Reduced Lung Function in Healthy Preterm Infants in the First Months of Life

    Department of Pediatrics, Pontifícia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Brazil

    ABSTRACT

    Rationale: Preterm delivery has been associated with a higher incidence of respiratory morbidity even in infants that do not have significant respiratory disease during the neonatal period. Reduced flows have been reported in children and adolescents born prematurely.

    Objective: The aim of this study was to assess lung function in healthy preterm infants in the first months of life.

    Methods: Preterm infants with less than 48 h of supplemental oxygen were recruited. Lung function was assessed by the raised-volume rapid thoracic compression in the first months of life. The control group consisted of full-term infants without a history of respiratory diseases.

    Measurements and Main Results: Sixty-two preterm (29 male) and 27 full-term (10 male) infants were tested. Adjusting for length, age, and sex, we found a mean significant reduction of 92 ml/s (22%) in FEF50, 73 ml/s (21%) in FEF25–75, and 19 ml (28%) in FEV0.5 in the preterm group. These differences in expiratory flows remained significant using another model that adjusts for lung volume (p < 0.01 for FEF50, FEF25–75, and FEV0.5, and p < 0.05 for FEF75). In the preterm group, after adjusting for length, male sex, lower gestational age, and increased weight were significantly and independently associated with reduced flows.

    Conclusions: Our findings confirm that prematurity is independently associated with reduced lung function and that this is detectable in the first months of life. Male sex, lower gestational age, and weight are important predictors for reduced expiratory flows in this group.

    Key Words: lung function tests  maximal expiratory flow–volume curves  preterm birth  premature infant

    Obstructive lung diseases remain important complications of a preterm birth, and are usually attributed to a combination of lung immaturity, oxygen therapy, and ventilatory support (1, 2). This is especially true for low-birth-weight infants with severe neonatal respiratory disease (3). However, preterm infants that did not initially demonstrate significant respiratory neonatal disease also have reduced lung function when examined later in life, suggesting that prematurity alone could be associated with a persistent obstructive disease (4–7).

    There are several studies showing reduced expiratory flows in infants who had significant neonatal respiratory disease (8–11). In contrast, measurements of maximal flows during the first year of life in preterm infants without significant respiratory neonatal disease are scarce. The study of lung function in premature infants who had not required ventilatory support would allow separating the effect of premature birth per se from the effects of high inspired oxygen concentration and positive-pressure ventilation, among other confounding factors. Although ventilatory abnormalities have been described in healthy preterm infants (12, 13), a single study has evaluated maximal flows in this group. Hoo and coworkers (14) used forced expiratory maneuvers with partial flow–volume curves in healthy preterm infants and demonstrated flows (maxFRC) in the normal range at 3 wk of life and reduced lung function when tested again at 1 yr of age, suggesting altered airway development during the first year.

    A modification of this method, the raised-volume rapid thoracic compression (RVRTC) technique, is being used to assess airway function in infants, with improved sensitivity when compared with measurements from partial flow–volume curves (15–18). We hypothesize that healthy preterm infants have lower lung function in the first months of life and this reduction in expiratory flows may be detected with a more sensitive lung function test. We also aimed to identify perinatal factors associated with lung function development in preterm infants. Some of the preliminary results of this study were presented in the form of abstract (19).

    METHODS

    Subjects

    The study group consisted of preterm newborns (< 37 wk of gestational age) without significant neonatal respiratory diseases (no assisted ventilation, < 48 h of supplemental oxygen), recruited from two university hospitals in Porto Alegre, Brazil (Hospital So Lucas and Hospital de Clínicas). Parents were interviewed and history was obtained from medical charts. Gestational age was assessed by date of mother's last menstrual period or ultrasound and by neonatal clinical assessment (20).

    The control group consisted of 27 healthy full-term infants and young children from 0 to 3 yr old recruited for a previous study to validate the use of the published equations in our population. A questionnaire about infants' health and tobacco exposure was completed by the parents before pulmonary testing. Infants with a history of respiratory diseases or recurrent wheezing, steroid or bronchodilator use, or other significant clinical conditions (malformations, cardiac or neurologic disorders or malignancies) were not included in this group.

    The ethics committee of both hospitals approved the study and informed, written consent was obtained from all parents.

    Lung Function Test

    Lung function testing was assessed by the RVRTC technique, after sedation with chloral hydrate (75–100 mg/kg), as previously published (21). In the preterm group, lung function tests were performed after 40 wk of postconceptional age, in the first months of life, before any lower respiratory illness had occurred. Infants were weighed, measured, and set in supine position, with an inflatable jacket wrapped around their abdomen and chest. All infants were tested at least 60 min postprandially to reduce the effect of gastric contents on lung volume. A pulse oxymeter was used during the tests. A facemask was positioned over the infant's face, covering mouth and nose, and the cervical region was maintained in an overextended position.

