Annals of the American Thoracic Society

Rationale: Bronchopulmonary dysplasia and the long-term consequences of prematurity are underrecognized entities, unfamiliar to adult clinicians. Well described by the pediatric community, these young adults are joining the ranks of a growing population of adults with chronic lung disease.

Objectives: To describe the quality of life, pulmonary lung function, bronchial hyperresponsiveness, body composition, and trends in physical activity of adults born prematurely, with or without respiratory complications.

Methods: Four groups of young adults born in Canada between 1987 and 1993 were enrolled in a cohort study: (1) preterm subjects with no neonatal respiratory complications, (2) preterm subjects with neonatal respiratory distress syndrome, (3) preterm subjects with bronchopulmonary dysplasia, and (4) subjects born at term. The following measurements were compared across the four groups: health-related quality of life, respiratory health, pulmonary function, methacholine challenge test results, and sedentary behavior and physical activity level.

Measurements and Main Results: Adult subjects who had bronchopulmonary dysplasia in infancy had mild airflow obstruction (FEV1, 80% predicted; FEV1/FCV ratio, 70) and gas trapping compared with others. They also had less total active energy expenditure and more time spent in sedentary behavior compared with subjects born at term. All preterm groups had a high prevalence of bronchial hyperresponsiveness compared with term subjects.

Conclusions: In a population-derived, cross-sectional study, we confirmed previous reports that adults 21 or 22 years of age who were born prematurely with neonatal bronchopulmonary dysplasia are more likely to have airflow obstruction, bronchial hyperresponsiveness, and pulmonary gas trapping than subjects born prematurely without bronchopulmonary dysplasia or at term. Clinicians who care for adults need to be better informed of the long-term respiratory consequences of premature birth to assist young patients in maintaining lung function and health.

Preterm birth has been an underrecognized global health issue, partly because of a lack of data on the extent of the problem. In 2015, an estimated 15 million preterm babies will be born worldwide. North America has the second highest rate of preterm birth worldwide, and preterm births are increasing in number. More than 1 million infants die every year because of prematurity, and those who survive have an increased risk of morbidities such as cerebral palsy, blindness, hearing loss, and chronic lung disease (1).

Bronchopulmonary dysplasia and the long-term respiratory consequences of prematurity are underrecognized entities, unfamiliar to many clinicians caring for adult patients. Well described by the pediatric scientific community, young adults who were born prematurely and developed respiratory complications are joining the ranks of a growing population of adults who suffer from chronic lung disease.

Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease that develops as a consequence of neonatal lung injury, and is one of the most important sequelae of preterm birth (1). BPD occurs most commonly in preterm infants who have needed mechanical ventilation and oxygen therapy for respiratory distress syndrome of the newborn (RDS) (2). BPD was first described 4 decades ago in children born slightly preterm with severe RDS who were exposed to aggressive mechanical ventilation and high concentrations of inspired oxygen (3). Over time, this has been largely replaced by a new form of the condition occurring in more extreme preterm infants, often with less severe RDS after pulmonary surfactant administration (4).

Despite notable advances in prenatal and neonatal care, BPD remains an important complication of preterm birth, frequently resulting in mortality as well as short-term and long-term morbidity, including airflow limitation and bronchial hyperresponsiveness (5).

This study aims to describe the health-related quality of life, pulmonary lung function, incidence of bronchial hyperresponsiveness, body composition, and trends in physical activity of young adults born prematurely, with or without respiratory complications such as RDS and BPD, and to compare these with young adults born at term.

Subjects, Study Design, and Setting

This was a cohort study comparing four groups of young adults born in Canada between 1987 and 1993 and who were living in the province of Quebec at the time of the study. Participants were included in one of four groups based on hospital discharge diagnosis at birth: (1) preterm subjects (born at less than 37 wk of gestation) with no respiratory complications (preterm), (2) preterm subjects with respiratory distress syndrome but without BPD (RDS), (3) preterm subjects with BPD (with or without preceding RDS) (BPD), and (4) subjects born at term without respiratory complications after birth (term).

