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An Unknown

Lung Growth and Development after Very Preterm Birth

Division of Pulmonary Biology Cincinnati Children's Hospital Cincinnati, Ohio

The airways are well formed by 20 weeks gestation in the human. The distal lung parenchyma transitions from the canalicular to the saccular stage of lung development at about the time of earliest extrauterine viability at 23 to 24 weeks gestation. Alveoli begin to appear after 32 weeks gestation, and perhaps 30% of the adult number of alveoli have formed by term (1). Lung development after preterm birth must proceed in the extrauterine environment while providing gas exchange. There are a number of reports demonstrating that preterm birth per se results in alterations in lung function that are most apparent in the early years of life and subsequently become less evident as children age. Most of the reports have focused on airway function and responses to bronchodilators. Recently, however, AJRCCM published a report from Hjalmarson and Sandberg (2) comparing lung function of "normal" preterm infants measured at term with term infants. The preterms, born at a mean gestational age of 29.5 weeks, had dysfunction of terminal respiratory units and higher elastic recoil. The results are consistent with altered alveolarization after preterm birth. Because airway development precedes development of the alveoli and the pulmonary microvasculature, disturbances of the parenchymal development might be anticipated to be more severe than airway abnormalities after very preterm birth.

There are limitations to the currently available information that confound our understanding of the degree, characteristics, and implications of preterm birth and any subsequent lung injury on lifelong lung function. A major concern is that more immature infants are surviving and are at risk of lung injury and subsequent abnormal lung development. In this issue of AJRCCM (1539–1543), Hofhuis and coworkers (3) report that ventilated infants with a mean birth weight of about 850 g and who were oxygen dependent at 36 weeks gestation had abnormal FEF rates at 6 and 12 months corrected postnatal age. That these infants with a history of bronchopulmonary dysplasia had quite abnormal airway function is not new. The surprising and new result is that the FEFs deteriorated between 6 and 12 months of age. Moreover, the infants ventilated with high frequency oscillation did not have the decreased FEFs noted for conventionally ventilated infants at 12 months of age. These results are provocative and cause concern because the expectation is for airway disease to abate with growth as the airways enlarge.

This first description of an increase in functional airway disease over the first year of life may represent the additive adverse effects of very preterm birth plus bronchopulmonary dysplasia at a time when the infants are growing very rapidly. They may be functionally growing out of their airways. The findings may result in part from how the patients were managed in the newborn period. The ventilation strategies were not described in any detail, and most of the infants were exposed to high dose, long-duration dexamethasone treatments. Glucocorticoids are known to delay alveolar septation in the developing lung (4).

The result that infants ventilated by high-frequency oscillation had abnormal but not deteriorating FEFs is quite speculative, I believe. The infants were not randomized for style of ventilation and were selected for the follow-up measurements of lung function based only on the presence of bronchopulmonary dysplasia. Any benefits of high-frequency oscillation over conventional ventilation are controversial and far from definitive, as again illustrated by two recently published large multicenter trials, one showing modest benefit and the other showing no benefit of high-frequency ventilation (5, 6). The bronchopulmonary dysplasia that occurs in very preterm infants is an evolving disease (7). Severe airway injury and parenchymal fibrosis is less common than was described for larger preterm infants before the era of increased survival of very preterm infants. This increased survival, but with a high incidence of bronchopulmonary dysplasia, is associated with the use of antenatal steroids, postnatal surfactant, and more careful attention to minimizing lung injury with mechanical ventilators (8, 9). High-frequency oscillation could result in less lung injury if the conventional ventilation provided inadequate positive end-expiratory pressure to maintain the functional residual capacity and to maintain the airways open during expiration. Muscedere and coworkers (10) clearly demonstrated that airway injury can be minimized by adequate positive end-expiratory pressure in an experimental model of surfactant deficiency. Differences in outcomes between conventional ventilators and oscillators may relate more to the way they are used than to the intrinsic characteristics of the devices.

This interesting report of decreased FEFs with age in very preterm infants may represent the tip of a very large iceberg, which is abnormal lung parenchymal development. Very small infants who have died of bronchopulmonary dysplasia have strikingly simplified lungs with increased alveolar sizes, decreased alveolar numbers, and a dysplastic pulmonary vasculature. These abnormalities persist for months in preterm baboons exposed to excessive oxygen and mechanical ventilation (11). Jacob and coworkers (12) reported in AJRCCM in 1998 that infants with birth weights of about 1 kg had decreased exercise capacity at 10 years of age. The 10-year-olds with a history of bronchopulmonary dysplasia used 93% of their ventilatory reserve during exercise relative to 59% for a term comparison group also tested at 10 years of age. Mitchell and Teague (13) also reported in AJRCCM in 1998 that somewhat larger infants with a history of bronchopulmonary dysplasia (1.4 kg average birth weight) had decreased carbon monoxide transfer during rest and exercise and decreased oxygen saturations during exercise relative to term controls when tested at 7 years of age. These abnormalities probably reflect significant and persistent disruptions of development of the gas exchange surface. We desperately need morphologic information about the lung parenchyma and airways of survivors of prematurity and bronchopulmonary dysplasia to be able to better interpret physiologic tests of lung function. Tissue could be collected from children who have survived prematurity and bronchopulmonary dysplasia and who occasionally die from nonpulmonary causes. The long-term prognosis for lung function with aging remains an unknown.

REFERENCES

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