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Asthma in pregnancy
REVIEW
Asthma in Pregnancy Kia Soong Tan, MD, Neil C. Thomson, MD Although about 1% of pregnant women have asthma, it is often underrecognized and suboptimally treated. The course of asthma during pregnancy varies; it improves, remains stable, or worsens in similar proportions of women. The risk of an asthma exacerbation is high immediately postpartum, but the severity of asthma usually returns to the preconception level after delivery and often follows a similar course during subsequent pregnancies. Changes in 2-adrenoceptor responsiveness and changes in airway inflammation induced by high levels of circulating progesterone have been proposed as possible explanations for the effects of pregnancy on asthma. Good control of
asthma is essential for maternal and fetal well-being. Acute asthmatic attacks can result in dangerously low fetal oxygenation. Chronically poor control is associated with pregnancy-induced hypertension, preeclampsia, and uterine hemorrhage, as well as greater rates of cesarian section, preterm delivery, intrauterine growth retardation, low birth weight, and congenital malformation. Women with well-controlled asthma during pregnancy, however, have outcomes as good as those in their nonasthmatic counterparts. Inhaled therapies remain the cornerstone of treatment; most appear to be safe in pregnancy. Am J Med. 2000;109:727–733. 䉷2000 by Excerpta Medica, Inc.
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likely than women without asthma to have hyperemesis gravidarum (4) and twice as likely to suffer uterine hemorrhage (4,5). This latter risk is greatest in those taking corticosteroids (5). A large retrospective analysis of 2,289 pregnant women with asthma found longer hospital stays and an almost twofold increase in preeclampsia, placenta previa, and cesarian sections (6). This study and others (7,8) suggest that pregnancy-induced hypertension is also two to three times more common in women with asthma, especially in those treated with corticosteroids (8). Premature labor is more common (4,6), perhaps markedly so (9), in corticosteroid-dependent patients. Women with asthma are also more likely to require induction of labor (14% versus 9% in controls) (4). However, other studies have demonstrated that maternal outcomes in those with mild asthma are no different from those in nonasthmatic women (8,10 –12). Our interpretation is that the risk of maternal morbidity is increased only in women with severe asthma, especially those requiring oral corticosteroids. There is little evidence of an association between asthma in pregnancy and maternal mortality (5,8,10 –12). In 1970, one prospective study reported only two deaths among 227 patients with asthma compared with none in 30,861 controls (13). In the ensuing 30 years, no other reports of asthma-related mortality in pregnancy have been published, perhaps reflecting improvements in disease management and obstetric care.
sthma is a common and potentially serious medical problem in pregnant women (1). Retrospective data suggest a prevalence of approximately 1% in pregnancy (2,3), but these estimates may be conservative due to lack of reporting and underdiagnosis. The objectives of asthma management are similar to those in nonpregnant patients, namely, to maximize lung function, control asthma symptoms, prevent exacerbations, and minimize drug side effects. To manage patients optimally, health professionals need to appreciate the effects of asthma on pregnancy, the influence of pregnancy on asthma control, and the efficacy and safety of asthma treatment in pregnant women. This article explores evidence for these objectives and discusses practical issues involved in treating pregnant women with asthma. To do so, we performed a Medline search of all English language reports of asthma and pregnancy from 1966 to 2000 using the keywords “asthma” and “pregnancy.” All relevant clinical studies were reviewed.
EFFECTS OF ASTHMA ON PREGNANCY Maternal Health Asthma in pregnancy can increase maternal morbidity (Table 1). Affected women are almost three times more
From the Department of Respiratory Medicine, Western Infirmary, Glasgow, Scotland. Requests for reprints should be addressed to Kia Soong Tan, MD, Department of Respiratory Medicine, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, Scotland, United Kingdom. Manuscript submitted August 26, 1999, and accepted in revised form August 9, 2000. 䉷2000 by Excerpta Medica, Inc. All rights reserved.
Fetal Health Adverse perinatal outcomes have been linked with asthma during pregnancy, although the outlook has improved recently (Table 2). Fetal compromise appears to 0002-9343/00/$–see front matter 727 PII S0002-9343(00)00615-X
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Table 1. Studies of the Effects of Asthma on Maternal Outcome
First Author (Reference)
Asthma
Control
Pregnancy-Induced Hypertension/ Preeclampsia
Gestational Diabetes
Uterine Hemorrhage
Asthma
Asthma
Asthma
Control
5* 1 — 2 18* 1
2 1 — 2 8 1
Control
Number of Patients Bahna (4) Stenius-Aarniala (8) Schatz (12) Jana (10) Alexander (5) Demissie (6)
381 198 486 182 817 2289
112,530 198 486 364 13,709 9156
Control
Percent 11* 14* 10 18 10 5*
5 5 7 17 11 2
— 2 1 2 1 —
— 3 1 2 2 —
* P ⬍0.05 compared with controls.