The hospital discharge diagnosis data at birth were obtained for a majority of subjects from the Régie de l’Assurance Maladie du Québec (RAMQ), using the International Classification of Diseases, 9th revision (ICD-9) diagnostic codes for preterm birth (765.**), RDS (769.*), and BPD (770.7). These data were obtained as part of a previously published cross-sectional study that surveyed the population of BPD, RDS, and a portion of the preterm subjects born in the province of Quebec during the same period of time (6, 7), using a mail-in or online survey on quality of life, respiratory health, and health care use. Subjects who lived within a 50-km radius of the research center and who had agreed to participate in further studies were contacted to take part in this cohort study.

Additional recruitment of subjects took place via a local advertisement. In this minority of cases, where the subjects were born in Canada but outside of the province of Quebec (BPD, RDS, preterm, or term subjects) or where the subjects were born in Quebec but had not participated in the initial cross-sectional study (preterm and term subjects only), birth information was obtained from a copy of the birth medical chart or the Canadian health and vaccination booklet containing the gestational age and the birth weight. The latter only applied to either preterm subjects without respiratory complications or to term subjects because the diagnosis of RDS and BPD could not have been confirmed.

The study period ranged between 2011 and 2014 and took place in the Respiratory Epidemiology and Clinical Research Unit of McGill University (Montreal, PQ, Canada). Data on subjects were collected during two different visits to the research center.

Variables and Measurements

A study questionnaire was used to assess medical and smoking history, Medical Research Council (MRC) dyspnea score, and education level; this questionnaire was administered verbally. When asking about medical conditions, it was specified to the participants that they should report only conditions that had been diagnosed by a health professional. The SF-36v2 (36-Item Short-Form Health Survey, version 2) and St. George’s Respiratory Questionnaire (SGRQ) were completed by participants to evaluate their quality of life and respiratory health, respectively.

Whole body plethysmography, slow vital capacity, spirometry, diffusion capacity of the lung for carbon monoxide (DlCO), and airway resistance (Raw) were determined in accordance with the American Thoracic Society (ATS) guidelines (810) in a BodyBox 5500 (Medisoft, Sorinnes, Belgium). Use of short-acting β-agonists was withheld on the day of the test. FVC, FEV1, FEV1/FVC, forced expiratory flow rate at 25–75% of FVC (FEF25–75%), inspiratory capacity (IC), FRC, TLC, VC, residual volume (RV), RV/TLC, DlCO, and Raw were recorded and considered acceptable if they followed the acceptability and reproducibility criteria of the ATS (810). The best FVC and FEV1 values were selected out of three acceptable maneuvers, the two best IC (from plethysmography or slow vital capacity) were averaged, the three best FRC were averaged, TLC was calculated on the basis of IC and FRC (TLC = IC + FRC), the best VC was selected, and RV was calculated on the basis of calculated TLC and measured VC (RV = TLC – VC). We used the European Community of Coal and Steel (ECCS) predicted set of values (11). Predicted lung volumes were adjusted for ethnicity other than white (10% diminution) (11).

Reversibility to bronchodilator was tested independently of the lung function test results. Salbutamol (200 μg) was administered after postexercise spirometry, and spirometry was repeated 15 minutes later. The test was considered positive if an increase of 12% and 200 ml in FEV1 and/or FVC was observed compared with the postexercise spirometry.

Methacholine challenge tests were performed by a qualified technician using the 2-minute tidal breathing dosing protocol (according to ATS guidelines [12]). Spirometry was performed with an Easy on-PC spirometry sensor (ndd Medical, Zurich, Switzerland). A diluent step (normal saline) was done before the first dose of methacholine was administered. Postdiluent FEV1 was used as the reference for the challenge. When participants had no history of asthma and/or symptoms and had a normal FEV1, the first dose of methacholine administered was 0.25 mg/ml. To ensure safety, the test was not performed if FEV1 at baseline or postdiluent was lower than 60% predicted and was supervised by a doctor if it was between 60 and 70%. The test was stopped when a 20% fall in FEV1 was observed or after the highest concentration. Salbutamol (200 μg) was administered if there was a fall of 10% or more in FEV1 or if the participant had any symptoms. When applicable (fall of 20% or greater in FEV1) and as recommended by the ATS, the PC20 (provocative concentration of methacholine causing a 20% fall in FEV1) was calculated using a logarithmic interpolation equation.

Total lean body mass and fat mass were assessed by dual-energy X-ray absorptiometry with a Lunar iDXA (GE Healthcare, Wauwatosa, WI).

