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(Chest. 1999;116:52-58.)
© 1999 American College of Chest Physicians

Comparison of Lung Function in Infants Exposed to Maternal Smoking and in Infants With a Family History of Asthma*

Shahid Sheikh, MD; Linda Jane Goldsmith, PhD; Laura Howell, CPNP; Linda Parry, CPFT and Nemr Eid, MD, FCCP

* From the Division of Pediatric Pulmonary, Department of Pediatrics (Drs. Sheikh and Eid, and Ms. Howell) and the 2Health Science Biostatistics Center (Dr. Goldsmith), University of Louisville, Louisville, KY; and the Infant Pulmonary Function Laboratory, Kosair Children's Hospital, Alliant Health System (Ms. Parry) Louisville, KY.

Correspondence to: Shahid Sheikh, MD, Allergy & Pediatric Pulmonary Medicine, Department of Pediatrics, Allegheny University Hospitals-Allegheny General, 320 East North Avenue, Pittsburgh, PA 15212-4772


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: To compare lung function in infants exposed to maternal smoking with lung function in infants with a family history of asthma. There are no published studies comparing lung function in both groups.

Design: Cross-sectional study.

Setting: A tertiary pulmonary care center at a children's hospital. Patients: One hundred five infants with daily wheezing. Thirty-five infants had persistent exposure to maternal smoking, and 70 had a family history of asthma in parents or siblings.

Measurements: Infant pulmonary function tests were compared between the two groups. The ratio of terminal to peak expiratory flow at tidal breathing at 25% of the previous expiration remaining and the ratio of terminal to peak expiratory flow with forced expiration at 25% of the previous expiration remaining (FEF25/PFEF) were used to evaluate peripheral airflow. A > 25% improvement in FEF25/PFEF after a bronchodilator challenge test was considered a positive response.

Results: Most infants in both groups had evidence of peripheral airflow obstruction with forced expiration. In infants exposed to maternal smoking, only 4 of 35 (11.4%) responded to a bronchodilator, compared to 51 of 70 (72.9%) in the group with a family history of asthma (p < 0.0005). There was no statistically significant difference in total respiratory system compliance, total respiratory system resistance, tidal volume, and degree of peripheral airflow obstruction at tidal breathing or after forced expiration in both groups.

Conclusion: Infants with exposure to maternal smoking and infants with a family history of asthma have altered lung function, and a positive response to a bronchodilator is one variable that seems to differentiate the two groups.

Key Words: family history of asthma • infants • maternal smoking • pulmonary function test • wheezing


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Predisposing factors for infantile wheezing include prenatal and postnatal exposure to maternal smoking,1 2 3 4 5 6 7 8 9 10 viral infections,11 12 gastroesophageal reflux-induced bronchospasm,13 and a family history of asthma.1 2 14 It is well known that infants exposed to maternal smoking have altered lung function after birth that may predispose them to develop respiratory symptoms, including wheezing.1 15 16 17 18 19 20 21 Some studies have shown that infants with a strong family history of asthma may also have altered lung function at birth15 21 and are at increased risk for developing infantile wheezing.

We have not found any studies in the medical literature that compare lung function of infants exposed to maternal smoking (prenatal and postnatal) and lung function of infants with a family history of asthma. Our objective was to look for variables that can differentiate these groups by measuring flow volume loops, passive respiratory mechanics, and forced expiratory flow (FEF), both before the bronchodilator challenge and after the bronchodilator challenge. This study may be helpful in understanding differences in the pathophysiology of infantile wheezing in the two groups.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Population and Methods
One hundred five otherwise healthy infants (ages, 4 to 18 months old) included in this cross-sectional study were referred to Pediatric Pulmonary Medicine at Kosair Children's Hospital (Louisville, KY) between January 1994 and June 1997 for evaluation of daily wheezing. Inclusion criteria were either a history of both prenatal and postnatal exposure to maternal smoking or a family history of asthma in a sibling or a parent. A family history of asthma was considered positive if a physician diagnosed asthma in siblings or parents either clinically or with the help of pulmonary function tests and if they required daily maintenance asthma therapy. The exclusion criteria were a history of respiratory syncytial virus or other upper-respiratory viral infections in the past, diagnosed by either enzyme immunoassay or culture (n = 21), and infants who required oxygen, chest tube placement, and noninvasive or invasive mechanical ventilation (n = 3). Infants with evidence of gastroesophageal reflux on 24-h esophageal pH monitoring according to the method of Sondheimer22 (n = 54) were also excluded. Significant acid reflux was defined as the mean fraction time for pH below 4, > 6% (normal, 3.4%; 95th percentile). We also excluded infants with a history of pneumonia, pleural effusion, and obstructive sleep apnea (n = 5) and infants with major congenital abnormalities (n = 4), a history of cardiac disease (n = 2), or cystic fibrosis (n = 2). Infants born at < 36 weeks of gestation or with a birth weight of < 2.5 kg (n = 42) were also excluded in order to limit this study to otherwise healthy infants born at term. Eight infants had both exposure to maternal smoking and a family history of asthma and were excluded from the study.