EFFECTS OF PREGNANCY ON ASTHMA
be related to poor asthma control. Recurrent acute asthma can lead to intrauterine growth retardation, prematurity, and low birth weight (10,14). Maternal hyperventilation, hypoxemia, and hypocapnia are thought to be underlying factors (15). For example, the mean birth weight of neonates born to mothers in India who required emergency treatment for acute asthma was about 400 g lower than that among neonates born to women not requiring admission or controls (10). Fitzsimmons et al (14) found that 19% of women who required emergency therapy for acute asthma had premature births, compared with 12% of those who did not require emergency treatment. They also observed a detrimental effect of poorly controlled asthma on birth weight. Conversely, another study found that the better the lung function—as measured by forced expiratory volume in 1 second—the lower the risk of intrauterine growth retardation (16). The concept that better asthma control improves pregnancy outcomes is also indirectly supported by studies that have reported similar outcomes among patients managed by asthma specialists and women without asthma (8,10,12,17,18).
Several studies have observed that pregnancy may alter the course of asthma (Table 3). Gluck et al (19) reviewed nine studies, performed between 1930 and 1967, that involved 1,087 pregnancies in asthmatic women. On average, asthma improved in 36% of women during pregnancy, remained unchanged in 41%, and deteriorated in 23%. These studies were retrospective, subject to recall bias, and used subjective questionnaire-based assessment of asthma control. More recent studies suggest that the effects of pregnancy on asthma are unpredictable, but that on average, a third of women worsen, a third improve, and a third remain unchanged (Table 3). Those with more severe disease before conception are at greater risk of deterioration (19,20). Symptoms tend to improve during the third trimester (20,21). Postpartum, 26% to 42% of women experience an exacerbation of asthma (20,21). Schatz et al (21) found that 59% of women had similar asthma control in successive pregnancies. There are few data on airway function in pregnant women with asthma. Sims et al (22) detected no change in spirometry values throughout pregnancy and after deliv-
Table 2. Studies of the Effects of Asthma on Perinatal Outcome First Author (Reference)
Prematurity (⬍ 37 weeks) Asthma
Control
Asthma
Control
Low Birth Weight (⬍ 2.5 kg) Asthma
Number of Patients Gordon (13) Bahna (4) Fitzsimmons (14) Jana (10) Schatz (12) Alexander (5) Demissie (6)
277 381 56 182 486 817 2289
30,861 112,530 General population 364 486 13,709 9156
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Asthma
Control
6* 3 0 0 2 — —
3 2 1 2 1 — —
Percent 14 7* 13 12 5 4 18*
* P ⬍0.05 compared with controls. 728
Control
Perinatal Mortality
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15 7* 17 17 4 5 9*
11 4 7 21 3 6 6
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Table 3. Studies of the Course of Asthma during Pregnancy First Author (Reference)
Number of Patients Worsened Same Improved Percent
Gluck (19) Gluck (19) Stenius-Aarniala (8) Schatz (21) White (20)
1087 47 198 366 31
23 43 42 35 9
41 43 40 33 22
36 14 18 28 69
ery in 27 asthma patients and controls. Another study measured airway hyperresponsiveness to methacholine, which is a direct smooth muscle bronchoconstrictor and an indirect marker of airway inflammation, in 16 pregnant women with asthma. Symptoms, drug requirements, and serum progesterone and estradiol levels before conception through confinement were also measured (23). There was a modest improvement in bronchial hyperresponsiveness during the second trimester, with a gradual return to the prepregnancy level by the third trimester. There was no correlation between progesterone levels and responsiveness to methacholine, refuting the hypothesis that progesterone might reduce airway smooth muscle contractility (24). Given that premenstrual exacerbations affect 33% to 40% of women with asthma (25–27), there are reasons to suspect that the cyclical rise and fall of levels of sex hormones may influence airway function, although initial clinical studies have been negative (28 –30). Recently, however, responsiveness to methacholine (31) and adenosine monophosphate (32) has been shown to increase during the luteal phase in women with asthma. Healthy women have a cyclical variation in lymphocyte 2-adrenoceptor density and responsiveness to isoprenaline (a nonselective -adrenoreceptor agonist), with higher levels during the luteal phase (33). This facilitatory effect on 2-adrenoceptors is most likely to be progesterone-mediated (34). However, this pattern is lost in women with asthma (32), in whom administering progesterone produces a “paradoxical” down-regulation in lymphocyte 2-adrenoceptor density and responsiveness (35). It is conceivable that the very high levels of progesterone in pregnancy may exert a similar effect, and thus worsen asthma control. However, it is uncertain whether lymphocyte 2-adrenoceptors provide a reliable surrogate marker for airway 2-adrenoceptors (36,37). Studies of the effects of progesterone and other hormones on 2adrenoceptor function and regulation during pregnancy are required. Fetal sex may influence asthma, providing additional evidence of possible hormonal effects. Among 34 pregnant women with asthma who were unaware of their child’s sex, those who gave birth to boys were more likely
to report improved asthma symptoms during pregnancy (38). Another study found that use of drugs to treat asthma was less common among mothers of boys (39). Female sex hormones have been shown to alter airway hyperresponsiveness in asthma (40) and influence skinprick tests to allergens (41). Thus the hormonal changes of pregnancy could influence underlying airway inflammation. This possibility has not been examined directly, probably because the use of bronchoalveolar lavage and bronchial biopsy—the “gold standard” for assessing airway inflammation—are unacceptable in pregnancy. Alternative, noninvasive methods for studying asthmatic airway inflammation are available: measurement of exhaled nitric oxide and analysis of induced sputum (42– 44). Exhaled nitric oxide is also elevated during the luteal phase in healthy women (45). Other causes of asthma deterioration in pregnancy have been suggested, including refractoriness to cortisol, prostaglandin F2␣-mediated bronchoconstriction, viral or bacterial respiratory infections, gastroesophageal reflux, stress, increased inflammatory mediators (eg, placental major basic protein) reaching the lungs, and reduced functional residual capacity (46). Further research is required to substantiate these hypotheses.
