Abstract
Rationale: Limited information is available about the long-term outcome of lung function and exercise capacity in young adults born prematurely.
Objective: To determine long-term effects of prematurity on lung function (volumes, diffusing capacity) and exercise capacity in ex-preterms compared with healthy peers.
Methods: In a prospective cohort study, children born with a gestational age of less than 32 wk and/or a birth weight under 1,500 g were followed up for 19 yr. Participants (n = 42; mean gestational age, 30 wk, and mean birth weight, 1,246 g) and healthy term control subjects (n = 48) were recruited for lung function and exercise tests.
Measurements: Spirometry, bodybox (TLCbox), diffusing capacity (DlCO), bicycle ergometer test.
Main Results: Preterm birth was associated with lower FEV1 (preterms, 95% predicted, vs. controls, 110% predicted; p < 0.001), DLCOsb (88% predicted vs. 96% predicted, p = 0.003), and exercise capacity (load, 185 vs. 216 W; p < 0.001; anaerobic threshold: mean, 1,546 vs. 1,839 ml/min; p < 0.001) compared with control subjects at follow-up. No differences between the groups were found in TLCbox, peak oxygen consumption (V̇o2), and breathing reserve. No significant differences in lung function and exercise parameters were found between preterms with and without bronchopulmonary dysplasia.
Conclusions: Long-term effects of prematurity were airway obstruction and a lower CO diffusing capacity compared with control subjects, although mean lung function parameters were within the normal range. Ex-preterms had a lower exercise level, which could not be explained by impaired lung function or smoking habits, but might be due to impaired physical fitness.
Respiration in preterm infants is compromised by anatomic immaturity of the lungs, impaired or delayed surfactant synthesis, underdeveloped chest wall anatomy, and inefficient clearing of lung secretions. These factors may cause edema of the pulmonary interstitium, disruption of alveolar capillary membranes, damage of the alveolar spaces and inadequate gas exchange immediately after birth. In the 1980s, treatment of this condition was supportive and consisted of artificial ventilation and administration of high concentrations of oxygen. Prolonged mechanical ventilation and/or oxygen supplementation treatment may contribute to irreversible damage of lung parenchyma and small airways. The question arises whether these pathologic changes at early age contribute to diminished lung function and exercise capacity in later life.
Limited information is available about the long-term outcome of lung function in young adults born prematurely. Follow-up studies on lung function show conflicting results: some authors report that preterm children regained normal lung function and exercise performance by school age (1, 2). Others describe obstruction of small airways and lower levels of fitness in adolescents born prematurely (3–5). Diffusing properties of lung tissue at school age were significantly lower after preterm birth compared with control subjects (6). Whether preterm birth is also associated with reduced exercise capacity later in life is yet unknown. Moreover, it is unclear whether or not poor lung function is the limiting factor in purported reduced exercise capacity.
The aim of the study was to investigate the long-term effects of prematurity on lung function and exercise capacity. This is the first time that lung function was performed in this cohort. Some of the results of this study have been previously reported in the form of an abstract (7).
In a prospective nationwide Dutch study (Project on Preterm and Small for Gestational Age Children [POPS]), all children born in 1983 with a gestational age of less than 32 wk and/or a birth weight under 1,500 g were followed up to 19 yr of age. Perinatal and neonatal data, collected prospectively, included gestational age, birth weight, duration of mechanical ventilation, supplemental oxygen therapy, and maternal smoking habits. Bronchopulmonary dysplasia (BPD) was identified by the need for oxygen for more than 28 d and by chronic changes on the chest X-ray. None of the neonates received exogenous surfactant. The POPS study consisted of 1,338 infants, constituting 94% of the eligible subjects. All 998 infants surviving the initial hospital stay were enlisted for follow-up. Mortality and morbidity data for this birth cohort have been published elsewhere (8). Between their birth and follow-up visit in 2002, 379 children died, leaving 959 living participants at age 19. The 99 participants visiting two hospitals in the northern part of the Netherlands (Groningen and Zwolle) were invited to participate in this study. We asked the participants to bring a healthy friend to participate in the present study as an age-matched control subject. For participants unable to bring a friend, age-matched (medical) students were recruited. A detailed history (partly by questionnaire) was taken and all participants underwent physical examination before the lung function tests. The control subjects were confirmed to be “healthy” (no symptoms, no special medication except usual medication such as contraception). To be informed on their physical activity, we asked the participants what kind of sports activities they performed. We asked the following questions (European Community Respiratory Health Survey II questionnaire): How often do you usually exercise so much that you get out of breath or sweat? How many hours a week do you usually exercise so much that you get out of breath or sweat? From the combination of responses to these questions, we derived the information presented in Table 1. The study was approved by the medical ethics committee, and all participants gave their written, informed consent.
