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Published ahead of print on June 1, 2004, doi:10.1164/rccm.200311-1552OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 527-533, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200311-1552OC

Original Article

Development of Lung Function in Early Life

Influence of Birth Weight in Infants of Nonsmokers

Ah-Fong Hoo, Janet Stocks, Sooky Lum, Angie M. Wade, Rosemary A. Castle, Kate L. Costeloe and Carol Dezateux

Portex Respiratory Unit and Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health; and Neonatal Unit, Homerton University Hospital, London, United Kingdom

Correspondence and requests for reprints should be addressed to Ah-Fong Hoo, Portex Respiratory Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. E-mail: a.hoo{at}ich.ucl.ac.uk


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This study aimed to compare lung growth and development during the first year of life in healthy term infants of low or appropriate birth weight for gestation. Paired measurements of forced expiratory volume in 0.4 second, FVC, and forced expiratory flow when 75% of FVC has been exhaled were obtained, using the raised volume technique, at about 7 weeks and 9 months of age in 80 infants (32 low and 48 appropriate birth weight for gestation) of white, nonsmoking mothers. Forced flows and volumes increased with growth. Longitudinal trends in results were compared between the two groups, using random effects modeling and adjusted for potential confounding factors. After adjustment for sex, age, and length, forced expiratory volume was significantly reduced by an average (95% confidence interval) of 9% (2 to 16%) in low birth weight compared with appropriate birth weight for gestation infants throughout the first year of life, with a similar trend in forced expiratory flow (8% [–2 to 17%]) and FVC (4% [–3 to 11%]). These findings suggest that lung function is reduced in low birth weight for gestation infants born to nonsmoking white mothers and that this is independent of somatic growth during infancy.

Key Words: fetal growth retardation • follow-up study • forced expiratory volume • infant • respiratory function tests

Barker proposed that "programming" of organ function, due to stimuli or insults acting during critical periods in early fetal life, can have lifelong consequences (1, 2). It has been postulated that factors operating during intrauterine life may not only restrict fetal weight gain, and hence birth weight, but irrecoverably constrain the growth of the lungs and airways. Similarly, the association between suboptimal lung function in childhood and later life has been increasingly linked with events occurring during fetal development and early infancy (3–6).

Findings from several studies suggest that fetal growth restriction is associated with increased respiratory morbidity and mortality during early childhood (7, 8). During the first year of life, infants of low birth weight for gestational age (commonly referred to as "small for gestational age" or SGA) are more likely to be admitted to hospital with respiratory tract infections (9, 10). The associations between maternal smoking in pregnancy and SGA infants (11–13), impaired airway function in infancy (14–17), and increased risk of lower respiratory illness in early childhood (18–23) are well recognized.

Although there is evidence of considerable "tracking" of lung function throughout early childhood (i.e., those with the lowest function initially retain this position thereafter) (24, 25), limited longitudinal data are available for healthy subjects during infancy and relatively little is known about the specific association between SGA and lung function during early life. We have reported reduced lung function in SGA infants when measured shortly after birth (26, 27). These differences persisted after adjustment for age, sex, body size, and pre- and postnatal smoke exposure when results from the entire cohort were examined (27). However, separate analysis of those not exposed to prior maternal smoking suggested that, in this particular subgroup, differences in lung function were largely explained by the impaired somatic growth of SGA infants rather than through a specific effect on lung and airway growth (26). There are no studies reporting subsequent lung growth and development in such infants. Reduced lung function has, however, been reported in older children and adults born SGA (7, 8, 28), suggesting that such differences may be evident during early life.

This article reports findings from serial measurements of lung function in infants who were SGA, or of appropriate birth weight for gestational age (AGA), and whose mothers did not smoke pre- or postnatally. We hypothesized that, when compared with AGA infants, healthy term infants born SGA have reduced lung and airway growth during the first year of life and that this is independent of body size.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
We recruited 234 healthy infants of white mothers, born after at least 35 weeks of gestation, into an epidemiologic study (26, 27). Infants were recruited from maternity units at Homerton University Hospital (London, UK) and University College London Hospital (London, UK) between January 1998 and May 2002. Full details of recruitment, eligibility criteria, and background characteristics of the entire cohort have been published previously (26, 27). Of the original cohort, 139 (59%) infants fulfilled the criteria for recruitment to the follow-up study in that they had been born to mothers who did not smoke pre- or postnatally, and had successfully completed measurements of lung function, including FVC, forced expiratory volume in 0.4 second (FEV0.4), and forced expiratory flow when 75% of FVC has been exhaled (FEF75) within the first 12 weeks of life before the occurrence, if any, of lower respiratory illnesses. Families of eligible infants were contacted by telephone. Local research ethics committee approval and informed written parental consent were obtained.

