We found that extreme preterm birth was associated with more than a twofold-increased risk of asthma medication prescription in young adulthood compared with term birth. Later preterm or postterm birth was not associated with asthma medication prescription. These findings from a large national cohort identify extreme prematurity, but not later prematurity, as a new potentially important risk factor for asthma, at least into young adulthood. Recognition of this risk factor by clinicians and patients may lead to better detection and treatment of asthma in susceptible individuals throughout their life course.
The few previous studies of association between preterm birth and asthma in young adults are much smaller and did not evaluate extreme preterm birth. A cross-sectional survey study of 690 randomly sampled Norwegian adults aged 20 to 24 years (including only 24 subjects who were born preterm)4
and a retrospective study of 567 British adults aged 18 to 25 years, who were registered in general medical practices (including only 31 who were born preterm),2
reported a nonsignificant association between preterm birth and self-reported asthma symptoms or an asthma diagnosis on medical chart review, respectively. A population-based survey study of 5192 Finnish adults aged 31 years (including 247 subjects who were born preterm) did not confirm an association between preterm birth and a self-report of physician-diagnosed asthma.3
A retrospective cohort study of 149 398 Swedish male conscripts aged 17 to 20 years (including 7876 subjects who were born preterm) also did not confirm an association between preterm birth and physician-diagnosed asthma on the basis of a medical interview at a compulsory military examination.5
Each of these studies was either unable to evaluate or did not report results for individuals who were born extremely preterm.
Studies of children and adolescents (up to 18 years old) are more numerous and most,12–26
but not all,27–33
have suggested an association between preterm birth and asthma. A meta-analysis of 19 studies, most of which focused on children and adolescents, found an overall OR of 1.07 for risk of asthma comparing individuals born at gestational ages less than 37 weeks to those born at 37 weeks or more.34
More detailed results for extreme preterm birth, however, were not available.
Proposed mechanisms by which preterm birth may affect subsequent risk of asthma involve genetic, perinatal, and environmental factors. Premature delivery results in loss of the normal structural complexity of the lung and greater susceptibility to subsequent injury from infection or environmental factors such as smoking.1
Genetic susceptibility factors also play a role in reduced immunologic regulation needed for normal lung development and function.1
It is possible that preterm birth and asthma have common genetic determinants.34
There is some evidence that maternal asthma may be associated with preterm delivery25,35
and that maternal asthma is associated with increased risk of asthma in their children.36,37
The current study has several limitations and strengths. One potential limitation is the use of asthma medication prescriptions as a surrogate measure for asthma. There are several features of this study, however, that enhance the validity of this as a proxy. First, as noted, asthma medications are expected to have their highest validity as a surrogate measure for asthma in a young adult population. β-2 Agonist and/or glucocorticoid inhalants are used to treat nonasthma conditions, such as respiratory infections associated with wheezing or chronic obstructive pulmonary disease, but young adults have a lower incidence of these conditions than children or older adults, respectively.10
Second, the positive predictive value of asthma medications (the proportion of individuals identified who actually have asthma) is improved by using criteria that include multiple classes of asthma medications or multiple prescriptions.9,10
Third, the sensitivity of asthma medications as a proxy for asthma (the proportion of asthmatics correctly identified) is enhanced by the availability of data from 2.5 years of follow-up, sufficiently long to detect a very high percentage of the individuals who have asthma.10
Other limitations include, first, the possibility of diagnostic bias. It is possible that individuals who were born extremely preterm were more likely to be treated for asthma because of greater contact with the health care system for comorbidities. We explored this possibility by analyzing oral contraceptives as a control medication. In contrast to the results for asthma medications, no association was observed between preterm birth and oral contraceptives, suggesting that it is unlikely that the observed associations between extreme prematurity and asthma medications are attributable to diagnostic bias. Second, estimation of gestational age was on the basis of maternal report of the last menstrual period rather than by ultrasound, which was not yet widely used at the time these study participants were born (1973–1979). Finally, the use of pharmacy data in this study did not allow for the inclusion of nonmedicated cases of asthma, which are perhaps mediated by nonatopic mechanisms and warrant additional study.
This study also has several unique strengths. To our knowledge, it is the largest study to date of the association between preterm birth and the subsequent risk of asthma and the first study with sufficient statistical power to evaluate this risk in young adults born extremely preterm (gestational age 23–27 weeks). Young adults are a relatively understudied age group, as well as the most appropriate age group for the use of asthma medications as a surrogate measure for asthma. Asthma medication data were obtained from all outpatient and inpatient pharmacies in all health care settings throughout Sweden, thus avoiding the possibility of self-reporting bias. Combinations of asthma medications from 2.5 years of follow-up were evaluated to enhance their positive predictive value for asthma.