Hindawi Publishing Corporation Journal of Pregnancy Volume 2010, Article ID 789748, 9 pages doi:10.

1155/2010/789748

Research Article Antenatal Steroid Therapy for Fetal Lung Maturation and the Subsequent Risk of Childhood Asthma: A Longitudinal Analysis
Jason D. Pole,1, 2, 3 Cameron A. Mustard,1 Teresa To,1, 3 Joseph Beyene,1, 3, 4 and Alexander C. Allen5
1 Dalla

Lana School of Public Health, University of Toronto, Toronto, ON, Canada M5T 3M7 Oncology Group of Ontario, Toronto, ON, Canada M5G 1V2 3 Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON, Canada M5G 1X8 4 Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, ON, Canada L8N 3Z5 5 Perinatal Epidemiology Research Unit, Departments of Obstetrics and Gynecology and Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada B3K 6R8
2 Pediatric

Correspondence should be addressed to Jason D. Pole, j.pole@utoronto.ca Received 26 January 2010; Accepted 6 April 2010 Academic Editor: Sam Mesiano Copyright 2010 Jason D. Pole et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This study was designed to test the hypothesis that fetal exposure to corticosteroids in the antenatal period is an independent risk factor for the development of asthma in early childhood with little or no eect in later childhood. A population-based cohort study of all pregnant women who resided in Nova Scotia, Canada, and gave birth to a singleton fetus between 1989 and 1998 was undertaken. After a priori specied exclusions, 80,448 infants were available for analysis. Using linked health care utilization records, incident asthma cases developed after 36 months of age were identied. Extended Cox proportional hazards models were used to estimate hazard ratios while controlling for confounders. Exposure to corticosteroids during pregnancy was associated with a risk of asthma in childhood between 35 years of age: adjusted hazard ratio of 1.19 (95% condence interval: 1.03, 1.39), with no association noted after 5 years of age: adjusted hazard ratio for 57 years was 1.06 (95% condence interval: 0.86, 1.30) and for 8 or greater years was 0.74 (95% condence interval: 0.54, 1.03). Antenatal steroid therapy appears to be an independent risk factor for the development of asthma between 3 and 5 years of age.

1. Introduction
Research on the etiology and natural history of asthma has identied a web of predisposing factors (e.g., genetics, atopy), causal factors that may sensitize the airways (e.g., animal dander, dust mites, workplace allergens) and contributing factors (perinatal events such as mode of delivery, exposure to cigarette smoke during pregnancy, gestational age and childhood respiratory infections, air quality, socioeconomic status, and pollution) [16]. Conclusions that can be drawn from this research outline a myriad of exposures and complex interactions in the etiology of pediatric asthma [710]. Given the complex nature of pediatric asthma etiology, factors in the perinatal period that would predispose individuals to asthma are of particular interest [11, 12].

Corticosteroid (CS) therapy, administered during labour and delivery to accelerate fetal lung maturation, has not been fully examined as a potential risk factor for the development of asthma in humans [13]. CS therapy has been shown to alter the development of the fetal lung and has been linked, in animal studies, to changes in brain chemistry and subsequent hypertension later in life [1428]. Complex timedependent relationships between CS therapy and subsequent lung function in animals has been noted [29]. The use of CS therapy, in Canada, among preterm infants before 34 weeks gestation has increased in the last 15 years from less than 25 percent to approximately 60 percent [30, 31]. This increase of CS therapy follows from randomized controlled trial evidence indicating increased infant survival among preterm infants exposed to antenatal CS therapy [32].

2 A limited number of previous studies have investigated lung function (not asthma) in childhood among those previously exposed to CS therapy [3336]. The small sample sizes and convenience samples of these studies do not provide sucient evidence for or against an association between CS therapy and asthma [13]. Therefore, a large populationbased cohort study where confounding by indication can be controlled is warranted. This study was designed to test the hypothesis that fetal exposure to corticosteroids in the antenatal period is an independent risk factor for the development of asthma in childhood. Further, the risk of asthma is hypothesized to be greater in the early childhood years and attenuated in later childhood.

Journal of Pregnancy (ICD-9-CM code 493) were considered to be asthmatic [40]. This denition captures all levels of asthma severity. A second more conservative denition of asthma was developed to examine the potential that the primary definition would be too encompassing and therefore have a high level of misclassication. The conservative denition of asthma was similar to the primary denition except that only interactions where asthma (ICD-CM code 493) was the primary diagnostic eld were considered. The primary exposure of interest is antenatal CS therapy. Maternal systemic steroid therapy is coded in the NSAPD [44]. The rst dose of the rst course of betamethasone or dexamethasone coupled with the timing of the administration is recorded. For this study, infants were considered exposed to CS therapy if either of these drugs was administered regardless of timing. Numerous potential risk factors for childhood asthma have been identied in the literature. Potential confounders considered in this analysis included the infants sex, gestational age at birth, maternal age, one minute Apgar score, administration of surfactant, infants birth weight, delivery by caesarian section, maternal smoking during the gestational period, socio-economic status (SES), hyaline membrane disease, bronchopulmonary dysplasia, maternal insulin dependant diabetes mellitus, gestational diabetes, number of siblings, and year of birth. The infants gestational age at birth, in completed weeks, was examined both continuously and as a dichotomous variable indicating full term/preterm, with full term being 37 or more completed weeks of gestation. Infants born at an early gestational age are at increased risk of poor lung function and preterm labour is often used as an indication for CS therapy [30, 4547]. 2.1. Confounding. Control for confounding by indication was achieved in this study given not all infants who are preterm or low birth weight were exposed to CS therapy and a portion of infants who are full-term or full birth weight will have been exposed. There is a portion of infants in each year of the cohort where the therapy is clinically indicated, but for various reasons not administered (e.g., where mothers presented to the hospital too late). Also, there is a portion of infants in each year of the cohort where the therapy is clinically indicated and administered, but for various reasons delivery was able to be delayed until the infant was delivered full term. Therefore, each year a proportion of preterm and low birth weight infants are unexposed and a portion of full-term infants are exposed to CS therapy allowing for dierences in the development of childhood asthma to be examined. Maternal age was examined continuously. Given maternal age has been shown to be related to preterm birth and related to obstetrical complications leading to the administration of CS, maternal age was only considered as a confounder in this analysis [31, 48]. The infants one minute Apgar score (examined in three categories, 03, 4 6, 710) has been shown to be an independent risk factor for childhood asthma [49]. Delivery by caesarean section

