Maternal Smoking and Infant Lung Function
Further Evidence for An In Utero Effect

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Maternal smoking has been clearly demonstrated to be associated with increased health problems in infants and in older children (1, 2). Among these are low birth weight, increased rates of sudden infant death syndrome, and increased rates of wheeze-associated lower respiratory illness (WRLI) and pneumonia (2, 3). Wheezing respiratory illnesses and pneumonia are a significant public health problem, occurring in 20 to 30% of all infants and toddlers (4). Lower respiratory illnesses caused by respiratory syncytial virus account for substantial morbidity each year, including approximately 91,000 hospitalizations in the United States each year and $300 million in medical costs (5). Although maternal smoking may also lead to increased rates of asthma later in life (3), much of the impact on respiratory health appears to occur in infancy and the preschool years (6).

During the last 15 years, we have learned much about the determinants of wheezing early in life through prospective population studies (4, 6), employing a combination of epidemiologic, physiologic, and immunologic tools. Several, if not all, of these studies have shown that diminished lung function early in life both precedes and predicts a greater risk for wheezing with viral infection (8). Martinez and colleagues (4, 7) first demonstrated that measurements of tidal expiratory flow patterns (4) and forced expiratory flows (7) compatible with diminished airway function were associated with this increased risk of wheezing illness. Furthermore, assessment of airway function by forced oscillation methodology (4) indicated that these reduced flows may have been due to reduced airway conductance as opposed to reduced elastance of the lung. This suggests that children who have apparently diminished lower airway function are at greater risk to wheeze when they develop a viral respiratory infection simply because they are starting out with relatively less conductive airways than those with higher levels of lung function (8). These findings combined with the high prevalence of wheezing illness in early life make it important to understand those factors that might alter early airway and lung development.

The analysis of tidal expiratory flow patterns is based upon the detection of a rapid, early expiration in subjects with airway obstruction. First described by Morris and Lane (9) in adults with asthma and obstructive lung disease, the ratio of the time to peak tidal expiratory flow to expiratory time (tPTEF:tE) likely represents the degree to which expiration is braked by a combination of glottic narrowing and/or persistence of postinspiratory diaphragmatic tone (10). In persons with airway obstruction and a long expiratory time constant, this braking appears to be decreased, resulting in an earlier rise to peak tidal expiratory flow and reduced tPTEF:tE. The index tPTEF:tE has also been shown to be related to measures of airway function. Yuksel and colleagues (11) studied 60 infants in the first 2 wk of life and demonstrated a reduction in both tPTEF:tE and specific airway conductance in those who later wheezed in the first year of life. Further, Banovcin and colleagues (12) studied infants with varying degrees of airway obstruction and found a moderate, but significant, correlation (0.63) between forced expiratory flows, adjusted for lung volume, and tPTEF:tE. Thus, it seems plausible that tPTEF:tE may be an indirect method of assessing lower airway function in young infants. It should, however, be noted that tPTEF:tE has substantial variability and remains to be fully standardized.

In 1992, Hanrahan and colleagues (13) demonstrated that infants whose mothers smoked during pregnancy had diminished maxFRC values measured in the first 6 wk of life. This reduction showed a dose-response association with maternal urine cotinine levels measured during pregnancy, and the investigators concluded that this strongly suggested an in utero effect of maternal smoking on lung development. This population of infants also had lung function measured three more times before they were 18 mo of age (14). The longitudinal lung function measurements confirmed the deleterious impact of maternal smoking on forced expiratory flows, particularly in girls. Multivariate analysis further suggested that this was accounted for by prenatal and not postnatal exposure to tobacco smoking. Further evidence that this alteration in lung function occurs prior to birth has been provided by two separate studies. First, Stick and colleagues (15) reported decreased tPTEF:tE values in infants born to smoking mothers when lung function was measured at a mean age of 58 h. In a multivariate regression this effect was independent of age, respiratory rate, maternal hypertension in pregnancy, or a family history of asthma. Carlsen and colleagues (16) studied tidal breathing parameters at 3 d of life and also demonstrated a significant reduction in tPTEF:tE in infants exposed in utero to maternal smoking. These findings suggest a possible explanation for the link between maternal smoking and increased risk for infantile wheezing lower respiratory tract illness. Maternal smoking seems to modify lung development so that the infant will have diminished lower airway function and, as a result, be at increased risk for developing wheezing upon viral infection of the bronchial tree. The reason the impact of maternal smoking on wheezing illness may diminish later in childhood could be that the growth of the airways renders geometry of the small airways less relevant in producing symptoms after the preschool years. This is supported by the dramatic reduction in the incidence of WLRI after infancy and by the fact that persistent wheezing at 6 yr of age is not associated with infant lung function but rather the development of the immune phenotype associated with asthma (17). In other words, children with early, transient wheezing literally grow out of their predilection to wheeze unless they have developed true asthma. Their lung function remains diminished compared with that of the population who did not wheeze in infancy (17), but they are asymptomatic.

One difficulty in determining the timing of the impact of maternal smoking on infant lung function has been that most measurements have been conducted in early infancy after a relevant period of postnatal, passive exposure to maternal smoking. This has made it difficult to know if the impact of maternal smoking was truly an in utero one or was due to postnatal ETS exposure. Nonetheless, the data of Tager and colleagues (14), Stick and colleagues (15), and Carlsen and colleagues (16) strongly suggest that the negative impact of maternal smoking on lung function is substantially prenatal in its timing. In this issue, the elegant study of Hoo and colleagues (18) offers strong confirmatory evidence that these in utero effects on lung function are occurring prior to the middle of the third trimester; indeed, prior to any significant effect of smoking on overall well-being as assessed by birth weight. They demonstrated that premature infants born at a mean gestational age of 33.4 wk to mothers who smoked during pregnancy had altered patterns of tidal expiration compatible with impaired airway function. They also demonstrated reduced maxFRC values in the exposed infants; however, after adjusting for potential confounders, this difference was no longer significant. Nonetheless, the premature infants exposed to maternal smoking in utero demonstrated a systematic alteration in tidal breathing that is associated with increased risk for wheezing later in life (4, 11) and did so prior to discharge from hospital; i.e., prior to any relevant postnatal exposure to ETS. Thus, it seems plausible that the findings of Hoo and colleagues do represent a reflection of diminished lung function in the infants exposed to maternal smoking in utero. It is likely that they will have increased risk for wheezing later in life related to this reduction. As noted by Stick and colleagues (10), however, it is difficult to be sure that this altered tPTEF:tE ratio does not represent an alteration in neural control of breathing. These findings are, however, very consistent with findings in other studies of the impact of maternal smoking on infant lung function.

There is no doubt that there are many compelling reasons for mothers to stop smoking during pregnancy (1, 2). The report by Hoo and colleagues (18), however, offers strong evidence that the reduced lung function in infants born to smoking mothers is in large measure due to an in utero alteration in lung development that occurs prior to the middle of the third trimester. These findings represent yet another reason to develop programs and intervention strategies to prevent the acquisition of the smoking habit in adolescents and to aid pregnant women in effective smoking cessation as soon as possible in pregnancy.

W. J. MORGAN

F. D. MARTINEZ

Department of Pediatrics

Arizona Respiratory Sciences Center

University of Arizona

Tucson, Arizona

	References

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