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American Journal of Epidemiology Advance Access originally published online on May 28, 2008
American Journal of Epidemiology 2008 168(2):170-178; doi:10.1093/aje/kwn105
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Perinatal Factors and the Risk of Asthma in Childhood—A Population-based Register Study in Finland

Johanna Metsälä1,2, Annamari Kilkkinen3, Minna Kaila4,5, Heli Tapanainen1, Timo Klaukka6, Mika Gissler7 and Suvi M. Virtanen1,2,8

1 Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki, Finland
2 Tampere School of Public Health, University of Tampere, Tampere, Finland
3 Department of Health and Functional Capacity, National Public Health Institute, Helsinki, Finland
4 Finnish Office for Health Technology Assessment, National Research and Development Center for Welfare and Health, Tampere, Finland
5 Pediatric Research Center, Tampere University Hospital, Tampere, Finland
6 Social Insurance Institution, Helsinki, Finland
7 Information Division, Alcohol and Drug Statistics and Reproduction Statistics, National Research and Development Center for Welfare and Health, Helsinki, Finland
8 Research Unit, Tampere University Hospital, Tampere, Finland

Correspondence to Johanna Metsälä, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland (e-mail: johanna.metsala{at}ktl.fi).

Received for publication October 31, 2007. Accepted for publication March 27, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The aim of the study was to assess whether perinatal factors are associated with the risk of asthma in childhood in a register-based, nested case-control study in Finland. All children born between January 1, 1996, and April 30, 2004, who were entitled to a special reimbursement for antiasthmatic drugs (i.e., had diagnosed asthma by 2006 and had purchased inhaled corticosteroids or montelukast at least once), were identified (n = 21,038). For each case, one matched control child was selected. The associations between perinatal factors, derived from the Finnish Medical Birth Register, and the risk of asthma were analyzed by conditional logistic regression. In the final multivariate model, maternal asthma, young age, smoking, previous miscarriages, and a high number of previous deliveries, as well as cesarean section, low gestational age, and low ponderal index, were associated with an increased risk of asthma in children diagnosed before the age of 3 years. Among children diagnosed at the age of 3 years or later, maternal asthma, low gestational age, and low ponderal index were associated with an increased risk, and a high number of previous deliveries was associated with a decreased risk of asthma. In conclusion, perinatal factors play a role in the development of asthma in childhood, but the etiology may differ in early and late-onset asthma.

asthma; cesarean section; child; cohort studies; gestational age; registries; risk factors

Abbreviations: ATC, Anatomical Therapeutic Chemical; CI, confidence interval; OR, odds ratio; SGA, small for gestational age


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The prevalence of asthma and allergic diseases in childhood has substantially increased during the last decades in several Westernized countries (1). This rise indicates that, besides the strong hereditary component, environmental factors play an important role in the development of allergic immune responses. Increasing evidence suggests that these environmental factors operate in early life or even in utero (2, 3).

Perinatal factors have been hypothesized to be associated with the risk of asthma and allergic disorders by several possible mechanisms (2–4). These mechanisms focus on the development of the immune system, especially changes in the production of type 1 and type 2 T-helper (Th-1, Th-2) cell-type cytokines. Changes in cytokine profiles in cord blood as a response to neonatal exposures may be related to the development of asthma and allergic diseases later in childhood (3, 4). An appropriate environmental stimulus, for example, microbial exposure, is crucial in the development of a healthy type 1 T-helper cell dominant immune response after birth (5). Diminished microbial exposure and factors influencing microbial exposure after birth may affect the development of an allergic immune response.

In epidemiologic studies, several perinatal factors have been suggested to be associated with the risk of asthma, but the evidence is not conclusive. Maternal smoking (6–9) and young age (6, 10, 11) have consistently been reported to be associated with an increased risk of wheeze or asthma in the offspring. Several studies have also shown that complications during pregnancy and delivery are associated with increased risk of asthma (12–14). Furthermore, both cesarean section (15) and prematurity (16) have been associated with increased risk of asthma in recent meta-analyses. Results regarding birth weight are contradictory (7, 9, 12, 17–21).

