Early origins of chronic obstructive lung diseases across the life course
Chronic obstructive lung diseases, like asthma and chronic obstructive pulmonary disease, have high prevalences and are a major public health concern. Chronic obstructive lung diseases have at least part of their origins in early life. Exposure to an adverse environment during critical periods in early life might lead to permanent developmental adaptations which results in impaired lung growth with smaller airways and lower lung volume, altered immunological responses and related inflammation, and subsequently to increased risks of chronic obstructive lung diseases throughout the life course. Various pathways leading from early life factors to respiratory health outcomes in later life have been studied, including fetal and early infant growth patterns, preterm birth, maternal obesity, diet and smoking, children’s diet, allergen exposure and respiratory tract infections, and genetic susceptibility. Data on potential adverse factors in the embryonic and preconception period and respiratory health outcomes are scarce. Also, the underlying mechanisms how specific adverse exposures in the fetal and early postnatal period lead to chronic obstructive lung diseases in later life are not yet fully understood. Current studies suggest that interactions between early environmental exposures and genetic factors such as changes in DNA-methylation and RNA expression patterns may explain the early development of chronic obstructive lung diseases. New well-designed epidemiological studies are needed to identify specific critical periods and to elucidate the mechanisms underlying the development of chronic obstructive lung disease throughout the life course.
KeywordsCohort study Child Asthma Chronic Obstructive Pulmonary Disease (COPD) Early origins
Chronic obstructive lung diseases during the life course are a major public health concern. Prevalences vary from 5 to 10 % for asthma in childhood , with even higher figures for asthma related symptoms such as wheezing in younger children , to 5–22 % for chronic obstructive pulmonary disease (COPD) among adults older than 50 years . COPD is presently the fourth most common cause of death worldwide . The most prevalent chronic obstructive lung disease among preterm born children is bronchopulmonary dysplasia . Bronchopulmonary dysplasia is defined as supplemental oxygen need for at least 28 days after birth, and occurs in 30 % among children born younger than 30 weeks of gestation. Chronic obstructive lung diseases in children and adults are related to a reduced quality of life and exercise tolerance, and are leading causes of hospitalisation and health care cost [6, 7, 8, 9]. The morbidity of these diseases remains high despite the availability of effective symptomatic treatments [10, 11]. The lack of curative options seems to be partly due to their unknown aetiology of chronic obstructive lung diseases [12, 13]. Furthermore, definitions of bronchopulmonary dysplasia, asthma and COPD as phenotypes of chronic obstructive lung disease are subject of debate [14, 15, 16, 17, 18]. Bronchopulmonary dysplasia, asthma and COPD have common clinical and physiological features, and may share similar pathogenetic mechanisms. For example, wheezing in childhood with or without lung function reversibility measured by spirometry might be due to bronchopulmonary dysplasia or asthma [19, 20]. Also, the development of COPD or declining lung function seems not fully explained by strong contributors as age and smoking only [3, 21, 22] suggesting that other possible risk factors or lung diseases seem to be important. An accumulating body of evidence suggest that these phenotypes originate in the earliest phase of life . Therefore, the challenge is to identify the specific underlying mechanisms for the associations of adverse exposures in early life with different expressions of chronic obstructive lung diseases, but also their shared early life underlying mechanisms and relation.