A subset of participants from the BPD and term groups were given a SenseWear Pro 3 armband activity monitor (BodyMedia, Pittsburgh, PA) and were asked to wear it for seven consecutive days. Gathered data were considered acceptable if the device was worn for at least one weekend day and 3 weekdays for a minimum of 10 hours each day and when asleep (13). Daily step count, energy expenditure, and time spent in sedentary behavior and in moderate physical activity were obtained by generating a report, using the SenseWear 7.0 Pro software. This program calculated averages for each day from midnight to midnight.

Bias

Selection bias was avoided by recruiting participants from the general population, using their birth hospital discharge diagnosis, and not subjects currently monitored in pediatric or adult respiratory medicine clinics, which is generally the case in the study of former preterm subjects. Use of the ICD-9 diagnostic codes for prematurity and BPD to properly identify a subject who was born prematurely or who had BPD at birth was validated previously by the authors (6).

Study Sample Size

The sample size calculation was based on the primary objective of detecting a significant difference in lung function (FEV1) between subjects with BPD and control subjects (preterm and term subjects). We defined a clinically significant difference in FEV1 as 150 ml (14). Assuming an α level of 0.025 and a standard deviation of 50 ml in FEV1 measurements, the observation of 30 cases per group was to allow the detection of a 150-ml difference with 80% power (15). This was based on simple difference in means per group.

Statistical Methods

One-way analysis of variance was used for continuous variables such as the SGRQ and SF-36v2 scores. For categorical variables such as demographic and past medical history data, the chi-square or Fisher test was used. Univariate analyses comparing the odds of various characteristics between individual groups were conducted using logistic regression. These analyses were also adjusted for age, sex, smoking history, and other item-specific important confounders.

Subgroup analyses were conducted by sex and for the presence of asthma across the four groups. Independent two-way t tests were performed to compare data acquired from the armband for the BPD and term subgroups.

Results of statistical tests with a P value not exceeding 0.05 were considered significant. Analysis of variances and regressions were performed with SPSS version 22 (IBM Corporation, Armonk, NY). Chi-square and Fisher exact tests for counts above 5 were performed using a table of contingency available online (http://vassarstats.net/fisher2x4.html); for counts below 5 the 9.2 statistical package (SAS Institute, Cary, NC) was used.

Institutional Review Board Approval

The institutional review board of McGill University and the McGill University Health Center approved the study before its initiation (IRB no. 10-149-BMB).

Participants and Demographics

The BPD group was composed of 31 subjects; the RDS group had 31; the preterm group had 26; and the term group had 35 subjects. From those, 30 BPD, 29 RDS, 17 preterm, and 10 term subjects initially took part in the preceding cross-sectional study and were identified using their ICD-9 discharge diagnosis at birth found in the RAMQ databases.

Table 1 summarizes the demographic and clinical information as well as the medical history across the four groups. The mean age of the cohort participants was between 21 and 22 years. Male subjects composed 35% of the BPD group and 31% of the term group, whereas 58% of the RDS group and 23% of the preterm group were male. The degree of dyspnea and the highest level of education achieved did not differ across the four groups. There were significantly more diagnoses of asthma, attention-deficit hyperactivity disorder, and learning disabilities in the preterm subjects who experienced respiratory complications at birth compared with preterm and term control subjects.