To clarify the role of maternal background and perinatal factors in the development of asthma in childhood, we conducted a register-based, nested case-control study including all children born between January 1, 1996, and April 30, 2004, in Finland and diagnosed with asthma by 2006.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population and data sources
The study population was derived from three nationwide registers. All children who were born in Finland between January 1, 1996, and April 30, 2004, and had received a special reimbursement for antiasthmatic drug costs by the end of 2005 were identified (n = 22,548). In Finland, a special reimbursement for certain prescribed drugs including antiasthmatic drugs is provided and recorded in the Special Reimbursement Register kept by the Social Insurance Institution of Finland. The reimbursement is divided into three compensation categories (basic; lower special, 75 percent; and higher special, 100 percent) with the lower special reimbursement category covering approximately 10 diseases, including asthma (22). To be eligible for this special reimbursement, a patient must have a certificate from a physician, in the case of a child mostly from a pediatrician, stating that the diagnostic criteria of asthma are fulfilled. For each case, one nonasthmatic control matched to the case by age (±28 days), gender, and the hospital district where the child was born was randomly selected from the Population Register of the Social Insurance Institution. Controls were allowed to be selected only once.

Information on the use of antiasthmatic drugs was obtained from the Drug Prescription Register of the Social Insurance Institution, and it includes information on drug class (Anatomical Therapeutic Chemical (ATC) Classification System), date of purchasing, and personal identity code. In Finland, all drugs prescribed by physicians and reimbursed by the National Sickness Insurance Scheme are registered in the Drug Prescription Register, established in 1993 and being almost complete in 1995.

In the present study, those children who were entitled to a special reimbursement for antiasthmatic drugs and purchased them at least once after the diagnosis were considered as asthma cases (n = 21,038). Selection of the antiasthmatic drugs was based on the Finnish Current Care Guidelines (23) and recommendations by the Social Insurance Institution. These drugs included inhaled corticosteroids (ATC code R03BA), a fixed combination containing inhaled corticosteroids and salmeterol (code R03AK06), a fixed combination containing inhaled corticosteroids and formoterol (code R03AK07), and montelukast (code R03DC03). Long-acting beta-agonists were included in the case definition because, despite the fact that they are neither licensed nor recommended, especially for children under the age of 4 years, they are increasingly used. In each of these drug groups, the concomitant use of a short-acting beta-agonist was allowed. In Finland, cromones (code R03BC) and teophyllines (code R03DA04) are used only as add-on therapy and, therefore, they were not included as antiasthmatic drugs. The total number of different drug purchases in 1995–2005 was calculated separately for two groups of cases: those diagnosed before the age of 3 years and at the age of 3 years or later.

A total of 415 control children had purchased inhaled corticosteroids (ATC code R03BA), a fixed combination containing inhaled corticosteroids and salmeterol (code R03AK06), a fixed combination containing inhaled corticosteroids and formoterol (code R03AK07), cromoglycate (code R03BC01), nedocromil (code R03BC03), montelukast (code R03DC03), xanthines (code R03DA) or xanthines, and adrenergics (code R03DB) before the asthma diagnosis of the case. They were excluded from the present study as we did not have information on whether they were just transient users of antiasthmatic drugs or asthma patients without a physician's confirmed diagnosis. Finally, 20,623 case-control pairs were included in the present study.

The data were completed by linkage with the Finnish Medical Birth Register, kept by the National Research and Development Center for Welfare and Health. The register includes information on maternal background and interventions during pregnancy and delivery and on the newborn's medical interventions and outcome up to the age of 7 days. Data from the Medical Birth Register were missing for 457 subjects (158 cases and 299 controls) included in the study population. Most of these children were not born in Finland. The variables used in this study were maternal previous miscarriages (no/yes); number of previous deliveries (0, 1, 2, 3, 4, ≥5); smoking during pregnancy (no/yes, including those who quit smoking during the first trimester); complications during pregnancy (none, maternal high blood pressure during pregnancy that had to be treated in the hospital, placental complications including placenta previa and placenta avulsion, abnormal presentation including breech and other abnormal presentation, and fetal asphyxia); and age at delivery (<25, 25–29, 30–34, and ≥35 years), as well as mode of delivery (normal vaginal delivery, assisted vaginal delivery, planned cesarean section, and emergency cesarean section), Apgar score at 1 minute (0–6, 7–8, 9–10), prematurity (gestational age, <37 weeks), low birth weight (birth weight, <2,500 g), and gestational age-adjusted birth weight, defined according to Finnish population-based growth curves: small for gestational age (SGA), –2 standard deviations or less of the mean birth weight for gestational age; appropriate for gestational age, within the mean ±2 standard deviations; large for gestational age, 2 standard deviations or more of the mean (24). In addition, children were stratified according to gestational age and ponderal index (birth weight/birth length3) at birth on the basis of the quartiles of the controls. Those mothers who were entitled to a special reimbursement for antiasthmatic drugs were considered as having asthma. No information on the father was available in the Medical Birth Register.

