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ORIGINAL RESEARCH |
From the 1Department of Respiratory and Sleep Medicine, John Hunter Hospital and Hunter Medical Research Institute, University of Newcastle; and 2Mothers and Babies Research Centre, Hunter Medical Research Institute, University of Newcastle, New South Wales, Australia.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Asthma exacerbations were evaluated in 146 women who were enrolled in a prospective cohort study of asthma and pregnancy. A severe exacerbation was defined as a hospital admission, emergency department presentation, or unscheduled doctor visit for asthma or a course of oral corticosteroids. Women were classified as having mild (n = 63), moderate (n = 34), or severe (n = 49) asthma.
RESULTS: Severe exacerbations occurred in 8% (95% confidence interval [CI] 1.3–14.6%) of women with mild asthma, 47% (95% CI 30.3–63.8%) of women with moderate asthma, and 65% (95% CI 52–78.6%) of women with severe asthma at a mean gestational age of 25.1 ± 0.9 (range 9–39) weeks of gestation. Among women who had severe exacerbations, there were 2 male stillbirths (P = .102) and a significantly increased rate of male low birth weight (P = .03). Maternal age, lung function, body mass index, gravidity, and parity were not different between women who did or those who did not have a severe exacerbation. Maternal pregnancy weight gain was significantly lower in women who had a severe exacerbation (P = .039). Forty-three percent of severe exacerbations occurred in winter, 34% were associated with self-reported viral infection, and 29% with nonadherence to inhaled corticosteroid medication.
CONCLUSION: The exacerbation rate among pregnant women with asthma is high and associated with poor outcomes for the male fetus. Improvements in asthma management to prevent severe exacerbations may lead to a better outcome for both mother and baby.
LEVEL OF EVIDENCE: II-2
It is important to estimate the frequency of asthma exacerbations in pregnant women because these events may put both the mother and fetus at risk of poor clinical outcomes. At present there are few studies that have examined this. Recently a large, multicenter study demonstrated that the risk of exacerbations of asthma during pregnancy increases with increasing asthma severity. Schatz et al9 found that of 1,739 women with asthma, 20% had a severe exacerbation during pregnancy that required medical intervention. Exacerbations increased with increasing asthma severity, with 52% of severe asthmatics having an exacerbation. This study did not examine perinatal outcomes in relation to asthma exacerbations during pregnancy. Australia has one of the highest rates of asthma in the world,10 and in this study we examine the relationship between severe exacerbations of asthma during pregnancy and perinatal outcomes.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Pregnant women with asthma who had at least 2 study visits (n = 146; 104 had 2 visits, 31 had 3 visits, 7 had 4 visits, 3 had 5 visits, and one woman had 7 visits) were included. Background asthma severity was classified as mild, moderate, or severe when stable, and exacerbation events were evaluated and classified as mild or severe. Details of the exacerbations were obtained from the study visit notes and confirmed by consulting the medical record if necessary. An exacerbation event was defined as severe if it required a hospital admission, emergency department presentation, an unscheduled doctor visit, or a course of oral steroids due to asthma. An exacerbation was defined as mild (loss of control) if it required increased medication use or was characterized by increased symptoms or decreased peak flow, which was managed by the subject and did not require medical intervention.
Background asthma severity was classified using the integrated severity score described in the Australian asthma management guidelines, which are similar to the guidelines from the National Heart, Lung, and Blood Institute.15,16 Women were assigned a severity rating of mild (n = 63), moderate (n = 34), or severe (n = 49) according to symptoms, asthma history, and other features, including forced expiratory volume at one second (FEV1) and peak expiratory flow (PEF). Women were assigned to the most severe category that applied for any one of the following criteria at their first study visit, when asthma was stable. Women with mild asthma had an FEV1 greater than 80% predicted, less than 25% variability in PEF, no nighttime or morning symptoms, infrequent ß2-agonist use, daytime symptoms less than 4 times per week, and no severe attacks in the previous year. Women with moderate asthma had an FEV1 of 60–80% predicted, less than 25% PEF variability, nighttime symptoms up to once per week, ß2-agonist use, and daytime symptoms on most days. Severe asthmatics had an FEV1 less than 60% predicted, greater than 25% variability in PEF, frequent nighttime symptoms, morning and daytime symptoms every day, ß2-agonist use 3–4 times per day, and limited physical activity.