All infants included in this study had daily wheezing and were receiving daily asthma medications: 1.25 mg nebulized albuterol sulfate with 2.5 mL of normal saline solution, 3 to 4 times a day and nebulized sodium cromoglycate 20 mg, 3 to 4 times a day. None of the infants in this study was receiving inhaled or nebulized steroids or long-acting symbol 98-adrenergic agents. No change in medications was made before the infant lung function studies. At the time of the lung function study, none of the infants had evidence of worsening of the chronic wheezing or had any nebulized medication for at least 4 h. Informed parental consent was obtained for all procedures and investigations. Pulmonary function tests were performed and analyzed by technicians who were blind to the infant's clinical history.

Infants were divided into two groups: infants with both prenatal and postnatal exposure to maternal smoking (n = 35) and infants with a family history of asthma in parents or siblings (n = 70). Infant lung function studies were compared between these two groups. Details of birth history, age of onset of wheezing, family history of asthma in either a sibling or parent, and history of prenatal and postnatal exposure to maternal smoking were obtained at the initial evaluation. This information was obtained during a clinical interview.

In the group exposed to maternal smoking, all infants had been exposed to > 1 pack (20 cigarettes) of cigarettes per day. A history of smoking exposure was based on smoking reported by the mothers. Because most of the mothers in our study were not working mothers, were at home with the infants for most of the time, and smoked inside the home, it was assumed that smoking took place in proximity to the infants. As only a few were exposed to > 1.5 packs a day, there were not enough patients to be divided into groups based on severity of exposure. Seven infants had exposure to both maternal and paternal smoking and to other smokers in the households. Since the number was small, we analyzed these seven infants as a part of the group exposed to maternal smoking. Since exposure to maternal smoking was a key factor for inclusion in the study, there was no infant in the study exposed to only paternal or other household smoking. In the group with a family history of asthma, a history of allergies was not obtained.

Infant Pulmonary Function Tests
Pulmonary function tests were performed on all infants by using a standard diagnostic instrument (model 2600; SensorMedics; Yorba Linda, CA). This system consists of an IBM-PS2/50Z computer (80286), with an outboard microprocessor-controlled analog-to-digital conversion module (8085). Details of the system are already mentioned in other studies.13 23 24 Measurements were taken with the infants placed supine and under mild sedation with chloral hydrate, 60 to100 mg/kg given po.

Partial expiratory flow-volume curves were recorded at tidal breathing by a standard technique.23 24 Passive pulmonary mechanics, including total respiratory system resistance (Rrs) and total respiratory compliance (Crs), were measured by using the single occlusion passive flow-volume technique.25 26 27 28 Flow was measured by a pneumotachograph (4500B series; Hans Rudolph; Kansas City, MO), with a flow range of 0 to 35 L/min. The pneumotachograph was fitted to a close-fitting mask (infant size) with an air-inflated cuff (model 5221; Vital Signs; Totowa, NJ) to avoid air-leak. Dead space of the system was 2.4 mL, and that of the face mask was approximately 20 mL. FEF was measured by using the rapid thoracoabdominal compression (RTC) technique.28 29 30 31 Infants were then given a bronchodilator, albuterol sulfate 1.25 mg with 2.5 mL of normal saline solution, and FEF measurements were repeated after 15 min by using the RTC technique to measure the response to the bronchodilator. We were careful to obtain a leak-free seal around the facemask, while not obstructing the nostrils. The head of the infant was maintained in the neutral position.