Preterm-born | Controls | |
|---|---|---|
| Number | 42 | 48 |
| Male/female | 21/21 | 16/32 |
| Birth weight, g | 1246 ± 232 (720–1,750) | N/A |
| Gestational age, wk | 30 ± 2 (26–36) | Term (37–42) |
| Duration of ventilator treatment, d | 6.3 ± 12 (0–51) | N/A |
| BPD, % | ||
| Yes | 9 (21) | 0 (0) |
| No | 32 (76) | 48 (100) |
| Unknown | 1 (2) | 0 (0) |
| Age, yr | 19 ± 0.3 (19–20) | 20.8 ± 1.2 (18–22) |
| Length, cm | 174.2 ± 7.6 (159–191) | 176.5 ± 9.9 (148–200) |
| Weight, kg | 65.3 ± 8.1 (48–88) | 69.1 ± 9.5* (43–87) |
| BMI, m/kg2 | 21.7 ± 3 (17–30) | 22.1 ± 2.4 (17–28) |
| Smoking, % | ||
| Yes | 13 (31) | 7 (15)† |
| No | 22 (52) | 38 (79) |
| Unknown | 7 (17) | 3 (6) |
| Exercise, h/wk | 1.9 ± 2 (0–7) | 2.9 ± 2* (0–7) |
| History of asthma, % | ||
| Yes | 4 (10) | 3 (6) |
| No | 35 (83) | 42 (88) |
| Unknown | 3 (7) | 3 (6) |
| Current asthma, % | ||
| Yes | 1 (2) | 0 (0) |
| No | 38 (90) | 45 (94) |
| Unknown | 3 (7) | 3 (6) |
| Maternal smoking, % | ||
| Yes | 18 (43) | 8 (17)‡ |
| No | 16 (38) | 37 (77) |
| Unknown | 8 (19) | 3 (6) |
| Maternal asthma, % | ||
| Yes | 0 (0) | 4 (8) |
| No | 33 (78) | 41 (85) |
| Unknown | 9 (22) | 3 (6) |
Lung function tests were undertaken in the lung function laboratory (Viasys Healthcare GmbH, Hoechberg, Germany) of the University Medical Center Groningen. All measurements were performed by professional lab technicians according to guidelines of the European Respiratory Society (ERS) (9, 10). FVC, FEV1, forced expiratory flow after 25, 50, 75% of VC expired (FEF25, FEF50, FEF75), and peak expiratory flow (PEF) were measured using a pneumotachograph. At least three similar curves were required before any spirometric test variable was accepted. The curve with the largest sum of FVC and FEV1 was used for analysis. Participants wore nose-clips during the tests.
Total and specific airway resistance (Raw, sRaw), specific airway conductance (sGaw), thoracic gas volume, total lung capacity (TLCbox), and residual volume (RV) were measured using whole body plethysmography. Diffusing capacity (DlCO and Kco) was measured by single-breath method. The results obtained in each group were evaluated as percentages of values predicted (ERS) based on actual height (10).