At the asthma assessment visits, a history of asthma was taken, including the number of hospital admissions, emergency department presentations, and oral steroid courses during the 2 years before the pregnancy, and lung function was measured by spirometry. Inhaled corticosteroid medication use (prescribed and nonadherence) was determined by direct questioning. Nonadherence was assessed at the study visits by asking the following question in a nonjudgmental and nonthreatening manner: "It can be difficult to remember all of your medicines when things get busy. How many times in the last week have you missed a dose of your preventer?" Participants were considered adherent if they took 80% of their prescribed doses.
Inhaled corticosteroid use was calculated for each trimester and expressed as the mean daily dose of beclomethasone dipropionate or equivalent, where 1 µg beclomethasone dipropionate was considered equivalent to 1 µg budesonide or 0.5 µg fluticasone propionate.17 All asthmatic women used the short-acting ß2-agonist, salbutamol, for symptom relief when required.
Results are presented as median (interquartile range) or mean ± standard deviation. Statistical analysis was performed using GraphPad Instat 3.05 (GraphPad Software, San Diego, CA) or Stata 7 (Stata Corporation, College Station, TX). Repeated measures analysis of variance (ANOVA) and the nonparametric equivalent (Friedman test) were used along with the appropriate post hoc test (Tukey-Kramer multiple-comparisons test or Dunn multiple-comparisons test). When comparing 2 groups, the unpaired t test or Mann Whitney test was used. When the 2 groups did not have equal variances, the unpaired t test with Welch correction was used (GraphPad Instat 3.05). Fisher exact test or the 2-sample test of proportion with Bonferroni correction (P < .017) were used to compare proportions. Normality was evaluated by graphical methods using Stata 7. P < .05 was considered significant.
Power analysis was conducted by using the PS Power and Sample Size Program 2.1.30 (Dupont WD, Plummer WD. PS power and sample size program available for free on the internet [letter]. Control Clin Trials 1997;18:274). Per journal style, letters may not be listed in Reference section. Reference was deleted and subsequent references renumbered. The primary outcome was to examine the frequency of severe exacerbations during pregnancy. We also examined the effect of these severe exacerbations on fetal outcomes, primarily birth weight. A previous study has described an increased frequency of exacerbations in pregnant women with severe asthma compared with those with mild asthma.9 To replicate this work and detect a difference in exacerbation rate between mild asthma (12.6%) and severe asthma (52%), with 
= 0.05 and power of 0.8, a sample size of 21 subjects per group was required.
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RESULTS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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When subjects were grouped based upon background asthma severity as mild (n = 63), moderate (n = 34), or severe (n = 49), there were 5 severe exacerbation events in women with mild asthma (8%, 95% confidence interval [CI] 1.3–14.6%), 16 severe exacerbation events in women with moderate asthma (47%, 95% CI 30.3–63.8%), and 36 severe exacerbation events in 32 women with severe asthma (65%, 95% CI 52.0–78.6 %). The frequency of severe exacerbation events was significantly higher in women with severe asthma compared with women with mild asthma (2-sample test of proportion with Bonferroni correction, P < .001), but not compared with women with moderate asthma (2-sample test of proportion, P = .098). Table 1 shows the number of hospital admissions, emergency department presentations, unscheduled doctor visits, and courses of oral steroids for the mild, moderate, and severe asthma groups and the percentage of subjects with these exacerbations within each group and overall. A total of 53 women did not use inhaled corticosteroid medication at any time during pregnancy, and 3 of these subjects (5.7%) had a severe exacerbation of asthma during pregnancy.