Six sets of each test were performed for partial expiratory flow-volume curves both at tidal breathing and with forced expiration. Each set was repeated until at least ten sequential flow-volume loops were superimposed. The mean of the six sets was used. The ratio of terminal to peak tidal expiratory flow at 25% of the remaining expiration (TEF25/PEF) was recorded and used as a parameter of peripheral airflow obstruction because in many other studies, this parameter has proven to be acceptable.13 23 24 32 A TEF25/PEF ratio of < 60% was considered as evidence of peripheral airflow obstruction, as recommended in the manufacturer's manual.33

The Crs in mL/cm H2O and Rrs in cm H2O/mL/s were measured by the passive flow-volume technique as previously described.13 25 26 27 28 Low Crs was defined as < 1 mL/cmH2O/kg, and high Rrs was defined as > 0.07 cm H2O/mL/s.

FEF measurements were done by using appropriate equipment (Infant Hugger model 2605; Equilibrated Bio Systems; Melville, NY), which was controlled by the SensorMedics 2600 system. The RTC technique was used. While infants were sedated, an inflatable jacket was placed around the infants' chests, extending from the axillae to the anterior superior iliac crest, with the arms outside the jacket. The jacket was tight enough to make contact with the chest when deflated and to still allow one finger to slip beneath the jacket at the chest level. The jacket was connected to a reservoir system. At end-inspiration, the jacket was pressurized in 10 cm H2O increments, from a minimum of 20 to a maximum of 80 cm H2O. At each increment, the inflation of the jacket was begun at end-inspiration and maintained until no additional airflow could be obtained. The maximum pressure applied was that at which no further increase in flow was obtained at functional residual capacity (FRC). In all the infants, maximum flow at FRC was reached between 40 to 80 cm H2O. Flow was measured with a pneumotachograph at the mouth. Before the RTC maneuver, a reproducible end expiratory point, FRC, was established by at least three tidal breaths. Expiratory flow-volume curves were measured both below and above FRC with a pneumatochograph placed over the infants' faces.

The ratio of terminal to peak expiratory flow with forced expiration at 25% of the previous expiration remaining (FEF25/PFEF) was measured. This parameter is similar to TEF25/PEF, but it was measured during RTC (forced expiration) instead of during tidal breathing. Infants were then given a bronchodilator, which contained albuterol sulfate 1.25 mg in 2.5 mL of normal saline solution, by way of a jet nebulizer system (Whisper Jet model 123015; Marquest Medical Products; Englewood, CO), with a standard compressed, pressure compensated, air flowmeter calibrated at the 50 lbs/inch2 gauge at 70°F and 760 mm Hg with a flow at 7 L/min. After 15 min, RTCs were repeated in the same manner as described earlier. A response to the bronchodilator was analyzed by using the three arbitrary cut-off points of 15%, 20%, and 25% improvement in the FEF25/PFEF after using the bronchodilator.

In children and adults, FEV1 reflects the function of larger airways, and although the FEF between 25% and 75% of the vital capacity (FEF25%-75%) reflects the function of smaller airways when it is compared to FEV1, FEF25%-75% is still a mixed measure that contains components of both large and small airway function. Standard criteria are established to evaluate a response to a bronchodilator. A > 12% change in FEV1 and a > 15% change in FEF25%-75% is considered a positive response.34 Unfortunately, thus far, no such criteria are established for infant lung function tests. To overcome this limitation, we used three arbitrary cut-off points (15%, 20% and 25% change in FEF25/PFEF after giving the bronchodilator), and a > 25% improvement was considered a positive response.