For DlCO and Kco, the reference values of the ERS were used (11). DlCO values corrected for hemoglobin (Hb) were analyzed. (The Hb was measured in almost all participants. Two participants did not give permission for taking blood samples.) Corrections for Hb concentrations were made according to American Thoracic Society (ATS) guidelines (12).
Maximal exercise capacity was measured using an incremental symptom- limited bicycle ergometer test. The ergometer is magnetically braked (type ER 900 L; Viasys Healthcare GmbH). Heart rate and rhythm were monitored with an electrocardiograph. Patients respired through a mouthpiece and wore a nose-clip. Minute ventilation (V̇e), V̇o2, and carbon dioxide output (V̇co2) were measured and calculated from a mixing chamber every 30 s (MMC Oxygon Champion, Viasys Healthcare GmbH). Calibration of the gas analyzers and flow transducers was performed before each test. The test required 3 min of seated rest on the ergometer for collecting baseline measurements. Subjects were then instructed to begin pedaling at 60 to 70 revolutions/min. After 3 min of unloaded cycling, load was increased every minute by 15 W. The participants were encouraged to cycle as long as possible. Dyspnea scores (Borg) were obtained during the test every minute (13). Peak values for all variables were obtained by averaging data over the last 20 s of maximum completed work. Peak V̇o2 was predicted using formulae for healthy subjects (14). Peak V̇e was predicted by the formula of Carter (37.5*FEV1) (15). Anaerobic threshold (AT) was obtained from the inflexion on the V̇o2/V̇co2 plot. The AT was expressed as a percentage of the predicted peak V̇o2.
To determine the limiting factor during exercise the following definitions were used. According to Wasserman and colleagues and ATS guidelines, cardiocirculatory limitation was defined as having no heart rate reserve (peak heart rate ⩾ predicted peak heart rate) (14, 16). A ventilatory limitation was defined as having a breathing reserve (i.e., the difference between the maximum voluntary ventilation and the maximal exercise ventilation) of less then 11 L · min−1 (14). An oxygen uptake limitation was defined as having an oxygen desaturation below 90%. A peripheral muscle limitation was defined as having none of the other limitations. Work efficiency was determined by the ratio of the increase in V̇o2 in response to a simultaneous increase in work rate (14, 16).
Normality of data distribution was checked using normal p-plots. The significance of differences among the two study groups was tested using unpaired t test or χ2 test. Linear regression analysis with lung function parameters as dependent variables and smoking and preterm birth as independent variables was performed to study whether differences remained after correcting for these potential confounders. Subsequently, linear regression analysis with exercise parameters as dependent variables and FEV1 and preterm birth as independent variables was performed. Data were analyzed using SPSS 12.0 (SPSS, Inc., Chicago, IL).
A total of 44 of 99 (44%) candidates agreed to participate in this study (Table 1). Two participants were not able to attend; one was able to perform lung function but not able to perform the incremental exercise test due to physical disabilities. No differences were found between the 44 responders and 55 nonresponders with regard to birth weight, duration of mechanical ventilation, percentage of participants with BPD, or school performance at the age of 14. The most important differences between the study group and the total cohort were the percentage of participants with BPD and the percentage of participants with a handicap. The percentage of participants with BPD was significantly lower in the total cohort (8 vs. 21% in the study group, p = 0.003). The percentage of participants with a handicap was higher in the total cohort (19 vs. 8% in the study group; p not significant due to small numbers). Other differences were small. The mean gestational age of the 44 responders was 1 wk less (30 wk) than that of the 55 nonresponders (31 wk; p = 0.003). The mean gestational age of the total cohort was 30 wk (see Tables E1–E4 in the online supplement). The control group consisted of 48 persons (Table 1): 12 friends of ex-preterm participants and 36 (medical) students. All subjects of the control group were born at term.
