Antenatal steroid therapy and childhood asthma: Is there a possible link?

Medical Hypotheses (2008) 70, 981–989

http://intl.elsevierhealth.com/journals/mehy

Antenatal steroid therapy and childhood asthma: Is there a possible link? Jason D. Pole a,b,c,*, Cameron A. Mustard Joseph Beyene a,c, Alexander C. Allen d

a,b

, Teresa To

a,c

,

a

Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada Institute for Work and Health, Toronto, Ontario, Canada c Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada d Perinatal Epidemiology Research Unit, Departments of Obstetrics and Gynecology and Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada b

Received 15 May 2007; accepted 17 July 2007

Summary This paper presents a hypothesis that fetal exposure to corticosteroids is an independent risk factor for the development of asthma in childhood. The prevalence of childhood asthma saw a dramatic rise from the 1980s up until the early 2000s. Among the explanations for the increase in asthma prevalence included interest in exposures arising in the gestational period. Overlapping the time period of the increasing prevalence of childhood asthma is the increased use of antenatal corticosteroid therapy for fetal lung maturation. Through an examination of the published literature, a time dependent association between year of birth (and hence exposure to the antenatal corticosteroids) and the relationship between preterm birth and childhood asthma is noted. A brief review of the trends in the prevalence of asthma, the use of antenatal corticosteroids including their established latent effects and the time dependant association between preterm birth and the risk of childhood asthma are provided. c 2007 Elsevier Ltd. All rights reserved.



Background Rapid increases in the prevalence of childhood asthma from the mid 1980s to the early 2000s has renewed research interest in understanding environmental factors in the etiology of asthma. The * Corresponding author. Address: Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario Canada. E-mail address: [email protected] (J.D. Pole).



relative contributions of specific causes of this increase in disease prevalence are unclear. Given the complex nature of the etiology of asthma coupled with an onset of the disease in childhood, factors in the peripartum period that would predispose individuals to asthma are of particular interest [1]. 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

0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.07.049

982 humans [2]. 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 [3,4]. The use of CS therapy, in Canada, among preterm infants before 34 weeks gestation has increased in the last 15 years [5,6]. This increase in the use of CS therapy supported by the results of several randomized controlled trials that clearly indicated increased infant survival among preterm infants exposed to antenatal CS therapy [7–9]. Similar trends in the use of corticosteroids have been seen in other developed nations [8,10,11]. Coupled with this increase in CS therapy is a rise in the incidence of preterm birth (birth before 37 completed weeks of gestation). In Canada, the preterm birth rate increased over 15% from 1981 to 1997 (preterm birth rate of 6.25% in 1981 and 7.19% in 1997) [12]. Similar trends have been reported for other countries [12]. Therefore, mothers with threatened preterm labour before 34 weeks gestation are usually routinely offered CS therapy to prevent neonatal complications such as hyaline membrane disease. Given the overlapping time period in the increase in prevalence of childhood asthma and the increased use of antenatal steroid therapy during the same time period, it is hypothesized that fetal exposure to corticosteroids in the antenatal period is an independent risk factor for the development of asthma in childhood. The objective of this paper is to develop this argument more fully and present evidence from the published literature to support this newly proposed hypothesis.

Trends in childhood asthma Time trends in the prevalence of asthma in developed nations demonstrated an increase in prevalence from the 1970s through to the turn of the century [13–15]. Since the early 2000s, reports of a levelling-off of the prevalence has been noted in many world-wide locations [15–20] although reports of a plateau in prevalence are not reported in every jurisdiction or among every study population [15,21]. Several hypotheses have been put forward to describe the increase in prevalence, ranging from increased diagnosis and case-finding to changes in environmental conditions, including reduced exposure to infectious pathogens at an early age [22–29]. Socioeconomic characteristics such as family income and parents education, geography (urban/rural locations), birth order, sex, gestational age, genetic factors, anthropometric measures, maternal smoking and maternal age at

Pole et al. birth have been found to influence the risk of childhood asthma [22–24,30–42].