Statistical Methods
Interval-level measurements were analyzed with t tests or analysis of covariance, as appropriate. For comparisons between proportions in independent groups, the {chi}2 test or Fisher's Exact Test was applied, as appropriate according to the number of expected observations per cell. Logistic regression was used according to the method outlined in Hosmer and Lemeshow35 in which variables are screened with univariate tests before inclusion in the logistic regression. A p value of < 0.02 was considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In infants exposed to maternal smoking, the onset of respiratory symptoms was at the mean (± SD) age of 3.37 ± 3.08 months, and the mean duration of symptoms was 8.82 ± 6.52 months. The infant pulmonary function tests (IPFTs) were performed at a mean age of 12.22 ± 6.47 months. In infants with a family history of asthma, the onset of respiratory symptoms was at the mean age of 3.50 ± 2.70 months, the mean duration of symptoms was 5.81 ± 3.80 months, and IPFTs were performed at a mean age of 9.39 ± 4.80 months (Table 1 ). There was some statistical difference in the groups for duration of symptoms (p < 0.02) and the age at which IPFTs were done (p < 0.02), suggesting that infants exposed to smoking were slightly older and had a longer duration of symptoms than infants with a family history of asthma had. There were more males than females in the group with a family history of asthma. All demographic variables were screened for possible inclusion in logistic regression to correct for effects of these variables on lung function. The results of the lung function studies have been corrected for these variables.


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  		Table 1. Demographic Parameters (Comparison Between Groups)*

 
Comparing the mean value of lung function variables in the two groups revealed no statistically significant difference in the mean tidal volume, the mean TEF25/PEF ratio (tidal breathing), the mean FEF25/PFEF ratio (forced expiration before and after the bronchodilator), the mean Crs, and the mean Rrs (Table 2 ).


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  		Table 2. Infant Lung Function Parameters (Comparison Between Groups)*

 
As expected in both groups, the mean FEF25/ PFEF ratio (forced expiration) was significantly less than the mean TEF25/PEF ratio (tidal breathing; p < 0.0005), revealing significantly increased peripheral airflow obstruction with forced expiration.

When the mean change in the FEF25/PFEF ratio before and after the bronchodilator challenge was compared within the groups, infants with a family history of asthma revealed significant improvement in the mean FEF25/PFEF ratio. There was a difference of 0.119 ± 0.036 (p < 0.0005), thereby reflecting the reversibility of airflow obstruction. There was no statistically significant change in the mean FEF25/PFEF ratio after the bronchodilator was administered in infants exposed to maternal smoking. There was a difference of 0.001 ± 0.004 (p = 0.89), thereby revealing the irreversibility of airflow obstruction.

When the mean change in the FEF25/PFEF ratio before and after the bronchodilator challenge, was compared between the two groups, infants with a family history of asthma had significantly more change in the mean FEF25/PFEF ratio after the bronchodilator was administered, compared to infants exposed to maternal smoking (0.119 ± 0.036 compared to 0.001 ± 0.004; p < 0.0005).

The number of infants with altered lung function was compared in both groups. Although more infants with a family history of asthma had a low TEF25/ PEF ratio (52 of 70) compared to infants exposed to maternal smoking (22 of 35), the difference was not statistically significant. With forced expiration, almost all of the infants in both groups had a low FEF25/PFEF ratio. Only 4 of 35 infants (11.4%) with exposure to maternal smoking revealed a positive response to the bronchodilator, compared to 51 of 70 infants (72.9%) with a family history of asthma (p < 0.0005). Only a few infants in both groups had low CRS and high RRS, and the difference was not statistically significant (Table 3 ).


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  		Table 3. Number of Infants With Abnormal Lung Function Parameters (Comparison Between Groups)*

