Adverse Effects of Smoking on Respiratory Function in Young Adults Born Weighing Less Than 1000 Grams
* Departments of Obstetrics and Gynaecology, and Paediatrics, the University of Melbourne, Melbourne, Australia
Division of Newborn Services, Royal Women’s Hospital, Melbourne, Australia
Department of Respiratory Medicine, Royal Children’s Hospital, Melbourne, Australia
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Objective. To determine whether active smoking has an adverse impact on respiratory function of young adults of extremely low birth weight (ELBW; birth weight <1000 g).
Methods. This was a cohort study of 60 consecutive ELBW survivors who were born during 1977–1980 at Royal Women’s Hospital, Melbourne, Australia. Respiratory function was measured on 44 (73%) of the subjects at a mean age of 20.2 years (standard deviation: 1.0 year). Respiratory function had also been measured on 42 of the 44 subjects at 8 years of age. Respiratory function was compared between the 14 smokers and the 30 nonsmokers.
Results. Several respiratory function variables reflecting airflow (the forced expired volume in 1 second [FEV1]/forced vital capacity [FVC] ratio; flow rates at 75%, 50%, and 25% of vital capacity; and mid-expiratory flow from 25% to 75% of vital capacity) were significantly diminished in smokers. The proportion with a clinically important reduction in the FEV1/FVC ratio (<75%) was significantly higher in smokers (64%) than in nonsmokers (20%). There was a significantly larger decrease in the FEV1/FVC ratio between ages 8 and 20 years in the smokers (mean change: –8.2%; 95% confidence interval: –14.1% to –2.4%)
Conclusions. Active smoking by young adult survivors of ELBW is associated with reduced respiratory function.
Key Words: smoking • respiratory function • extremely low birth weight
Abbreviations: ELBW, extremely low birth weight • FEV1, forced expiratory volume in 1 second • FVC, forced vital capacity • SD, standard deviation • BPD, bronchopulmonary dysplasia • TLC, total lung capacity • RV, residual volume • V’EMAX75%, flow rate at 75% vital capacity • V’EMAX50%, flow rate at 50% vital capacity • V’EMAX25%, flow rate at 25% vital capacity • FEF25–75%, maximum expiratory flow between 25% and 75% of vital capacity • CI, confidence interval • OR, odds ratio
Many extremely low birth weight (ELBW; birth weight <1000 g) children require prolonged periods of assisted ventilation and oxygen therapy after birth to survive. Despite these potential insults to the developing lung, tests of respiratory function later in childhood in the survivors have been surprisingly good.1,2 However, exposure to passive smoking has been associated with reduced respiratory function in some preterm survivors.3,4
Inevitably, many ELBW survivors would actively smoke later in life, which is associated with reduced respiratory function in adulthood.5,6 Even in adolescence, when most smokers begin, respiratory function is adversely affected by active smoking.7 For example, the forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio of adolescent heavy smokers is 2% lower than in nonsmokers.7 However, there are no separate reports of the effects of active smoking on respiratory function in ELBW survivors at any age. The aim of this study was to determine the relationship between active smoking and respiratory function in early adulthood in ELBW survivors.
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METHODS |
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This was a cohort study comprising 60 consecutive surviving subjects who had a birth weight <1000 g and were born during a 4-year period from 1977–1980, inclusive, at Royal Women’s Hospital, Melbourne, Australia, the largest of the 3 level III perinatal centers in the state of Victoria. Details of the survival rate and early neonatal care of this cohort have been described.8,9 Growth in the uterus was determined by birth weight z scores (standard deviation [SD] scores).10 Bronchopulmonary dysplasia (BPD) was defined as clinical signs of respiratory distress with an abnormal chest radiograph11 and an oxygen requirement after 28 days of age.
Subjects were assessed in early adulthood by a research nurse who obtained a clinical history and measured their height and weight. Subjects who required bronchodilators within the previous year for attacks of wheezing were considered to have asthma. Data on smoking were obtained by inquiring about the number of cigarettes smoked daily. Exposure to smoke was confirmed, where possible, by measuring the urinary nicotine metabolites cotinine and 3-hydroxy cotinine by radioimmunoassay,12 and the results were expressed relative to the creatinine concentration, as the cotinine/creatinine ratio (µg/mmol). Laboratory technicians were blinded to smoking history of the subjects.