Peripartum exposures and risk of childhood asthma Given the complex nature of asthma etiology coupled with an onset of the disease in childhood, factors in the peripartum period that would predispose individuals to asthma are of particular interest [28,43]. Research in this area has identified several risk factors measured in the infant including low birth weight, malpresentation, gestational age at birth and anthropometric measures (head circumference, femur length) [25,29,44– 52]. Maternal risk factors have also been associated with childhood asthma including maternal history of asthma, breastfeeding, smoking during pregnancy, early or threatened preterm labour, placental insufficiency, respiratory infections during gestation, hyperemesis, hypertension, preeclampsia, antepartum hemorrhage, restricted uterine growth, maternal age and mode of delivery [1,37,44,48,50,52–69]. Several of the infant and maternal factors may be proxy measures for the same underlying risk factor while others may be independent. For example, the use of antenatal corticosteroids to promote lung maturity can be linked to obstetrical decisions as a direct result of preterm labour, mode of delivery, gestational age at birth, anthropometric measures and pre-eclampsia. Antenatal corticosteroids as an independent risk factor for the development of childhood asthma have not been well established in the literature to date.

Corticosteroid therapy for fetal lung maturation In the late 1960s researchers observed that administration of corticosteroids (CS) to pregnant ewes improved overall lamb survival and decreased lung disease [70]. Since this time, numerous trials in animals and humans have been undertaken to examine the relationship between CS therapy and fetal lung maturation [70–74]. CS has a wide ranging effect on the developing fetus [75]. CS affect both the epithelial and mesenchymal cells of the lung, altering cell differentiation and structural development [70]. CS also induce the production of surfactant and surfactant associated proteins [70]. In 1994, the National Institutes of Health in the United States published a consensus statement on

Antenatal steroid therapy and childhood asthma: Is there a possible link? the effects of CS use for fetal lung maturation and perinatal outcomes in an effort to increase CS use [9]. In Canada, a dramatic rise in the use of CS therapy among preterm infants before 34 weeks gestation has been seen in the last 15 years [5,6]. In 1988, less than 25% of preterm infants (<34 weeks) were exposed to CS, while in 1997 close to 60 percent were exposed [6] Mothers with threatened preterm labour before 34 weeks gestation in Canada are routinely offered CS therapy to prevent fetal complications such as hyalines membrane disease [9,73,74]. The Society of Obstetrics and Gynaecology of Canada, in 2003 published new clinical guidelines with respect to CS therapy [7]. The guidelines state that expectant mothers who are between 24 and 34 weeks gestation and are at risk of preterm delivery within 7 days should be considered for CS therapy. The standard therapy consists of two 12 mg doses of betamethasone intramuscularly (IM) 24 hours apart or four 6 mg doses of dexamethasone IM 12 hours apart. The guideline also states that repeat courses of CS should not be used routinely. The increased use of CS coincides with publication of clinical guidelines and also occurs in a period were the prevalence of childhood asthma was seen to rise.

Latent effects of antenatal corticosteroid therapy Although a mechanistic link between antenatal CS therapy and the onset of asthma in childhood has not been fully established, wide ranging effects of CS therapy have been demonstrated. The alteration in brain chemistry and the hypothalamicpituitary-adrenal (HPA) axis, the shift in immune function and other wide-ranging latent effects such as changes in kidney development and subsequent hypertension all provide biological plausibility for a link to childhood asthma. An assessment of published studies revealed an increasing risk in the association between preterm birth and asthma within the same time period as CS therapy increased. Although a competing hypothesis could be the increasing survival of very preterm infants and their increased risk for the development of childhood asthma, the biological effects of CS on fetal development leads us to question if the increasing risk of childhood asthma is exclusively due to increased survival of premature infants or if other factors such as CS therapy also play a role. Currently, childhood asthma is thought to arise from a weighting of the immune system to dominance by type 2 helper T cells (Th2) [24,76–80]. Th2 cells secrete various interleukins that stimu-