TREATMENT There are few consensus treatment guidelines for managing pregnant women with asthma. The National Asthma Education and Prevention Program issued specific guidelines in the United States in 1993 (47). The most recent British (48) and American (49) guidelines on the general management of asthma offer no specific advice about its treatment during pregnancy. Little is known about the effects of treatment on congenital malformations (50). However, the American College of Allergy, Asthma and Immunology’s Registry for Allergic, Asthmatic Pregnant Patients will collect data on 800 women who require inhaled corticosteroids during pregnancy (51). This and other studies will facilitate determining the efficacy and safety of asthma medications in pregnancy (52).
2-Adrenoceptor Agonists
Inhaled 2-adrenoceptor agonists are the most frequently used asthma treatment. Two studies have examined the effects of short-acting agents, mainly metaproterenol, terbutaline, and albuterol, during pregnancy (53,54). No adverse effects on rates of congenital malformation, perinatal mortality, low birth weight, or complications of labor and delivery were observed, and it has been concluded that these drugs are safe in pregnancy (54). Little is known, however, about the safety of long-acting 2-adrenoceptor agonists (eg, salmeterol and formoterol), and they should therefore be used only after consultation with an asthma specialist about alternate treatments. Intrave-
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nous 2-adrenoceptor agonists are sometimes required to treat severe acute asthma. However, these drugs should be used with caution in pregnant women because of their association with pulmonary edema (55,56), especially if they are administered with systemic corticosteroids to accelerate fetal lung maturation.
Corticosteroids Inhaled corticosteroid therapy remains the mainstay of the anti-inflammatory treatment of asthma (57). These agents are very effective in preventing asthma exacerbations during pregnancy (11,58). In a prospective study of 504 pregnant women with asthma, those taking inhaled corticosteroids were four times less likely than their nontreated counterparts to suffer an exacerbation (11). One randomized controlled trial found a 55% reduction in readmission rates for acute asthma in pregnant women taking inhaled beclomethasone (58). Based on animal studies, there were some initial fears about teratogenicity of inhaled corticosteroids (59). However, inhaled beclomethasone and budesonide, and oral prednisone and prednisolone, have not been associated with congenital malformations, stillbirths, or fetal mortality in most studies of women (14,17,54,60,61), although there have been exceptions (6). One study did find that cleft palate was more common in the children of nonasthmatic women who took systemic corticosteroids during the first trimester (62). Corticosteroids may worsen maternal morbidity, especially among patients who require oral administration for severe asthma. Their use has been associated with gestational diabetes (9), pregnancy-induced hypertension (8), and antepartum and postpartum hemorrhage (5). However, not all studies have reported an association with uterine hemorrhage or preeclampsia (9,17). If corticosteroids do increase maternal morbidity, it is not evident whether this is due to a direct pharmacologic effect or because they are a marker for worse disease. It is not known if oral corticosteroid use in pregnant women with asthma increases fetal morbidity. Lowbirth-weight infants may be more common (9,63), and preterm delivery rates may be increased (9). Again, these effects may be drug-related, indicators of asthma severity, or both. However, the use of oral corticosteroids (17) and the combination of inhaled beclomethasone and oral corticosteroids (14,60) among pregnant women treated in specialized pulmonary units did not worsen outcomes, as compared with the general population. Physicians appear to be reluctant to prescribe corticosteroids for pregnant women. A multicenter study found that pregnant women with asthma were significantly less likely to be prescribed corticosteroids in the emergency department: only 44% of pregnant women were treated with corticosteroids compared with 66% of nonpregnant women (64). Those who were admitted to the hospital 730
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were less likely to be treated with corticosteroids at discharge, and were almost three times more likely to experience a subsequent exacerbation, compared with nonpregnant women (64). Inhaled beclomethasone and budesonide have been widely used during pregnancy, and both appear to be safe. There are few studies, however, of the use of triamcinolone, flunisolide, or fluticasone during pregnancy. Thus it would seem prudent to initiate treatment in pregnant women with either inhaled beclomethasone or budesonide.