Linkages between the registers were based on unique personal identity codes assigned to all Finnish citizens shortly after birth (25). The study was approved by the national data protection authority, the institutions keeping the registers, and the Institutional Review Board of the National Public Health Institute.

Statistical analysis
For examination of the associations between maternal background factors and perinatal factors among controls, the Pearson chi-squared test for two categorical variables, the Mann-Whitney U test for the combination of a continuous and a dichotomous variable, and the Spearman rank correlation for two continuous variables were used. The associations between perinatal factors and the risk of asthma were analyzed by conditional logistic regression, and the results are displayed as odds ratios with 95 percent confidence intervals. A model including only one explanatory variable at a time was fitted first; the ponderal index, the Apgar score at 1 minute, the mode of delivery, and complications were, however, adjusted for gestational age in univariate analysis. Interactions among maternal age, smoking, asthma, and perinatal factors were investigated. The multivariate model included possible interaction terms and all the variables used in the univariate analysis, except for prematurity, low birth weight, gestational age-adjusted birth weight, the Apgar score, and pregnancy complications. In the final multivariate model, the nonsignificant variables were eliminated one by one. Variables were entered into the multivariate models in the categorical mode. Statistical significance was set at the 5 percent level, and two-sided p values were used.

All analyses were done separately for children diagnosed with asthma before the age of 3 years (early onset) and at the age of 3 years or later (late onset), because the diagnosis of asthma is more challenging in the younger age group, and the diagnostic criteria of asthma in children younger than 3 years differ from those of older children (23, 26). Further analyses were conducted by excluding premature children and cases with only one or two purchases of antiasthmatic drugs during the 3 years after diagnosis. All analyses were performed using STATA, version 9.1, software (StataCorp LP, College Station, Texas).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The mean age of asthma cases at diagnosis was 2.2 years, ranging from 0 months to 9 years; two thirds (n = 13,679) of the cases were diagnosed before the age of 3 years. Asthma was more common in boys (64 percent of cases) than in girls (36 percent) (p < 0.001). Inhaled corticosteroids and short-acting beta-agonists were the most often purchased antiasthmatic drugs (table 1). Short-acting beta-agonists were always used concomitantly with other antiasthmatic drugs; the majority of cases purchasing corticosteroids had also purchased short-acting beta-agonists (84 percent of cases diagnosed before the age of 3 years and 81 percent of cases diagnosed at 3 years of age or later).


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  		TABLE 1. Total number of purchases of antiasthmatic drugs after the diagnosis during 1996–2005 in cases born in Finland between January 1, 1996, and April 30, 2004 (n = 20,623), by different drug groups

 
Maternal background factors were associated with several perinatal factors. Among controls, cesarean section was prevalent among older mothers, mothers with no previous deliveries, and low gestational age (table 2). Maternal smoking during pregnancy was related to young age and no previous deliveries. Previous miscarriages were prevalent among women with older age and a low number of previous deliveries. The only clinically relevant correlation observed was between maternal age and number of previous deliveries (r = 0.4, p < 0.001).


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  		TABLE 2. Cesarean section, maternal smoking during pregnancy, and previous miscarriages related to maternal age, previous deliveries, and gestational age among controls born in Finland between January 1, 1996, and April 30, 2004 (n = 20,623)

 
Maternal asthma was the strongest predictor of asthma in children diagnosed before the age of 3 years (odds ratio (OR) = 3.41, 95 percent confidence interval (CI): 3.08, 3.77) (table 3). Young maternal age, smoking during pregnancy, previous miscarriages, and high number of previous deliveries were also associated with an increased risk of asthma. We observed an interaction between maternal age and number of previous deliveries (figure 1); in the analysis stratified by number of previous deliveries of the mother, the risk of asthma decreased with increasing maternal age among children with older siblings, while no association was observed among mothers without previous deliveries.


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  		TABLE 3. Maternal background and perinatal factors related to asthma in childhood in children born in Finland between January 1, 1996, and April 30, 2004, and diagnosed before the age of 3 years

 

Figure 1
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  		FIGURE 1. Maternal age at delivery and the risk of childhood asthma by number of maternal previous deliveries (0, 1, 2, ≥3) in children diagnosed before the age of 3 years, Finland, 1996–2005. Data points are crude odds ratios in maternal age groups <25, 25–29, 30–34, and ≥35 years, with points placed at the mean maternal age within each age group. Bars, 95% confidence intervals.

