Prevalence of asthma in preterm and associated risk factors based on prescription data from the Korean National Health Insurance database

To our knowledge, this is the first study in Korea to highlight the importance of respiratory disease prognosis after preterm birth in later life. This study showed that preterm infants in Korea are at a significantly higher risk of developing asthma based on asthma diagnostic code and asthma-related medication prescriptions. In addition, preterm asthmatics were also prescribed asthma treatment more frequently than infants born term. We also found that asthma medications were prescribed more frequently to preterm asthmatic patients who were also extremely preterm and male, with extremely low birth weight, BPD, or RDS.

Most studies have reported the risk of chronic respiratory disorders among preterm infants. A meta-analysis reported that the incidence of childhood asthma among preterm infants was 1.37–1.71 times higher than that in term infants^11,12. Structured questionnaires were collected from caregivers of preterm infants born before 29 weeks of gestation who visited a pediatrician at an outpatient clinic at 6 and 12 months of corrected age¹³. Overall, 27% of the patients had a cough, 20% had wheezing, and 3% had frequent wheezing. During the follow-up period, 14% of patients were prescribed bronchodilators, and 8% were prescribed steroids. Preterm survivors had more wheezing events, resulting in significantly impaired quality of life during adulthood⁹.

Several hypotheses have been proposed for the cause of wheezing in preterm infants. Pulmonary structural development was disrupted in preterm infants born without a sufficient period for lung maturation in utero¹⁴. Several studies have suggested that antenatal steroids may play a role in the development of asthma via the impairment of the hypothalamic-pituitary axis, immune dysfunction, and secondary hypertension¹⁵. Besides anatomical origins, several studies have proposed additional dynamic development in the airways of preterm born infants with an ongoing disease that may be caused by preterm birth or postnatal environmental factors^16,17. One cohort study suggested that preterm birth is an independent risk factor for persistent biological stress via ongoing airway inflammation with rapid progression of telomere shortening¹⁸. Preterm birth also causes frequent injuries, including sepsis, respiratory infections, and hypoxia after birth¹⁹. Pathogenesis may contribute to the dose–response relationship between GA and chronic respiratory outcomes, including wheezing disorders.

Asthma is a heterogeneous disease characterized by inflammatory pathogenesis, bronchial hyperresponsiveness, and chronic airway obstruction. Whether the mechanism of asthma in preterm infants is the same as that in term infants is debatable. Several studies have shown that children born preterm have a lower incidence of atopic disorders over the long term^20,21. Asthma patients born term is mainly induced by contact with allergens, however, asthma in preterm infants may be triggered by respiratory infections, reduced airway size, and decreased lung function²⁰. Compared with term infants, preterm infants reportedly to secrete more respiratory cytokines, which may promote airway inflammation thereby predisposing them to asthma²². One study reported no evidence of steroid-sensitive inflammation within the lung assessed by fractional exhaled nitric oxide but suggested the possibility of increased systemic elastic turnover⁹. Several studies have reported that lung function in preterm infants decrease; changes include obstructive patterns, air trapping, and airway hyper-responsiveness, even in adults^9,14,23. Consequently, preterm children should be evaluated for the development of asthma and receive aggressive treatment when detected.

In preterm infants, the risk factors for asthma include atopic dermatitis in infancy, allergic family history, antibiotic treatment within the first 3 years of life, and prematurity²⁴. Similarly, male sex, prematurity, and BPD were associated with an increased risk of asthma among children born preterm in a previous study²⁵. A previous study reported that female sex and SGA were associated with decreased risk of developing asthma^26,27. The authors suggested that certain forms of fetal stress may result in accelerated development of the lungs, and maturation of the lungs is slower in men than in women. However, these results remain controversial. Some studies have also reported that intrauterine growth retardation increases bronchial hyperresponsiveness regardless of atopy tendency²⁸.

This study has some limitations. First, the NHISS did not provide detailed clinical data and depended on physician registrations. The proportion of preterm births is estimated to be approximately 4.4–7.2% in Korea²⁹; however, the proportion of registered preterm infants was 0.2–3.06%. Data on preterm births were limited due to the low registration rate of the diagnostic code and the low relative proportion of preterm infants. The diagnostic code registration rate was low in the early stages of establishing the national information data. Nevertheless, the registration rate increased as the national preterm infant care support system expanded. Preterm infants have an underlying medical history; therefore, the possibility of increased hospital resource utilization is also increased. In addition, a limitation exists in that the data were analyzed only when asthma treatment was performed in a medical institution in Korea. However, health claims data from the NHI are representative, as they cover approximately 98% of the Korean population³⁰, and no additional operational definition was implemented to prevent selection bias. These are long-term data accumulated over 17 years of tracking, beginning with the conditions at birth, which can facilitate a better understanding of the overall health care of asthma patients. This study defined the diagnosis of asthma based on diagnosis codes and prescriptions for asthma-related drugs; however, this represents a limitation because this definition does not include detailed clinical information of the patient and radiological examination or pulmonary function test results. In actual clinical practice, there is a possibility that the diagnosis is incorrectly recorded, or asthma related drugs may be prescribed regardless of asthma diagnosis. To overcome errors in the diagnosis registration, characterizing asthma based on prescriptions for more than two asthma medications with a diagnosis of asthma is helpful. In addition, it is possible that preterm infants were diagnosed with asthma with a relatively more sensitive predictive value compared to term infants, because the former have a higher hospital utilization rate.

This study revealed a higher prevalence of asthma among preterm infants than that in term infants based on diagnosis code and asthma-related medication using the NHI database in Korea. Our findings also showed that preterm infants with asthma were prescribed ICSs and SABAs more frequently. Furthermore, preterm asthma patients were reportedly prescribed ICSs and SABAs, which are inhaled asthma-related drugs, more frequently than term asthma patients. Male sex, extreme prematurity, extremely low birth weight, BPD, and RDS were risk factors for asthma among preterm infants. The results of this study will guide pulmonary prognostication and follow-up strategies for preterm infants as well as directions for future studies on asthma prevention.