Most lung function measurements were within the normal range for both groups (Table 2). FEF25, FEF50, and FEF75 (as percentage predicted) of preterms were abnormally low. FVC, FEV1, FEV1/FVC, PEF, and sGaw of ex-preterms were significantly lower than those of control subjects. TLCbox tended to be smaller in the prematurely born, but this difference was not significant. The transfer factor (diffusion capacity) for carbon monoxide (DlCO) was significantly lower in the preterm group than in the control subjects. Hb concentrations did not differ between the groups. These results remained the same after adjustment for smoking habits using linear regression analysis.
Preterm-born (n = 42) | Controls (n = 48) | p Value | |
|---|---|---|---|
| FVC, % pred | 97.7 ± 13.7 | 106.0 ± 10.8 | 0.002 |
| FEV1, % pred | 95.4 ± 15.9 | 109.6 ± 13.4 | < 0.001 |
| FEV1/%FVC | 82.2 ± 8.2 | 87.4 ± 6.6 | 0.002 |
| FEF25, % pred | 81.4 ± 22.2 | 106.2 ± 20.1 | < 0.001 |
| FEF50, % pred | 75.3 ± 24.6 | 100.4 ± 26.8 | < 0.001 |
| FEF75, % pred | 75.3 ± 25.9 | 100.5 ± 34.3 | < 0.001 |
| PEF, % pred | 87.1 ± 21.8 | 107.5 ± 17.1 | < 0.001 |
| TLCbox, % pred | 100.1 ± 9.9 | 103.3 ± 9.7 | 0.125 |
| TGV, % pred | 106.8 ± 21.9 | 104.9 ± 17.8 | 0.659 |
| RV, % pred | 99.4 ± 28.3 | 90.3 ± 25.3 | 0.117 |
| RV/%TLC | 24.6 ± 5.3 | 22.2 ± 5.3 | 0.046 |
| Raw, % pred | 81.5 ± 37.2 | 60.3 ± 23.9 | 0.002 |
| sGaw, % pred | 146.3 ± 63.7 | 179.6 ± 54.4 | 0.009 |
| DlCOsb, % pred | 88.4 ± 13.7 | 96.3 ± 9.9 | 0.003 |
| Kco, % pred | 95.5 ± 15.8 | 99.6 ± 12.2 | 0.165 |
Workload (Wmax) was 15% lower in ex-preterms than in control subjects (Table 3). The anaerobic threshold, V̇emax, and maximum heart rate as percentage predicted were significantly lower in the ex-preterms compared with the healthy control subjects. No differences were observed between the groups in maximal V̇o2, breathing frequency, ventilatory reserve, oxygen uptake–work relationship, and Borg score. Fatigue and dyspnea were the most frequent reasons to stop bicycling in both groups. All subjects fulfilled the criteria for a cardiocirculatory limitation of maximal exercise capacity. No subjects reached the criteria for a ventilatory limitation, oxygen uptake limitation, or muscular limitation. Additional adjustment for lung function did not change these results.
Preterm-born (n = 41) | Controls (n = 47) | p Value | |
|---|---|---|---|
| Heart rate, max, % pred* | 87.8 ± 5.9 | 91.2 ± 5.6 | 0.007 |
| Heart rate reserve, %† | 12.2 ± 5.9 | 8.5 ± 5.5 | 0.004 |
| Load max, W | 185.4 ± 36.9 | 216.4 ± 41.2 | < 0.001 |
| Load max, % pred | 99.1 ± 15 | 119.7 ± 22 | < 0.001 |
| Breathing frequency, breaths/min | 16 ± 3 | 14 ± 3 | < 0.001 |
| Maximal breathing frequency, breaths/min | 35 ± 7 | 36 ± 6 | 0.414 |
| Vt, L | 0.53 ± 0.12 | 0.63 ± 0.26 | 0.0326 |
| Vtmax, L | 2.0 ± 0.5 | 2.2 ± 0.5 | 0.085 |
| V̇emax, L/min‡ | 70.0 ± 17.9 | 80.9 ± 20.8 | 0.011 |
| Ventilatory reserve§ | 49.4 ± 10.1 | 48.2 ± 11.5 | 0.600 |
| V̇o2 rest, ml/min/kg | 5.2 ± 1.0 | 4.6 ± 0.8 | 0.003 |