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Overall, there were no significant differences in perinatal outcomes between women who had a severe asthma exacerbation during pregnancy (n = 52) and women who did not (n = 92, Table 2, P > .05). However, there were nonsignificant trends to lower mean birth weight and an increased rate of low birth weight in women with severe exacerbations. When data were analyzed based upon the sex of the fetus, there were no significant differences in outcomes for female neonates (Table 2, P > .05). However, male neonates were significantly smaller when their mothers had a severe asthma exacerbation during pregnancy, compared with male neonates of mothers who did not have a severe exacerbation (Table 2 and Fig. 2, unpaired t test with Welch correction, P = .049). The study had 74% power to detect this difference.
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There was also a significantly increased rate of male low birth weight (13%) among women who had a severe exacerbation compared with those who did not (0%, Fisher exact test, P = .03). There were 2 male stillbirths (9%) among women with a severe exacerbation, but this was not a significant increase compared with women who did not have a severe exacerbation (0%, Fisher exact test, P = .102). The rate of preterm delivery was not significantly different between the women who had a severe exacerbation and women who did not have a severe exacerbation (9% versus 4% male neonates, 3% versus 0% female neonates, Fisher exact test, P > .05). The study was underpowered to detect differences in low birth weight, still birth, or preterm delivery between the exacerbation and no-exacerbation groups.
There were no significant differences between women who had a severe exacerbation and those who did not have a severe exacerbation in terms of maternal age, maternal height, maternal weight or body mass index, gravidity, parity, or maternal lung function (Table 3). However, women who had a severe exacerbation during pregnancy gained significantly less weight during pregnancy than did women who did not have a severe exacerbation (unpaired t test, P = .039). Women who had a severe exacerbation attended significantly more study visits with the asthma educator (median 2, interquartile range 2–3) than did women who did not have a severe exacerbation (median 2, interquartile range 2–2, Mann Whitney test, P = .005).
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Maternal demographics for women classified as having mild, moderate, or severe asthma are shown in Table 4. Women with severe asthma had a significantly lower percentage of predicted FEV1 (Kruskal-Wallis Test, P = .015, Dunn multiple-comparisons test, P < .05), lower FEV1:forced vital capacity (FVC) (ANOVA, P = .025, Tukey-Kramer multiple-comparisons test), and higher parity (Kruskal-Wallis test, P = .044, Dunn multiple-comparisons test, P < .05) than did women with mild asthma. Asthma severity did not significantly influence any other maternal characteristics, including weight gain (ANOVA, P = .07).
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Women who had a severe exacerbation had a significant increase in inhaled corticosteroid intake from first to second and first to third trimesters (Fig. 3A, Friedman test, P < .001, Dunn multiple-comparisons test, P < .05), whereas, in women who did not have a severe exacerbation during pregnancy, there was no increase in inhaled corticosteroid use during pregnancy (Fig. 3B, Friedman test, P = .002, Dunn multiple-comparisons test, P > .05). Inhaled corticosteroid dose (µg/d) was significantly higher in the first trimester in women who had a severe exacerbation (median 250 µg/d, interquartile range 0–1,000 µg/d) compared with those who did not (median 0 µg/d, interquartile range 0–500 µg/d, Fig. 3C, Mann Whitney test, P = .047).
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Thirty-four percent of exacerbations were associated with a potential viral infection (patients reported having a cold, flu, or upper respiratory tract infection), 28% occurred in women who smoked, 3% occurred in women who were not prescribed inhaled corticosteroid, and 29% were associated with self-reported nonadherence to inhaled corticosteroid medication before the exacerbation. Forty-three percent of exacerbations occurred in winter, 27% in autumn, 14% in spring, and 16% in summer.
Prepregnancy rates of hospitalization, emergency department presentations (without subsequent hospitalization), and oral steroid use were compared with pregnancy rates, adjusted for the number of years and number of subjects examined. During pregnancy, the rate of hospitalization (0.107 events per year per subject) was higher than before pregnancy (0.058 events per year per subject) and the rate of emergency department presentations during pregnancy (0.036 events per year per subject) was lower than before pregnancy (0.144 events per year per subject), resulting in an increased hospitalization:emergency department ratio during pregnancy (2.97 versus 0.403 before pregnancy). The rate of oral steroid use was decreased during pregnancy (0.205 events per year per subject) compared with the prepregnancy rate (0.288 events per year per subject).