2. Methods
A population-based cohort study of all pregnant women who resided in Nova Scotia, Canada and gave birth to a singleton fetus between January 1, 1989, and December 31, 1998, and lived to discharge was undertaken. Data from The Maternal-Child Health Database (MCHD) were used. The MCHD is a longitudinal population-based database of all mothers and infants delivered while resident in Nova Scotia that is linked to health services utilization data. Four independently collected linked databases comprise the MCHD used in this study including data from the Nova Scotia Atlee Perinatal Database (NSAPD), the Nova Scotia physician visits Medical Services Insurance File database, the Nova Scotia Vital Statistics Database and the Nova Scotia portion of the Canadian Institute for Health Information hospital admissions database. Pregnancies that resulted in the birth of more than one infant (twins, triplets, quadruplets) dier from singleton pregnancies both physiologically and obstetrically and therefore were not eligible for inclusion. Mothers who suer from thyroid conditions (due to higher levels of hormones already present) and mothers experiencing active asthma during the gestational period (due to increased risk of obstetrical complications and the possibility of fetal exposure to steroids because of the pharmaceutical interventions used to manage the mothers asthma) were also excluded [3739]. Previous work in Canada has established that health service administrative records can be used to identify and describe children with asthma [4043]. The denition of asthma employed in this study was based on this previous work, determined by examining physician visits or hospitalizations where the primary diagnostic eld was for asthma or asthma-like conditions (asthma: ICD-9-CM code 493, bronchitis: ICD-9-CM code 490, or bronchiolitis: ICD9-CM code 466). Subjects who experienced at least two health care interactions in any 365 day period, starting at 156 weeks post birth (3 years), where the diagnosis was asthma or an asthma-like condition and at least one visit was not in the winter period (December to March inclusive), or experienced one hospitalization specically for asthma

Journal of Pregnancy was examined as a dichotomous variable where, regardless of other obstetrical interventions during delivery (e.g., the use of forceps prior to surgery), if the infant was ultimately born by caesarean section it was considered a caesarean section. Delivery by caesarean section is related to CS therapy and CS therapy has been shown to be associated with poor lung function in the infant [49, 50]. Maternal smoking during pregnancy was examined as a dichotomous variable. Cigarette exposure during the gestational period has been shown to be related to the development of childhood asthma and risk of obstetrical complications (including prematurity) that are related to the administration of CS [47, 5156]. Dierences in the complication rate and the potential for threatened preterm labour is increased when the mother is diagnosed with either type 1 diabetes mellitus or gestational diabetes. Hyaline membrane disease is a respiratory condition in the infant that is often associated with preterm delivery and subsequent morbidity. CS therapy was primarily instituted to ameliorate this disease. However, the administration of surfactant to alleviate various respiratory diculties in the infant after birth, such as hyaline membrane disease, has been shown to be related to both long term lung function and the use of CS therapy [5760]. Due to the declining incidence of asthma over the time period under study, the year of birth was used to control for birth cohort eects (temporal eects). A greater number of older siblings in a household has been shown to be associated with reduced risk of childhood asthma and forms part of the basis for the hygiene hypothesis [6163]. Also related to the hygiene hypothesis is the socioeconomic status of the infants family [64, 65]. Mothers who are of low socioeconomic status are also more likely to have various pregnancy complications that include threatened preterm labour [66]. Therefore, two socioeconomic status measures were used in this study. Marital status at the time of delivery (married or common law versus single, widowed, divorced, or separated) and quintiles of neighbourhood income (based on the postal code of residence at the time of delivery). 2.2. Analysis. Extended Cox proportional hazards regression models were used to analyse the data [67]. Time zero was recorded as the date of birth. Duration of follow-up was measured in weeks. Subjects were censored the week they were identied as having asthma, died or were lost to followup. Given the outcome of asthma was not considered before 156 weeks the minimum amount of follow-up time required to be included in this analysis was therefore 156 weeks. A Cox proportional hazards regression stratied by antenatal steroid therapy was utilized to assess the time dependant hazard comparing subjects that received and did not receive steroid therapy. A kernel smoothing method was utilized to remove the extreme variability in the time-specic hazard estimates [68, 69]. Given that one mother may give birth to more than one infant in the cohort an examination of robust variance estimates was undertaken using a sandwich estimator. The