Infants were classified according to birth weight and gestational age. Z (or standard deviation) scores for birth weight and other anthropometric measurements were calculated on the basis of Child Growth Foundation algorithms (29). Infants were considered SGA if birth weight was at or less than the 10th centile for gestation.

Measurements of lung function for both SGA and AGA infants were performed by the same investigators, using identical equipment and protocol, in the infant lung function laboratories at either Homerton University Hospital or the Institute of Child Health (London, UK).

Cotinine assay of maternal saliva and infant urine samples, collected at the time of testing, was undertaken to corroborate maternal report of nonsmoking and of infant exposure to environmental tobacco smoke, respectively (26, 27). Low concentrations of cotinine, compatible with levels observed in nonsmokers, were found in maternal saliva (median [interquartile range]: 0.2 [0.1–1.1] ng · ml–1 for the SGA group and 0.1 [0.1–0.5] ng · ml–1 for the AGA group) (30, 31). Similarly, levels of infant urine cotinine suggested minimal exposure to environmental tobacco smoke in this population (4.0 [1.3–6.8] and 3.3 [1.4–8.9] ng · ml–1 for the SGA and AGA groups, respectively). Episodes of respiratory illnesses between the two test occasions were determined from parental report. Criteria for a lower respiratory illness included parental report of wheeze and/or doctor-diagnosed wheeze, asthma, pneumonia, bronchiolitis, wheezy bronchitis, and prescription of ß-agonist, ipratropium bromide, or antibiotics.

Lung Function Measurements
The initial lung function tests and anthropometry were performed at about 6–7 weeks of age, with measurements being repeated at about 6–9 months. All measurements were performed when infants were well and had been free from any respiratory tract infections for at least 3 weeks, after sedation with chloral hydrate (60–100 mg/kg) according to a standardized protocol as described previously (26, 32).

Lung function was assessed from forced expiratory maneuvers using the raised volume rapid thoracoabdominal compression technique, with an inflation pressure of 3 kPa (26, 33, 34). Full forced expiratory maneuvers were repeated until at least three technically acceptable flow–volume curves were obtained. Values of FVC, FEV0.4, FEV0.5, and FEF75 were reported from the "best" flow–volume curve, defined as the technically acceptable maneuver with the highest sum of FVC and FEV0.4 (26, 33, 34).

Sample Size and Statistical Analysis
Previous estimates based on cross-sectional data from this department suggested that, among healthy infants, sex, length at test, and corrected postnatal age (i.e., postnatal age calculated from the expected delivery date rather than birth date) would account for about 50% of the between-subject variability in volume parameters derived from the raised volume technique. On the basis of these estimations, 80 infants would provide 80% power to detect an additional 5% difference in FEV0.4 or FVC attributable to birth weight status on either test occasion (35). By contrast, because sex, age, and body size account for about 15% of between-subject variability in forced flows in health, 80 infants would provide 80% power to detect an additional 9–10% variability in flow parameters attributable to birth weight status (35).

In this study, the main outcome variable was FEV0.4 as this, rather than FEV0.5, is possible to record in most healthy infants during the first 3 months of life when forced expiration is achieved rapidly (26, 32). However, no reference data are currently available for this parameter. To compare our results with published reference data, values of FEV0.5 were also calculated and, together with FVC and FEF75, expressed as Z scores, using reference equations published by Jones and coworkers (36). These were based on 155 healthy term infants, 30% of whom were exposed to maternal smoking during pregnancy and 50% to smoking postnatally.