| V̇o2 at AT, ml/min/kg | 23.8 ± 4.1 | 26.6 ± 4.7 | 0.004 |
| V̇o2max, ml/min/kg | 35.3 ± 6.9 | 37.4 ± 6.3 | 0.143 |
| V̇o2 max, % pred | 93 ± 10 | 105 ± 20 | < 0.001 |
| AT, ml/min | 1546 ± 289 | 1839 ± 447 | 0.001 |
| AT/V̇o2 pred | 63.4 ± 10 | 74.5 ± 12.7 | < 0.001 |
| ΔV̇o2/ΔWR, ml/min/W | 9.7 ± 0.9 | 9.9 ± 1.1 | 0.271 |
| Respiratory exchange ratio, max∥ | 1.2 ± 0.09 | 1.2 ± 0.07 | 0.738 |
| Borg score | 7 ± 3 | 7 ± 3 | 0.358 |
Preterm women had significant lower TLCbox as percentage predicted than female control subjects (mean, 98 vs. 104%; p = 0.03). RV as percentage predicted was higher in preterm men than in male control subjects (mean, 115 vs. 93%; p = 0.02). Also, the ratio of RV to TLC was significantly higher in preterm men (mean preterm, 26, control subjects, 21; p = 0.008). Kco tended to be lower in preterm men (98 vs. 108%, p = 0.07). Preterm women showed a significant lower maximal V̇o2 (30 vs. 35 ml/min/kg, p < 0.001) and tended to have a lower oxygen uptake–work relationship (9.1 vs. 9.6, p = 0.07).
The premature group consisted of a rather large percentage of participants with BPD (21%), so we decided to analyze the results of the participants with and without BPD to investigate whether BPD accounts for the found differences in lung function and exercise parameters. The participants with BPD were almost all males (89%). We compared the males with BPD (n = 8) with ex-preterm males without BPD (n = 12) who completed the tests. No significant differences in lung function and exercise parameters were found between these groups (Table 4 and 5).
With BPD (n = 8) | Without BPD (n = 12) | p Value | |
|---|---|---|---|
| FVC, % pred | 96.4 ± 13.1 | 99.2 ± 13.7 | 0.656 |
| FEV1, % pred | 90.1 ± 19.8 | 99.2 ± 17.9 | 0.302 |
| FEV1/%FVC | 78.8 ± 8.1 | 82.5 ± 11.1 | 0.455 |
| FEF25, % pred | 76.7 ± 28.0 | 83.1 ± 21.1 | 0.569 |
| FEF50, % pred | 66.7 ± 29.8 | 80.1 ± 25.9 | 0.298 |
| FEF75, % pred | 63.2 ± 30.2 | 87.0 ± 29.2 | 0.095 |
| PEF, % pred | 86.3 ± 25.7 | 91.3 ± 21.4 | 0.758 |
| TLCbox, % pred | 102.2 ± 8.9 | 102.5 ± 8.3 | 0.944 |
| TGV, % pred | 123.8 ± 14.1 | 121.3 ± 15.0 | 0.831 |
| RV, % pred | 122.7 ± 25.4 | 111.2 ± 29.1 | 0.372 |
| RV/%TLC | 116.6 ± 22.5 | 106.5 ± 27.6 | 0.394 |
| Raw, % pred | 82.4 ± 37.8 | 70.6 ± 52.3 | 0.593 |
| sGaw, % pred | 129.9 ± 64.5 | 170.5 ± 83.4 | 0.263 |
| DlCOsb, % pred | 91.4 ± 10.5 | 94.5 ± 18.0 | 0.748 |
| Kco, % pred | 98.6 ± 21.5 | 97.3 ± 17.0 | 0.800 |
With BPD (n = 8) | Without BPD (n = 12) | p Value | |
|---|---|---|---|
| Heart rate, max, % pred* | 92.3 ± 4.4 | 86.8 ± 6.0 | 0.041 |
| Heart rate reserve, %† | 7.7 ± 4.4 | 13.2 ± 6.0 | 0.040 |
| Load max, W | 211.8 ± 16.9 | 206.2 ± 37.9 | 0.700 |
| Load max, % pred | 91.9 ± 9 | 94.0 ± 10 | 0.653 |
| Breathing frequency, breaths/min | 17 ± 2 | 18 ± 3 | 0.394 |
| Maximal breathing frequency, breaths/min | 37 ± 10 | 33 ± 6 | 0.277 |
| Vt, L | 0.54 ± 0.07 | 0.56 ± 0.09 | 0.561 |
| Vtmax, L | 2.25 ± 0.48 | 2.37 ± 0.53 | 0.622 |
| V̇emax, L/min‡ | 79.0 ± 18.2 | 76.3 ± 18.1 | 0.754 |
