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Published ahead of print on September 14, 2006, doi:10.1164/rccm.200606-782OC
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American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 1292-1298, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200606-782OC

Original Article

Elevated Exhaled Nitric Oxide in Newborns of Atopic Mothers Precedes Respiratory Symptoms

Philipp Latzin, Claudia E. Kuehni, David N. Baldwin, Hanna L. Roiha, Carmen Casaulta and Urs Frey

Departments of Pediatrics and Social and Preventive Medicine, University of Bern, Bern, Switzerland

Correspondence and requests for reprints should be addressed to Urs Frey, M.D., Ph.D., Pediatric Respiratory Medicine, Department of Pediatrics, University of Berne Inselspital, 3010 Bern, Switzerland. E-mail: urs.frey{at}insel.ch


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Exhaled nitric oxide (NO) is a well-known marker of established airway inflammation in asthma. Its role in the disease process before the onset of respiratory symptoms remains unclear.

Objectives: To examine whether elevated NO in newborns with clinically naive airways is associated with subsequent respiratory symptoms in infancy.

Methods: We measured exhaled NO concentration and output after birth and prospectively assessed respiratory symptoms during infancy in a birth cohort of 164 unselected healthy neonates. We examined a possible association between NO and respiratory symptoms using Poisson regression analysis.

Results: In infants of atopic mothers, elevated NO levels after birth were associated with increased risk of subsequent respiratory symptoms (risk ratio [RR], 7.5; 95% confidence interval [CI], 1.7–32.4 for each nl/s increase in NO output; p = 0.007). Similarly, a positive association between NO and symptoms was seen in infants of smoking mothers (RR, 6.6; 95% CI, 2.3–19.3; p = 0.001), with the strongest association in infants whose mothers had both risk factors (RR, 21.8; 95% CI, 5.8–81.3; p < 0.001).

Conclusions: The interaction of NO with maternal atopy and smoking on subsequent respiratory symptoms is present early in life. Clinically, noninvasive NO measurements in newborns may prove useful as a new means to identify high-risk infants. Future confirmation of a role for NO metabolism in the evolution of respiratory disease may provide an avenue for preventative strategies.

Key Words: allergy • asthma • cough • wheeze



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
Exhaled nitric oxide (NO) is a well-known marker of established airway inflammation in allergic asthma. It is not known yet whether NO plays a role in the evolution of the disease before the onset of respiratory symptoms.

What This Study Adds to the Field
In infants of atopic and smoking mothers, changes in NO metabolism occur before the onset of clinical symptoms. This suggests that NO plays a role in respiratory disease pathogenesis and may help to identify high-risk infants.

 
Exhaled nitric oxide (NO) has been widely accepted as a diagnostic marker in bronchial asthma (1–4) and for monitoring airway inflammation and corticosteroid therapy in adults and children (5–7). Its role in the pathogenesis of this disease remains unclear (8). In the microenvironment of the healthy lung, NO has bronchodilatory, bronchoprotective, and antiinflammatory effects (9). Within the inflamed airways of chronic asthmatics, the inducible form of nitric oxide synthase (iNOS) is activated (10), leading to elevated NO in exhaled air of these patients (1, 4).

Whether elevation of NO occurs as a consequence of asthmatic airway inflammation or represents a pathophysiologic mechanism of asthma evolution and is thus elevated before the onset of clinical symptoms remains unknown (8). The latter hypothesis is supported by elevated NO levels in healthy atopic subjects without clinical symptoms of asthma (11) and by an increase of exhaled NO in asymptomatic patients with asthma preceding subsequent exacerbations (7, 12, 13). Thus, it is necessary to focus on the inductive phase of the disease process and measure NO at an early age before inflammatory processes and structural changes of the airways occur (14). Although there is no direct association between maternal atopy and NO levels at birth in healthy infants (15), we have shown that maternal atopic disease modifies the influence of environmental factors (e.g., tobacco exposure) on NO levels in their offspring (15).

The early postnatal phase is known to be crucial for lung growth and for the development of pulmonary disease (16–19). Respiratory symptoms during infancy may reflect the influence of prenatal factors, such as maternal smoking during pregnancy, or parental asthmatic disease or postnatal events, such as environmental tobacco smoke (ETS) exposure and childcare (20–22). Furthermore, children exposed to these risk factors and having serious respiratory morbidity early in life are also thought to be at higher risk of developing recurrent lung disease later in life (14, 23–26). However, the exact mechanisms that connect prenatal and early life exposures to subsequent respiratory morbidity are unclear.