Theophylline Current evidence suggests that theophyllines are safe in pregnancy (54). Clearance may be reduced by 20% to 35% during the third trimester (65), however, requiring close monitoring of serum levels. The use of intravenous aminophylline has no additional benefit over systemic corticosteroids in the treatment of acute asthma in pregnant women (58). Studies of oral theophylline during pregnancy have had conflicting results and are of little practical help. In one study, patients who had been treated with oral slow-release theophylline had more asthma exacerbations than controls, but disease severity was not accounted for (66). Use of theophylline has been associated with a reduced (67) or increased (66) incidence of preeclampsia. Randomized trials are needed to assess the effectiveness of oral theophylline in pregnancy.
Anti-Allergy Medications The use of sodium cromoglycate (8,54), sympathomimetics such as phenylephrine and pseudoephedrine (54,60,67), and antihistamines such as chlorpheniramine (54) during pregnancy has not been associated with increased incidence of congenital malformations. However, studies have involved small numbers and may have been underpowered to detect small differences. Taking available evidence into account, these agents appear to be safe. There are no published data on the safety of leukotriene receptor antagonists in pregnancy, and therefore their routine use cannot be recommended.
Practical Considerations We recommend that all pregnant women with asthma, except those with the mildest disease, should be treated by an obstetrician and a pulmonologist (Figure). Control of asthma should be optimized preconception; patient education is of paramount importance to this end. The appropriate inhaler device should be chosen to suit individual technique and ease of use. Twice-daily monitoring of peak expiratory flow and regular review of peak flow charts may benefit patients with moderate to severe asthma. A personalized self-management plan constructed according to the patient’s needs, understanding, and motivation facilitates care. This provides guidance for the management of deteriorating symptoms or flows.
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slow, as patients deteriorate at different rates following withdrawal. Reductions should take place every 1 to 3 months by decreasing the dose by 25% to 50% at each step. For those whose symptoms continue despite an adequate dose of inhaled corticosteroids, the addition of a long-acting 2-adrenoceptor agonist, such as salmeterol or formoterol, may be necessary (68 –70). This treatment step should be made in consultation with a pulmonologist or allergist, because of the uncertainty about the safety of those medications. As an alternative, or in addition, the inhaled corticosteroid dose may be increased to a maximum daily dose of 2,000 g of beclomethasone or equivalent, together with the use of a regular bronchodilator. Addition of oral slow-release theophylline could be considered at this point, although its efficacy is uncertain. Persistent symptoms at this stage require systemic corticosteroids. Once asthma is controlled, consideration should be given to stepping down treatment at 1- to 3-month intervals. The management of acute severe asthma during pregnancy is essentially the same as that of the nonpregnant patient and is described in several sets of guidelines (47– 49).
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Figure 1. Management of asthma during pregnancy.
Patients should seek immediate medical help if an asthma exacerbation is severe, therapy does not provide rapid improvement, sustained improvement is not achieved, or further deterioration occurs. In the absence of an up-to-date consensus about treatment, we generally follow guidelines developed for nonpregnant adults (47). For those with mild intermittent asthma, the occasional use of an inhaled 2-adrenoceptor agonist for symptom relief is adequate. Patients requiring bronchodilator use at least once daily should be started on regular anti-inflammatory treatment (57). Inhaled beclomethasone or budesonide (100 to 800 g daily) are the most commonly used agents during pregnancy. The dose should be titrated against symptoms, 2-adrenoceptor agonist requirements, and peak expiratory flow. Patients should be maintained on the minimum dose of inhaled corticosteroid necessary to control symptoms. Stepping down the dose of inhaled corticosteroid once asthma is controlled is important. The reduction in dose should be
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65. Carter BL, Driscoll CE, Smith GD. Theophylline clearance during pregnancy. Obstet Gynecol. 1986;68:555. 66. Stenius-Aarniala B, Riikonen S, Teramo K. Slow-release theophylline in pregnant asthmatics. Chest. 1995;107:642– 647. 67. Dombrowski MP, Bottoms SF, Boike GM, Wald J. Incidence of preeclampsia among asthmatic patients lower with theophylline. Am J Obstet Gynecol. 1986;155:265–267. 68. Greening A, Ind P, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet. 1994;334:219 –224. 69. Woolcock A, Lundback B, Ringdal N, Jacques L. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med. 1996;153:1481–1488. 70. Pauwels R, Lofdahl C, Postma D, et al. Effect of inhaled formoterol and budesonide on exarcebations of asthma. N Engl J Med. 337: 1997:1405–1411.