| Ventilatory reserve§ | 53.1 ± 12.5 | 47.5 ± 9.0 | 0.258 |
| V̇o2 rest, ml/min/kg | 5.5 ± 0.4 | 5.7 ± 1.2 | 0.649 |
| V̇o2 at AT, ml/min/kg | 27.0 ± 4.3 | 25.2 ± 3.9 | 0.207 |
| V̇o2max, ml/min/kg | 40.8 ± 5.3 | 40.6 ± 5.1 | 0.952 |
| V̇o2 max, % pred | 93 ± 0.1 | 92 ± 0.1 | 0.843 |
| AT, ml/min | 1804 ± 199 | 1593 ± 254 | 0.065 |
| AT/V̇o2 pred | 63.2 ± 0.09 | 57.8 ± 0.09 | 0.208 |
| ΔV̇o2/ΔWR, ml/min/W | 10.2 ± 0.7 | 10.3 ± 0.9 | 0.773 |
| Respiratory exchange ratio, max∥ | 1.2 ± 0.06 | 1.1 ± 0.07 | 0.550 |
| Borg score | 8 ± 2 | 8 ± 2 | 0.522 |
This study demonstrated that ex-preterms at young adulthood show mildly decreased airway patency, DlCO, and exercise capacity as compared with healthy control subjects. However, the pulmonary differences between the two groups did not account for the reduced maximal exercise capacity, as all participants showed a normal cardiocirculatory limitation. Instead, the ex-preterms showed a significantly lower anaerobic treshold than healthy control subjects, and tended to have lower work efficiency.
The study population might not be exactly the same as the total cohort. Taking into account that some participants with a handicap are not able to perform lung function and exercise tests, this study group approximates the total population as much as possible. The use of medical students might select for a particularly fit population. In a study by Peterson and colleagues, students were fitter than published norms, but the average age of the students in their study was older compared with our study group (17). However, “to be fit” was not a selection criterion in our study. No differences existed between the students and other control subjects. Therefore, we have the impression that the students were representative for their age group and could be used as control subjects.
Preterm birth was associated with airway obstruction, specifically in the medium caliber and small airways, as shown by significantly lower results in FVC, FEV1, FEV1/FVC, PEF, FEF25,50,75, and sGaw, and a higher Raw. These results are in line with previous publications (3, 5). Quality and quantity of the airways and lungs are probably largely determined during gestation. The two major pregnancy-related determinants of lung development are fetal growth and duration of gestation (18). Premature delivery in the last trimester does not affect normal alveolar proliferation or growth in airway size (19). However, the airways are small and have a relative increase in smooth muscle mass and mucus-secreting cells, which is accentuated by ventilator therapy (20). Arrested alveolar development has been observed in very premature infants and/or infants who are small for gestational age (21, 22). Repair of damaged airways (remodeling) can be an important factor in the development and persistence of increased bronchial responsiveness. Several studies in children born prematurely found increased prevalence of asthma, which was associated with reduced expiratory flow rates (23, 24). In this study, asthma prevalence was low.