Respiratory function was measured in the Department of Respiratory Medicine at Royal Children’s Hospital, Melbourne, Australia, as described previously.1,2 Respiratory technicians were blinded to clinical details, including asthma and smoking history of the subjects. Spirometry and lung volumes were measured using a Jaeger Bodyscreen II-Bodybox (Jaeger, Germany), with Masterlab (ML3) software. Maximum expiratory flow-volume curves were recorded while the subject sat in the body plethysmograph with the door open. Flow was measured with a pneumotachograph, and volume was obtained by integration of flow. Total lung capacity (TLC) and residual volume (RV) were measured in the body plethysmograph. Variables reflecting airflow were FEV1; flow rates at 75% (V’EMAX75%), 50% (V’EMAX50%), and 25% (V’EMAX25%) of VC; and forced mid-expiratory flow (FEF25–75%). Lung volumes included FVC, TLC, and RV. Results at body temperature and pressure saturated with water vapor were expressed as a percentage predicted for age, height, and sex.13 A few subjects who lived in other states of Australia had equivalent respiratory function tests. Subjects with a FEV1/FVC ratio <75% were to be given an inhaled bronchodilator and the FEV1/FVC measurement was repeated. Not all subjects could complete all respiratory function tests because of either poor cooperation or unavailability or malfunction of equipment on the day of testing. Most of the subjects had also had respiratory function tests at 8 years of age, as previously described,1 and results were expressed as a percentage predicted for age, height, and sex relative to Australian children free of lung disease.14 The change in respiratory function between 8 years of age and early adulthood was calculated for each subject with data at both ages.
All subjects gave written informed consent to participate in the study at 20 years of age, including the respiratory function and urine tests, which was approved by the Research and Ethics Committees of Royal Women’s Hospital. Data were edited and analyzed using SPSS for Windows programs.15 Dichotomous variables were contrasted by 
2 analysis and continuous variables by t test, or Mann-Whitney U test if the data were skewed. Data were also analyzed by stepwise linear regression and logistic regression to adjust for the potentially confounding variables of maternal smoking in pregnancy, sex, birth weight SD score, BPD, asthma, and age when assessed. Mean differences and 95% confidence intervals (CI), or odds ratios (OR) and 95% CI were computed, where appropriate.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Respiratory function was measured on 44 (73%) of the 60 survivors at a mean age of 20.2 years (SD: 1.0 year). Of the 16 subjects without respiratory function tests, 6 refused to be tested, 4 were inaccessible (1 lived in a remote country region, 1 lived in another state, and 2 lived in other countries), 3 were lost to follow-up, and 3 were too disabled from neurosensory impairments to complete the tests. There were no substantial differences in perinatal variables between subjects who did and those who did not have respiratory function tests (Table 1).
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Of the 44 subjects with respiratory function measurements, 14 (32%) were active smokers. They reported a median daily consumption of 12.5 cigarettes per day (interquartile range: 9–25). We did not record the age of starting to smoke or the fluctuations in daily consumption over time. There were no substantial differences in perinatal variables between subjects who were smoking and those who were not smoking; however, more smokers had asthma in early adulthood (Table 2). The mean ages when assessed were not significantly different between smokers (mean: 20.2 years; SD: 1.1 years) and nonsmokers (mean: 20.2 years; SD: 1.0 years; mean difference: 0; 95% CI: –0.7 to 0.7). In the subjects with data, the urinary cotinine/creatinine ratios just overlapped between the nonsmokers (n = 16, µg/mmol; median: 0; range: 0–58) and the smokers (n = 7, µg/mmol; median: 219; range: 57–804), but the difference between the 2 groups was highly statistically significant (Mann-Whitney U test: z = 3.8; P < .001).
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At 20 years of age, several respiratory function variables reflecting airflow (FEV1/FVC ratio, FEF25–75%, V’EMAX75%, V’EMAX50%, and V’EMAX25%,) were significantly diminished in smokers (Table 3). There were no significant differences in variables reflecting lung volumes. The proportions with FEV1 <75% predicted were 36% (5 of 14) in smokers and 13% (4 of 30) in nonsmokers, a nonsignificant difference (
2 = 2.9, P = .09). However, the proportion with an FEV1/FVC ratio <75% was significantly higher in smokers, at 64% (9 of 14) compared with 20% (6 of 30) in nonsmokers (2 = 8.3; P < .01). Although the intent was to give bronchodilators only to those with an FEV1/FVC ratio <75%, 4 of the 15 subjects with an FEV1/FVC ratio <75% were not given bronchodilators (the FEV1/FVC ratio in 3 subjects was 74%, and in the other, it was 73%), and 3 of 29 with an FEV1/FVC ratio 
75% were given bronchodilators. In 7 smokers, the FEV1/FVC ratio improved significantly after the bronchodilator (mean change: 6.5%; 95% CI: 1.5%–11.2%). In 7 nonsmokers, the mean improvement in the FEV1/FVC ratio after the bronchodilator was 3.4% (95% CI: –1.5 to 7.8%), a nonsignificant increase.