Early origins of chronic obstructive lung diseases
Early growth and development
Previously, low birth weight was proposed as an important early risk factor for wheezing and asthma in childhood [108, 109, 110, 111], and COPD and lower pulmonary function in later adult life [88, 89, 112, 113, 114, 115]. Recent studies suggested that low birth weight is not the causal factor per se leading to respiratory morbidity [109, 116, 117, 118]. Previous published findings seem not consistent [108, 109, 110, 111, 119, 120], which may be due to differences in study populations and in definitions of outcomes. Furthermore, the observed associations of low birth weight with increased risks of respiratory morbidity may additionally be confounded by preterm birth or catch-up growth in infancy. The lungs of preterm children have not yet been fully developed, which makes them prone for suboptimal further development [121, 122, 123]. A recent meta-analysis of pooled data observed that preterm birth was associated with an increased risk of wheezing disorders [odds ratio (OR) (95 % confidence interval) 1.46 (1.29, 1.65); 17 studies including 874,710 children], and particularly among children born very preterm [<32 weeks gestation; OR 2.81 (2.55, 3.12)] . Most children with a low birth weight show catch-up growth in infancy . Recent studies suggested that catch-up growth is associated with a lower pulmonary function, and increased risks of childhood asthma [118, 126, 127]. A meta-analysis of individual data from 147,252 children up to the age of 10 years participating in 31 European cohort studies assessed the strength, consistency, and independence of the associations of gestational age, birth weight and infant weight gain with the risks of preschool wheezing and school-age asthma . Remarkably, the authors observed that the associations with preschool wheezing and childhood asthma were not only present for preterm birth below 36 weeks of gestation but across the full range of gestational age at birth. The inverse associations of birth weight with preschool wheezing and school-age asthma were explained by gestational age at birth. Higher infant weight gain was independently associated with higher risks of preschool wheezing and school-age asthma. The highest risk of school-age asthma was observed in children born preterm with high infant weight gain, compared to term born children with normal infant weight gain [OR 4.47 (2.58, 7.76)]. Mechanisms underlying the associations of growth characteristics in early life with asthma outcomes in later childhood might include smaller airways and lungs . The highest rates of airway and alveolar development occur in early life, and growth and development of the airways and alveoli might continue until the age of 21 years [129, 130]. Extreme preterm born children with respiratory distress syndrome or bronchopulmonary dysplasia commonly have an impaired lung function in later life [131, 132]. The forced expiratory volume in 1 s (FEV1) was 16–19 % lower in preterm children compared with term born children, and also 7 % lower in those children without bronchopulmonary dysplasia, according to a recent meta-analysis of 59 studies . Even less extreme preterm born children had lower FEV1 relative to forced vital capacity (FEV1/FVC) and forced expiratory flow at 25–75 % of FVC (FEF25–75) in childhood than term born children . Follow-up studies in preterm children showed persistently lower lung volumes and reduced airway calibre in later life [132, 133, 134, 135, 136]. Other potential underlying pathways for the association between preterm birth and low birth weight and asthma are not disentangled yet but might include underdeveloped anatomical or immunological mechanisms [137, 138, 139], increased allergen sensitization, inflammation and bronchial hyperreactivity [140, 141, 142, 143], interaction with environmental factors, such as smoke exposure and chorioamnionitis [144, 145], or genetic factors . Also, the degree of immaturity, therapeutic interventions and co-morbidity might be important. These different underlying mechanisms may lead to various phenotypes of chronic obstructive lung disease with onset at different ages. The associations of high infant weight gain with childhood asthma may be explained by immunological active factors from adipose tissue, such as leptin  which is suggested to have an immunomodulatory role . High infant weight gain might also have a direct mechanical effect on lung function . Further studies are needed to identify the early developmental adaptations of the lungs and immune system that may explain the associations of preterm birth and infant weight gain with childhood asthma.
Fetal and infant growth patterns
Low birth weight is not only the starting point of infant growth, but also the result of various fetal growth patterns. Studies with information about fetal growth characteristics in different periods of pregnancy enable identification of critical fetal periods that might be important for the risk of asthma and other respiratory diseases [150, 151], as previously described in detail . In summary, two birth cohort studies, either prospectively  or retrospectively  designed, observed that a lower fetal head circumference, abdominal circumference or fetal size was associated with (non)atopic preschool wheezing or asthma in children aged 10 years. However, a prospective population-based cohort study among 5,125 children observed that not fetal growth, but infant weight gain acceleration in early infancy was associated with increased risks of asthma symptoms in preschool children, independent of fetal growth . The associations of longitudinally measured growth patterns from the embryonic to early childhood period with various phenotypes of asthma, lung function and lung structure in childhood and later life adjusted for potential confounders remain to be studied in further detail.