Group characteristics were compared using t tests and exact tests (StatXact, version 4.01; Cytel, Cambridge, MA). The extent to which airway function differed in infants of differing birth weight status was investigated by multiple regression analysis (SPSS for Windows, release 10.1.3; SPSS, Chicago, IL) on each of the two test occasions, after accounting for potential confounding factors including corrected postnatal age, weight and length at test, sex, parental occupational status, maternal height, and both family and maternal history of asthma. Random effects models (37) were used to compare longitudinal trends in measurements after adjusting for the same factors. Lung function results were log transformed when appropriate.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study Population
We excluded 95 (41%) of the 234 infants in the original cohort from this follow-up because their mothers smoked, leaving 139 eligible infants (55 SGA and 84 AGA) born to nonsmoking mothers. There was no bias according to test site with respect to birth weight status of the infants included in the follow-up (42% of those measured at Homerton University Hospital and 40% at the Institute of Child Health being SGA). Figure 1 shows details of infants who were or were not followed up in the current study, together with reasons for nonattendance. Consent to participate was obtained for 86 (62%) of the eligible population. Among infants of nonsmoking mothers, there were no differences in background characteristics or initial lung function between those who did or did not attend for follow-up tests (data not shown). Of the 53 infants from nonsmoking mothers who were not followed up, 3 became ineligible, as their mothers had resumed smoking. Of those whose parents consented to take part, four did not attend for testing. The test results from two infants who attended were excluded from statistical analysis: one because of failure to meet lung function quality control criteria and one because of reclassification of the mother as a smoker (maternal salivary cotinine at the time of second test being 201 ng · ml–1). Thus, data were available from 80 infants (32 SGA and 48 AGA) and form the basis of this report.



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  		Figure 1. Number of infants, according to birth weight status, who did or did not attend for follow-up measurements of lung function. Note: For details of original cohort, please refer to Reference 27. SGA and AGA = low and appropriate birth weight for gestational age, respectively; VSD = ventricular septal defect.

 
With the exception of the expected differences in body size at birth, no significant differences were observed with respect to either the background or family characteristics between the SGA and AGA groups that were followed up (Table 1). Details of age, anthropometry, and lung function results on each test occasion are summarized in Table 2. When initially tested at about 6–7 weeks, SGA infants remained significantly smaller than those born AGA. Despite being nearly 3 weeks older at the time of follow-up, the SGA group remained significantly lighter but of similar length to the AGA group. Once adjusted for age, Z scores for weight, length, and head circumference remained significantly lower in the SGA group, the magnitudes of these differences being similar to those observed on the first test occasion. The relative rate of somatic growth between test occasions in SGA and AGA infants was assessed by comparing the within-subject change in Z scores for weight and length between the two groups. This took into account the nonlinear pattern of somatic growth during the first year of life, and variations in test age and interval between tests within individuals. Both groups showed a slight increase in weight and length Z scores with growth (Table 2). There was, however, no significant difference between groups in the change in weight Z scores between tests (95% confidence interval [CI] [SGA–AGA], –0.26 to 0.61; p = 0.43), with a nonsignificant tendency for length to increase at a slighter faster rate among those born SGA (95% CI [SGA–AGA] for change in length Z score, –0.05 to 0.65; p = 0.09).


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  		TABLE 1. Infant characteristics at birth according to birth weight status

 

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  		TABLE 2. Infant characteristics and respiratory function results according to birth weight status and test occasion

 
On the basis of parental report, there was no significant difference in the proportion of infants experiencing lower respiratory illness episodes before the second test (6% in both groups). By contrast, a higher proportion of SGA infants experienced more than one episode of upper respiratory tract illness (defined as nasal discharge or respiratory symptoms in the absence of any cough, wheeze, or use of antibiotics) (13 versus 2% in the AGA group).

Lung Function
Paired measurements of FEV0.4, FVC, and FEF75 were obtained from all infants, whereas FEV0.5 could not be measured on the first test occasion in five infants (two SGA and three AGA) because of limited duration of forced expiration (32). There was an increase in all measured parameters of lung function in absolute terms for every subject between the two test occasions (Figure 2). However, on both test occasions, average values were lower among those born SGA (Table 2). The association of FEV0.4 with length according to birth weight status is shown in Figure 2, which also illustrates within-subject variability in the rate of increase in FEV0.4 in relation to somatic growth between the two tests. A similar pattern was seen for the two groups when FEV0.5, FVC, and FEF75 results were plotted against length at test (data not shown). There was a highly significant relationship between changes in FEV0.4 and FVC between test occasions (r2 = 0.80). Although there was a significant reduction in FEV0.4/FVC between tests for both groups, there was no significant difference in this ratio between SGA and AGA infants on either test occasion.



