Fetal and infant origins of asthma

Liesbeth Duijts 0 1 2 0 L. Duijts (&) Division of Respiratory Medicine (Sp-3435), Department of Pediatrics, Erasmus Medical Center , PO Box 2060, 3000 CB Rotterdam, The Netherlands 1 L. Duijts Department of Epidemiology and Pediatricsdivision of Respiratory Medicine, Erasmus Medical Center , Rotterdam, The Netherlands 2 L. Duijts Department of Epidemiology, Erasmus Medical Center , Rotterdam, The Netherlands Previous studies have suggested that asthma, like other common diseases, has at least part of its origin early in life. Low birth weight has been shown to be associated with increased risks of asthma, chronic obstructive airway disease, and impaired lung function in adults, and increased risks of respiratory symptoms in early childhood. The developmental plasticity hypothesis suggests that the associations between low birth weight and diseases in later life are explained by adaptation mechanisms in fetal life and infancy in response to various adverse exposures. Various pathways leading from adverse fetal and infant exposures to growth adaptations and respiratory health outcomes have been studied, including fetal and early infant growth patterns, maternal smoking and diet, children's diet, respiratory tract infections and acetaminophen use, and genetic susceptibility. Still, the specific adverse exposures in fetal and early postnatal life leading to respiratory disease in adult life are not yet fully understood. Current studies suggest that both environmental and genetic factors in various periods of life, and their epigenetic mechanisms may underlie the complex associations of low birth weight with respiratory disease in later life. New well-designed epidemiological studies are needed to identify the specific underlying mechanisms. This review is focused on specific adverse fetal and infant growth patterns and exposures, genetic susceptibility, possible respiratory adaptations and perspectives for new studies. - Asthma in childhood has a high prevalence across many countries worldwide [1]. The reported prevalence of asthma is around 510% among school-age children and figures are even higher for asthma related symptoms, such as wheezing, in younger children. Childhood asthma is related to a reduced quality of life and exercise tolerance, and higher risks of school absenteeism and hospitalization [2]. Despite the availability of effective treatments for symptoms, the morbidity remains high [3]. The lack of curative options seems to be largely due to the unknown aetiology of asthma [4]. Furthermore, one general definition of asthma is difficult to define [5]. Objective tests, including spirometry or bronchial hyperresponsiveness, are not easy to conduct in young children, and have limited applicability. In epidemiological studies it is currently well accepted that a diagnosis of asthma is based on parental- or self-reported symptoms [6]. Because of these different asthma definitions, it is important to identify the specific underlying mechanisms for the associations of exposures in fetal life and infancy with different asthma related outcomes, which might reflect different specific structural and functional adaptations. Several studies, of which some have been published in the European Journal of Epidemiology have suggested that asthma, like other common diseases, has at least part of its origin early in life [4, 741]. Long term follow up studies in different populations have shown that impaired respiratory health or lung function in early childhood is associated with asthma and other respiratory diseases in later life [4248]. These studies suggest that lung function and susceptibility for various respiratory diseases track from early childhood onwards. Thus, risk factors for wheezing and asthma or low airway function in childhood might predispose for respiratory diseases in later life. Examples of known major risk factors in early childhood for development of respiratory disease or low airway function include exposure to parental smoking or air pollution, no or shorter period of breastfeeding, obesity, larger family size, daycare attendance, infectious diseases in early childhood and acetaminophen use [4956]. Developmental origins of childhood asthma Recently, low birth weight has also been shown to be associated with increased risks of asthma, chronic obstructive airway disease, and impaired lung function in adults [5761]. In term born children, it was found that low birth weight is associated with increased risks of respiratory symptoms in the first 7 years of life [62]. Low birth weight per se is not likely to be the causal factor leading to asthma. The same birth weight might be the result of various growth patterns and different fetal exposures [10, 63]. The developmental plasticity hypothesis suggests that the associations between low birth weight and diseases in later life are explained by early adaptation mechanisms in response to various adverse exposures in fetal life and early childhood [64]. This hypothesis is supported by extensive epidemiological evidence showing strong and consistent associations of low birth weight with the risk of common diseases in adulthood, including cardiovascular disease, type 2 diabetes and COPD [10, 6466]. Developmental adaptations in fetal life and infancy might also result in impaired lung growth, leading to smaller airways, decreased lung volume, and subsequently to an increased risk of asthma or COPD throughout postnatal life [46, 58, 60, 66, 67]. Reduced diameter of central and small airways can contribute to the development of childhood asthma [6870]. Airway caliber is a key determinant of total airway resistance and might be related to asthma and COPD [71]. Other mechanisms underlying the associations of low birth weight with asthma and respiratory diseases in childhood and adulthood might include an innate or T helper 2 skewed immune system, increased allergen sensitization, inflammation and bronchial hyperreactivity [7275]. These different underlying mechanisms may lead to various phenotypes of asthma with onset at different ages. Fetal growth characteristics 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 [76, 77]. A recent study suggested no associations of fetal growth characteristics with the risk of ever wheeze until the age of 3 years [78]. However, when the outcome wheeze was combined with atopic status of the child, the authors showed that a SD lower fetal head circumference growth between 11 and 19 weeks was associated with a 10% higher risk of nonatopic wheeze, and a SD lower fetal abdominal circumference growth between 19 and 34 weeks of gestation was associated with a 20% higher risk of atopic wheezing. Another study with retrospectively collected fetal measurements observed that reduced fetal size in first trimester is associate (...truncated)