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Asthma in Pregnancy Kia Soong Tan, MD, Neil C. Thomson, MD Although about 1% of pregnant women have asthma, it is often underrecognized and suboptimally treated. The course of asthma during pregnancy varies; it improves, remains stable, or worsens in similar proportions of women. The risk of an asthma exacerbation is high immediately postpartum, but the severity of asthma usually returns to the preconception level after delivery and often follows a similar course during subsequent pregnancies. Changes in 2-adrenoceptor responsiveness and changes in airway inflammation induced by high levels of circulating progesterone have been proposed as possible explanations for the effects of pregnancy on asthma. Good control of
asthma is essential for maternal and fetal well-being. Acute asthmatic attacks can result in dangerously low fetal oxygenation. Chronically poor control is associated with pregnancy-induced hypertension, preeclampsia, and uterine hemorrhage, as well as greater rates of cesarian section, preterm delivery, intrauterine growth retardation, low birth weight, and congenital malformation. Women with well-controlled asthma during pregnancy, however, have outcomes as good as those in their nonasthmatic counterparts. Inhaled therapies remain the cornerstone of treatment; most appear to be safe in pregnancy. Am J Med. 2000;109:727–733. 䉷2000 by Excerpta Medica, Inc.
A
likely than women without asthma to have hyperemesis gravidarum (4) and twice as likely to suffer uterine hemorrhage (4,5). This latter risk is greatest in those taking corticosteroids (5). A large retrospective analysis of 2,289 pregnant women with asthma found longer hospital stays and an almost twofold increase in preeclampsia, placenta previa, and cesarian sections (6). This study and others (7,8) suggest that pregnancy-induced hypertension is also two to three times more common in women with asthma, especially in those treated with corticosteroids (8). Premature labor is more common (4,6), perhaps markedly so (9), in corticosteroid-dependent patients. Women with asthma are also more likely to require induction of labor (14% versus 9% in controls) (4). However, other studies have demonstrated that maternal outcomes in those with mild asthma are no different from those in nonasthmatic women (8,10 –12). Our interpretation is that the risk of maternal morbidity is increased only in women with severe asthma, especially those requiring oral corticosteroids. There is little evidence of an association between asthma in pregnancy and maternal mortality (5,8,10 –12). In 1970, one prospective study reported only two deaths among 227 patients with asthma compared with none in 30,861 controls (13). In the ensuing 30 years, no other reports of asthma-related mortality in pregnancy have been published, perhaps reflecting improvements in disease management and obstetric care.
sthma is a common and potentially serious medical problem in pregnant women (1). Retrospective data suggest a prevalence of approximately 1% in pregnancy (2,3), but these estimates may be conservative due to lack of reporting and underdiagnosis. The objectives of asthma management are similar to those in nonpregnant patients, namely, to maximize lung function, control asthma symptoms, prevent exacerbations, and minimize drug side effects. To manage patients optimally, health professionals need to appreciate the effects of asthma on pregnancy, the influence of pregnancy on asthma control, and the efficacy and safety of asthma treatment in pregnant women. This article explores evidence for these objectives and discusses practical issues involved in treating pregnant women with asthma. To do so, we performed a Medline search of all English language reports of asthma and pregnancy from 1966 to 2000 using the keywords “asthma” and “pregnancy.” All relevant clinical studies were reviewed.
EFFECTS OF ASTHMA ON PREGNANCY Maternal Health Asthma in pregnancy can increase maternal morbidity (Table 1). Affected women are almost three times more
From the Department of Respiratory Medicine, Western Infirmary, Glasgow, Scotland. Requests for reprints should be addressed to Kia Soong Tan, MD, Department of Respiratory Medicine, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, Scotland, United Kingdom. Manuscript submitted August 26, 1999, and accepted in revised form August 9, 2000. 䉷2000 by Excerpta Medica, Inc. All rights reserved.
Fetal Health Adverse perinatal outcomes have been linked with asthma during pregnancy, although the outlook has improved recently (Table 2). Fetal compromise appears to 0002-9343/00/$–see front matter 727 PII S0002-9343(00)00615-X
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Table 1. Studies of the Effects of Asthma on Maternal Outcome
First Author (Reference)
Asthma
Control
Pregnancy-Induced Hypertension/ Preeclampsia
Gestational Diabetes
Uterine Hemorrhage
Asthma
Asthma
Asthma
Control
5* 1 — 2 18* 1
2 1 — 2 8 1
Control
Number of Patients Bahna (4) Stenius-Aarniala (8) Schatz (12) Jana (10) Alexander (5) Demissie (6)
381 198 486 182 817 2289
112,530 198 486 364 13,709 9156
Control
Percent 11* 14* 10 18 10 5*
5 5 7 17 11 2
— 2 1 2 1 —
— 3 1 2 2 —
* P ⬍0.05 compared with controls.