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  		Figure 2. Paired measurements of FEV0.4 plotted as a function of crown–heel length at test in SGA and AGA infants, respectively. SGA and AGA = low and appropriate birth weight for gestational age, respectively.

 
Those with the lowest lung function initially tended to retain this position at follow-up, that is, demonstrated tracking of lung function; Spearman correlations between values on the first and second test occasion were 0.57, 0.55, 0.51, and 0.53 for FEV0.4, FEV0.5, FVC, and FEF75, respectively (p < 0.01 for all). Within-subject longitudinal trends in airway function were compared using random effects models. After adjusting for length, age, and sex, none of the remaining potential confounding factors, including current weight, were significant and they were therefore removed from the model. After adjustment, SGA infants had, on average, an important and statistically significant reduction of 9% (95% CI, 2 to 16%) in FEV0.4 during the first year of life. A similar but nonsignificant reduction was observed for other parameters, with reductions of 6% (–1 to 11%), 4% (–3 to 11%), and 8% (–2 to 17%), respectively, for FEV0.5, FVC, and FEF75 among SGA infants.

There was a small and nonsignificant tendency for the relative increase in forced expiratory volume with growth to be less for the SGA infants, as shown by inclusion in the model of the relevant interaction terms. The mean (95% CI) percentage differences per centimeter increase in length for SGA infants compared with AGA infants were –0.3% (–0.9 to 0.3%) for FVC, –0.4% (–1.0 to 0.2%) for FEV0.4, and –0.5% (–1.1 to 0.1%) for FEV0.5. After accounting for changes in FVC, the relative rate of increase in FEV0.4 was similar in both groups (95% CI [SGA–AGA], –0.5 to 0.3%/cm increase in length). There was no difference between groups in terms of the relative rate at which FEF75 increased with growth (95% CI of difference, –1.3 to 1.1).

Similar results were observed when cross-sectional analysis of the data was undertaken, using multiple linear regression analyses. After adjusting for length and sex, none of the remaining potential confounding factors, including current weight and postnatal age, were significant and they were therefore removed from the multivariate model. At time of follow-up, after adjusting for sex and length at test, FEV0.4 was significantly lower in SGA infants by an average (95% CI) of 18 ml (0.6 to 35.9 ml; p = 0.04), representing a reduction of about 7% in airway function (see Table 1E in the online supplement). This remained significantly lower after adjusting for FVC (mean [95% CI], 12 [0.6 to 23.3] ml). Similarly, there was a trend for adjusted FEV0.5 (95% CI, 2.6 to 36.6 ml; see Table 2E in the online supplement) and FEF75 (95% CI, 5.0 to 86.0 ml · second–1; see Table 4E in the online supplement) to be lower among the SGA infants. By contrast, after correction for body length and sex, the difference observed on univariate analysis in FVC between the birth weight groups was no longer significant (see Table 3E in the online supplement). The reduction in FEV0.4 among the SGA infants on the second test occasion remained significant after adjusting for any (i.e., upper or lower) prior respiratory illness (95% CI, 3 to 40 ml). When expressed as Z scores (36), FEV0.5 was lower in the SGA group on both test occasions, reaching significance on the second visit. There was no significant difference between groups in the within-subject change in FEV0.5 Z score between test occasions (95% CI [SGA–AGA], –0.3 to 0.5; p = 0.6).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Findings from this follow-up study demonstrate that, after adjustment for length and sex, FEV0.4 is significantly lower during the first year of life in SGA infants than in those born AGA, with similar tendencies observed for FEV0.5 and FEF75. These changes in airway function were independent of exposure to maternal smoking. Interpretation of these findings is dependent on several factors including the accuracy of measurements, the lack of any bias, and the extent to which results can be generalized.

Population
The findings from this study are generalizable to healthy white infants of low and appropriate birth weight for gestation whose mothers did not smoke pre- or postnatally. Paired measurements of lung function were obtained in 58% of eligible infants. The attrition among potentially eligible infants reflected the high mobility of London families, as well as maternal employment and reluctance to take time off work to participate in research. We anticipated this attrition in the study design, recruiting sufficient numbers initially to ensure adequate power of study at follow-up.