983

late allergic inflammation [81,82]. Type 1 helper T cells (Th1) initiate the destruction of foreign organisms and viruses [81,82]. The Th1 and Th2 cells are considered to be in a regulatory loop where Th1 cells inhibit the formation of Th2 cells and Th2 cells inhibit the formation of Th1 cells [81,82]. The priming of this system is thought to occur in late gestation when the placenta polarizes the neonate to Th2 dominance [35,39,82]. Asthma is postulated to occur when the shift from Th2 to Th1 does not fully occur just before or right after birth [82,83]. Of note, CS therapy is initiated in the 3rd trimester of the pregnancy (between 24 and 34 weeks) just before birth [7]. Time dependent complications associated with antenatal CS therapy have been demonstrated [84,85]. Corticosteroids have been shown to affect the HPA axis development in primates, sheep and to a limited extent in humans [3,86–88]. The HPA axis is important in regulating the physical growth and organ development of the neonate [87]. The timing of exposure to CS within a species, late in gestation, has been shown by Matthews to be critical with regard to the effect on the HPA axis [86,89]. Sex differences in the effect of CS exposure have also been noted with males having a higher activity level in the HPA axis than females [90,91]. Differential sex effects could explain gender differences in the prevalence of childhood asthma. Recent, unpublished, work by Clifton in Australia indicate that CS exposure not only alters the HPA axis but also influences the Th1/Th2 ratio in favour of Th2 [92]. Other latent effects of antenatal CS exposure have been seen with regard to hypertension and kidney development [4,93–95]. Wintour has been establishing the effect of neonatal exposure and the programming of adult disease [93,96,97]. Specifically, Wintour has shown in sheep that kidney development (nephron number) can be adversely effected by exposure to CS in early critical periods of fetal development [95]. Similarly, Wintour has shown that a brief antenatal exposure to CS in sheep predisposes both male and female adult sheep to be hypertensive [98]. The postulated mechanism for the development of hypertension is the renin–angiotensin system [99]. There has been evidence that the retarded kidney development and hypertension are not related to the HPA axis [100]. In sheep, time dependant effects of CS therapy have shown a diminished inflamation reaction caused by endotoxins for several days, [101] but after the initial decreased period the inflammatory reaction returns but to higher than initial levels [101]. This phenomenon is postulated to be an

984 inhibition of inflamation followed by a induction of maturation [101,102]. Currently, more research is being conducted to further outline these complex time dependent effects of CS therapy [102]. All of the animal studies on the latent effects of antenatal CS therapy serve to demonstrate that CS may have a lasting and potentially time-dependant effect after antenatal exposure that persists after birth.

Previous studies examining the long term effects of antenatal corticosteroid therapy on lung function A literature search in Medline, coupled with an inspection of works cited from retrieved articles and contact with 10 worldwide childhood asthma experts revealed only 3 published studies that have examined exposure to antenatal CS therapy and lung function in childhood [103–106]. These 3 studies examined lung function as an outcome, no study was specifically examining asthma as a chronic respiratory condition. Although correlated, lung function and asthma are clinically different. These studies employed selective, small samples of children thereby bringing into question their power and generalizability [2]. Doyle et al. followed 130 infants born in Australia, between 1980 and 1982, where their birth weight was less than 1500 g. Approximately, 50% of the cohort had been exposed to a single dose of betamethasone. Doyle and colleagues concluded that CS therapy did not adversely affect lung function measured at age 14 years. Smolder-de Haas et al. followed 119 infants born in the Netherlands, between 1974 and 1977, 61 of whom were exposed to antenatal betamethasone, from a double blind, randomized control trial examining the effect of betamethasone and neonatal respiratory distress syndrome. The children were contacted 10–12 years after birth to appraise rates of infectious disease, physical growth, neurological and ophthamological development and lung function. With the exception of an increased number of infections within the exposed group in the first year of life, no differences were noted. Wiebicke et al. studied a total of 19 infants, 8 of whom were exposed to antenatal dexamethasone from the Collaborative Group on Antenatal Steroid Therapy randomized control trial. The trial started data collection in Canada, in 1976 with 739 infants being followed. Lung volumes and expiratory flow were examined in children approximately 6 years of age. No difference were noted between the two groups.