3 nonindependence altered the variance estimates by less than 5 percent so no consideration of this nonindependence was given in subsequent analysis. To quantitatively assess if the hazard ratio for the association between exposure to antenatal corticosteroids and the subsequent development of asthma changes with time, an extended Cox proportional hazards regression with time-dependant covariates was used. The eect of steroid administration through time was described by three hazard ratios; one when time was between 156 and 260 weeks, one when time was between 261 and 364 weeks and one when time was greater than 364 weeks. These time periods were selected based on an examination of the smoothed gure derived from the stratied Cox model. All potential confounders were examined with nested models with the time-dependant covariates for steroid administration. Each potential confounders eect on the parameter estimates for antenatal steroid therapy (early, mid and late) was assessed by examining the percentage dierence in the parameter estimates from a model with and without the potential confounder. Dierences larger than 10 percent in any one of the parameter estimates was considered evidence of confounding [70]. Potential cofounders that did not demonstrate evidence of confounding were not retained in the nal models. Thus, the statistical model for the nal analysis was as follows: h(t , X (t )) = h0 (t ) exp 1 (steroid)g1 (t ) + 2 (steroid)g2 (t ) +3 (steroid)g3 (t ) + x , (1) where g1 ( t ) = g2 ( t ) = g3 ( t ) = 1 if 156 < t 260 weeks, 0 if t < 260 weeks, 1 if 261 t 364 weeks, 0 if t < 261 or t > 364 weeks, 1, 0, if t 365 weeks, if t < 365 weeks,

(2)

x = x other covariates. All statistical analyses were performed using SAS version 8.2.

3. Results
There were a total of 113,145 births between January 1, 1989, and December 31, 1998, in Nova Scotia. Exclusions included 1,325 fetal, neonatal or infant deaths that occurred before 1 year of age, 2,408 infants who were delivered from a multiple gestation, 4,958 infants who were born to mothers experiencing active asthma during the gestational period and a further 89 infants were excluded because they were born to mothers experiencing endocrine abnormalities.

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Table 1: Descriptive characteristics of the study sample by asthma status. Asthma No % Total Birth year 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 Antenatal steroid exposure Number of siblings 0 1 2 3+ Preterm birth (<37 weeks) Caesarean section Income Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 Surfactant administration 1 Minute Apgar score 03 46 710 Maternal smoking Married/Common law Hyaline membrane disease Bronchopulmonary dysplasia Duration: weeks (mean, SD) Birth weight: grams (mean, SD) Gestational age: weeks (mean, SD) Maternal age: years (mean, SD) Num 59,975 3,823 5,816 5,671 6,020 6,135 6,524 6,503 6,793 6,465 6,225 773 25,916 21,753 8,691 3,608 2,534 10,873 12,693 12,619 11,368 12,435 9,873 139 1,309 4,375 54,070 16,421 42,671 672 97 512.3 3,487.4 39.5 26.7 Row 74.6 65.1 66.5 67.2 71.7 74.0 75.9 77.4 80.7 81.8 84.3 68.1 72.2 75.1 78.1 80.7 68.1 71.9 73.6 74.3 75.2 74.6 75.7 59.9 70.4 71.9 74.9 72.6 74.6 62.3 54.2 155.3 554.7 1.7 5.3 Column 100.0 6.4 9.7 9.5 10.0 10.2 10.9 10.8 11.3 10.8 10.4 1.3 43.2 36.3 14.5 6.0 4.2 18.1 21.5 21.4 19.3 21.1 16.7 0.2 2.2 7.3 90.5 27.4 71.1 1.1 0.2 Num 20,473 2,051 2,931 2,773 2,374 2,152 2,067 1,896 1,629 1,440 1,160 362 9,972 7,199 2,435 864 1,189 4,253 4,547 4,359 3,749 4,235 3,174 93 550 1,712 18,137 6,211 14,566 406 82 287.2 3,444.3 39.3 26.4 Row 25.4 34.9 33.5 32.8 28.3 26.0 24.1 22.6 19.3 18.2 15.7 31.9 27.8 24.9 21.9 19.3 31.9 28.1 26.4 25.7 24.8 25.4 24.3 40.1 29.6 28.1 25.1 27.4 25.4 37.7 45.8 116.6 592.1 1.9 5.2 Yes % Column 100.0 10.0 14.3 13.5 11.6 10.5 10.1 9.3 8.0 7.0 5.7 1.8 48.7 35.2 11.9 4.2 5.8 20.8 22.7 21.7 18.7 21.1 15.8 0.5 2.7 8.4 88.9 30.3 71.1 2.0 0.4

Journal of Pregnancy

Total Num 80,448 5,874 8,747 8,444 8,394 8,287 8,591 8,399 8,422 7,905 7,385 1,135 35,888 28,952 11,126 4,472 3,723 15,126 17,240 16,978 15,117 16,670 13,047 232 1,859 6,087 72,207 22,632 57,237 1,078 179 455.0 3,476.5 39.4 26.6 % 100.0 7.3 10.9 10.5 10.4 10.3 10.7 10.4 10.5 9.8 9.2 1.4 44.6 36.0 13.8 5.6 4.6 18.8 21.4 21.1 18.8 20.7 16.2 0.3 2.3 7.6 89.8 28.1 71.1 1.3 0.2 176.2 564.7 1.7 5.3

Note: All totals do not add to grand total given missing values for some variables. Percent of total cohort.