    Lung inflation pressure was set at 30 cm H2O and, at this point, thoracic compression was initiated and maintained until residual volume was reached. Forced expiratory maneuvers were repeated with increases of 5 to 10 cm H2O in jacket pressure until maximum expiratory flows were obtained. The best curve was selected as that with the highest product of FVC and forced midexpiratory flow (FEF25–75).

    Statistical Analysis

    The statistical program SPSS version 11.5 (SPSS, Inc., Chicago, IL) was used in statistical analysis. Quantitative and qualitative variables were described, respectively, through means/SD and frequencies/percentiles. Group characteristics were compared by t tests and exact tests. The lung function variables were compared after allowing for confounding factors by multiple linear regression analysis. In addition, multiple regression analysis was also used to evaluate the impact of perinatal factors in the lung function parameters in the preterm group. Race, smoking during pregnancy, oxygen requirement, steroid use, gestational age, presence of intrauterine growth retardation, sex, length, and weight at test date were used as independent variables. Lung function variables were also expressed as a z score using the published regression equation (22). Length and weight were also transformed to z scores according to published equations (23, 24). Weight and corrected age at test date were removed from the models due to strong collinearity with length. Birth weight was highly collinear with gestational age and also removed from the multivariable analysis (r > 0.8). Intrauterine growth retardation was defined by birth weight below the 10th percentile for gestational age (25).

    RESULTS

    Lung function tests were successfully performed in 62 preterm infants and in 27 healthy full-term infants and young children before the development of any lower respiratory disease. The groups were similar in respect to sex, race, and smoke exposure. In the preterm group, one or more doses of dexamethasone were given to 36 (58%) mothers before the birth and 23 (37%) infants received supplemental oxygen in the first 48 h of life. Nine preterm infants (15%) were small for gestational age. Due to the differences in the recruitment method, the preterm group was tested earlier than the control group. Infant pulmonary function tests were performed before 12 wk of corrected age in 51 (82%) preterm infants. The main characteristics of both groups are shown in Table 1.

    The individual results of pulmonary function plotted against length for both groups are shown in Figure 1. Previously published equations from normal infants are also included in the plot as a reference for normal limits. FVC was above the fifth percentile for all subjects in both groups (Figure 1A). However, there is a noticeable reduction in expiratory flows in the preterm group compared with control infants and reference values (FEF50; Figure 1B). Moreover, in the preterm group, 19 (31%) subjects had flows below the fifth percentile for FEF50, 20 (32%) had flows below the fifth percentile for FEF75, 20 (32%) had flows below the fifth percentile for FEF25–75, and 6 (10%) had flows below the fifth percentile for FEV0.5 (see Figures E1–E5 of the online supplement).

    Prematurity and Lung Function

    Table 2 presents the estimated unadjusted and adjusted differences in lung function between control and preterm groups. In univariate analysis, the preterm group had significantly lower values for FVC and flows, although this could be attributed to the differences in size and age at test date. After allowing for the differences in length, age, and sex, the difference in FVC became negligible, but we were still able to detect a mean significant reduction in flows in FEF50, FEF25–75, and FEV0.5 of 91 ml/s (22%), 71 ml/s (20%), and 20 ml/s (13%) in the preterm group, respectively. The multivariate analysis is displayed in detail in Table E4.

    However, using a model that adjusts for FVC, age, and sex, the differences between control and preterm groups became more evident, reaching statistical significant for all flow variables (p < 0.05 for all variables). We found mean reductions of 135 ml/s (29%), 55 ml/s (28%), 109 ml/s (28%), and 30 ml/s (18%) for FEF50, FEF75, FEF25–75, and FEV0.5, respectively, in the preterm group when compared with control infants. Smoking exposure, weight at test date, and race were not associated with lung function variables and not included in the models (Table E5).

    Significantly reduced flows in the preterm group were also confirmed by comparing the z scores of lung function variables in both groups (p < 0.01 for forced expiratory flows; Table E3 and Figure E6). There was no difference between groups for FVC and FEV0.5.

    Effect of Sex, Gestational Age, and Weight on Lung Function in Premature Infants

    To detect which perinatal factors were implicated in the observed reduction of expiratory flows, multiple linear regression was performed in the preterm group. Using a model that adjusts for the differences in body size, we found male sex and lower gestational age significantly and independently associated with reduced flows in our group of preterm infants. In addition, we also detected a significant negative association between z score of weight and expiratory flows.