EFFECTS OF PREGNANCY ON ASTHMA
be related to poor asthma control. Recurrent acute asthma can lead to intrauterine growth retardation, prematurity, and low birth weight (10,14). Maternal hyperventilation, hypoxemia, and hypocapnia are thought to be underlying factors (15). For example, the mean birth weight of neonates born to mothers in India who required emergency treatment for acute asthma was about 400 g lower than that among neonates born to women not requiring admission or controls (10). Fitzsimmons et al (14) found that 19% of women who required emergency therapy for acute asthma had premature births, compared with 12% of those who did not require emergency treatment. They also observed a detrimental effect of poorly controlled asthma on birth weight. Conversely, another study found that the better the lung function—as measured by forced expiratory volume in 1 second—the lower the risk of intrauterine growth retardation (16). The concept that better asthma control improves pregnancy outcomes is also indirectly supported by studies that have reported similar outcomes among patients managed by asthma specialists and women without asthma (8,10,12,17,18).
Several studies have observed that pregnancy may alter the course of asthma (Table 3). Gluck et al (19) reviewed nine studies, performed between 1930 and 1967, that involved 1,087 pregnancies in asthmatic women. On average, asthma improved in 36% of women during pregnancy, remained unchanged in 41%, and deteriorated in 23%. These studies were retrospective, subject to recall bias, and used subjective questionnaire-based assessment of asthma control. More recent studies suggest that the effects of pregnancy on asthma are unpredictable, but that on average, a third of women worsen, a third improve, and a third remain unchanged (Table 3). Those with more severe disease before conception are at greater risk of deterioration (19,20). Symptoms tend to improve during the third trimester (20,21). Postpartum, 26% to 42% of women experience an exacerbation of asthma (20,21). Schatz et al (21) found that 59% of women had similar asthma control in successive pregnancies. There are few data on airway function in pregnant women with asthma. Sims et al (22) detected no change in spirometry values throughout pregnancy and after deliv-
Table 2. Studies of the Effects of Asthma on Perinatal Outcome First Author (Reference)
Prematurity (⬍ 37 weeks) Asthma
Control
Asthma
Control
Low Birth Weight (⬍ 2.5 kg) Asthma
Number of Patients Gordon (13) Bahna (4) Fitzsimmons (14) Jana (10) Schatz (12) Alexander (5) Demissie (6)
277 381 56 182 486 817 2289
30,861 112,530 General population 364 486 13,709 9156
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Asthma
Control
6* 3 0 0 2 — —
3 2 1 2 1 — —
Percent 14 7* 13 12 5 4 18*
* P ⬍0.05 compared with controls. 728
Control
Perinatal Mortality
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15 7* 17 17 4 5 9*
11 4 7 21 3 6 6
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Table 3. Studies of the Course of Asthma during Pregnancy First Author (Reference)
Number of Patients Worsened Same Improved Percent
Gluck (19) Gluck (19) Stenius-Aarniala (8) Schatz (21) White (20)
1087 47 198 366 31
23 43 42 35 9
41 43 40 33 22
36 14 18 28 69
ery in 27 asthma patients and controls. Another study measured airway hyperresponsiveness to methacholine, which is a direct smooth muscle bronchoconstrictor and an indirect marker of airway inflammation, in 16 pregnant women with asthma. Symptoms, drug requirements, and serum progesterone and estradiol levels before conception through confinement were also measured (23). There was a modest improvement in bronchial hyperresponsiveness during the second trimester, with a gradual return to the prepregnancy level by the third trimester. There was no correlation between progesterone levels and responsiveness to methacholine, refuting the hypothesis that progesterone might reduce airway smooth muscle contractility (24). Given that premenstrual exacerbations affect 33% to 40% of women with asthma (25–27), there are reasons to suspect that the cyclical rise and fall of levels of sex hormones may influence airway function, although initial clinical studies have been negative (28 –30). Recently, however, responsiveness to methacholine (31) and adenosine monophosphate (32) has been shown to increase during the luteal phase in women with asthma. Healthy women have a cyclical variation in lymphocyte 2-adrenoceptor density and responsiveness to isoprenaline (a nonselective -adrenoreceptor agonist), with higher levels during the luteal phase (33). This facilitatory effect on 2-adrenoceptors is most likely to be progesterone-mediated (34). However, this pattern is lost in women with asthma (32), in whom administering progesterone produces a “paradoxical” down-regulation in lymphocyte 2-adrenoceptor density and responsiveness (35). It is conceivable that the very high levels of progesterone in pregnancy may exert a similar effect, and thus worsen asthma control. However, it is uncertain whether lymphocyte 2-adrenoceptors provide a reliable surrogate marker for airway 2-adrenoceptors (36,37). Studies of the effects of progesterone and other hormones on 2adrenoceptor function and regulation during pregnancy are required. Fetal sex may influence asthma, providing additional evidence of possible hormonal effects. Among 34 pregnant women with asthma who were unaware of their child’s sex, those who gave birth to boys were more likely
to report improved asthma symptoms during pregnancy (38). Another study found that use of drugs to treat asthma was less common among mothers of boys (39). Female sex hormones have been shown to alter airway hyperresponsiveness in asthma (40) and influence skinprick tests to allergens (41). Thus the hormonal changes of pregnancy could influence underlying airway inflammation. This possibility has not been examined directly, probably because the use of bronchoalveolar lavage and bronchial biopsy—the “gold standard” for assessing airway inflammation—are unacceptable in pregnancy. Alternative, noninvasive methods for studying asthmatic airway inflammation are available: measurement of exhaled nitric oxide and analysis of induced sputum (42– 44). Exhaled nitric oxide is also elevated during the luteal phase in healthy women (45). Other causes of asthma deterioration in pregnancy have been suggested, including refractoriness to cortisol, prostaglandin F2␣-mediated bronchoconstriction, viral or bacterial respiratory infections, gastroesophageal reflux, stress, increased inflammatory mediators (eg, placental major basic protein) reaching the lungs, and reduced functional residual capacity (46). Further research is required to substantiate these hypotheses.