There were 104,365 infants eligible for record linkage. Birth records for 18,627 infants could not be successfully linked to the health care follow-up data due to errors or missing information with the provincial unique identier. Due to deaths, migration, and other events an additional

3,484 infants did not have 156 or more weeks of followup time. A further 1,671 infants did not have either a birth weight or gestational age recorded (which is required for the analysis), 135 infants were greater than or less than three standard deviations from their mean sex-specic birth

Journal of Pregnancy
Table 2: Rates of antenatal steroid therapy administration and preterm birth by year of birth. Total births Preterm Num Year of birth 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 Total 5,874 8,747 8,444 8,394 8,287 8,591 8,399 8,422 7,905 7,385 80,448 Num 26 49 58 79 69 68 78 99 106 99 731 Rate 109.24 129.63 164.31 201.02 195.47 181.82 186.16 235.71 261.08 254.50 196.35 Num 18 18 28 40 36 48 34 46 60 76 404 Steroid administration Full term Rate 3.19 2.15 3.46 5.00 4.54 5.84 4.26 5.75 8.00 10.86 5.27 Preterm birth Num Rate 238 378 353 393 353 374 419 420 406 389 3,723 40.52 43.21 41.80 46.82 42.60 43.53 49.89 49.87 51.36 52.67 46.28

Note: Rate is per 1,000 births.

weight for gestational age and therefore were excluded. This left 80,448 infants for analysis. Table 1 provides descriptive statistics for the study sample by asthma status. Both a row and column percentage is provided to assist in the interpretation of the relationships. The asthma incidence among birth cohorts peaked in 1989 and has been on a decline since. The number of siblings, income, marital status, mean birth weight, mean gestational age and mean maternal age at birth are similar between asthmatics and nonasthmatics. Infants born preterm had an elevated incidence of asthma over the follow-up period. As expected, children who developed asthma had higher prevalence of caesarean section, surfactant administration, maternal smoking, hyaline membrane disease and bronchopulmonary dysplasia compared to children who did not develop asthma. The median overall follow-up time was nearly 8.5 years (440 weeks). On average asthma developed in this cohort at approximately 5.5 years of age (287 weeks). Table 2 provides the rates of antenatal steroid therapy administration and preterm birth by year of birth. The use of antenatal steroid therapy increased 3-fold over the 10-year time period of the study, from a rate of 7.5 in 1989 to 23.7 per 1,000 births in 1998. The preterm birth rate increased approximately 30 percent over the same period, from a rate of 40.5 in 1989 to 52.7 per 1,000 live births in 1998. Figure 1 provides the smoothed adjusted hazard function over time, stratied by antenatal steroid therapy. Adjustments were made for the infants sex, gestational age at birth and year of birth. Given the smoothing algorithm used a bandwidth of 75 weeks, the tales of the curves have not been estimated. The gure provides evidence that the hazard for developing asthma diers by antenatal steroid therapy dependant on time. The dierence is greatest in the early period, diminishing over the middle period with little dierences noted beyond 7 years (400 weeks). Table 3 contains the estimated adjusted hazard ratios for the development of asthma for antenatal steroid therapy from 3 to 5, 6 to 7 and 8, or greater years of age along

104

18 16 14 12 10 8 6 4 2 0 200 300 400 500 600 700 Time in weeks (bandwidth = 75) 800

Hazard Function

Steroids No Yes

Figure 1: Smoothed Hazard Function Estimates by Antenatal Steroid Therapy. Note: Adjusted for gender, gestational age and year of birth.

with the estimates for all other confounders in the model. Adjustments were made for infants sex, gestational age at birth and an indicator for perterm birth, one minute Apgar score, administration of surfactant, infants birth weight, delivery by caesarian section, maternal smoking during the gestational period, hyaline membrane disease, bronchopulmonary dysplasia, number of siblings and year of birth. Unadjusted hazard ratio estimates are also provided for the antenatal steroid exposure. The eect of antenatal steroid therapy on the development of asthma is seen to be larger in early childhood (HR = 1.19, 95% CI: 1.03, 1.39) with no eect noted in mid childhood (HR = 1.06, 95% CI: 0.86, 1.30) and potentially a protective eect in late childhood (HR = 0.74, 95% CI: 0.54, 1.03). When considering the more conservative denition of asthma the prevalence of asthma dropped from 25.4% to 18.0%. The estimated adjusted hazard ratios for the

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Table 3: Association between antenatal steroid therapy exposure and childhood asthma. Adjusted HR Antenatal steroid exposure 35 years 67 years 8+ years Male gender Preterm birth (<37 weeks) Number of siblings 0 1 2 3+ Bronchopulmonary Dysplasia Hyaline Membrane Disease Surfactant Administration 1 Minute Apgar Score 03 46 710 Caesarean section Maternal smoking Birth weight (per 500 grams) Gestational age (weeks) Birth year 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998
Note: Adjustment for all other confounders in table.