Table 1. Demographic and clinical information on study participants

 BPDRDSPretermTermP Value
(n = 31)(n = 31)(n = 26)(n = 35)
Demographic and clinical information     
 Age (yr), mean (SD)22 (2)21 (2)22 (2)22 (2)0.041
 Male, n (%)11 (35)18 (58)6 (23)11 (31)0.037
 BMI, mean (%)*24 (6)23 (3)24 (5)23 (3)0.223
 Current smoker, n (%)5 (16)2 (6)1 (4)3 (9)0.450
 MRC dyspnea score, mean (SD)1.45 (0.68)1.32 (0.54)1.46 (0.71)1.11 (0.32)0.054
 Education (finished high school level)15 (48)17 (55)18 (69)25 (71)0.179
 Birth weight, kg (SD)1.06 (0.37)1.96 (0.78)2.17 (0.80)3.45 (0.42)<0.001
 ELBW (≤1 kg), n (%)15 (48)3 (10)4 (15)0 (—)<0.001
 VLBW (≤1.5 kg), n (%)27 (87)12 (39)5 (19)0 (—)<0.001
 GA, d (SD)192 (18)224 (25)230 (23)277 (10)<0.001
 Apgar score at 1 min (SD)§5 (2)5 (3)7 (2)8 (1)<0.001
 Apgar score at 5 min (SD)§6 (2)7 (2)8 (1)9 (1)<0.001
 Multiple gestations, n (%)1 (3)1 (3)0 (—)1 (3)
 Caesarean section, n (%)18 (58)14 (45)9 (35)6 (17)0.006
 Maternal smoking during pregnancy, n (%)6 (19)3 (10)0 (—)1 (3)0.027
Medical historyǁ     
 Childhood asthma, n (%)12 (39)10 (32)6 (23)10 (29)0.641
 Asthma, n (%)9 (29)5 (16)3 (12)1 (3)0.024
 Anxiety disorder, n (%)3 (10)4 (13)3 (12)1 (3)0.433
 Obesity,** n (%)3 (10)1 (3)4 (15)3 (9)0.468
 ADHD, n (%)9 (29)4 (13)0 (—)1 (3)0.001
 Learning disability,†† n (%)6 (19)6 (19)0 (—)0 (—)0.001
 Atopy,‡‡ n (%)9 (29)7 (23)12 (46)8 (23)0.175
 Familial asthma,§§ n (%)8 (26)8 (26)7 (27)15 (43)0.349
 Maternal asthma, n (%)2 (6)2 (6)3 (12)2 (6)0.850

Definition of abbreviations: ADHD = attention-deficit hyperactivity disorder; BMI = body mass index; BPD = bronchopulmonary dysplasia; ELBW = extremely low birth weight; GA = gestational age; MRC = Medical Research Council; RDS = respiratory distress syndrome; VLBW = very low birth weight.

*BMI calculated on the basis of iDXA-determined body weight (except in the case of two participants with BPD and two term participants who did not undergo dual-energy X-ray absorptiometry).

BW from health booklet or chart. BW missing for one term participant.

Missing GA for one participant with RDS. GA for term participants who did not know the exact number of weeks was assumed to be 40 weeks.

§Missing data on Apgar scores: 6 BPD, 8 RDS, 13 preterm, and 18 term participants.

ǁExcept when specified, medical conditions were reported by participants who were specifically asked to say yes only when it was diagnosed by a doctor.

Missing childhood asthma data for one term participant.

**Obesity refers to a BMI greater than 30.

††As reported by participant.

‡‡Atopy refers to respiratory allergies: dust, animals, pollen, seasonal allergies, and so on.

§§Familial asthma if brother/sister, father, mother, or grandparents have asthma.

Pulmonary Function

Participants with BPD had mild but significant airflow obstruction compared with the others, defined using an FEV1/FVC ratio of 70 or less. The group with BPD also had significantly more gas trapping, with a mean residual volume of 158% of predicted. The diffusion capacity was also diminished compared with the other groups but was still within the lower limit of normal (Figure 1 and Table 2).

Table 2. Results of pulmonary function testing in study participants

 BPDRDSPretermTermP Value
 (n = 31)(n = 31)(n = 26)(n = 35) 
FEV1, % predicted (SD)80 (18)94 (12)94 (14)98 (9)<0.001
FVC, % predicted (SD)100 (15)99 (9)104 (14)109 (10)0.006
FEV1/FVC70 (12)81 (9)79 (7)79 (7)<0.001
FEF25–75%, % predicted (SD)68 (26)92 (19)89 (26)96 (18)<0.001
IC,* % predicted (SD)108 (20)97 (14)109 (16)108 (20)0.04
FRC, % predicted (SD)121 (22)119 (18)114 (15)120 (16)0.447
TLC, % predicted (SD)114 (13)107 (9)111 (9)113 (12)0.069
VC, % predicted (SD)97 (13)96 (10)101 (15)107 (13)0.002
RV, % predicted (SD)158 (43)138 (31)134 (34)125 (26)0.001
RV/TLC157 (43)137 (31)133 (34)123 (26)0.001
DlCO, % predicted (SD)86 (11)93 (19)98 (18)99 (10)0.002
Va, % predicted (SD)95 (11)93 (11)96 (11)98 (8)0.24
DlCO/Va, mean (SD)5.54 (0.31)5.45 (0.33)5.59 (0.27)5.49 (0.29)0.328
Raw, % predicted (SD)186 (93)124 (45)130 (45)124 (34)<0.001