 
Demographic variables in Table 1 were evaluated for possible inclusion in logistic regression. The duration of symptoms and the age at which lung function tests were done were qualified as candidates, whereas age at onset of symptoms was never a candidate. Gender was a candidate only in the 15% cut-off point group. In the group with a family history of asthma, the response to the bronchodilator was significant when compared to the group with exposure to smoking, even after correcting for these variables in the logistic regression. Thus, we can conclude that the response to the bronchodilator, whether defined as 15%, 20%, or 25% improvement in FEF25/PFEF after the bronchodilator challenge, is significantly different in the two groups, even when corrected for variables, such as age at which lung function studies were done, gender, and duration of symptoms. For confirmation, an analysis of covariance, which corrected for age at which lung function tests were done (the other covariates were not significant), was performed between the two groups to evaluate the numeric response to the bronchodilator. The significant difference between the groups persisted, reinforcing our conclusion that had been made after using logistic regression.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In infants exposed to prenatal and postnatal cigarette smoking, studies evaluating different variables of infant lung function have determined that these infants have altered lung function.1 15 16 17 18 19 20 21 The data suggest that these limitations in lung function may be secondary to smaller lung size, and less maturity of lungs may be secondary to in utero lung growth retardation because of persistent exposure of the lungs to nicotine.36 37 38 One study has also shown increased bronchial responsiveness after birth in infants exposed to maternal smoking.39 It is known that infants with smoking exposure are at an increased risk of developing asthma later in life.2 3 4 5 6 7 8 9 10 It is not clear, however, whether increased bronchial reactivity after birth plays a role, if any, in the development of asthma. It is also not clear whether the increased bronchial reactivity in these infants is purely genetic40 41 or whether it is the result of lung injury from exposure to cigarette smoke.

Lung function in infants with a family history of asthma is not fully understood. Martinez and colleagues noted that such infants might have normal lung function in infancy.1 Another group noted that a family history of asthma is associated with reduced respiratory function after birth.15 Both of these studies were conducted in infants before they developed respiratory symptoms. It is possible that some infants with a family history of asthma may have normal lung function at birth, and early respiratory symptoms may be a risk factor for developing abnormal lung function. It is also possible that some infants with a family history of asthma may have altered lung function at birth, as noted by the other group.15 Our current study evaluated lung function in older infants with daily wheezing and the response to a bronchodilator. Interestingly, most infants with either a family history of asthma or exposure to maternal smoking had abnormal lung function, and a significant number of infants with a family history of asthma responded to a bronchodilator when compared to infants exposed to prenatal and postnatal maternal cigarette smoking.

A family history of asthma has been linked to increased severity of respiratory symptoms in preschool children, and increased severity may be mediated by an increased bronchial responsiveness.14 Another study noted that in infants with a family history of asthma, increased bronchial responsiveness is present soon after birth.39 It has been suggested that increased bronchial responsiveness present in such infants has a genetic basis and may not be secondary to environmental atopy.40 41 It is possible that increased bronchial responsiveness may be a factor in the reversibility of peripheral airflow limitation in our group with a family history of asthma.

Other studies have noted that a family history of asthma is also a risk factor for developing asthma and atopy in childhood.1 Infants with a family history of asthma (maternal asthma) have increased total IgE levels in blood at 9 months, which remains high at 6 years of age.1 These infants also have an increased incidence of eczema and rhinitis apart from colds in the first year of life and have an increased incidence of atopy (skin test reactivity to aeroallergens). In the same study, infants without a maternal history of asthma and with exposure to maternal smoking had normal IgE levels from the cord blood at 9 months and 6 years of age, and they had no increased incidence of rhinitis, eczema, and atopy.1 Since a family history of asthma is a risk factor for childhood atopic asthma, it is possible that increased bronchial reactivity in these infants may have some atopic component. As this was not the focus of our study, we did not look for a history of atopic disease in the parents or families.

In our study, a positive response to the bronchodilator was the distinguishing variable between the two groups. Infants exposed to maternal smoking were more likely to have no response to the bronchodilator, suggesting the irreversibility of the bronchospasm. Infants with exposure to maternal smoking had no other known precipitating factor, and a lack of response to the bronchodilator seems to be a differentiating factor in this group. Since the response to the bronchodilator can differentiate these groups, it is possible that abnormal lung function in both groups may have different underlying causes and may represent different pathophysiologic mechanisms.

Some studies have noted altered passive respiratory mechanics either after birth or before the development of respiratory symptoms in infants who are exposed to cigarette smoking.16 17 Similar results were found in the infants with a family history of asthma.21 In our study, the mean total Crs and Rrs in both groups was within normal limits. About 75% of the infants in both groups had normal Crs, and most of the infants in both groups had normal Rrs. It is possible that many of these infants had low passive respiratory mechanics at birth. With advancing age, as the size of the smaller airways and the elastic recoil pressure of lungs improved, the Crs of the chest wall decreased, and the Crs and the Rrs also improved. With advancing age, low peripheral airflow may be the only altered lung function.

