associations between paternal unemployment, child's sex, ethnicity and asthma related outcomes remained largely unexplained. CONCLUSIONS: This study showed differences between the socioeconomic and sociodemographic correlates of wheezing and asthma compared to the correlates of FeNO and Rint at age 6 years. Several socioeconomic and sociodemographic factors were independently associated with wheezing and asthma. Child's ethnicity was the only factor independently associated with FeNO. We encourage further studies on underlying pathways and public health intervention programs, focusing on reducing socioeconomic or sociodemographic inequalities in asthma.