Journal of Pregnancy

Unadjusted 95% CI 1.031.39 0.861.30 0.541.03 1.211.28 0.951.12 0.880.93 0.740.82 0.620.72 0.741.31 1.011.30 0.821.40 0.861.05 0.790.95 1.071.15 1.091.16 0.981.01 0.960.98 1.371.59 1.351.56 1.391.60 1.191.37 1.121.30 1.061.23 1.041.20 0.921.07 0.951.11 HR 1.55 1.36 0.98 95% CI 1.361.77 1.121.65 0.721.34

1.19 1.06 0.74 1.24 1.03 1.00 0.90 0.78 0.67 0.98 1.14 1.07 1.00 0.95 0.87 1.11 1.12 1.00 0.97 1.47 1.45 1.49 1.28 1.21 1.14 1.12 0.99 1.02 1.00

development of asthma for antenatal steroid therapy from 3 to 5, 6 to 7 and 8 or greater years of age were HR = 1.37 (95% CI: 1.15, 1.62), HR = 1.17 (95% CI: 0.93, 1.49) and HR = 0.92 (95% CI: 0.67, 1.26), respectively. Adjustments were made for the same confounders as in the main model.

4. Discussion
Antenatal steroid therapy appears to be an independent risk factor for the development of childhood asthma after controlling for confounding. The risk appears to be timedependent with the highest risk early in childhood and diminishing as the child ages. The reasons for this increase

risk are not obvious but many animal studies have established latent eects of corticosteroid exposure in utero. Although a mechanistic link between antenatal corticosteroid therapy and the onset of asthma in childhood has not been fully established [71], wide ranging eects of corticosteroid therapy have been demonstrated. The alteration in brain chemistry and hypothalamic-pituitary-adrenal (HPA) axis, the shift in immune function and other wide-ranging latent eects such as changes in kidney development and subsequent hypertension all provide biological plausibility for a link to childhood asthma. Time-dependent complications associated with antenatal corticosteroid therapy have been demonstrated [15, 16]. Corticosteroids have been shown to aect HPA development in primates, sheep and to a limited extent in humans [1720].

Journal of Pregnancy The HPA axis is important in regulating the physical growth and organ development of the neonate [18]. The timing of exposure to corticosteroids within a species, late in gestation, has been shown by Matthews to be critical with regard to the eect on the HPA axis [17, 21]. Published and unpublished work by Clifton in Australia indicates that corticosteroid exposure not only alters the HPA axis but also inuences the Th1/Th2 ratio in favour of Th2 [72]. Strengths of this study are rooted in the large population cohort that were assembled and followed for extended lengths of time. The availability of potential confounders for control was extensive. Control for confounding by indication was also inherent in this study design providing considerable methodological strength. The retrospective nature of this study design has a number of limitations. The reliability and validity of an asthma diagnosis in the MSI data is unknown. Errors in the primary reason for admission in the CIHI Hospital Discharge Data may occur when several competing causes of admission are present in any one individual. Errors of this sort, with both databases, would have a conservative eect on the estimate of association generated in this study. When considering the more conservative denition of asthma the pattern of early childhood risk for the development of asthma after antenatal exposure to corticosteroids remains the same as with the main asthma denition. As expected with this denition the risk estimate, particularly in the early childhood period is greater. This sensitivity analysis lends credence to the hazard ratio estimates using the main asthma denition. Limitations in the measure of exposure exist, in that there is no measure of the CS that crosses the placenta and is biologically available to each fetus. Information that pertains to multiple exposure to CS therapy and the actual amount of medication administered is not recorded in the NSAPD. With all data limitations outlined, bias would only result if there was a systematic dierence between those exposed to CS therapy and those not exposed. There is no indication that physician billing or hospital discharge records would be dierent based on exposure. Given that this study is focussed on mothers and infants from the province of Nova Scotia, Canada, any ndings from this current study would need to be replicated in other populations to strengthen external validity. Although no factors specically related to the biological eects of CS therapy are postulated to dier between this population and others, other factors related to childhood asthma may dier. The trend in asthma incidence by birth year for this population appears to be dierent than that of other populations and therefore replication of these ndings in dierent populations is warranted. Continued research into the perinatal factors in the etiology of childhood asthma is warranted. Information continues to surface that draws attention to the potential long term consequences of exposures in utero and subsequent disease risk. Cohort studies that examine the time-dependant eects are crucial in establishing periods of disease susceptibility. Although only a small, but signicant, elevated risk for childhood asthma and antenatal steroid exposure was

7 demonstrated in the current study, further research into the smallest possible dose required for the steroid to achieve the desired post-natal eect could be undertaken potentially limiting the long term consequences such as childhood asthma.

Acknowledgments
The authors acknowledge the operational funding from the Canadian Institutes of Health Research (CIHR) (Funding Reference no. MOP-77693) and the Allergy, Genes and Environment Network (AllerGen NCE Inc.) (Project no. FP2005-1). Dr. J. D. Pole contributed to the conception of the study, study design, analysis, and interpretation of the data, editorial preparation, and review of the manuscript. Dr. J. D. Pole also had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs. C. A. Mustard, T. To, J. Beyene and A. C. Allen contributed to the study design, interpretation of the data, editorial preparation and review of the manuscript. All authors have no conict of interest or nancial interests related to this study. This work was funded by and operating grant from the Canadian Institutes of Health Research and the AllerGen Networks of Centres of Excellence.