Findings from the current study may underestimate the magnitude of the effect of low birth weight for gestation on respiratory function during infancy. Our SGA population was biased toward those with milder impairment of growth in utero, as we excluded preterm infants delivered before 35 weeks of gestation as well as those with respiratory problems at birth, due to known adverse associations of these factors with airway function (24). Similarly, to examine the effects of intrauterine growth retardation independently of the known detrimental effects of prenatal smoke exposure (17), we excluded those whose mothers smoked, using cotinine analysis to corroborate maternal reports. Although we do not have prospective data on maternal nutrition in our study, mothers who consented to participate in the original and follow-up study were older and better educated than the general population (27). There was no evidence of any differences between infants who were and were not followed up according to birth weight status, initial lung function, or background characteristics (27).

According to parental report, a higher proportion of SGA infants experienced more than one episode of upper respiratory tract illnesses between the two test occasions when compared with AGA infants. This contributed to the slightly older average age at which SGA infants were followed up, because tests were postponed for at least 3 weeks after such infections. Although there are well-recognized difficulties in distinguishing parental report of upper and lower respiratory infections, every effort was made to adhere to strict criteria in this study. Although in our study the reduction in airway function among SGA infants was not associated with increased respiratory morbidity, it may have implications for airway size attained during childhood and adolescence.

Reliability of Lung Function Measurements
To our knowledge, this is the first study to use the raised volume technique to assess and compare the growth of lung function in healthy infants according to birth weight status. All results were checked to ensure adherence to quality control criteria by an independent observer masked to the birth weight status of the infants. The raised volume technique has been used to assess lung function in both healthy infants (32, 36, 38) and those with airway disease (39–42) with increasing evidence that indices derived from this technique are sensitive to impaired lung function. In older children and adults, FEV1 and FEF75, respectively, are traditionally considered to reflect primarily large and peripheral airway function, but such relationships are less clear when these measures are obtained in early life (32). During infancy, measurement of FEV1 is rarely feasible because of the rapidity of lung emptying during a forced expiration. Hence, FEV0.4 or FEV0.5 is usually reported. As these timed expiratory volumes still encompass the majority of the forced expiration, they probably reflect the integrated output from both central and peripheral airways. The observed reduction in FEV observed in SGA infants, which remained significant after adjustment for FVC, could potentially be attributable to a number of factors, including differences in airway caliber, airway tone, or the compliance of lungs, chest wall, or airway wall.

Control Group or Reference Values
Prospective recruitment of a healthy, appropriately grown, control group of infants was believed to be important in this study because of the lack of internationally agreed-on standards for the raised volume technique and any reference data for FEV0.4. However, there are also advantages in expressing results in relation to published reference data, especially because similar equipment and techniques were used in this study as when generating such reference data. On the first test occasion, the AGA group had Z scores for FEV0.5, FVC, and FEF75 that were close to those predicted (36) (i.e., mean [SD] approaching 0 [1]). However, by time of follow-up, there was an average increase of about 0.4 Z score for FEV0.5 and FEF75 in both groups. Thus, although there were still significant differences in Z scores between the groups, had the SGA group been studied in isolation they would have appeared to have experienced "catch-up" growth in airway function because they were no longer significantly different from the published norms. The reasons for this discrepancy are unclear, but may be related to the fact that we had a highly selected population that, in contrast to the American cohort, had been exposed to minimal environmental tobacco either pre- or postnatally. A similar explanation might explain the relative increase in weight and length Z scores for both the AGA and SGA infants in this study (Table 2), and emphasizes the value of including an appropriate control group.

Longitudinal Changes in Lung Function
Infancy is a period of rapid lung growth and development, with implications for airway size, structure, and function. It is well recognized that serial assessments of lung function are more valuable than isolated measurements (43, 44) and are the only reliable way to assess growth and development of lung function. However, there are few studies reporting serial measurements during infancy, reflecting the difficulties of performing such measurements in this age group (20, 22, 42, 45). In this study, the absolute magnitude of differences in lung function between the groups increased with age (Table 2). There was also evidence of tracking of all lung function parameters, supporting previous suggestions that airway function during later life may be largely determined by that present shortly after birth (24, 25, 46–48).