 
Emergency cesarean section and low gestational age were also associated with an increased risk of asthma (table 3). Compared with the risk for full-term and normal-weight children, a substantially increased risk of asthma was observed for premature children (OR = 2.77, 95 percent CI: 2.53, 3.03), for children with low birth weight (OR = 1.40, 95 percent CI: 1.20, 1.60), and for children who were SGA (OR = 2.00, 95 percent CI: 1.73, 2.31), respectively. A low Apgar score at 1 minute (for scores 0–6 vs. 9–10, OR = 1.32, 95 percent CI: 1.17, 1.49) and placental complications (for none vs. placental complications, OR = 1.61, 95 percent CI: 1.10, 2.36) were also associated with an increased risk of asthma. In the multivariate model, maternal age, asthma, smoking during pregnancy, and previous miscarriages as well as previous deliveries, both planned and emergency cesarean sections, gestational age, and ponderal index were associated with the risk of asthma in children diagnosed before the age of 3 years (table 3). All variables remained significant also in the final multivariate model.

Maternal asthma was also the strongest predictor of asthma in children diagnosed at the age of 3 years or later (OR = 3.70, 95 percent CI: 3.22, 4.33) (table 4). Young maternal age, a low number of previous deliveries, and short gestational age, as well as emergency cesarean section, were associated with an increased risk of asthma. Ponderal index was at borderline significance. Prematurity (OR = 1.34, 95 percent CI: 1.16, 1.54) and low Apgar score at 1 minute (OR = 1.19, 95 percent CI: 1.00, 1.42) were associated with an increased risk of asthma, while no association was observed for maternal smoking, previous miscarriages, planned cesarean section, low birth weight, or SGA status. In the final multivariate model, maternal asthma, number of previous deliveries, gestational age, and ponderal index were associated with the risk of asthma.


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  		TABLE 4. Maternal background and perinatal factors related to asthma in childhood in children born in Finland between January 1, 1996, and April 30, 2004, and diagnosed at the age of 3 years or later

 
The prevalence of prematurity was higher among cases than controls (11 percent vs. 5 percent). The majority of premature cases were diagnosed before the age of 3 years (80 percent). The exclusion of premature children from further analysis did not substantially change the results (data not shown). The only exception was ponderal index, which dropped out from the final multivariate model in both age groups.

Of those cases followed up for at least 3 years after diagnosis (i.e., cases born during 1996–2002, n = 13,505), 1,716 had only one or two purchases of inhaled corticosteroids or montelukast during the 3 years after the diagnosis. The majority of these children were diagnosed before the age of 3 years (79 percent). Exclusion of these children from the analyses did not substantially change the results (data not shown). The number of those cases diagnosed before the age of 7 months was 1,486. Exclusion of these children from further analyses did not substantially change the results (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In the present large, population-based study, maternal asthma, short gestational age, and low ponderal index were associated with increased risk of childhood asthma. In addition, young maternal age, smoking, a high number of previous deliveries, and cesarean section were associated with an increased risk of asthma in children diagnosed before the age of 3 years. In children diagnosed at the age of 3 years or later, a high number of previous deliveries was associated with decreased risk of asthma.

There is general consensus on the importance of a genetic component in the development of asthma (27). In the present study, maternal asthma was the strongest predictor for asthma. This is consistent with previous epidemiologic studies reporting that maternal asthma is a risk factor for both early and late-onset wheeze (11, 28–30). It has been suggested that maternal asthma may modify the associations between early environmental exposures, such as day-care attendance (31), and risk of asthma. However, we did not observe any effect modification by maternal asthma.

In the present study, the number of maternal previous deliveries was associated with an increased risk of asthma in children diagnosed before the age of 3 years but with a decreased risk in children diagnosed at the age of 3 years or later. Several studies have reported a decreased risk of hay fever among children with older siblings or attending day care with other children, while results for asthma and wheeze have been more inconsistent (32). Recent large studies have demonstrated that the presence of older siblings is associated with a higher risk during the first years of life (6, 7, 32) but a lower risk of late-onset asthma or wheeze (6, 12, 32). It is possible that respiratory infections from older siblings increase the risk of early transient wheezing symptoms. Development of wheezing or asthma after the age of 3 years may involve atopic mechanisms, when the explanation focuses more on immune maturation or in utero programming (32).