Pole et al. Smolder-de Haas et al. and Wiebicke et al. used convenience samples in that randomized trials were used to study CS therapy and a given outcome. The authors extended follow-up of established trial subjects (or attempted to make contact much later in time) to include the outcome [105,106]. This type of convenience sample can be cost-effective but neither author addressed the potential bias that could result due to loss to follow-up. Although all authors concluded that CS therapy did not result in adverse effects there was no discussion with regard to internal (e.g., selection bias, confounding, sample size) or external validity. Also, none of these secondary studies had sufficient statistical power to test the hypothesis. Each of the three studies examined births that occurred between 1974 and 1982.

Association between preterm birth and childhood asthma Studies that have examined the association of perinatal factors with childhood asthma have identified preterm birth (defined as birth before 37 completed weeks of gestation) as an independent risk factor. A review of the published literature was undertaken, examining studies where the primary focus of the study examined the association between preterm birth and the risk of childhood asthma or the published study provided data in sufficient detail to allow for an estimate of the relationship between preterm birth and the risk of childhood asthma. In total 40 studies were located. A summary of the study design characteristics, including the sample size and effect estimates is provided in Table 1. Of the 40 studies analysed, 27 were cohort studies (67.5%) with approximately the same proportion of cross-sectional and case control studies 6 (15%) and 7 (17.5%) respectively). The average follow-up time of the studies was 11.2 years (standard deviation, 7.5 years) ranging from as little as 1 year to a maximum of 33 years. Although 5 studies did not define preterm birth explicitly, 26 studies (65%) used a consistent definition for preterm delivery as birth before 37 completed weeks gestation with a comparison group of births at 37 weeks or greater gestation. The sample sizes varied greatly from 92 to 170,960 births with a median sample size of 3639 births. Overall, 30 studies (75%) provided sufficient data to estimate the association un-adjusted for other co-variates.

Selected design characteristics of the published studies included in the analysis Time of birth

Average years of follow-up

Country

Study design

Study sample size

Preterm delivery contrast

Asthma definition

Adjusted

Estimate (95% CI)

Stachan et al. (1996) Annesi-Maesano et al. (2001) Gordon et al. (1970)

1958 1958 1960

7 33 10

United Kingdom United Kingdom United States

Cohort Cohort Cohort

3147 4153 30,861

<37 vs >=37 <37 vs >=37 <37 vs >=37

Yes No No

1.12 (0.67–1.87) 1.25 (0.91–1.73) 0.76 (0.54–1.08)

Pekkanen et al. (2001) Schwartz et al. (1990) Svanes et al. (1998) Lewis et al. (1995) Lewis et al. (1998) Leadbitter et al. (1999) Steffensen et al. (2000)

1966 1965–1996 1967–1971 1970 1970 1972–1973 1973–1975

31 11 22 16 16 21 20

Finland United States Norway Ireland United Kingdom New Zealand Denmark

Cohort Cross-sectional Cohort Cohort Cohort Cohort Cohort

4919 5627 690 1205 7249 652 4794

<37 vs >=37 yes vs no <37 vs >=37 <37 vs >=37 <35 vs >=39 <37 vs >=37 <37 vs >=37

Yes Yes Yes No Yes No No

1.16 1.28 2.56 1.31 1.13 0.75 1.04

(0.70–1.94) (0.81–1.94) (0.83–7.88) (0.67–2.56) (0.72–1.78) (0.31–1.81) (0.67–1.61)

Barback et al. (1998) Bager et al. (2003) Katz et al. (2003) Rasanen et al. (2000) von Mutius et al. (1993) Juhn et al. (2005) Fergusson et al. (1997)

