The Effects of Preterm Birth on Asthma Development in Adulthood

Preterm birth can have lasting effects on lung development and respiratory health. Individuals born before 37 weeks of gestation are at increased risk for obstructive lung function deficits that may persist from childhood into adulthood. Club cell secretory protein (CC16) is a protein with anti-inflammatory and protective functions in the lungs, often studied as a biomarker for lung diseases and fetal airway growth. Infants born preterm, or before 37 weeks, typically show lower airway levels of CC16, and previous research has linked reduced CC16 to a higher likelihood of developing obstructive lung disease and asthma.  

The goal of this study was to investigate whether lower circulating levels of CC16 help explain the impact of preterm birth on lung function and asthma in young adulthood. Using a longitudinal study design, researchers followed participants from birth to age 26, tracking both their plasma CC16 levels and respiratory health. The results showed that preterm birth was significantly associated with both lower lung function and a higher risk for asthma from childhood to young adulthood. Participants born preterm showed notably lower plasma CC16 levels than those born at term, indicating decreased lung function.  

This study highlights the potential of CC16 as a tool for identifying individuals at higher risk for obstructive lung disease among those born preterm. These findings focus on the importance of prevention and targeted interventions to support long-term lung health for at-risk preterm populations. Exploring one possible approach is supplementing CC16 as a treatment for people born preterm who experience respiratory problems. If future studies confirm that low CC16 directly contributes to lung disease, this strategy could become an effective therapeutic option.  

What were the methods of data collection and analysis? 

Participants were drawn from the Barn/Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) cohort, an observational, population-based birth cohort that originally enrolled 4,089 children born in Stockholm between 1994 and 1996. After reviewing baseline and follow-up data, 2,557 individuals with complete information on age, plasma CC16 levels, and lung function were included in the study.  

Asthma information was collected through questionnaires completed by parents when participants were 8, 12, and 16 years old, and by the participants themselves at ages 24 and 26. Asthma was defined by meeting at least two of the following three criteria: a doctor’s diagnosis of asthma, use of asthma medication in the past 12 months, or wheezing/breathing difficulties in the past 12 months. 

Preterm birth was defined as live births before 37 weeks of gestation; births at or after 37 weeks were classified as term births. To measure CC16 levels, plasma CC16 concentrations were measured at ages 8 and 24, and nasal tissue cells were also collected at age 24 for RNA sequencing. Lung function measurements were conducted using pre- and postbronchodilator tests, a 2-part lung function test that measures a person's inhalation and exhalation capacity with a bronchodilator medication. These tests were administered at ages 8, 16, 24, and 26 years. Lung function analyses focused on the ratio between forced expiratory volume (FEV) and forced vital capacity (FVC), both of which measure the amount of air someone can forcefully exhale. Air flow limitation at each age was defined as the ratio (ppFEV1/FVC) being less than the lower limit of normal, as defined by the Global Lung Function Initiative reference equations. 

Epidemiological analyses examined three main questions: (1) how preterm birth influences respiratory outcomes, (2) how preterm birth relates to plasma CC16 levels, and (3) how plasma CC16 levels in turn relate to respiratory outcomes in adulthood. Mediation analyses were also conducted, which evaluated whether CC16 mediates the relationship of preterm birth to pre- and postbronchodilator ppFEV1/FVC and to asthma in adult life. In other words, these analyses tested whether lower CC16 levels help to explain why individuals born preterm experience worse lung function as adults, using statistical models that separate the overall effect of preterm birth from the portion that operates specifically through CC16. 

What were the results of this study? 

Among the 2,557 participants included in this study, researchers collected 10,603 asthma observations and 6,109 lung function measurements. Preterm birth accounted for 5.4% of the cohort. Plasma CC16 levels increased from age 8 to 24 and were generally lower in boys than in girls during childhood.  

Preterm birth was associated with both lower lung function and a higher risk for asthma from childhood to young adulthood. Participants born preterm also showed notably lower plasma CC16 levels, averaging 1.15 ng/mL lower than those born at term. Additionally, preterm individuals had reduced ppFEV1/FVC values, indicating poorer lung function, and were more likely to have asthma, as seen in Figure 1. Individuals born preterm were over twice as likely to be in the lowest CC16 tertile compared with peers born at term.  

In contrast, plasma CC16 showed a weak relationship with nasal CC16 expression. Although preterm birth was associated with lower plasma CC16 at age 24, it did not appear to influence nasal CC16 expression at that same age. 

Figure 1. Associations of preterm birth with ppFEV1/FVC (A) and asthma (B).  

Secondary analyses found consistent effects of premature birth on risk for subsequent airflow limitation, with preterm birth being associated with 74% increased odds for airflow limitation. Similarly, the researchers observed a significant association between lower CC16 levels and increased risk for airflow limitation.   

The mediation analyses suggested that CC16 mediated 16% and 9% of the effects of preterm birth on ppFEV1/FVC and asthma in adult life, respectively. These findings show that approximately 16% of the association with lung function deficits and 9% of the association with asthma could be attributed to lower CC16 levels, even after accounting for relevant confounders. Similar results for post-bronchodilator lung function suggest that CC16 may be involved in pathways leading to more persistent airway impairment.  

What is the importance of measuring CC16 levels in infants? 

This study demonstrates how lower circulating CC16 levels may help explain why people born preterm are more likely to have reduced lung function and develop asthma as young adults. In other words, CC16 appears to play an important role in the development of obstructive lung disease among individuals born prematurely. The results suggest that CC16 deficits in those born preterm may directly contribute to their higher risk of poor lung function and asthma later in life. Reduced CC16 production in preterm individuals may also affect their susceptibility to infections and their ability to control airway inflammatory responses, which can lead to airway obstruction. Club cells, the main producers of CC16, begin differentiating during the canalicular phase in the latter half of pregnancy. Because of this, being born prematurely may interrupt normal club cell development. Previous research on CC16 has shown its protective role in reducing inflammation, repairing damaged lung lining, fighting oxidative damage, and defending against infection. Individuals born prematurely are more likely to have lower CC16 levels, meaning that their lungs have less protection and defense against infection compared to those born at full term.  

This study also found that preterm birth was linked to lower circulating CC16 levels but not to lower nasal CC16 expression. This suggests that the deficit may not stem from reduced gene expression but from disrupted maturation or distribution of club cells, thus interfering with the distribution of CC16. Since impaired lung function early in life is a precursor to early-onset obstructive lung disease, these findings highlight the importance of prevention and targeted interventions to support long-term lung health in at-risk preterm populations.