Definition of abbreviations: BPD = bronchopulmonary dysplasia; DlCO = diffusing capacity of the lung for carbon monoxide; FEF25–75% = forced expiratory flow rate at 25–75% of FVC; IC = inspiratory capacity; Raw = airway resistance; RDS = respiratory distress syndrome; RV = residual volume; Va = alveolar volume.

*Average of the two best maneuvers from plethysmography and slow vital capacity.

One RDS participant was unable to perform the DlCO maneuver.

Of the subjects with BPD, 46% had significant bronchodilator response compared with RDS (18%), preterm (12%), and term (6%) participants (P < 0.0001). Seven subjects did not undergo bronchodilator reversibility testing using salbutamol: three BPD (one pregnant, one did not want to receive salbutamol, one did not feel well after exercise), three RDS (one did not feel well after exercise, one dropped out after the first visit, one did not want to receive salbutamol), and one term (dropped out after the first visit).

Results of methacholine challenge can be seen in Table 3. Of the subjects with BPD, 71% had evidence of bronchial hyperresponsiveness. This was not significantly different from results for the RDS group and the preterm group with 62 and 69%, respectively, although 25% of the subjects with BPD could not undergo the challenge because of an FEV1 that was less than 60% of predicted.

Table 3. Results of methacholine challenge in study population*

 BPDRDSPretermTermP Value
 (n = 21)(n = 29)(n = 26)(n = 33)
PC20, mean (mg/ml) (SD)2.68 (2.72)2.54 (2.85)3.65 (3.15)4.11 (3.76)0.369
PC20 ≤ 8 mg/ml, n (%)15 (71)18 (62)18 (69)15 (45)0.169
Not done (FEV1 < 60%), n (%)7 (25)0 (—)0 (—)0 (—)<0.001

Definition of abbreviations: BPD = bronchopulmonary dysplasia; PC20 = provocative concentration of methacholine causing a 20% fall in FEV1; RDS = respiratory distress syndrome.

*Methacholine challenge was performed only in subjects with an FEV1 greater than 60% predicted.

Percentage calculated over total number of participants included in the group.

Respiratory Health and Quality of Life

The symptoms, activity, and impacts scores of the SGRQ were not significantly different across the four groups or different when compared with the general population. The total scores and standard deviations on the SGRQ were 11 (12), 8 (8), 10 (12), and 5 (5) for the BPD, RDS, preterm, and term subjects, respectively (P value, 0.060). Similar findings were found with the SF-36v2 health survey questionnaire, where the physical component summary and mental component summary scores were not different across the four groups (data not shown).

Lean Body Composition

The lean body weights measured on the basis of iDXA scans were not different across the four groups when taking into account the sex distribution of each group (Table 4).

Table 4. Lean body weight of study participants*

Group (no. female, no. male)FemaleMale
[% (SD)][% (SD)]
BPD (18, 11)65.8 (8.3)80.3 (7.9)
RDS (13, 18)66.4 (6.2)79.8 (6.0)
Preterm (20, 6)66.6 (8.7)78.3 (12.5)
Term (23, 10)69.9 (6.3)81.4 (7.7)

Definition of abbreviations: BPD = bronchopulmonary dysplasia; RDS = respiratory distress syndrome.

*iDXA scans were not done for two participants with BPD (pregnant) and two term participants (dropped out after the first visit).

Physical Activity

Despite relatively similar MRC dyspnea score and health-related quality of life between the BPD and term subjects, we identified significant differences in the total duration of physical activity, the total active energy expenditure, as well as the time spent in sedentary behavior between a subgroup of BPD (68% of the BPD group) and term subjects (71% of term subjects) in whom physical activity data were recorded (Table 5).