Both planned and emergency cesarean sections were associated with an increased risk of asthma in children diagnosed before the age of 3 years. Previous findings regarding cesarean section and the risk of asthma are contradictory; while some studies have showed that cesarean section is a risk factor for subsequent asthma (33–37), others have failed to find an association (28, 38, 39), and only a few studies have reported results for planned and emergency sections separately (36, 37, 39). It has been hypothesized that an increased risk of asthma in children born by cesarean section could be due to different microbial exposures related to cesarean section and vaginal delivery. The gut microflora in children born by cesarean section differ from those of children born vaginally (40). This might affect the development of allergic diseases, as intestinal microflora play an important role in the development of the immune system (41, 42). However, our results do not fully support this microflora theory, as we did not observe an association between cesarean section and asthma diagnosed at the age of 3 years or later. Another possible mechanism by which cesarean section increases the risk of asthma is that asthma may be predisposed by respiratory problems identified in some newborns born by section (43, 44).

In the present study, prematurity and short gestational age were associated with an increased risk of asthma. These findings are consistent with some (11, 16, 45), although not all (20, 21), previous studies. The prematurity-asthma association has been explained by the fact that prematurity causes reduced lung growth and reduced airway caliber, which may increase wheezing symptoms during respiratory infections and in turn increase asthma diagnoses (16). In addition, prematurity may predispose the child to respiratory tract infections, which would further strengthen these associations. However, caution must be taken when interpreting the results, because distinguishing asthma from the chronic lung disease of infancy caused by prematurity is most challenging. The observation that most premature asthma cases were diagnosed during their first years of life probably reflects these same difficulties in clinical practice. However, exclusion of premature children did not substantially change the results.

In children diagnosed before the age of 3 years, low birth weight was associated with increased risk of asthma. Previous studies on birth weight and the risk of asthma are even more contradictory with both inverse (12) and direct (17, 18), as well as null (7, 19–21), associations being reported. These inconsistent results may in part be due to differences in methodology among the studies, but they may also indicate that the association is only weak or is caused by bias.

The personal identity code system used in Finland gave us the opportunity to link several national registers shown to have nearly complete population coverage and high validity and accuracy (46), thus providing comprehensive information from a large population-based sample. By using the registers, we were also able to avoid recall bias related to questionnaire-based data. Furthermore, the definition of asthma cases can be considered rather reliable, because to have a special reimbursement for antiasthmatic drug costs, it is required that asthma be diagnosed by a physician or a pediatrician. The main limitation of our study is that we could not identify different wheezing phenotypes, especially in the youngest children. Early onset transient wheezing is characteristic of children under 3 years of age (26) and, despite the definition of asthma cases based on physician-diagnosed asthma and information on purchases of certain more potent asthma drugs, we cannot rule out the possibility that some of our asthma cases had only transient wheezing symptoms rather than persistent wheeze or true asthma. However, children with early onset persistent wheeze have been shown more often to have physician-diagnosed asthma in early life than children with early onset transient wheeze (47). Restricting the analysis only to those with potentially more true asthma, that is, several purchases of antiasthmatic drugs, did not substantially change the results. We attempted to investigate the effect of age at onset of asthma on the relation of perinatal factors and risk of asthma by doing separate analyses for children diagnosed before 3 years of age and 3 years of age or later. The diagnosis age-dependent effects in our study may be due to heterogeneity of respiratory symptoms in children under the age of 3 years and difficulty in making a diagnosis of asthma in children at that age compared with the situation in older children. In addition, limitations of relying on the pharmacy records include a rough estimation of drug use; that is, because of the absence of information on actual usage of the dispensed drugs, subjects who failed to take their drugs have been incorrectly classified as users. However, this only dilutes the association and biases the relative risks toward unity.

We conclude that perinatal factors, especially maternal asthma, number of previous deliveries, and gestational age, play a role in the development of asthma in childhood. Although asthma diagnoses before the age of 3 years and at 3 years or later have some common early environmental exposures, our results indicate some differences in the etiologies of asthma diagnosed at these times.


   ACKNOWLEDGMENTS
 
Grants were received from the Yrjö Jahnsson Foundation (grant no. 5663) and the Juho Vainio Foundation.

The authors thank Dr. Raili Salmelin for her contribution to this study.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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