TREATMENT There are few consensus treatment guidelines for managing pregnant women with asthma. The National Asthma Education and Prevention Program issued specific guidelines in the United States in 1993 (47). The most recent British (48) and American (49) guidelines on the general management of asthma offer no specific advice about its treatment during pregnancy. Little is known about the effects of treatment on congenital malformations (50). However, the American College of Allergy, Asthma and Immunology’s Registry for Allergic, Asthmatic Pregnant Patients will collect data on 800 women who require inhaled corticosteroids during pregnancy (51). This and other studies will facilitate determining the efficacy and safety of asthma medications in pregnancy (52).
2-Adrenoceptor Agonists
Inhaled 2-adrenoceptor agonists are the most frequently used asthma treatment. Two studies have examined the effects of short-acting agents, mainly metaproterenol, terbutaline, and albuterol, during pregnancy (53,54). No adverse effects on rates of congenital malformation, perinatal mortality, low birth weight, or complications of labor and delivery were observed, and it has been concluded that these drugs are safe in pregnancy (54). Little is known, however, about the safety of long-acting 2-adrenoceptor agonists (eg, salmeterol and formoterol), and they should therefore be used only after consultation with an asthma specialist about alternate treatments. Intrave-
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nous 2-adrenoceptor agonists are sometimes required to treat severe acute asthma. However, these drugs should be used with caution in pregnant women because of their association with pulmonary edema (55,56), especially if they are administered with systemic corticosteroids to accelerate fetal lung maturation.
Corticosteroids Inhaled corticosteroid therapy remains the mainstay of the anti-inflammatory treatment of asthma (57). These agents are very effective in preventing asthma exacerbations during pregnancy (11,58). In a prospective study of 504 pregnant women with asthma, those taking inhaled corticosteroids were four times less likely than their nontreated counterparts to suffer an exacerbation (11). One randomized controlled trial found a 55% reduction in readmission rates for acute asthma in pregnant women taking inhaled beclomethasone (58). Based on animal studies, there were some initial fears about teratogenicity of inhaled corticosteroids (59). However, inhaled beclomethasone and budesonide, and oral prednisone and prednisolone, have not been associated with congenital malformations, stillbirths, or fetal mortality in most studies of women (14,17,54,60,61), although there have been exceptions (6). One study did find that cleft palate was more common in the children of nonasthmatic women who took systemic corticosteroids during the first trimester (62). Corticosteroids may worsen maternal morbidity, especially among patients who require oral administration for severe asthma. Their use has been associated with gestational diabetes (9), pregnancy-induced hypertension (8), and antepartum and postpartum hemorrhage (5). However, not all studies have reported an association with uterine hemorrhage or preeclampsia (9,17). If corticosteroids do increase maternal morbidity, it is not evident whether this is due to a direct pharmacologic effect or because they are a marker for worse disease. It is not known if oral corticosteroid use in pregnant women with asthma increases fetal morbidity. Lowbirth-weight infants may be more common (9,63), and preterm delivery rates may be increased (9). Again, these effects may be drug-related, indicators of asthma severity, or both. However, the use of oral corticosteroids (17) and the combination of inhaled beclomethasone and oral corticosteroids (14,60) among pregnant women treated in specialized pulmonary units did not worsen outcomes, as compared with the general population. Physicians appear to be reluctant to prescribe corticosteroids for pregnant women. A multicenter study found that pregnant women with asthma were significantly less likely to be prescribed corticosteroids in the emergency department: only 44% of pregnant women were treated with corticosteroids compared with 66% of nonpregnant women (64). Those who were admitted to the hospital 730
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were less likely to be treated with corticosteroids at discharge, and were almost three times more likely to experience a subsequent exacerbation, compared with nonpregnant women (64). Inhaled beclomethasone and budesonide have been widely used during pregnancy, and both appear to be safe. There are few studies, however, of the use of triamcinolone, flunisolide, or fluticasone during pregnancy. Thus it would seem prudent to initiate treatment in pregnant women with either inhaled beclomethasone or budesonide.