References
[1] The National Asthma Control Task Force, The Prevention and Management of Asthma in Canada: A Major Challenge Now and in the Future, Health Canada, Ottawa, Canada, 2000. [2] W. Cookson, Genetic factors in asthma, Advances in Experimental Medicine and Biology, vol. 409, pp. 5560, 1996. [3] C. E. Donovan and P. W. Finn, Immune mechanisms of childhood asthma, Thorax, vol. 54, no. 10, pp. 938946, 1999. [4] J. P. Hanrahan and M. Halonen, Antenatal interventions in childhood asthma, European Respiratory Journal, Supplement, vol. 12, no. 27, pp. 46s51s, 1998. [5] W. W. Busse, Determinants of risk factors for asthma, Canadian Respiratory Journal, vol. 6, no. 1, pp. 97101, 1999. [6] A. J. Sandford and P. D. Pare, The genetics of asthma: the important questions, American Journal of Respiratory and Critical Care Medicine, vol. 161, no. 3, part 2, pp. S202S206, 2000. [7] M. I. Asher, Worldwide variations in the prevalence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC), European Respiratory Journal, vol. 12, no. 2, pp. 315335, 1998. [8] A. L. Wright, Epidemiology of asthma and recurrent wheeze in childhood, Clinical Reviews in Allergy and Immunology, vol. 22, no. 1, pp. 3344, 2002. [9] A. H. Liu and S. J. Szeer, Advances in childhood asthma: hygiene hypothesis, natural history, and management, Journal of Allergy and Clinical Immunology, vol. 111, no. 3, pp. S785S792, 2003. [10] M. A. Brown and M. Halonen, Perinatal events in the development of asthma, Current Opinion in Pulmonary Medicine, vol. 5, no. 1, pp. 49, 1999. [11] C. A. Jones, J. A. Holloway, and J. O. Warner, Does atopic disease start in foetal life? Allergy, vol. 55, no. 1, pp. 210, 2000.

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[12] J. A. Warner, A. C. Jones, E. A. Miles, B. M. Colwell, and J. O. Warner, Prenatal origins of asthma and allergy, CIBA Foundation Symposium, no. 206, pp. 220232, 1997. [13] A. H. Jobe, Glucocorticoids in perinatal medicine: misguided rockets? Journal of Pediatrics, vol. 137, no. 1, pp. 13, 2000. [14] J. D. Merrill and R. A. Ballard, Antenatal hormone therapy for fetal lung maturation, Clinics in Perinatology, vol. 25, no. 4, pp. 983997, 1998. [15] C. J. Lanteri, K. E. Willet, S. Kano, et al., Time course of changes in lung mechanics following fetal steroid treatment, American Journal of Respiratory and Critical Care Medicine, vol. 150, no. 3, pp. 759765, 1994. [16] A. H. Jobe, Glucocorticoids, inammation and the perinatal lung, Seminars in Neonatology, vol. 6, no. 4, pp. 331342, 2001. [17] S. G. Matthews, Antenatal glucocorticoids and programming of the developing CNS, Pediatric Research, vol. 47, no. 3, pp. 291300, 2000. [18] J. R. G. Challis, S. G. Matthews, W. Gibb, and S. J. Lye, Endocrine and paracrine regulation of birth at term and preterm, Endocrine Reviews, vol. 21, no. 5, pp. 514550, 2000. [19] S. G. Matthews, Early programming of the hypothalamopituitary-adrenal axis, Trends in Endocrinology and Metabolism, vol. 13, no. 9, pp. 373380, 2002. [20] S. G. Matthews, Antenatal glucocorticoids and the developing brain: mechanisms of action, Seminars in Neonatology, vol. 6, no. 4, pp. 309317, 2001. [21] F. Dean and S. G. Matthews, Maternal dexamethasone treatment in late gestation alters glucocorticoid and mineralocorticoid receptor mRNA in the fetal guinea pig brain, Brain Research, vol. 846, no. 2, pp. 253259, 1999. [22] M. Dodic, A. Peers, J. P. Coghlan, and M. Wintour, Can excess glucocorticoid, in utero, predispose to cardiovascular and metabolic disease in middle age, Trends in Endocrinology and Metabolism, vol. 10, no. 3, pp. 8691, 1999. [23] M. Dodic, T. Abouantoun, A. OConnor, E. M. Wintour, and K. M. Moritz, Programming eects of short prenatal exposure to dexamethasone in sheep, Hypertension, vol. 40, no. 5, pp. 729734, 2002. [24] M. Dodic, K. Moritz, I. Koukoulas, and E. M. Wintour, Programmed hypertension: kidney, brain or both? Trends in Endocrinology and Metabolism, vol. 13, no. 9, pp. 403408, 2002. [25] K. M. Moritz, M. Dodic, and E. M. Wintour, Kidney development and the fetal programming of adult disease, BioEssays, vol. 25, no. 3, pp. 212220, 2003. [26] M. Dodic, V. Hantzis, J. Duncan, et al., Programming eects of short prenatal exposure to cortisol, The FASEB Journal, vol. 16, no. 9, pp. 10171026, 2002. [27] M. Dodic, R. Baird, V. Hantzis, et al., Organs/systems potentially involved in one model of programmed hypertension in sheep, Clinical and Experimental Pharmacology and Physiology, vol. 28, no. 11, pp. 952956, 2001. [28] M. Dodic, E. M. Wintour, J. A. Whitworth, and J. P. Coghlan, Eect of steroid hormones on blood pressure, Clinical and Experimental Pharmacology and Physiology, vol. 26, no. 7, pp. 550552, 1999. [29] S. G. Kallapur, B. W. Kramer, T. J. M. Moss, et al., Maternal glucocorticoids increase endotoxin-induced lung inammation in preterm lambs, American Journal of Physiology, vol. 284, no. 4, pp. L633L642, 2003. [30] S. K. Lee, D. D. McMillan, A. Ohlsson, et al., Variations in practice and outcomes in the Canadian NICU network: 19961997, Pediatrics, vol. 106, no. 5, pp. 10701079, 2000.