The aim of the current study was to investigate whether exhaled NO levels in the newborn before the first respiratory tract infection are associated with respiratory symptoms during the first year of life. We also tested whether this relationship is influenced by maternal atopy and smoking because these factors are known to influence NO and symptoms of asthma (27, 28). Some of the results of this study have been presented in the form of an abstract (20, 29).


   METHODS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
This prospective birth cohort study comprised a group of unselected, healthy neonates recruited antenatally in the region of Bern, Switzerland. The Ethics Committee of the Region of Bern approved the study, and written consent was obtained at enrollment.

Study Design
We used a standardized questionnaire to assess sociodemographic conditions and prenatal and postnatal exposure to putative risk factors for respiratory disease (e.g., number of siblings and pre- or postnatal ETS exposure). We validated antenatal smoking history by cotinine levels in the first urine of the newborn (gas-liquid chromatography; ITS, Lausanne, Switzerland). Parental atopic disease was defined as self-reported, doctor-diagnosed asthma, hay fever, or eczema, verified by a standardized interview by the study physician. In a subgroup of 104 mothers, maternal atopy was also ascertained by skin prick tests to eight common allergens.

We performed NO measurements at a median age of 34 d (range, 25–57 d). Exhaled NO concentration (eNO) was measured, and NO output (VNO) was calculated as previously validated and described (15, 30).

During the first year of life, research nurses phoned the mothers weekly to assess the health status of their child, focusing on respiratory symptoms and changes in environmental factors. Respiratory symptoms (including cough and wheeze) were assessed using a standardized score that groups symptoms into four levels according to severity, with a high sensitivity for lower respiratory tract symptoms (31). The effect of upper respiratory tract symptoms without cough (e.g., rhinitis, pharyngitis, ear infections) was not investigated in the current study.

To focus on infants most likely to develop asthmatic airway disease later in life, we used "weeks with severe respiratory symptoms" as the main outcome measure for this study, defined as total number of weeks a child had respiratory symptoms with a day or night symptom score of >= 3, independent of the nature of the respiratory symptom (cough or wheeze). This outcome reflects repeated sleep interruptions during nighttime or GP consultations during daytime and thus moderate or severe respiratory morbidity, clinically relevant for the family (31). We focus on more severe symptoms because it has been postulated that children with the most severe asthma started to have significant respiratory morbidity early in life (14, 23, 32). Other outcome measures were "audible wheeze" and "weeks with mild respiratory symptoms," defined as a symptom score of <= 2 (e.g., cough with neither sleep disturbance nor GP consultation).

Statistical Methods
Poisson regression was used for analysis of the association between NO values and weeks with respiratory symptoms. Results are expressed as incidence risk ratios (IRR) with 95% confidence intervals (CIs) based on robust variance estimation (33). It is well known that smoking and atopy influence NO values and respiratory morbidity and thus act as potential confounders or effect modifiers of the relationship between NO and respiratory symptoms. To clearly disentangle these associations, we first stratified the cohort by clinically relevant maternal atopic disease, maternal skin prick test positivity, and maternal smoking during pregnancy. Because these stratified analyses indicated effect modification by atopy and smoking, final results were calculated using a common model that included interaction terms.

Adjustment for confounders (sex and age) and for nonconfounding risk factors for respiratory symptoms and asthma (number of siblings and nursery care) (34) and sensitivity analysis with additional outcome measures produced results similar to the main analysis.

Further details of the methods are given in the online supplement.


   RESULTS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study Subjects
The study enrolled 188 infants; data from 164 (87%) infants were used for analysis. Reasons for exclusion were technical problems or insufficient duration of quiet sleep (n = 13), any sign of upper or lower respiratory tract infection before or at the time of measurement (n = 9), and dropout from follow-up (n = 2). One child without a history of prenatal smoke exposure was regarded as being exposed to prenatal tobacco smoke because elevated urine cotinine levels (93 ng/ml) suggested significant prenatal nicotine exposure. Ninety-one (55%) of the subjects were male. Fifty-one (31%) had one and 28 (17%) more than one older sibling. Sixty-one mothers (37%) reported an atopic disorder, including 18 (11%) with doctor-diagnosed asthma. For fathers, corresponding numbers were 67 (41%) and 23 (14%). Twenty-three mothers (14%) smoked during pregnancy, and 43 fathers (26%) were smokers, with a total of 48 infants (29%) exposed to postnatal ETS. Thirty-seven infants (23%) went to childcare during the first year of life. The anthropometric and lung function data and the frequency of respiratory symptoms of the 164 infants are given in Table 1.