Obesity, inadequate diet and intake of micronutrients
Suboptimal fetal nutrition, due to maternal obesity or underweight, insufficient dietary intake, or placental dysfunction might also affect fetal growth and lung development [113, 155, 156, 157, 158].
Maternal pre-pregnancy obesity and gestational weight gain are suggested to be associated with respiratory morbidity of their children. A meta-analysis of 14 studies including 108,321 mother–child pairs observed that maternal overweight or obesity during pregnancy, and to a lesser extent gestational weight gain, were associated with ever asthma or wheeze combined [OR 1.31 (1.16, 1.49)], compared with normal maternal weight during pregnancy and normal gestational weight gain . Only two birth cohorts mutually adjusted for pre-pregnancy weight gain and gestational weight gain, and observed independent and even larger effect estimates of these weight factors for wheeze or asthma [103, 104]. Also, these birth cohorts observed that the associations of maternal pre-pregnancy obesity or gestational weight gain with wheezing or asthma could not be explained by many confounders including child’s growth, infectious and atopic mechanisms, or maternal hypertensive disorders. Thus, further analyses on possible residual confounders specifically focussed on the preconception period and underlying mechanisms, and long-term consequences are needed, as well as prospective randomized trials of maternal weight management before and during pregnancy.
Diet during pregnancy
Insufficient maternal dietary intake of macronutrients during pregnancy may lead to an increased risk of asthma in childhood [155, 160, 161, 162, 163, 164, 165, 166, 167] either directly or through impaired fetal body, lung and airway growth [168, 169]. A systematic review of prospective cohort studies observed that maternal diets rich in fruits and vegetables, fish , and foods containing vitamin D, and Mediterranean dietary patterns seem associated with lower risk for asthma or asthma related diseases such as allergy or eczema in their children . Additionally, it has been hypothesized that a shifted balance in maternal consumption of fatty acids during pregnancy with a higher intake of n-6 poly unsaturated fatty acids (n-6 PUFAs) and a lower intake of n-3 PUFAs might have implications for the immature and developing fetal immune system and subsequent risk of asthma and related diseases . Specifically, n-6 PUFAs are suggested to promote sensitization to allergens and to increase allergic disease activity, whereas n-3 PUFAs seem to have an anti-inflammatory effect [171, 172, 173, 174]. So far, previous prospective studies reported inconsistent results on the associations of maternal fatty acid profiles with the risks of childhood asthma and related diseases [175, 176, 177, 178, 179, 180, 181, 182], which seem mainly due to methodological issues. Further studies are needed to explore critical periods of exposure, pathways and causality. The mechanisms by which dietary patterns affect body and lung growth development may include DNA methylation [183, 184]. Lower intake of micronutrients such as folate, and vitamin B12 in mother’s diet may induce epigenetic changes, since folate and vitamin B12 are important methyl donors during pregnancy . Vitamin E has the potential to influence airway development via epigenetic mechanisms because it influences gene expression and airway epithelial cell signalling . The role of epigenetic mechanisms regarding the association of low maternal vitamin D intake during pregnancy with a higher incidence of asthma and wheeze in children is not known yet [186, 187, 188, 189, 190]. Epidemiological studies are currently established worldwide to examine associations of maternal micronutrients intake with DNA methylation levels of their children and subsequent risk of child asthma and related diseases. The importance of the maternal intake of these micronutrients on respiratory health in childhood and adulthood might differ between developing and Western countries, since the nutritional status of mothers and children in these countries are different.
Not only maternal diet, but also placental dysfunction might contribute to respiratory disease in children. Placental dysfunction is strongly related to fetal growth and childhood cardiovascular adaptations , but its direct associations with respiratory health in the offspring are not fully understood yet.