The exposure to maternal smoking was higher in the preterm group, which is also associated with airway obstruction (24–27). Parental smoking during pregnancy as well as during the early years of the child may have adverse effects on pulmonary function in children (28, 29). It is likely that some of this effect is attributable to in utero exposure because smoking during pregnancy has adverse effects on pulmonary development reflected in an impaired lung function measured in the neonatal period (30). Postnatal environmental tobacco smoke exposure has been associated with small declines in pulmonary function as well, but the mechanism underlying this effect has not been identified. Parental smoking during childhood and adolescent peer pressure are commonly cited as predictors of teenage smoking. However, others found weak and inconsistent associations between parental and adolescent smoking (31). Moreover, recent follow-up studies showed a lack of any significant association between becoming a teenage smoker and parental smoking or the number of smokers in the home in childhood in their analyses (32). Sibling and peer smoking show higher associations with adolescent smoking. In our cohort, we could not find a significant association between maternal smoking and smoking habits of the participants (χ2, p = 0.09). The percentage of preterm participants who smoke was high compared with the control subjects. In general, current smokers have a lower FEV1 and an accelerated decline in FEV1, compared with those who formerly or never smoked. A relatively low FEV1 by middle age and a faster-than-expected annual fall in FEV1 are the two most useful findings in identifying smokers who are likely to develop severe pulmonary impairment (33). In our study, results remained after adjustment for smoking habits using linear regression analysis.
The preterm group showed a lower DlCO compared with the control subjects, although Kco was only reduced in the males. DlCO reflects the total diffusion capacity of the alveolar–capillary membrane of the lung, which is important for proper oxygen uptake during exercise. One of the major problems of preterm birth is the immaturity and/or underdevelopment of the lungs with reduced numbers of alveoli. Intensive treatment can lead to reduced postnatal alveolar proliferation. A possible explanation for the observed lower DlCO is a decreased surface area for gas exchange because of a reduced number of alveoli. Other explanations could be thickening of membranes (because of cicatrization, fibrosis, or pulmonary vascular disease), ventilation–perfusion mismatch (inhomogeneity of air distribution), or a disturbed binding with Hb. A former study in school-aged children also showed significantly lower DlCO values and normal Kco (6). The difference in Kco between men and women could be due to the more severe health problems boys have compared with girls during the neonatal period, which could result in more serious pathology (34).
Maximal exercise testing provides information of the level of exercise a subject can perform. Ex-preterms reached a 15% lower load than healthy peers at adulthood. This is partly in line with previous studies in younger age groups, demonstrating low maximal oxygen consumption, suggesting a lower level of fitness for extremely low birth weight children compared with normal birth weight children (4, 35–37). Others found normal cardiopulmonary function of ex-preterms by school age (2, 35–37).
We anticipated that ex-preterms might show decreased maximal exercise capacity because of a ventilatory or oxygen uptake limitation. However, the mean breathing reserve was approximately 50% and no one demonstrated an oxygen desaturation. In addition, no differences were found between the two groups in ventilatory reserve, breathing frequency, Vt, and Borg dyspnea score. This means that ventilation and oxygen uptake were not the limiting factors in ex-preterms and that normal compensatory mechanisms such as increase in Vt and breathing frequency augmented total ventilation. Analyses of results of participants with and without BPD did not show significant differences. Therefore, BPD seems not to account for the found differences. Unexpectedly, the preterms showed a lower anaerobic threshold, which points to early lactate production. Anaerobic threshold normally occurs at 50 to 60% of predicted V̇o2max and may rise with training. The anaerobic threshold of the ex-preterms occurred at a normal but significantly lower level than that of the control subjects.
Although their heart rate was less close to the predicted maximum than that of the control subjects, the respiratory exchange ratio was equal between the groups. Furthermore, no signs of poor effort were found in the ex-preterms. Together, our results suggest that ex-preterms have signs of muscular deconditioning. Interestingly, ex-preterms reported fewer hours of exercise per week than the control subjects, which might explain their lower level of physical fitness.