The relative (i.e., percentage) reduction in all measured parameters of lung function among SGA infants was similar on both test occasions, and random effects modeling suggested that there was no difference between birth weight groups in the relative rate at which FEV0.4, FVC, and FEF75 increased between the two test occasions. Whereas the reduction in FVC in the SGA group appeared to be mediated primarily through body size, those for FEV0.4 and FEF75 were independent of such differences. Because the reduction in FEV0.4 on the second occasion remained significant even after adjusting for FVC, it would be tempting to suggest that this provides evidence that the rate of airway growth was lagging behind that of lung growth in SGA infants, that is, that dysanapsis of airway growth was more marked in such infants. Although this may be true, considerable caution should be exercised not to overinterpret these data, because a much larger number of infants would have to be studied to attain sufficient power of study to address such a hypothesis. Furthermore, to gain greater insight into the relative rate of lung and airway growth during the critical first year of life, simultaneous assessments of resting lung volume or, ideally, total lung surface area, would have been required in these children, neither of which was feasible in this study. In older subjects, the FEVt/FVC ratio is regularly used to relate airway function to lung size, but this has not been shown to be a sensitive measure of lung function during infancy in either health or disease (32, 49). There was no difference in FEVt/FVC between the groups on either test occasion in this study. This may be at least partially attributed to the strong negative age dependency of this index during early life, with marked intersubject variability in the rate of change with growth (32, 50).

We have previously reported data from the entire cohort of 234 infants at 6–7 weeks of age, when FEV0.4 remained significantly reduced among those born SGA after adjusting for relevant maternal and infant characteristics, including sex, body size, and maternal smoking (27). By contrast, when analysis was limited to the 103 infants born to nonsmoking mothers (of whom 38 had birth weight less than the 10th centile), the 10–15% reduction in airway function observed in SGA infants shortly after birth on univariate analysis appeared to be primarily mediated through impaired somatic growth (26). Although this discrepancy could be attributed to greater power of study when examining the entire cohort, it more likely reflects a complex causal pathway with respect to interactions between maternal smoking, socioeconomic disadvantage, fetal growth retardation, and subsequent rates of lung and somatic growth in infancy (27).

Comparisons with Previous Studies
Dahms and coworkers (51) conducted a small study of infants, nine of whom were small for gestational age, and concluded that, relative to preterm infants, functional residual capacity was normal and dynamic compliance and crying vital capacity were elevated in the SGA infants. With this exception, we are unaware of any studies that have examined the association between low birth weight for gestational age and airway function during infancy. Studies in both school age children (7, 8) and adults (28, 47) have, however, reported significant associations between airway function and birth weight status.

Importantly, our study demonstrates a failure of early postnatal growth to compensate for the diminution in airway function seen shortly after birth in the SGA group. Although body size is an important determinant of airway function, our analyses suggest that there is a disproportionate impact of being born with low birth weight for gestation on airway function, and that the decrement is not simply due to the fact that small babies have small lungs. By selecting mothers who did not smoke in pregnancy, we have excluded tobacco use as a major contributing factor but might speculate that factors operating at the period of maximal airway development in the fetus (i.e., before Week 16 of gestation) may be important.

Conclusion
There is increasing recognition that airway function in adult life is an important and independent indication of mortality risk (52). Evidence to suggest that reduced size at birth is associated with impaired airway function in adult life is accumulating, but the biological and social pathways that mediate these associations remain unclear (5, 53, 54). Findings from our study provide evidence to suggest that such a reduction is present during the first year of life in low birth weight for gestation infants born to white, nonsmoking mothers, and that this is independent of somatic growth during infancy. A longer term follow-up of this cohort is now planned to establish the relevance of these findings to subsequent airway growth and to determine whether the magnitude of impaired airway function persists during the preschool and school age years.


   Acknowledgments
 
The authors are grateful to the families and infants who participated in the study. They thank Anne Cantarella, Sarah Davies, Dr. Iris Goetz, and Dr. Jane Hawdon for help with recruitment and data collection.


   FOOTNOTES
 
Supported by the Dunhill Medical Trust, the Foundation for the Study of Infant Deaths, and Portex Ltd. A.-F. Hoo was supported by Great Ormond Street Hospital for Children NHS Trust. Research at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from R&D funding received from the NHS Executives.

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

Conflict of Interest Statement: A.F.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.M.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.A.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.L.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form November 14, 2003; accepted in final form May 31, 2004


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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