Journal of Pregnancy
[31] A. Allen, R. Attenborough, L. Dodds, E. Luther, and J. Pole, Perinatal Care in Nova Scotia: 1988 to 1995, The Reproductive Care Program of Nova Scotia, Nova Scotia, Canada, 1996. [32] J. Crane, A. Armson, M. Brunner, et al., Antenatal corticosteroid therapy for fetal maturation, Journal of Obstetrics and Gynaecology Canada, vol. 25, no. 1, pp. 4552, 2003. [33] L. W. Doyle, G. W. Ford, A. L. Rickards, et al., Antenatal corticosteroids and outcome at 14 years of age in children with birth weight less than 1501 grams, Pediatrics, vol. 106, no. 1, p. E2, 2000. [34] H. Smolders-de Haas, J. Neuvel, B. Schmand, P. E. Treers, J. G. Koppe, and J. Hoeks, Physical development and medical history of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome: a 10to 12-year follow-up, Pediatrics, vol. 86, no. 1, pp. 6570, 1990. [35] W. Wiebicke, A. Poynter, and V. Chernick, Normal lung growth following antenatal dexamethasone treatment for respiratory distress syndrome, Pediatric Pulmonology, vol. 5, no. 1, pp. 2730, 1988. [36] L. W. Doyle, M. M. H. Cheung, G. W. Ford, A. Olinsky, N. M. Davis, and C. Callanan, Birth weight <1501 g and respiratory health at age 14, Archives of Disease in Childhood, vol. 84, no. 1, pp. 4044, 2001. [37] J. D. Pole, C. A. Mustard, T. To, J. Beyene, and A. C. Allen, Antenatal steroid therapy for fetal lung maturation: is there an association with childhood asthma? Journal of Asthma, vol. 46, no. 1, pp. 4752, 2009. [38] S. Alexander, L. Dodds, and B. A. Armson, Perinatal outcomes in women with asthma during pregnancy, Obstetrics and Gynecology, vol. 92, no. 3, pp. 435440, 1998. [39] S. W. Wen, K. Demissie, and S. Liu, Adverse outcomes in pregnancies of asthmatic women: results from a Canadian population, Annals of Epidemiology, vol. 11, no. 1, pp. 712, 2001. [40] A. L. Kozyrskyj, C. A. Mustard, and A. B. Becker, Identifying children with persistent asthma from health care administrative records, Canadian Respiratory Journal, vol. 11, no. 2, pp. 141145, 2004. [41] L. Huzel, L. L. Roos, N. R. Anthonisen, and J. Manfreda, Diagnosing asthma: the t between survey and administrative database, Canadian Respiratory Journal, vol. 9, no. 6, pp. 407412, 2002. [42] A. L. Kozyrskyj, C. A. Mustard, and A. B. Becker, Childhood wheezing syndromes and healthcare data, Pediatric Pulmonology, vol. 36, no. 2, pp. 131136, 2003. [43] T. To, S. Dell, P. Dick, et al., Burden of Childhood Asthma, Institute for Clinical Evaluative Sciences, Toronto, Canada, 2004. [44] The Reproductive Care Program of Nova Scotia, Nova Scotia Atlee Perinatal Database Coding Manual, The Reproductive Care Program of Nova Scotia, Nova Scotia, Canada, 7th edition, 2000. [45] R. Beasley, P. Leadbitter, N. Pearce, and J. Crane, Is enhanced fetal growth a risk factor for the development of atopy or asthma? International Archives of Allergy and Immunology, vol. 118, no. 24, pp. 408410, 1999. [46] W. H. James, Handedness, birth weight, mortality and Barkers hypothesis, Journal of Theoretical Biology, vol. 210, no. 3, pp. 345346, 2001. [47] J. F. Oliveti, C. M. Kercsmar, and S. Redline, Pre- and perinatal risk factors for asthma in inner city AfricanAmerican children, American Journal of Epidemiology, vol. 143, no. 6, pp. 570577, 1996.