After birth, specific infant feeding patterns may lead to reduced lung and airway growth and increased risk of childhood asthma [192, 193, 194, 195, 196]. A recent meta-analysis of 75 studies observed that breastfeeding was associated with a reduced risk of ever asthma, recent asthma, and recent wheezing illness [pooled ORs 0.78 (0.74, 0.84), 0.76 (0.67, 0.86), and 0.81 (0.76, 0.87), respectively] . Longer duration and exclusiveness of breastfeeding tended to be associated with a stronger reduced risk of asthma. Furthermore, it was observed that the protective effect of breastfeeding for respiratory morbidity was the strongest at age 0–2 years, diminished thereafter but was still present at school age. Underlying mechanisms that have been suggested to explain the associations of shorter duration or smaller amount of breastfeeding with the risks of asthma are breast milk components that stimulate the infant’s innate immune system and growth [198, 199, 200] but might be mediated by genetic susceptibility, atopic and infectious mechanisms [194, 195, 201, 202]. Further studies are needed to explore in detail the role of atopy, infections, suboptimal lung growth , epigenetic changes , other dietary macro- and micronutrient components or other possible underlying mechanisms for the associations between breastfeeding and asthma.
Exposure to tobacco smoke, allergens and respiratory infections
Maternal tobacco smoking
The most important adverse exposure for chronic obstructive lung diseases in childhood is maternal tobacco smoking [106, 205, 206, 207, 208, 209, 210, 211, 212]. Identifying critical periods of exposure to maternal smoking is necessary. Recently, it was observed that not first trimester smoking but continued maternal smoking throughout pregnancy was associated with an increased risk of preschool wheezing independent of paternal smoking, smoke exposure in childhood and being small for gestational age suggesting a direct adverse effect of fetal tobacco smoke exposure on lung development . In contrast with this study, a recent meta-analysis among 21,600 children of European birth cohorts observed that specifically maternal smoking during first trimester of pregnancy was associated with a 1.45 and 2.10 fold increased risk of preschool wheezing and childhood asthma, respectively, with a dose–response effect . The number of subjects included or the use of different confounders might explain differences in findings. The results suggest that the embryonic and maybe the preconception period might be vulnerable periods for adaptations of the lungs and immune system and subsequently development of chronic obstructive lung disease in later life. In the last few years, electronic cigarettes have been suggested to generate less tar and carcinogens than regular cigarettes . However, the use, dosage and frequency of electronic cigarettes by mothers during pregnancy and the risk of chronic obstructive lung diseases of their children have not been studied. Thus, use of electronic cigarettes should be discouraged. The mechanisms by which maternal smoking during pregnancy affect child’s chronic obstructive lung disease are not fully understood, but may include suboptimal development of the respiratory tract system, which results in reduced airway calibers and lower lung function [215, 216, 217, 218]. Previous studies suggest that children with asthma already have a reduced lung function in the first months of life, and that this deficit tracks or progresses into childhood and early adulthood [219, 220]. This process might be accelerated by any additional adverse exposures in a period of the highest airway and alveolar development rates . This is supported by a pooled data analysis of 20,000 children, which reported that independent of current passive smoke exposure, maternal smoking during pregnancy seems associated with lower lung function in childhood . According to a recent randomized clinical trial, the adverse effect of maternal smoking during pregnancy on respiratory morbidity of the child might be weakened by vitamin C use during pregnancy, but its beneficial effects on lung function is less clear . Alternatively to suboptimal development of the respiratory tract system, recent studies propose that maternal smoking during pregnancy changes the expression of asthma susceptibility genes by a reduction of histone deacetylase activity and changes in DNA-methylation patterns [224, 225, 226]. Specific genetic variants related to asthma, many of them located in chromosomal region 17q12–q21, seem modified by tobacco smoke exposure during pregnancy and other environmental factors [225, 226, 227, 228]. Thus far it is not known to what extent these epigenetic changes persist throughout life or which specific critical periods for epigenetic changes are important to have a long lasting effect on the risk of impaired lung function and chronic obstructive lung diseases in later life.