1973–1975 1973–1977 1975–1978 1975–1979 1978–1980 1976–1982 1980

18 21 15 16 10 7 16

Sweden Denmark England Finland Germany United States New Zealand

Cohort Cohort Cohort Cohort Cross-sectional Cohort Cohort

148,213 9722 3246 3968 4827 6980 869

<37 vs >=37 <37 vs >=37 <37 vs >=37 <37 vs >=37 yes vs no <37 vs >=37 <37 vs >=37

No No No No No No No

1.04 0.75 0.94 0.92 1.44 1.73 1.16

(0.94–1.14) (0.54–1.04) (0.49–1.79) (0.65–1.29) (0.97–2.12) (1.16–2.59) (0.57–2.38)

Rona et al. (1993) Li et al. (2005) Kelly et al. (1995) Halvorsen et al. (2004)

1979–1984 1978–1986 1982–1988 1982–1985

9 5 8 16

United Kingdom United States England Norway

Cross-sectional Case Control Case Control Case Control

3036 691 3746 92

<37 vs >=37 yes vs no yes vs no <=28 vs >=37

No No Yes No

1.07 1.95 1.41 1.99

(0.76–1.50) (1.25–3.04) (1.06–1.87) (0.61–6.49)

Vrijlandt et al. (2005) Schaubel et al. (1996) Dik et al. (2004) Oliveti et al. (1996)

1983 1984–1985 1980–1990 1983–1989

19 6 6 8

Netherlands Canada Canada United States

Case Control Cohort Cohort Case Control

1818 16,207 170,960 262

<33 <37 <36 <37

No Yes Yes No

3.03 1.34 1.28 2.03

(1.90–4.84) (1.02–1.77) (1.18–1.37) (1.07–3.84)

Jaakkola et al. (2004)

1987

Finland

Cohort

58,841

<37 vs >=37

No

1.63 (1.38–1.94)

Merchant et al. (2005) Siltanen et al. (2004) Miller, 2001

1985–1989 1987–1988 1988

9 10 3

United States Finland United States

Cohort Case Control Cohort

611 104 6159

yes vs no <34 vs >=37 <36 vs >=36

No No No

2.46 (1.21–5.00) 2.38 (0.67–8.47) 1.62 (1.22–2.15)

Bernsen et al. (2005) Debley et al. (2005) Bolte et al. (2004) Oddy et al. (2004) Chen et al. (1999) Oddy et al. (1999) Sherriff et al. (2001) Hermann et al. (2005) Benn et al. (2002) Raby et al. (2004) Yuan et al. (2003)

1988–1990 1987–1994 1990–1991 1989–1992 1991–1992 1989–1992 1991–1992 1991–1992 1992–1994 1994–1996 1996–1997

6 6 5 6 4 6 3 5 5 6 1

Netherlands United States Germany Australia Canada Australia United Kingdom Denmark Denmark United States Denmark

Cohort Case Control Cross-sectional Cohort Cross-sectional Cohort Cohort Cross-sectional Cohort Cohort Cohort

1666 6612 715 1485 5840 2178 6971 3532 3003 454 9694

<36 vs >=36 <37 vs >=37 <37 vs >=37 <37 vs >=37 <37 vs >=37 <37 vs >=37 <37 vs >=37 <39 vs >=39 <37 vs >=37 36–38.5 vs > 38.5 <37 vs >=37

Self-report asthma or wheeze Self-report Physician diagnosis, medical records Self-report physician diagnosis Self-report physician diagnosis Self-report signs and symptoms Self-report wheeze Self-report wheeze Self-report and spirometry Physician diagnosis, medical records Physician diagnosis Self-report physician diagnosis Self-report physician diagnosis Self-report physician diagnosis Self-report physician diagnosis Self-report physician diagnosis Physician diagnosis, medical records Self-report Self-report physician diagnosis Self-report physician diagnosis Physician diagnosis and spirometry Self-report physician diagnosis Hospital admission Physician billing record Physician diagnosis, medical records Physician/hospital/medication Billing record Self-report physician diagnosis Physician diagnosis Physician diagnosis, medical records Physician diagnosis Hospitalization Self-report physician diagnosis Self-report physician diagnosis Self-report physician diagnosis Self-report physician diagnosis Self-report wheeze Self-report wheeze Hospital admission Self-report physician diagnosis Prescription for asthma