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DISCUSSION |
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We compared pregnancy outcomes in women who had a severe exacerbation of asthma during pregnancy and those who had no severe exacerbation. Overall, there were only nonsignificant trends to an adverse effect of exacerbations on perinatal outcomes because the study was underpowered to detect differences in the rate of low birth weight, still birth, or preterm delivery. We examined our data separately based on the sex of the fetus to control for the known confounding effect of fetal sex on birth weight in asthmatic pregnancies, which we have previously described.11,14 In the sex-specific analysis, we found that the male fetus was most at risk of reduced birth weight, with a significantly higher rate of low birth weight, and there were 2 male stillbirths among women who had a severe exacerbation of asthma during pregnancy. The mean birth weight of male neonates was approximately 300 g lower when mothers had a severe exacerbation of asthma during pregnancy. This is greater than the effect of maternal smoking during pregnancy, which is known to result in a doubling of the rate of low birth weight and approximately a 150- to 200-g decrease in birth weight.18,19 Two previous studies have described a reduction in birth weight in association with hospitalization due to asthma during pregnancy,6,7 but a sex-specific effect has not been described. Another possible explanation of our finding is that the effects of exacerbations during pregnancy are not sex-specific and may be explained by the confounding effect of reduced birth weight in female neonates when mothers did not use inhaled steroids and did not have an exacerbation.11 Alternatively, this could be a chance finding, and we are conducting further studies with larger samples sizes to investigate these possibilities.
We examined potential maternal risk factors for exacerbation, such as age, parity, smoking, body mass index, and lung function, but found no differences between the women who had a severe exacerbation and those who did not. A similar analysis was undertaken by Kircher et al,20 but this study investigated maternal features that may contribute to worsening versus improved asthma during pregnancy. The classification into these groups (worse and improved) was based on patient perception toward the end of gestation, and no significant differences in maternal height, weight, smoking, body mass index, or infant sex were found. We also found that there were no differences between women who had a severe exacerbation and those who did not, in maternal weight or body mass index in early pregnancy, but women who had a severe exacerbation during pregnancy gained significantly less weight than women who did not have a severe exacerbation and this was not specifically due to having chronic severe asthma. Reduced pregnancy weight gain could potentially lead to compromised fetal growth as a result of altered maternal nutritional status.
The cause of asthma exacerbations during pregnancy is unknown. The 2 most common self-reported triggers of the severe exacerbations in our study were nonadherence to inhaled corticosteroid medication (29%) and potential viral infection (34%). A similar finding was reported by others,21 including Apter et al22 who studied 28 pregnancies in adolescents with asthma and reported that 27% of exacerbations (hospitalizations and emergency department presentations) were due to discontinuation of medications and 59% were due to a suspected viral infection. No studies have confirmed the presence of viruses or identified the viruses involved in asthma exacerbations during pregnancy. A prospective cohort study of 101 pregnant women with asthma and 77 control women found that 35% of the asthmatics had a urinary or upper respiratory tract infection compared with only 5% of nonasthmatic women.23 In addition, women with severe asthma had a higher rate of infection than women with mild asthma.23 It has been hypothesized that changes in the maternal immune system during pregnancy may make pregnant women more susceptible to viral infection. The implications of this for pregnant women with asthma are unclear, and further investigation into virus-induced asthma during pregnancy is warranted.