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  		TABLE 1. ANTHROPOMETRIC AND LUNG FUNCTION DATA AND RESPIRATORY SYMPTOMS DURING THE FIRST YEAR OF LIFE OF THE 164 STUDY CHILDREN

 
Association between NO and Severe Respiratory Symptoms in the First Year of Life
No association was found between NO measured at 1 mo and occurrence of respiratory symptoms during the first year when assessed for the entire cohort. This was independent of symptom severity. However, previous studies have shown maternal atopy to influence children's NO values (27) and the association between environmental factors and exhaled NO in infants (15). We therefore stratified the association between NO and severe respiratory symptoms for clinically diagnosed maternal atopic disease, maternal smoking during pregnancy, and maternal skin prick test results. NO values were comparable in all strata (Table 2).


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  		TABLE 2. EXHALED NITRIC OXIDE VALUES AND RESPIRATORY SYMPTOMS DURING THE FIRST YEAR OF LIFE BY SUBGROUPS DEFINED BY MATERNAL ATOPIC DISEASE, MATERNAL SKIN PRICK TEST RESULTS, AND MATERNAL SMOKING DURING PREGNANCY

 
In infants of mothers with clinically diagnosed atopic disease, NO at 1 mo of age was positively associated with subsequent severe respiratory symptoms (Table 3). In contrast, we found a trend toward a negative association between NO and severe respiratory symptoms in infants of nonatopic mothers. Thus, the direction of the association between exhaled NO and subsequent severe respiratory symptoms was modified by the presence of maternal atopic disease (p values for interaction <= 0.01 in all models on VNO and <= 0.065 in models for eNO). In a subgroup of 104 infants, skin prick test results of their mothers were used for stratification. In infants of mothers who had positive skin prick tests, values for VNO and eNO were positively associated with severe respiratory symptoms in the first year of life, whereas this effect was not observed in infants of mothers who had negative skin prick tests (Table 4).


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  		TABLE 3. ASSOCIATION BETWEEN EXHALED NITRIC OXIDE IN NEWBORNS AND NUMBER OF WEEKS WITH SEVERE RESPIRATORY SYMPTOMS* DURING INFANCY BY MATERNAL ATOPIC DISEASE

 

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  		TABLE 4. ASSOCIATION BETWEEN EXHALED NITRIC OXIDE IN NEWBORNS AND SUBSEQUENT SEVERE RESPIRATORY SYMPTOMS DURING INFANCY* BY SKIN PRICK TEST RESULTS IN MOTHERS

 
When stratifying for maternal smoking during pregnancy, a similar effect modification was found, although with a weaker interaction than for maternal clinical atopic disease (Table 5). In the presence of maternal smoking during pregnancy, elevated exhaled NO was related to more frequent episodes of severe respiratory symptoms. This was not the case in offspring of nonsmoking mothers.


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  		TABLE 5. ASSOCIATION BETWEEN EXHALED NITRIC OXIDE IN NEWBORNS AND NUMBER OF WEEKS WITH SEVERE RESPIRATORY SYMPTOMS* DURING INFANCY BY MATERNAL SMOKING DURING PREGNANCY

 
Because there was an interaction between NO and clinically diagnosed maternal atopic disease and smoking, the association between NO after birth and subsequent severe respiratory symptoms was calculated in a more comprehensive statistical model. This model with three interaction terms (NO x maternal atopy x maternal smoking during pregnancy) showed a multiplicative effect of clinically diagnosed maternal atopic disease and smoking during pregnancy on the association between NO after birth and subsequent severe respiratory symptoms when both risk factors were acting together (Figure 1). In this model, the age- and sex-adjusted IRR of having severe respiratory symptoms during the first year of life was 3.4 (95% CI, 0.7–17.0) for infants of atopic mothers, 4.6 (95% CI, 1.0–22.0) for infants of mothers who smoked during pregnancy, and 21.8 (95% CI, 5.8–81.3) for infants of mothers, where both risk factors were present (Figure 1).


Figure 1
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  		Figure 1. Association between nitric oxide output (VNO) in newborns and subsequent severe respiratory symptoms during infancy depending on atopic and smoking history of the mother. The risk ratio for severe respiratory symptoms during the first year of life is given per nl/s increase in VNO in newborns calculated with a common model including three interaction terms (NO x atopy x smoking). The risk ratio is divided into the following groups of the total 164 infants: 88 infants of nonatopic mothers who did not smoke during pregnancy (left), 53 infants of atopic mothers who did not smoke during pregnancy (left middle), 15 infants of nonatopic mothers who smoked during pregnancy (right middle), and eight infants of atopic mothers who smoked during pregnancy (right). The left marks denote the crude risk ratio, the marks with the asterisk denote the risk ratio adjusted for age and sex, and the marks with 95% confidence interval denote the risk ratio additionally adjusted for number of siblings and childcare (as known risk factors for respiratory disorders). Note the logarithmic scale of the y axis. p Values were calculated using the Wald Test.