Journal of Pregnancy
[48] F. Rusconi, C. Galassi, G. M. Corbo, et al., Risk factors for early, persistent, and late-onset wheezing in young children. SIDRIA Collaborative Group, American Journal of Respiratory and Critical Care Medicine, vol. 160, no. 5, part 1, pp. 1617 1622, 1999. [49] B. Xu, J. Pekkanen, and M.-R. Jarvelin, Obstetric complications and asthma in childhood, Journal of Asthma, vol. 37, no. 7, pp. 589594, 2000. [50] B. Xu, J. Pekkanen, A. L. Hartikainen, and M. R. Jarvelin, Caesarean section and risk of asthma and allergy in adulthood, Journal of Allergy and Clinical Immunology, vol. 107, no. 4, pp. 732733, 2001. [51] J. Chen and W. J. Millar, Birth outcome, the social environment and child health, Health Reports, vol. 10, no. 4, pp. 57 67, 1999. [52] C. Infante-Rivard, D. Gautrin, J. L. Malo, and S. Suissa, Maternal smoking and childhood asthma, American Journal of Epidemiology, vol. 150, no. 5, pp. 528531, 1999. [53] D. R. Gold, H. A. Burge, V. Carey, D. K. Milton, T. Platts-Mills, and S. T. Weiss, Predictors of repeated wheeze in the rst year of life: the relative roles of cockroach, birth weight, acute lower respiratory illness, and maternal smoking, American Journal of Respiratory and Critical Care Medicine, vol. 160, no. 1, pp. 227236, 1999. [54] C. Dezateux, J. Stocks, I. Dundas, and M. E. Fletcher, Impaired airway function and wheezing in infancy: the inuence of maternal smoking and a genetic predisposition to asthma, American Journal of Respiratory and Critical Care Medicine, vol. 159, no. 2, pp. 403410, 1999. [55] S. M. Stick, P. R. Burton, L. Gurrin, P. D. Sly, and P. N. LeSouef, Eects of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants, The Lancet, vol. 348, no. 9034, pp. 10601064, 1996. [56] R. I. Ehrlich, D. Du Toit, E. Jordaan, et al., Risk factors for childhood asthma and wheezing: importance of maternal and household smoking, American Journal of Respiratory and Critical Care Medicine, vol. 154, no. 3, part 1, pp. 681688, 1996. [57] L. R. Blackmon, E. F. Bell, W. A. Engle, et al., Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants, Pediatrics, vol. 109, no. 2, pp. 330338, 2002. [58] R. F. Soll, Early postnatal dexamethasone therapy for the prevention of chronic lung disease, Pediatrics, vol. 108, no. 3, pp. 741748, 2001. [59] A. H. Jobe and M. Ikegami, Lung development and function in preterm infants in the surfactant treatment era, Annual Review of Physiology, vol. 62, pp. 825846, 2000. [60] M. A. A. Moussa, M. B. Skaik, O. Y. Yaghy, S. B. Salwanes, and S. A. Bin-Othman, Factors associated with asthma in school children, European Journal of Epidemiology, vol. 12, no. 6, pp. 583588, 1996. [61] W. Nystad, Daycare attendance, asthma and atopy, Annals of Medicine, vol. 32, no. 6, pp. 390396, 2000. [62] T. M. Ball, J. A. Castro-Rodriguez, K. A. Grith, C. J. Holberg, F. D. Martinez, and A. L. Wright, Siblings, daycare attendance, and the risk of asthma and wheezing during childhood, The New England Journal of Medicine, vol. 343, no. 8, pp. 538543, 2000. [63] C. Infante-Rivard, D. Amre, D. Gautrin, and J. L. Malo, Family size, day-care attendance, and breastfeeding in relation to the incidence of childhood asthma, American Journal of Epidemiology, vol. 153, no. 7, pp. 653658, 2001.

9
[64] J. T. Chen, N. Krieger, S. K. Van Den Eeden, and C. P. Quesenberry, Dierent slopes for dierent folks: socioeconomic and racial/ethnic disparities in asthma and hay fever among 173,859 U.S. men and women, Environmental Health Perspectives, vol. 110, no. 2, pp. 211216, 2002. [65] Y. Chen, R. Dales, and D. Krewski, Asthma and the risk of hospitalization in Canada: the role of socioeconomic and demographic factors, Chest, vol. 119, no. 3, pp. 708713, 2001. [66] S. Lewis, D. Richards, J. Bynner, N. Butler, and J. Britton, Prospective study of risk factors for early and persistent wheezing in childhood, European Respiratory Journal, vol. 8, no. 3, pp. 349356, 1995. [67] D. G. Kleinbaum and M. Klein, Survival Analysis: A SelfLearning Text, Springer, New York, NY, USA, 2nd edition, 2005. [68] H. Ramlau-Hansen, Smoothing counting process intensities by means of Kernel functions, The Annals of Statistics, vol. 11, no. 2, pp. 453466, 1983. [69] P. D. Allison, Survival Analysis Using SAS: A Practical Guide, SAS Institute, Cary, NC, USA, 1995. [70] K. J. Rothman and S. Greenland, Modern Epidemiology, Lippincott-Raven, Philadelphia, Pa, USA, 2nd edition, 1998. [71] J. D. Pole, C. A. Mustard, T. To, J. Beyene, and A. C. Allen, Antenatal steroid therapy and childhood asthma: is there a possible link? Medical Hypotheses, vol. 70, no. 5, pp. 981989, 2008. [72] S. L. Prescott and V. Clifton, Asthma and pregnancy: emerging evidence of epigenetic interactions in utero, Current Opinion in Allergy and Clinical Immunology, vol. 9, no. 5, pp. 417426, 2009.