Theophylline Current evidence suggests that theophyllines are safe in pregnancy (54). Clearance may be reduced by 20% to 35% during the third trimester (65), however, requiring close monitoring of serum levels. The use of intravenous aminophylline has no additional benefit over systemic corticosteroids in the treatment of acute asthma in pregnant women (58). Studies of oral theophylline during pregnancy have had conflicting results and are of little practical help. In one study, patients who had been treated with oral slow-release theophylline had more asthma exacerbations than controls, but disease severity was not accounted for (66). Use of theophylline has been associated with a reduced (67) or increased (66) incidence of preeclampsia. Randomized trials are needed to assess the effectiveness of oral theophylline in pregnancy.
Anti-Allergy Medications The use of sodium cromoglycate (8,54), sympathomimetics such as phenylephrine and pseudoephedrine (54,60,67), and antihistamines such as chlorpheniramine (54) during pregnancy has not been associated with increased incidence of congenital malformations. However, studies have involved small numbers and may have been underpowered to detect small differences. Taking available evidence into account, these agents appear to be safe. There are no published data on the safety of leukotriene receptor antagonists in pregnancy, and therefore their routine use cannot be recommended.
Practical Considerations We recommend that all pregnant women with asthma, except those with the mildest disease, should be treated by an obstetrician and a pulmonologist (Figure). Control of asthma should be optimized preconception; patient education is of paramount importance to this end. The appropriate inhaler device should be chosen to suit individual technique and ease of use. Twice-daily monitoring of peak expiratory flow and regular review of peak flow charts may benefit patients with moderate to severe asthma. A personalized self-management plan constructed according to the patient’s needs, understanding, and motivation facilitates care. This provides guidance for the management of deteriorating symptoms or flows.
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slow, as patients deteriorate at different rates following withdrawal. Reductions should take place every 1 to 3 months by decreasing the dose by 25% to 50% at each step. For those whose symptoms continue despite an adequate dose of inhaled corticosteroids, the addition of a long-acting 2-adrenoceptor agonist, such as salmeterol or formoterol, may be necessary (68 –70). This treatment step should be made in consultation with a pulmonologist or allergist, because of the uncertainty about the safety of those medications. As an alternative, or in addition, the inhaled corticosteroid dose may be increased to a maximum daily dose of 2,000 g of beclomethasone or equivalent, together with the use of a regular bronchodilator. Addition of oral slow-release theophylline could be considered at this point, although its efficacy is uncertain. Persistent symptoms at this stage require systemic corticosteroids. Once asthma is controlled, consideration should be given to stepping down treatment at 1- to 3-month intervals. The management of acute severe asthma during pregnancy is essentially the same as that of the nonpregnant patient and is described in several sets of guidelines (47– 49).
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Figure 1. Management of asthma during pregnancy.
Patients should seek immediate medical help if an asthma exacerbation is severe, therapy does not provide rapid improvement, sustained improvement is not achieved, or further deterioration occurs. In the absence of an up-to-date consensus about treatment, we generally follow guidelines developed for nonpregnant adults (47). For those with mild intermittent asthma, the occasional use of an inhaled 2-adrenoceptor agonist for symptom relief is adequate. Patients requiring bronchodilator use at least once daily should be started on regular anti-inflammatory treatment (57). Inhaled beclomethasone or budesonide (100 to 800 g daily) are the most commonly used agents during pregnancy. The dose should be titrated against symptoms, 2-adrenoceptor agonist requirements, and peak expiratory flow. Patients should be maintained on the minimum dose of inhaled corticosteroid necessary to control symptoms. Stepping down the dose of inhaled corticosteroid once asthma is controlled is important. The reduction in dose should be
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65. Carter BL, Driscoll CE, Smith GD. Theophylline clearance during pregnancy. Obstet Gynecol. 1986;68:555. 66. Stenius-Aarniala B, Riikonen S, Teramo K. Slow-release theophylline in pregnant asthmatics. Chest. 1995;107:642– 647. 67. Dombrowski MP, Bottoms SF, Boike GM, Wald J. Incidence of preeclampsia among asthmatic patients lower with theophylline. Am J Obstet Gynecol. 1986;155:265–267. 68. Greening A, Ind P, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet. 1994;334:219 –224. 69. Woolcock A, Lundback B, Ringdal N, Jacques L. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med. 1996;153:1481–1488. 70. Pauwels R, Lofdahl C, Postma D, et al. Effect of inhaled formoterol and budesonide on exarcebations of asthma. N Engl J Med. 337: 1997:1405–1411.
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