 
All results remained essentially unchanged when alternative measures of moderate or severe respiratory symptoms were used as outcome parameters (weeks with audible wheeze, total symptom score, and average symptom score). For example, when audible wheeze was considered as an outcome measure, similar results to the main outcome were obtained with an IRR of 0.19 (95% CI, 0.04–1.01) in infants of mothers who had negative skin prick tests and of 5.56 (95% CI, 0.97–32.04) in infants of mothers who had positive skin prick tests. This confirms that maternal skin prick positivity modifies the effect of NO on subsequent wheeze during infancy (p value for interaction = 0.004). No association was seen between NO and mild respiratory symptoms.

NO as a Mediating Factor on the Causal Pathway between Maternal Smoking and Respiratory Symptoms
To further elucidate the role of NO metabolism in the evolution of respiratory disease, we investigated whether the strength of the association between maternal smoking during pregnancy and respiratory symptoms in infants of atopic mothers changed when we introduced NO into the statistical model. The risk ratio for severe respiratory symptoms if the mother had smoked during pregnancy changed from 2.94 (95% CI, 1.34–6.48) to 1.95 (95% CI, 0.86–4.43) when we adjusted for VNO and to 1.42 (95% CI, 0.63–3.21) when we adjusted for eNO.


   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We assessed prospectively the association between eNO measured shortly after birth and subsequent respiratory symptoms in healthy infants. We showed that high NO values after birth are associated with severe respiratory symptoms in the first year of life if the mother had an atopic disease or had been smoking during pregnancy. The association was strongest in infants in whom both factors were present. Findings were unchanged if the models were adjusted for confounders and known risk factors for respiratory disease in infants or when maternal skin prick test positivity was used for stratification instead of clinical atopic disease.

We found this effect modification by maternal atopy and maternal smoking only for severe respiratory symptoms or wheezing episodes. From a public health and epidemiologic perspective, severe respiratory symptoms in early childhood are an important problem. In large cohort studies, "tracking" of severe respiratory symptoms and wheezing throughout childhood and later life has been clearly demonstrated (23, 35, 36), and an early age at onset of wheezing predicts relapse later in life (23). Young children with persistent wheeze and poor lung function are more likely to continue to wheeze later in childhood (37). In addition, children with the most severe asthma have symptoms beginning in early life (14).

In the present study, no association was found between NO values and mild respiratory symptoms during infancy. The presence of minor respiratory symptoms may be determined more by environmental factors, such as viral infections leading to mild upper respiratory symptoms. Moreover, epidemiologic studies show a strong association of severe symptoms and persistent wheeze, whereas mild upper respiratory symptoms may be associated with reduced risk for persistent wheeze and asthma at school age (38).

NO and Atopy
Our findings may improve our understanding of NO metabolism in relation to the evolution of asthma in early life. Our data support the hypothesis that NO metabolism is involved in the pathophysiology of respiratory disease, in particular in infants of atopic mothers. These findings are novel for infants but are supported by similar observations in older children. In established asthma, a stronger association between NO and allergy was found in wheezing children compared with children without current wheeze (39). Franklin and colleagues demonstrated an association between NO and airway hyperresponsiveness (AHR) only in atopic children (40). A similar modification by atopy of the association between NO and AHR was also found in a study of 181 men (41). Even though these different studies showed an association between NO and respiratory symptoms or AHR in atopic subjects, the question of the possible pathophysiologic role of NO in respiratory disease has not been answered. We show that this association is present during the first month of life preceding the onset of respiratory symptoms. This supports a possible role of NO metabolism in the pathogenesis of allergic asthma and underlines that these processes take place early in infancy (14).

NO and Smoking
Maternal smoking during pregnancy modified the relationship between exhaled NO in infants and subsequent severe respiratory symptoms in the first year of life. An effect of smoking on exhaled NO has been known for long time (1). In adult smokers, chronic smoking leads to a decrease in exhaled NO, whereas acute smoking increases NO values (42). The observed association between NO and later respiratory symptoms in infants of atopic mothers was much stronger if the mother had also smoked during pregnancy. This underlines the importance of gene–environment interactions.