Nonadherence to medications is a significant, but potentially preventable problem among pregnant women. Common misconceptions about the safety of inhaled corticosteroid use during pregnancy are held by both patients and some health care providers,24,25 which may contribute to significant anxiety for mothers with asthma. An international internet-based survey of 166 women found that 44% of women were worried about how both asthma medications and asthma attacks would affect their baby.24 Surveys of patient perceptions have also demonstrated that at least one third of patients intended to be or were nonadherent to inhaled corticosteroid medication use during pregnancy.24,25 We found that 29% of women who had a severe exacerbation requiring medical intervention reported that they had been nonadherent with their inhaled corticosteroid medication before the exacerbation. Because we used self-reporting as a measure of nonadherence, this may be an underestimation of the problem. More education is required to inform women that a severe asthma attack presents more of a risk to the fetus than the use of asthma medications because of the potential for a reduction in the supply of oxygen to the fetus.26,27
During pregnancy, treatment approaches for pregnant women with severe exacerbations may differ from those in nonpregnant women. We examined the rates of hospitalizations, emergency room presentations, and oral steroid courses during pregnancy and before pregnancy in this group of women with asthma. We found that hospitalizations were more common during pregnancy, whereas emergency department visits were less common. Although these data are limited by the potential for recall bias on the part of the participants, they suggest that a higher number of presentations to hospital result in an admission as opposed to treatment in the emergency department. This could be due to different medical approaches to the care of pregnant women or may be a result of exacerbations being of a more severe nature during pregnancy. Reported oral steroid use was also lower during pregnancy than before pregnancy, which may reflect reluctance to use this medication during pregnancy. A U.S. study found that pregnant women with asthma were less likely to receive oral steroid treatment in the emergency department and on discharge than were nonpregnant women with asthma.28 Recent studies have associated oral steroid use with an increased risk of preterm delivery,2,4 although it is difficult to separate the effect of the medication from the effect of the exacerbation that resulted in the medication being taken. We found no significantly increased rate of preterm delivery in asthmatic women who had a severe exacerbation during pregnancy.
In conclusion, there is a high rate of severe asthma exacerbations requiring medical intervention among pregnant women with asthma. Nonadherence to medication and viral infection are likely to be common causes of these exacerbations. Mean birth weight was significantly reduced among male neonates when mothers had a severe exacerbation during pregnancy. Larger studies are needed to confirm these findings. Improvements in asthma management during pregnancy that reduce the rate of exacerbations are likely to improve clinical outcomes for the fetus as well as the mother with asthma.
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Footnotes |
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Corresponding author: Dr. Vanessa Murphy, Department of Respiratory and Sleep Medicine, John Hunter Hospital, Locked Bag 1, Hunter Region Mail Centre, Newcastle, New South Wales, 2310, Australia; e-mail: vanessa.murphy{at}newcastle.edu.au.
doi:10.1097/01.AOG.0000185281.21716.02
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REFERENCES |
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2. Bracken MB, Triche EW, Belanger K, Saftlas A, Beckett WS, Leaderer BP. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies. Obstet Gynecol 2003;102:739–52.
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10. Kurinczuk JJ, Parsons DE, Dawes V, Burton PR. The relationship between asthma and smoking during pregnancy. Women Health 1999;29:31–47.
11. Murphy VE, Gibson PG, Giles WB, Zakar T, Smith R, Bisits AM, et al. Maternal asthma is associated with reduced female fetal growth. Am J Respir Crit Care Med 2003;168:1317–23.
12. Clifton VL, Giles WB, Smith R, Bisits AT, Hempenstall PA, Kessell CG, et al. Alterations of placental vascular function in asthmatic pregnancies. Am J Respir Crit Care Med 2001;164:546–53.
13. Murphy VE, Zakar T, Smith R, Giles WB, Gibson PG, Clifton VL. Reduced 11beta-hydroxysteroid dehydrogenase type 2 activity is associated with decreased birth weight centile in pregnancies complicated by asthma. J Clin Endocrinol Metab 2002;87:1660–8.
14. Clifton VL, Murphy VE. Maternal asthma as a model for examining fetal sex-specific effects on maternal physiology and placental mechanisms that regulate human fetal growth. Placenta 2004;25 suppl A:S45–52.
15. National Institutes of Health. Guidelines for the diagnosis and management of asthma. Bethesda (MD): National Heart, Lung and Blood Institute; 1997.
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