Exposure to allergens in early life and the development of IgE-mediated sensitisation and eventually allergic diseases are not fully understood. It has been proposed that an increased exposure to allergens, for example dust mite, leads to an increased risk of specific sensitization and asthma [229, 230]. However, results of studies are inconsistent. Furthermore, children vary widely in the clinical expression of atopic diseases, ranging from mild symptoms of rhinitis, asthma, or eczema to severe life-threatening anaphylactic shock. This implies a more complex association of allergen exposure with the development of IgE-sensitisation patterns and allergic diseases. Recent research suggests that atopic diseases may be accurately reflected by atopic phenotypes consisting of distinct IgE-mediated sensitization patterns for foods and inhalant allergens. Four recent birth cohort studies of 500–1,000 children aged 2–18 years have identified such phenotypes [105, 231, 232, 233]. Although the specific categorization of the atopic phenotypes differed across cohorts, they observed that a multiple or mixed food and inhalant sensitization atopic phenotype was most strongly associated with asthma [ORs 11.9 (7.3, 19.4) to 29.3 (11.1, 77.2)], compared with the never sensitization phenotype, while inconsistent results were observed for lung function outcomes, allergic rhinitis, and eczema. Identification of these atopic phenotypes will enable better identification of specific dietary and environmental exposures, and (epi)genetic mechanisms that might be involved in the development of asthma and other atopic diseases. Also, associations of allergen exposure in early fetal and childhood life, and its possible cumulative and dose-response effect, with chronic obstructive lung and related diseases need to be explored. Data are currently lacking .
Respiratory tract infections
Childhood asthma symptoms or wheezing are predominantly related to respiratory tract infections in the preschool age [235, 236, 237, 238, 239]. Respiratory infectious diseases in infancy might also predict the risk of asthma and other respiratory diseases in childhood and adulthood [91, 240, 241, 242]. Viral respiratory infections, of which respiratory syncytial virus and human rhinovirus have been studied the most, are related with an increased risk of asthma [237, 243, 244]. A meta-analysis observed that a history of respiratory syncytial virus was associated with a 3.8 fold increased risk of asthma in childhood  but that this risk declined for asthma at older ages. Mechanisms that lead from viral infections to asthma comprise various immunological pathways but viral infections and asthma might also be the result of the same impaired developed immune system, low lung function or genetic susceptibility . Signs of evidence for a causal relationship have recently been observed. A randomized control trial among 429 healthy preterm infants reported a 61 % reduction of wheezing in the first year of life when children were given respiratory syncytial virus prophylaxis compared with those children who received a placebo . Human rhinovirus infections in early life have been associated with a 2.9 fold-increased risk of asthma [244, 248] and even stronger if children are IgE-sensitised. Their underlying mechanisms need to be further explored but genetic susceptibility might be involved . Not only viral, but also bacterial respiratory infections are associated with asthma symptoms . Wheezing episodes seem associated with overall presence of H. influenzae, M. catarrhalis, or S. pneumoniae [OR 2.9 (1.9, 4.3)], independent of virus infections, or previous colonization of the airways with these bacterial pathogens . Whether these associations reflect causal mechanisms or a common underlying factor, such as susceptible lung, is not known. Also, the effect of maternal infections during pregnancy on childhood asthma needs to be fully explored. Maternal antibiotic use during pregnancy has been associated with increased risk of hospital admission for childhood asthma, outpatient attendance and corticosteroid use [adjusted incidence rate ratio (95 % CI) 1.24 (1.18, 1.30), 1.22 (1.18, 1.26), and 1.18 (1.15, 1.20), respectively] providing indirect observational evidence. Moreover, maternal antibiotic use not only during pregnancy, but also 80 weeks before pregnancy was associated in a dose dependent manner with hospital admission, outpatient attendance and corticosteroid use of their children . This implies that not only the fetal period, but also the preconceptional period seems important for the development of childhood asthma.