In preterm women, the maximal V̇o2 was lower than in healthy peers. A subanalysis on the limiting factors of exercise capacity did not show a significant difference between women who were born prematurely and female control subjects (data not shown). However, the numbers for comparisons between the sexes are small and findings must be interpreted with caution. Previous studies have shown that peak V̇o2 is strongly related to activity pattern (38). The lower peak V̇o2 in women again could be an indicator for reduced physical fitness. Further investigations are needed to determine whether these young adults engage in less physical activity because of physiologic (and/or psychologic) limitations and whether exercise capacity can be improved with the introduction of a training program.
Muscular efficiency in this study was determined by the net muscular efficiency: ΔV̇o2/ΔW ratio. This ratio takes the metabolism at rest of a person into account. The preterm women tended to have a lower oxygen uptake–work relationship, which could point to a less coordinated way of bicycling, or to a less efficient release of energy in the muscle. A reduced ratio of increase in V̇o2 to increase in work rate (ΔV̇o2/ΔWR) is also reported in cardiovascular disease, in some patients with mitochondrial myopathy, and in patients with cystic fibrosis (39). However, a low ΔV̇o2/ΔWR may be useful in identifying an abnormal relationship but is relatively nonspecific in establishing etiology (i.e., O2 delivery vs. O2 utilization dysfunction). A remarkable result is the higher V̇o2 at rest in ex-preterms, which might reflect a higher metabolism at rest. Because the breathing frequency at rest is higher in ex-preterms, we speculate that they have a higher metabolism at rest due to greater work of breathing. Further research is needed to verify this with indirect calorimetric measurement of resting energy expenditure. Other explanations could be excitement, fear, or nonfitting reference values for this age group. In future research it would be interesting to measure the compliance of the lungs.
Apart from cardiorespiratory factors, three physiologic derangements may contribute significantly to exercise intolerance: obesity, anemia, and carboxyhemoglobinemia secondary to cigarette smoking. Compared with control subjects, the weight of the ex-preterms was significantly lower. They did not differ from their peers by Hb content. However, a higher percentage of the ex-preterms smoked cigarettes. Linear regression analysis showed that the differences in exercise capacity remained after correction for smoking habits.
If we had not included a control group in our study, we would have reached different conclusions about the lung function of the preterm group (namely, that almost all participants had lung function values within the normal range). This highlights the importance of control groups when recent reference data are not available.
Although mean lung function parameters were within the normal range, ex-preterms tended to have more bronchial obstruction and lower diffusion capacity than control subjects. Subtle but possibly important lung function abnormalities after preterm birth may persist into young adulthood. This may have impact at later phases of life, since it has been shown that young adults with submaximal lung function will reach the danger zone of impaired lung function in elderly age more quickly. This might even be more pronounced in smokers. V̇o2 per kilogram at rest is higher in preterm than in healthy participants, which might be an indication of a higher metabolism at rest. More research is needed to verify the rest metabolism.
Exercise capacity in prematurely born adults is lower than in healthy peers. This may be explained by impaired physical fitness. Diminished exercise capacity seemed not to be due to impaired lung function (values were corrected for FEV1) or limited ventilation. No studies, so far, have determined the efficacy of training. Encouragement of all children born prematurely to participate in sports at an early age could probably improve the exercise performance of this group.
The authors thank Nick H.T. ten Hacken and Anthony E.J. Dubois for advice and support. The POPS study at 19 years of age was supported by grants from the Netherlands Organization for Health Research and Development (ZonMw), Edgar Doncker Foundation, Foundation for Public Health Fundraising Campaigns, Phelps Foundation, Swart-van Essen Foundation, Foundation for Children's Welfare Stamps, TNO Prevention and Health, Netherlands Organization for Scientific Research (NWO), Dutch Kidney Foundation, Sophia Foundation for Medical Research, Stichting Astmabestrijding, Royal Effatha Guyot group.
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