No No No Yes No Yes No No No No No

2.41 1.19 2.17 1.39 1.40 1.75 1.74 1.63 2.30 3.74 1.83

7

vs vs vs vs

>=33 >=37 40 >=37

(1.24–4.70) (0.91–1.55) (0.92–5.11) (0.75–2.61) (1.00–1.95) (1.30–2.35) (1.29–2.36) (1.25–2.12) (1.00–5.20) (1.88–7.44) (1.24–2.69)

985

Study

Antenatal steroid therapy and childhood asthma: Is there a possible link?

Table 1

986

Pole et al.

Upon examination this review of published studies revealed little or no association with preterm birth from the late 1950s until the mid-1980s when the use of antenatal steroid therapy for threatened preterm labour was not widely used clinically (see Fig. 1). From the mid-1980s forward, an increasing association with preterm birth is noted mirroring the same time period of increasing use of antenatal steroid therapy.

measure of childhood asthma, identifiable groups of subjects exposed and not exposed to antenatal corticosteroids and adequate control for confounding by indication. Possibly the most difficult element would be the control for confounding by indication as a means to ameliorate doubt with regard to alternate explanations of any association noted.

Summary Increasing survival of preterm births: an alternate explanation Underlying the time period of increasing association of asthma and preterm birth is the increasing delivery of preterm births and their subsequent increasing survival rates [12,107–110]. The preterm birth rate in Canada has risen from 54.9 preterm births per 1000 live births in 1987 to 59.3 preterm births in 1994 [107]. Mortality of infants born prematurely has decreased between 22 and 26%, over the same time period, depending on the birth weight of the infant due largely to improved neonatal care [108]. Similar trends of increasing preterm birth rates and decreasing mortality amongst preterm infants has been noted in the United States [109]. Similar trends in survival among preterm infants would be expected in Europe and the United Kingdom. Increasing delivery and survival of preterm births could explain a portion of the time-dependant association noted.

Testing the hypothesis In order to test this hypothesis in a human population there are three main elements required: a

The prevalence of childhood asthma saw a rapid rise from the early 1980s up until the early part of this decade. Over this same time period the clinical use of corticosteroids to mature the fetal lung has also risen mirroring the rise in asthma prevalence. This review of 40 published studies demonstrates the time dependent association between preterm birth and childhood asthma and lends credibility to the feasibility of an association between antenatal corticosteroid therapy and an increased risk for childhood asthma. Given the established latent effects of antenatal corticosteroid therapy it is reasonable and appropriate to speculate that changes in the fetal immune system along with physical changes to the lung tissue, after exposure to the corticosteroids, could give rise to breathing difficulties several years after birth. Given suggestions in the literature in regard to the large dose of antenatal corticosteroids currently recommended and administered coupled with the lack of attention in the original clinical trials in assessing the smallest dose required to mature the fetal lung antenatal corticosteroids could represent a modifiable risk factor for the development of asthma [2].

Relationship Between Year of Birth and Association of Asthma and Preterm Birth 4.00 3.50

Estimate

3.00 2.50 2.00 1.50 1.00 0.50 1955

1960

1965

1970

1975

1980

1985

1990

1995

Year of Birth

Figure 1

Relationship between year of birth and association of asthma and preterm birth.

Antenatal steroid therapy and childhood asthma: Is there a possible link?

Acknowledgements The authors acknowledge operational funding from the Canadian Institutes of Health Research (CIHR) (Funding Reference Number: MOP-77693) and the Allergy, Genes and Environment Network (AllerGen NCE Inc.) (Project No. FP-2005-1).

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