    Sex was significantly associated with lower values for FEF50, FEF75, and FEF25–75 (p < 0.01). The results of the multivariate analysis showed that male infants had an average reduction of 70 ml/s (17%; 95% confidence interval [CI],7–26%) for FEF50, 71 ml/s (34%; 95% CI, 22–42%) for FEF75, and 75 ml/s (21%; 95% CI, 11–30%) for FEF25–75. Sex had no detectable association with FVC and FEV0.5 in our group of preterm infants (Table 3).

    Maximal expiratory flows FEF50, FEF75 and FEF25–75 were all significantly and independently associated with gestational age (all p < 0.01). For every week of gestational age, we estimated an average gain of 14 ml/s (4%; 95% CI, 1–7%) for FEF50, 10 ml/s (7%; 95% CI, 2–11%) for FEF75, and 13 ml/s (5%; 95% CI, 1–8%) for FEF25–75. Gestational age was not significantly associated with FVC and FEV0.5.

    Weight at test date, expressed as z score, was associated with expiratory flows. For each unit increase in weight for age z score there was a significant average decrease of 8 ml (7%) in FEF50, 24 ml (11%) in FEF75, 17 ml (8%) in FEF25–75, and 23 ml (4%) in FEV0.5.

    We were unable to detect the effect of race, antenatal steroid use, oxygen requirement, intrauterine growth retardation, and smoking exposure on lung function variables with this sample.

    DISCUSSION

    This study compared lung function in healthy preterm and full-term infants using the RVRTC technique, and we have shown that in the first months after birth and before additional adverse respiratory events, healthy preterm infants have lower expiratory flows than older infants and children who survived infancy without ill health. The forced expiratory maneuvers were obtained from raised volumes generated by the rapid compression technique. Previous publications demonstrated that this technique achieves flow limitation in infants and has improved sensitivity to detect airway obstruction (15, 16, 18).

    The increased risk of wheezing, chronic cough, and hospital readmissions early in life suggests that some degree of airway obstruction is present even in preterm infants without neonatal respiratory diseases (26–28). Ventilatory abnormalities, like impairment of gas-mixing efficiency and reduced FRC, have been described in healthy, asymptomatic, preterm infants in the first year of life (13). These abnormalities could be part of a continuum of chronic lung disease associated with prematurity (29). Our results offer additional evidence of the impairment of the lung function in healthy, asymptomatic, preterm infants and that reduced flows are present earlier than previously believed.

    An arbitrary and strict definition of a "healthy preterm" (i.e., premature infants who did not require significant ventilatory support, and without previous lower respiratory infection) was adopted. This was necessary to prevent the inclusion of infants with respiratory dysfunction that could be attributed to prolonged oxygen or viral infections. A minority of subjects required supplemental oxygen in the first 2 d of life and in the multivariate analysis, this variable was not associated with lower flows.

    Our findings are in conflict with a previous study that failed to show reduced flows in healthy preterm infants very early in life (14). Differences in age at test date and methodology of the lung function test should be taken into account. In our study, we measured maximal flows referenced to fixed lung volumes (RVRTC technique) in sedated infants. Hoo and coworkers measured maximal flows from partial flow–volume loops in very young infants during normal sleep (14). As suggested by the authors, dynamic elevation of the end-expiratory level may overestimate the true maxFRC, particularly in very young, unsedated infants. It is possible that differences in age, sedation, and the use of RVRTC technique may explain the observed differences.

    To investigate the impact of prematurity on early-life lung function parameters, we have used both a more "traditional" approach that adjusts these measures by age, length, and sex, and another model that adjusts for age, length, and FVC. Although the model that includes FVC is more sensitive, we have added the data adjusted by length for comparison with other studies. The reduction in expiratory flows in asymptomatic preterm infants goes from 20 to 30% (depending on the adjusted model; see Table 2, FEF25–75) and this finding may have important clinical implications. It presents additional data to explain the increased rate of morbidity and mortality due to respiratory diseases in premature infants. The magnitude of lung function loss in this group of healthy preterm infants was similar to that observed in asymptomatic infants with history of obstructive respiratory disorders (30) or cystic fibrosis (16). The extended range of gestational age in this study, which included infants from 27 to 36.9 wk of gestational age, may have diluted the effect of prematurity on expiratory flows.