The most important limitation of our study is the lack of control groups, that is, a group of nonwheezing infants and a group of wheezy infants with no risk factors. We were not able to recruit enough nonwheezing infants for IPFTs, especially because of the requirements of sedation and forced expiration (RTC) maneuvers. To overcome this shortcoming, we used standard reference values of PFT parameters established by other authors in healthy infants.1 17 23 24 Although the standard reference values for PFT variables differ slightly from laboratory to laboratory, it is still important to have a reasonable number of normal infants of the same age studied in the same reporting laboratory and using the same pulmonary tests. Because of the lack of control groups, our data could be interpreted as meaning that subjects who were exposed to tobacco smoke showed less responsiveness than normal subjects did or that subjects who have a family history of asthma showed more responsiveness than did the rest of the population. Future studies with appropriate control groups would be helpful.

Another limitation of our study is the lack of standard criteria on infant IPFTs with which to evaluate a response to a bronchodilator. We used a > 25% improvement in FEF25/PFEF after giving the bronchodilator as the criterion for a positive response. We feel that there is a strong need for standard criteria, and more studies are needed to determine whether our findings are valid.

To evaluate peripheral airflow obstruction, we used a TEF25/PEF ratio at tidal breathing. This criterion has been tested by other groups , and it has been shown to be reliable.13 23 24 32 However, we must caution that except for one study,13 most of the studies that were performed by using this variable involved awake newborn infants during tidal breathing. More studies are needed to evaluate the usefulness of this variable in measurements of sedated older infants. For forced expiration, the same criterion of TEF25/PEF was used, but the expiratory flow was forced not tidal (FEF25/PFEF), and a response to the bronchodilator was evaluated by using this variable. There are no standard references on the ratio of FEF25/PFEF, so a response to the bronchodilator should be interpreted with caution until a standard criterion is established with normal controls.

As mentioned earlier, environmental factors, such as exposure to cigarette smoke, and genetic predispositions, such as a family history of asthma, may affect lung function in infants and may predispose them to wheezing and asthma in later life. It is known that many infants with either of these predisposing factors may have increased bronchial responsiveness early in life, though it is not clear whether this bronchial hyper-responsiveness is genetic or atopic in nature. It is also not clear which of the two factors (genetic or environmental) are more important predictors of wheezing and asthma. So far, it has not been possible to differentiate infants with wheezing into groups based on lung function variables. But in our study, we were able to make this distinction based on the reversibility of the bronchospasm. Therefore, it is possible to speculate that the underlying pathophysiologic mechanisms for wheezing in these two groups of infants may be different. It is possible that exposure to maternal smoking can lead to alterations of the structure and function of infant airways during the sensitive period of fetal or early postnatal life. Based on our study, however, we cannot determine whether other household exposure has any additional effect on lung function. Furthermore, altered lung development and structural changes in airway anatomy may be more prominent factors in asthma associated with tobacco exposure. Since bronchospasm in infants with a family history of asthma is reversible, it is possible that in these infants, genetic predisposition may be a more prominent factor.

More studies with a larger number of infants and with appropriate controls are needed to confirm our findings that infants with wheezing can be differentiated on the basis of their lung function, especially by their ability to respond to a bronchodilator. This finding may have important implications for developing different modalities for management of respiratory symptoms in these infants and may be helpful in understanding pathophysiologic differences in subgroups of infants with infantile wheezing.


   Footnotes
 
This study was presented in part at the 1998 American Thoracic Society meeting in Chicago, IL.

Abbreviations: Crs = total respiratory system compliance; FEF = forced expiratory flow; FEF25/PFEF = ratio of terminal to peak expiratory flow with forced expiration at 25% of the previous expiration remaining; FEF25%-75% = FEF between 25% and 75% of the vital capacity; FRC = functional residual capacity; IPFT = infant pulmonary function tests; Rrs = total respiratory system resistance; RTC = rapid thoracoabdominal compression; TEF25/PEF = ratio of tidal flow at 25% of the remaining expiration to peak tidal expiratory flow

Received for publication September 8, 1998. Accepted for publication February 9, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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