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From the linear regression analyses, there were no statistically significant relationships between respiratory function at 20 years of age and the potentially confounding variables of maternal smoking in pregnancy, sex, BPD, birth weight SD scores, or age when assessed, except that the FEV1/FVC ratio was significantly higher in female subjects (mean difference: 11.4%; 95% CI: 4.2%–18.6%). Asthma was associated with significant reductions in some variables reflecting flow (FEV1, FEF25–75%, V’EMAX75%, V’EMAX50%, and V’EMAX25%). After adjusting for the confounding variables of sex and asthma, where necessary, smoking remained significantly associated with reductions in the FEV1/FVC ratio, V’EMAX75%, and V’EMAX50%, but the previously significant reductions in the V’EMAX25%, and FEF25–75% became nonsignificant (Table 3). On logistic regression analysis, smoking was associated with an increase in the odds of an FEV1/FVC ratio <75% in smokers (unadjusted OR: 7.2; 95% CI: 1.6–31.5), and adjusting for sex had little effect on the size of the OR for smoking, which remained statistically significant (adjusted OR: 6.6; 95% CI: 1.4–31.7).
At 8 years of age, 42 of the 44 subjects had had respiratory function assessed. No child was known or suspected to be a smoker at 8 years of age. At 8 years of age, 8 (57%) of the 14 eventual smokers had asthma, a higher rate than the 5 (18%) of 28 eventual nonsmokers with asthma (2 = 6.7; P < .01). Four of the 8 eventual smokers with asthma at 8 years of age outgrew the diagnosis by 20 years of age, as did 4 of the 5 eventual nonsmokers. There were no statistically significant differences in respiratory function variables at 8 years of age between the groups who were smokers at 20 years of age and those who were not (Table 3). Between 8 and 20 years of age, there was a significantly greater decrease in the FEV1/FVC ratio in smokers compared with nonsmokers (Table 3). The FEV1/FVC ratio also fell significantly between 8 and 20 years of age if the mother had smoked in pregnancy (mean difference: –10.2%; 95% CI: –17.6% to –2.8%), but adjustment for maternal smoking did not alter the statistical conclusions concerning active smoking (Table 3). There were no other statistically significant changes over time between smokers and nonsmokers. There were no other potentially confounding variables associated with changes between 8 and 20 years of age that altered the conclusions concerning active smoking.
In the 14 smokers, correlation coefficients for the relationships between the number of cigarettes reported to be smoked per day and respiratory function variables at 20 years of age ranged between –0.27 for the V’EMAX75% and 0.40 for the FVC. No correlations were statistically significant.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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In our small study of young adults who had ELBW, several respiratory function variables reflecting airflow were significantly diminished in active smokers. The reduction in airflow with smoking was clinically important, resulting in a significantly higher proportion of smokers than nonsmokers with an FEV1/FVC ratio <75%.
We previously reported that passive smoking was associated with reduced flow rates and air trapping in a separate cohort of children of birth weight <1501 g at 11 years of age,4 consistent with observations in nonpreterm children free of lung disease.16 Although we did not find any difference in respiratory function with passive smoking earlier in childhood at 8 years of age,1 Chan et al3 reported reduced flow rates with passive smoking by mothers in children of birth weight <2000 g at 7 years of age. Because passive smoking was associated with detrimental effects on respiratory function earlier in childhood in those who were born preterm and because many ELBW children have received considerable insults to their lung in the newborn period, we were concerned that active smoking might have even worse effects on respiratory function in our ELBW survivors.4
Active cigarette smoking is associated with airway obstruction in adulthood.5,6 Moreover, there is a dose-response effect, with greater reductions in airflow with increasing smoking exposure. Adverse effects of active smoking have also been reported in adolescence; Gold et al7 studied >10 000 subjects between 10 and 18 years of age, measuring their respiratory function annually for 8 years. Although birth weight was not stated, because subjects were selected from normal schools, it can be assumed that most (>90%) were of normal birth weight (>2499 g), and few (<1%) would have been ELBW. Increasing cigarette exposure was associated with greater reductions in airflow variables and with reduced rates of lung growth. In their study, the FEV1/FVC ratio of heavy smokers (15 or more cigarettes per day) was approximately 2% lower than in nonsmokers, in both boys and girls. In our study, there were no statistically significant dose-response relationships between the number of cigarettes consumed per day and any respiratory function variable, but with only 14 smokers, the power to detect such a relationship was low; for example, we had only 50% power to detect a correlation coefficient >0.5.