Table 5. Physical activity measurements in subjects with bronchopulmonary dysplasia and term study subjects

 BPDTermP Value
 (n = 20)(n = 24)
 [Avg/d (SD)][Avg/d (SD)]
Total energy expenditure, kJ9,306 (2,087)10,260 (2,089)0.17
Physical activity duration, min88 (56)126 (68)0.05
Active energy expenditure, kJ1,588 (1,048)2,567 (1,352)0.02
Number of steps8,487 (3,245)11,692 (3,839)0.01
Moderate physical activity, min83 (52)112 (61)0.11
Sedentary time, min*1,303 (72)1,251 (91)0.05

Definition of abbreviation: Avg = average; BPD = bronchopulmonary dysplasia.

*Armband not worn enough nights and excluded from analysis: one subject with BPD and one term subject.

In this population-based, cross-sectional cohort study, subjects born prematurely with neonatal bronchopulmonary dysplasia were more likely to have mild airflow obstruction at the age of 21–22 years than other subjects the same age who were born prematurely without BPD or at term. As young adults, 25% of the subjects born prematurely with BPD had an FEV1 less than 60% of predicted, placing them in the category of moderate airflow obstruction.

We did not measure changes in lung function over time. However, it is well known that the FEV1 value peaks at age 25 years and then assumes a steady decline over time at a rate ranging from 30 ml/year in nonsmokers to 60 ml/year in susceptible smokers (16). The annual rate of decline of the FEV1 in subjects with BPD over time has still not yet been clearly defined. There is a theoretical risk that the subjects with BPD will have an accelerated loss of lung function with time, similar to what is seen in the chronic obstructive pulmonary disease population.

The high prevalence of bronchial hyperresponsiveness in all preterm subjects found in this study is well supported by previously published population studies that describe a fourfold increase in the incidence of asthma for individuals born preterm (7, 17). This raises an interesting issue of delineating the phenotypic features of a preterm lung from true asthma and a possible overlap between the two conditions.

A study looking at subjects born extremely prematurely in Norway between the years 1982 and 1985 revealed similar findings regarding the high prevalence of bronchial hyperresponsiveness in preterm subjects compared with term control subjects. Similarly, their subjects with BPD also showed significant gas trapping, as demonstrated by an increase in the ratio of residual volume to total lung capacity (18). In another study reviewing the short- and long-term respiratory morbidity associated with prematurity and BPD, most studies concluded that subjects who had BPD after a preterm birth experienced reductions in airflow before age 18 years, compared with control subjects, and that those reductions persisted into adulthood (19).

There is growing recognition that premature infants with chronic lung disease have a different clinical course and pathology than had been first described 3 decades ago, before the introduction of routine surfactant use and other advances in neonatal care. Classically, BPD was considered a fibroproliferative disorder of the lung parenchyma, similar to the adult respiratory distress syndrome (20). With the knowledge that alveolar development in the human takes place between 36 weeks of gestation and continues until 18 months after birth, it is now believed that lung injury caused by prematurity, mechanical ventilation, infections, and other factors during this critical period of lung development results in abnormal alveolarization (21). This resulting disruption of distal lung growth, which in turn leads to abnormal microvascular development, is thought to be the basis for the development of BPD (22, 23). Lung histology, rather than showing prominent signs of barotrauma and fibroproliferative reactions seen in severe cases of respiratory distress syndrome, shows signs of truncated lung growth, with abnormal alveolarization and dysmorphic vascular growth.

Originally ascribed to oxygen toxicity (24), the development of BPD is now recognized as having a multifactorial etiology (25). Barotrauma, resulting from ventilator-associated lung injury in the setting of neonatal RDS, is believed to be involved in the development of BPD (26). This belief has resulted in avoidance of high tidal volume use and improved resuscitation techniques in the delivery room. Patent ductus arteriosus and fluid overload, potentially via an increase in pulmonary vascular congestion, have been shown to be associated with BPD (27, 28). BPD was found to occur more frequently in infants whose mother had chorioamnionitis. This led to the belief that intraamniotic endotoxin exposure could result in disruption of alveolar development and subsequent BPD (29). Genetic factors, such as ethnic origin and sex, are believed to affect the severity of RDS, which in turn could affect the occurrence of BPD. As well, a family history of asthma was found to carry an odds ratio of 4.83 for the development of BPD in a premature cohort (3032). Other factors, such as neonatal inflammation/infections (33, 34), nutritional factors (35), the use of prenatal and neonatal corticosteroids (36), and some vascular growth factors such as vascular endothelial growth factor and the major histocompatibility molecule HLA-A2, were found to have an impact on BPD, and are thus considered modulators of the disease (3739).