    Our data show that the expired volume (FVC) measured from a point near total lung capacity to residual volume was in the normal range for all patients, suggesting that lung growth was proportional to somatic growth in our sample. One could speculate that the airways are not growing as fast as the alveolar volume in response to somatic growth, suggesting an arrested structural development of the airways. Lower flows in infants born prematurely may be secondary to a reduction in airway caliber due to inflammation and airway thickening (31). However, Hjalmarson and Sandberg reported no difference in specific conductance in preterm infants when compared with full-term infants, suggesting that large airways growth is preserved during the first year of life (13). It is possible that the observed reduced flows are a result of changes in the structural characteristic of the airways in premature infants and not necessarily airway caliber. Increased compliance of airway walls could also potentially explain the observed reductions in flows. Further studies are required to understand the flow limitation mechanisms in preterm infants, particularly concerning airway wall mechanisms.

    This study demonstrates an independent effect of gestational age on expiratory flows (up to 7% increase per week of gestation) and reinforces the hypothesis that prematurity alone has an important role in the development of persistent airway obstruction. The estimate is a linear average over the full range of gestational ages in this sample and may be even higher in the more premature infants. Our observations of a direct association between premature birth and reduced forced expiratory flows, in a group of infants without other confounding factors, such as mechanical ventilation, extended supplementary oxygen, and lower respiratory infections, suggest that the interruption of lung development is an important determinant of the subsequent reduction of airway function and increased respiratory morbidity. It is important to recognize that these observed associations between preterm birth and reduced flows do not imply causality. Events known to elicit premature labor may also be relevant and should be better addressed in future studies.

    Our finding of lower flows in boys has been observed in lung function studies in full-term infants (22, 32). In premature infants, Stocks and colleagues reported a tendency for lower flows (maxFRC) in preterm boys that did not reach statistical significance after adjustment for size (33). In our sample, after adjusting for length, gestational age, and weight, flows were up to 30% lower in males, a greater effect than previously reported in full-term infants (32, 34). One could speculate, from the magnitude of lung function loss, that the described disadvantage of male infants in relation to respiratory disorders is heightened by prematurity. This might contribute to the increased neonatal morbidity and mortality related to respiratory illness for preterm male infants (6, 27, 35, 36).

    We also were able to detect an unexpected negative association between weight at test date and expiratory flows. This association was recently reported by Lucas and coworkers (37) in full-term infants. They estimated a reduction of 11% in maxFRC per z score of weight gain, the same magnitude we found in FEF75 in our sample of premature infants. Our data offer additional support for the hypothesis that high rates of weight gain are associated with impaired lung growth in infants.

    By contrast with reports in healthy full-term infants (38) and in preterm infants (39), smoking exposure in utero was not associated with lower flows in our sample. The absence of association was unexpected and may reflect the limitation of self-reported smoking among the mothers and possible misclassification. There was a relatively small percentage of mothers who reported smoking, which could make it more difficult to detect an effect.

    This study has some limitations that need to be contemplated. The differences in the recruitment method between groups resulted in a control group that was older and larger at the time of testing than the premature group. We believe that the analysis used to compare lung function between groups, which adjusts for the differences in length, age, sex, and lung volume, adequately correct these differences. In addition, the rate of lung emptying during forced expiration decreases with increasing age during infancy; this occurs primarily from the faster increase in lung volume than from airway caliber (40). This "age effect" would bias our measurements of volume-corrected flows, making older subjects in the control group look more "obstructed" and potentially reduce our ability to detect the differences between groups. An alternative approach to that of using our older control group was to use published predicted values generated from full-term infants (22). This approach generated similar results: the calculated z scores (or percent predicted) of the flow variables were all significantly reduced in the preterm group (see Table E3 and Figure E6).

    The use of a control group of infants with no previous history of wheezing may have introduced some selection bias in our analysis toward higher than normal lung function (when compared with a "true" randomly selected population). Another limitation of this study is that it was not specifically designed to study the effect of other intervening variables, such as smoking, maternal use of steroids, maternal perinatal infections, and other variables. The results of these subanalyses might be influenced by inadequate power of the study to detect significant differences.

    In conclusion, our findings confirm that prematurity per se is associated with reduced lung function and that this is detectable in the first months of life. Male sex, lower gestational age, and increased weight at test date are important predictors for reduced expiratory flows in this group. Further follow-up of these infants will address whether these differences persist. The understanding of the mechanisms associated with lower expiratory flows in preterm infants, particularly in the first years of life, might have potential implications in the prevention of respiratory diseases in this group.

    Acknowledgments

    The authors thank the infants and their parents for participating in this study. They are indebted to Dr. Marcelo Goldani, Hospital de Clínicas de Porto Alegre, for help with recruitment for the pulmonary function test and data collection.

    FOOTNOTES

    Supported by CAPES/Brazil.

    This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

    Originally Published in Press as DOI: 10.1164/rccm.200503-444OC on December 1, 2005

    Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

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