Genetic susceptibility and epigenetics
Previous candidate gene studies and linkage studies identified more than 100 genes associated with asthma [251, 252]. However, most of these associations could not be replicated. More recent genome wide approaches (GWAS) in large study populations successfully identified and replicated genetic variants related to asthma in children [253, 254, 255, 256, 257, 258, 259, 260, 261, 262] or COPD  and related lung function in adults [264, 265, 266, 267]. Most consistent reported asthma-related loci were observed at or near ORMDL3–GSDMB genes on chromosome 17, but for childhood asthma only . Other examples of reported asthma-related loci are CHI3L1, IL6R, and DENND1B on chromosome 1, IL1RL1–IL18R1 on chromosome 2, PDE4D and RAD50–IL13 on chromosome 5, HLA-DQ on chromosome 6, IL33 on chromosome 9, SMAD3 on chromosome 15, and IL2RB on chromosome 22 [253, 254, 255, 256, 257, 258, 259, 260, 261]. For COPD, GWAS studies reported related loci at or near genes for HHIP and FAM13a on chromosome 4, CDH6 at chromosome 5, CSMD1 at chromosome 8, PARD3, ADARB2 and TMEM72-ASI at chromosome 10, RIN3 at chromosome 14, and 15q25 and 19q13 loci . Associations of genetic variants with lung function have been reported for 7 genes located on chromosome 11 including MIR129-2, PRDM11, PTCH1, TMEM26, ANK3, FOXA1 and HSD17B12 and also for EFEMP1 on chromosome 2, BMP6 on chromosome 6, WWOX on chromosome 12, the IL16/STARD5/TMC3 locus on chromosome 15 and KCNJ2 on chromosome 21 [264, 265, 266, 267]. Taken together, GWAS studies have provided important new information on the mechanisms involved in pathogenesis of chronic obstructive lung diseases and lung function. However, observed effects are weak and account for only a small proportion of the heritability of the disease, and so far seem to have little prognostic utility.
The effects of early life exposures such as maternal smoking and diet, breastfeeding and infant infectious diseases on the risk of asthma and COPD might be modified by a genetic susceptibility [167, 224, 227, 269, 270, 271, 272], but results are not consistent. An accumulating body of evidence suggests that the underlying molecular mechanisms leading from adverse exposures in early life to respiratory adaptations and diseases in later life include epigenetic modifications. Epigenetic modifications are changes in the genetic material that do not affect the DNA sequence and include DNA methylation, histone modifications and non-coding RNAs . DNA methylation is the most well understood mechanism in epidemiological population-based studies. Changes in DNA methylation of CpG dinucleotides of specific gene regions frequently occur in early life. These changes are influenced by several environmental exposures and might affect gene expression. Recent studies showed general and biological pathway-specific differences in DNA methylation in children from mothers who smoked during pregnancy and in mothers and children with specific dietary patterns [183, 184, 226, 274, 275, 276, 277, 278]. Studies focusing on the role of epigenetics on the development of respiratory outcomes showed that DNA methylation status related to specific genes is associated with both the presence and severity of COPD , decreased lung function , asthma , and other atopic diseases [226, 274, 282, 283, 284, 285]. However, these studies assessed candidate gene-specific epigenetic modifications, and were not able to relate selected loci with gene expression, and subsequently to lung structure, lung function and respiratory disease. Thus, future studies are needed to relate adverse fetal exposures with DNA methylation, repeatedly measured in early life, and with RNA and protein expression and subsequent structural, functional and clinical respiratory outcomes in childhood, adolescence and adulthood.
Chronic obstructive lung diseases from birth until adulthood are heterogeneous, and the underlying origins remain partly unknown. Several lines of research suggest that chronic obstructive lung diseases such as asthma and COPD have at least part of their origins in fetal life and early childhood. Further exploration of critical periods are needed and therefore focus for further research should be on the embryonic and preconception period to identify specific embryonic, fetal and infant growth patterns, their specific adverse exposures and gene-environment interactions leading to chronic obstructive lung disease across the life course. Specific early exposures of interest include maternal obesity, diet and dietary patterns, intake of macro- and specific micronutrients and supplements, smoking, and child’s diet, allergen exposure, and respiratory infectious diseases in early life. Developmental adaptation mechanisms in early life that need to be studied in epidemiological study design include DNA methylation, RNA expression, and detailed imaging and functional assessments of the airways and lungs. Newly identified contributing factors to the origins of chronic obstructive lung diseases might ultimately contribute to the development of novel strategies for the early identification of high-risk groups, and for targeted primary prevention in population-based settings.
Liesbeth Duijts received funding from the Lung Foundation Netherlands (no 3.2.12.089; 2012).
Conflict of interest
The authors have no conflict of interest.
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