Despite the abnormalities found in pulmonary function, it is encouraging to see that the respiratory health and health-related quality of life do not differ significantly among the four groups, despite a higher incidence of attention-deficit hyperactivity disorder and learning difficulties in the BPD and RDS groups.

In 1987, neonatologists began to hear about the Barker hypothesis, which proposed that suboptimal maternal and fetal nutrition can have profound and sustained effects on the health of a person later in life, including cardiovascular disease (40). It has been shown that low birth weight is associated with later adult disease such as diabetes mellitus type II, hypertension, obesity, ischemic heart disease, and cerebrovascular accidents and a number of metabolic abnormalities, such as insulin resistance, dyslipidemia, and procoagulation state (41). Aberrant adiposity and altered regional adiposity have been documented in 45 school-age children born prematurely, using dual-energy X-ray absorptiometry (42), but no studies have looked at altered body composition in the adult population and more specifically in subjects with BPD and how it could be linked to their exercise capacity and its correlation with lung function.

With this knowledge in mind, it is reassuring that we could not find a significant difference in lean body weight across the four groups when correcting for the sex distribution in each group.

In a population believed to be at higher risk for metabolic abnormalities and accelerated atherosclerosis, the finding that subjects with BPD tend to be more sedentary and did not reach the minimal recommended moderate physical activity level per week (150 min) and average steps per day (10,000 steps) is rather alarming (43).

Limitations and Generalizability

The main limitation of this study is the lack of data on the postnatal use of surfactant and corticosteroid therapy in the study population, which may limit the generalizability of our findings to individuals born preterm subsequently. The routine use of surfactant therapy was introduced in clinical practices around 1990 but varied widely from center to center. Surfactant therapy did not follow strict guidelines until much later. What differentiates this study and makes the issue of a potential selection bias less significant is that, contrary to many studies on former preterm subjects, our subjects were not selected from a cohort of subjects currently monitored because of their prematurity, but were selected from the general population.

Another limiting factor is the high prevalence of bronchial hyperresponsiveness and the high percentage reporting childhood asthma in our term group (29%), compared with the general population (11.5%) (4446). This raises possibility that individuals with underlying lung disease such as asthma might have been more prone to participate in a study on lung health. This bias would not likely create differences between our preterm and term groups that are not present in the population as a whole.

In a population-derived cohort of adults 21 or 22 years of age, subjects born prematurely with neonatal bronchopulmonary dysplasia were more likely to have airflow obstruction, bronchial hyperresponsiveness, and pulmonary gas trapping than subjects born prematurely or at term without BPD.

The impact of preterm birth with associated neonatal lung disease has lasting consequences on respiratory health. Clinicians caring for adult patients need to be better informed about adult respiratory manifestations of premature birth to better assist young patients in maintaining health and lung function. Prevention and education focusing on smoking avoidance or smoking cessation, health lifestyle, and physical activity may be key factors in ensuring that our young patients born prematurely will maintain best achievable respiratory health and quality of life as they age.

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Correspondence and requests for reprints should be addressed to Jennifer S. Landry, M.D., M.Sc., Montreal Chest Institute–McGill University Health Center, 1001 boulevard Décarie, Room D05.2044, Montreal, PQ, H4A 3J1 Canada. E-mail:

Supported by a research grant from the Fond de Recherche en Santé du Québec (FRSQ). This governmental agency had no role in the study design, conduct, and reporting of this study.

Author Contributions: J.S.L. designed the study protocol, supervised the study, performed some of the analyses and wrote the manuscript. G.M.T. supervised most study participants’ tests, built the database, performed some of the analyses and review/commented on the manuscript. P.Z.L. performed some of the analyses and review/commented on the manuscript. C.W. supervised some study participants’ tests, contributed to the database data entry, performed some of the analyses and review/commented on the manuscript. A.B. provided key guidance for the data analysis, protocol design and review/commented on the manuscript. T.T. provided key guidance for the data analysis and protocol design and review/commented on the manuscript.

Author disclosures are available with the text of this article at www.atsjournals.org.

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