Given the known adverse association between active smoking and impaired respiratory function in adults and adolescents who were not ELBW, it may not be surprising that our ELBW subjects who were actively smoking also had impaired respiratory function. In our study, however, not only were several respiratory function variables reflecting flow reduced in ELBW survivors who had been smoking but also the sizes of the reductions with smoking were larger. The FEV1/FVC ratio was 10% lower in smokers in our study, a substantially greater difference than the 2% described by Gold et al.7 Adjustment for sex did not substantially affect the reduction in the FEV1/FVC ratio with active smoking, and there were no other confounding variables, including asthma. Active smoking in ELBW survivors may be even more detrimental to respiratory function than in normal birth weight or term survivors. Some of the reduction in airflow with smoking was reversible, with a statistically significant improvement in the FEV1/FVC ratio in the smokers who were given a bronchodilator. This suggests that if the young adults who were ELBW gave up smoking, then their respiratory function may improve.
A history of active smoking was mostly reliable in this cohort, because there was minimal overlap in urinary cotinine/creatinine ratios between the groups. However, the number of subjects with both history and urine tests was small. Others have documented in large numbers of adolescents the unreliability of history to determine the amount and duration of smoking accurately.17 Because we did not collect data about duration and average consumption of cigarettes over time and because our sample of smokers was small, we could not adequately address the dose-response issue between the amount of smoking and adverse respiratory function.
We acknowledge that our diagnosis of asthma, based on a history of requiring asthma therapy in the preceding 12 months, does not equate with airway hyperresponsiveness, but it does reflect what happens in clinical practice. We did not want to inflict any bronchial challenge on our subjects because we want them to return for respiratory function at later ages. That we have been able to measure respiratory function at 20 years of age on 73% of consecutive ELBW survivors recruited from birth, having also tested 95% of the same subjects at 8 years of age, is testament both to our ability to follow the cohort for such a long time and to their willingness to cooperate with the program. There are no other such longitudinal cohort studies of respiratory function in ELBW subjects and no studies of the effects of active smoking in such subjects of which we are aware. Of course, it would have been desirable to test all survivors, but some were too disabled to cooperate, and others were inaccessible or refused.
Significantly more eventual smokers had asthma at both 8 and 20 years of age. Gold et al7 also noted that a higher proportion of their smokers had asthma. A possible reason for the higher rate of asthma in smokers may be behavioral, with some smoking despite their asthma. An alternative explanation, at least at 20 years of age, might be that smoking has triggered asthma in some subjects. In this case, adjustment for asthma might be considered an overadjustment; hence, we have reported both adjusted and unadjusted results. Whatever the explanation, the higher rate of asthma in the smokers was not the sole reason for the lower flow rates in smokers. As expected, some flow rates were reduced in individuals with asthma, but several flow rates, including the FEV1/FVC ratio, remained significantly reduced in smokers after adjustment for asthma.
Growth restriction18 and maternal smoking19 in pregnancy are associated with abnormal respiratory function early in childhood. In our study, there was no significant relationship between any respiratory function variable and growth in the uterus as reflected by the birth weight SD score. A history of maternal smoking was associated with a significant decrease in the FEV1/FVC ratio between 8 and 20 years; however, the number of mothers who smoked during pregnancy was small (n = 7). We speculate that events in the uterus are probably not the explanation for the adverse association between abnormal respiratory function and active smoking at 20 years of age because there were no significant differences in respiratory function variables at 8 years of age between those who were smokers at 20 years and those who were not. Moreover, adjustment for maternal smoking had little effect on the important decrease in the FEV1/FVC ratio between 8 and 20 years in smokers.
The findings in the current study of reduced flow rates with active smoking in early adulthood in some of the same subjects studied earlier in childhood indicate that our concern about the detrimental effects of active smoking in ELBW survivors was justified.4 However, some caution is warranted because the total number of subjects is small and not all respiratory function variables were adversely affected. The small sample size means that the CIs for the effects, if any, of active smoking are wide, ranging from clinically unimportant to potentially very important differences. Clearly this cohort needs to be followed for a longer time, and other cohorts of ELBW subjects should also have respiratory function assessed in adulthood to determine the effects of active smoking. We remain fearful that active smoking will cause a more rapid decline in respiratory function in survivors of birth weight <1000 g, and their respiratory health will deteriorate markedly in early adult life.
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ACKNOWLEDGMENTS |
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The work was supported in part by a grant from the Royal Women’s Hospital Research Foundation.
Urinary nicotine metabolites and creatinine concentrations were measured in the Department of Biochemistry, Royal Children’s Hospital, Melbourne, Australia.
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FOOTNOTES |
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Received for publication Aug 29, 2002; Accepted Feb 13, 2003.
Reprint requests to (L.W.D.) Department of Obstetrics and Gynaecology, Royal Women’s Hospital, 132 Grattan St, Carlton 3053, Australia. E-mail: lwd{at}unimelb.edu.au
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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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