We found statistical evidence that at least part of the effect of maternal smoking on respiratory symptoms might be mediated via NO. Because this analysis incorporated small numbers of infants, our results need confirmation with further studies.

The Possible Role of NO Synthase
Although the underlying mechanisms of our findings remain unclear, we hypothesize that the contribution of the different NO synthase (NOS) isoforms to the concentration of NO may explain its diverging effects in diseases like asthma (10, 43). One might speculate that NO in infants of atopic or smoking mothers (in a proinflammatory microenvironment) may be produced by iNOS with its assumed negative effects, whereas NO in infants of nonatopic mothers (in a healthy microenvironment) may be produced mainly by constitutive/endothelial (c/e)NOS and therefore exhibits protective effects on the airways of these infants (44). Whether the pathogenetic contribution of NOS to allergic asthma is driven by alterations in NOS-isoform expression (45) or by polymorphisms in NOS genes, as recently shown for iNOS and eNOS (46, 47) is not known. To explore this, in addition to genetic analysis, it is necessary to determine the expression of NOS in infants of atopic and nonatopic mothers before the onset of respiratory symptoms or different environmental exposures. Future research in this area might open up new possibilities for the prevention of asthma in high-risk infants (e.g., with NOS inhibitors) (48, 49).

Methodologic Aspects
We assessed respiratory symptoms prospectively with weekly phone calls to the mothers, thus obtaining reliable data on respiratory morbidity and its relevance for the family (31). Although we assume that some episodes with mild symptoms might have been due to upper respiratory infections, this is unlikely for episodes with severe symptoms. The fact that, relative to the general population, fewer smokers and more atopic parents took part in this study does not change the findings, but results of the nonatopic and atopic smoking groups should be interpreted carefully due to small numbers. NO measurements were done using a previously validated method with the advantage of correction for expiratory flow (30). Only sparse data on NO values in infants are available, but our eNO and flow values are comparable to results from older infants (27). The mean flow during the expiratory cycle, when NO measurements were taken, was 45 (interquartile range, 37–55) ml/s, which is close to the flow of 50 ml/s recommended in the American Thoracic Society/European Respiratory Society guidelines for measurement of single-breath exhaled NO (3). To minimize any potential influence by possible circadian rhythm of NO, all measurements were performed between 9:00 A.M. and 1:00 P.M. Other non–disease-related factors possibly affecting eNO values in adults (e.g., food, beverage, or medication intake) (3) can be neglected in our healthy and fully breast-fed infants. Measurements were performed in naturally sleeping infants with a face mask. At this age the nasal sinuses are not developed, and a potential contribution of the upper airways to NO values seems unlikely; however, this would not affect the interpretation of this study.

The definition of maternal atopy in our analysis was based on clinically relevant, doctor-diagnosed maternal atopic disease and in a subgroup of 104 mothers on skin prick test results. For maternal smoking during pregnancy, validity of reported exposure could be verified by comparisons with cotinine levels in the first urine of the newborn, permitting regrouping of possibly misclassified children.

Conclusions
We show that maternal atopic disease and smoking during pregnancy modifies the association between NO in newborns and severe respiratory symptoms in infancy. This relationship is enhanced in infants of mothers who are atopic and smoked during pregnancy. Because this newly described association is present during the first months of life, we speculate that NO metabolism may play a role in the pathophysiology of respiratory disease. More studies, perhaps even in infants directly after birth, are necessary to elucidate whether this association represents a primary or secondary effect. Early noninvasive NO measurements in high-risk newborns in conjunction with maternal history or skin prick testing could have a potential value as a diagnostic or prognostic tool. Our findings should encourage further research toward new preventative strategies in this area.


   Acknowledgments
 
The authors thank the study nurses Christine Becher and Monika Graf for performing the weekly phone calls to the parents and for performing the skin prick testing. They also thank Isabelle Pramana, M.D., and Sylvie Besson for their help in the analysis of the measurements; Ben Spycher, M.Sc., and Marcel Zwahlen, Ph.D., for their helpful advice in the statistical analysis; and Nicolas Regamey, M.D., for critical appraisal of the manuscript.


   FOOTNOTES
 
Supported by Swiss National Foundation grant 3200-B0-112099 (U.F. and P.L.) and Swiss National Foundation PROSPER grants 3233-069348 and 3200-069349 (C.K.).

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

Originally Published in Press as DOI: 10.1164/rccm.200606-782OC on September 14, 2006

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form June 13, 2006; accepted in final form September 12, 2006


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 ABSTRACT
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 METHODS
 RESULTS
 DISCUSSION
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