INTRODUCTION — Asthma is a common medical condition that impacts 3 to 8 percent of all pregnancies [1-3]. Pregnancy may be associated with changes in the course of asthma, and asthma may affect the outcome of pregnancy. The principles of pharmacologic therapy for asthma during pregnancy are similar to those in nonpregnant patients. When considering the use of asthma medications in a person who is pregnant or anticipates pregnancy, concerns about potential risks of asthma medication are generally outweighed by the potential adverse effects of untreated asthma.
The management of asthma in pregnancy, including the safety data for specific asthma medications, general management, and recommended pharmacotherapy for acute and chronic asthma in pregnancy, is reviewed here. An overview of asthma management and the physiology and clinical course of asthma in pregnancy are discussed separately. (See "An overview of asthma management" and "Asthma in pregnancy: Clinical course and physiologic changes".)
ASSESSING DRUG SAFETY IN PREGNANCY — Information about potential adverse effects must be interpreted with an understanding that the baseline frequency of complications in pregnancy is relatively high, even in the absence of asthma or other disorders. In the United States, major congenital anomalies occur in 2 to 4 percent of live-born infants. An overview of congenital malformations and a discussion of genetic and environmental causes are provided separately. (See "Birth defects: Approach to evaluation".)
There is a small but significant increase in complications of pregnancy in patients with asthma at baseline [4]. A large representative study suggests that patients with asthma, on average, have a 15 to 20 percent increased risk of perinatal mortality, preeclampsia, preterm delivery, or low birth weight infants compared with those without asthma, and that patients with more severe asthma have a 30 to 100 percent increased risk (table 1) [4].
The US Food and Drug Administration (FDA) has discontinued use of letter categories to designate pregnancy risk and now requires information from available human and animal studies about: (1) known or potential maternal or fetal risks, (2) dose adjustments needed during pregnancy and the postpartum period, and (3) benefit/risk considerations [5].
Of note, a drug that has a strong relative contraindication to use in the first trimester may have a good safety profile when used later in pregnancy when organogenesis has been completed (eg, palate has closed).
In addition to the safety of the medication itself, a topical (inhaled) medication would appear to be preferable to a systemic one due to reduced likelihood of systemic circulation and transplacental transfer to the fetus. An older medication with a "track record" may be preferable to a newer one. Finally, absolute and relative efficacy must also be considered in the choice of a medication for use during pregnancy.
MAINTAINING ASTHMA CONTROL — Asthma may improve, worsen, or remain unchanged in severity during pregnancy [6]. The potential mechanisms involved and clinical implications of these findings are discussed separately. (See "Asthma in pregnancy: Clinical course and physiologic changes".)
The two primary goals of asthma management, ie, prevention of acute exacerbations and optimization of ongoing asthma control, are unchanged in the setting of pregnancy and should serve to maximize both maternal and fetal health [7]. While use of any medication during pregnancy raises concerns about potential adverse effects on the mother or fetus, the benefit of active treatment to maintain asthma control and prevent exacerbations outweighs the potential risks of routinely used asthma medications. For example, one study of 91,000 patients with asthma during pregnancy found that those with poor asthma control had a higher incidence of recurrent (≥3) pregnancy loss compared with those whose asthma was well-controlled (odds ratio 1.6) [8].
Most routinely used controller medicines are safe during pregnancy. Potential adjustments to pharmacologic therapy are discussed further below.
Adjustments to pharmacologic therapy in pregnancy — The general principles of pharmacologic therapy for asthma during pregnancy are similar to those in nonpregnant patients and involve a step-wise approach to achieve and maintain asthma control, as recommended by national and international guidelines (table 2) [9-11]. The details of this approach are discussed separately. (See "An overview of asthma management" and "Treatment of intermittent and mild persistent asthma in adolescents and adults".)
Current guidelines emphasize the following points [9-12]:
●All patients should have access to an inhaler for quick relief of asthma symptoms. Choices include a short-acting beta-agonist (eg, albuterol) or a combination inhaler with formoterol and a low-dose inhaled glucocorticoid (eg, formoterol-budesonide).
●For patients with mild persistent or more severe asthma, inhaled glucocorticoids reduce exacerbations during pregnancy, and cessation of inhaled glucocorticoids during pregnancy increases the risk of an exacerbation. Budesonide has been the preferred inhaled glucocorticoid for use during pregnancy, as more published gestational human data are available for that medication [13,14]. However, other inhaled glucocorticoids could be continued if the patient was well-controlled on one of these medications prior to pregnancy, and more recent data for fluticasone have been reassuring regarding the risk for low birth weight (<2500 grams), small for gestational age (<10th percentile for babies of same gestational age), preterm birth (<37 weeks) [15], and major congenital malformations [16].
●Salmeterol has been recommended as the inhaled long-acting beta agonist of choice in the United States due to the longer duration of clinical experience with this agent compared with formoterol. However, retrospective cohort studies provide reassuring data for both salmeterol and formoterol [15,17]. Neither of these agents should be used in asthma without an inhaled glucocorticoid.
●Although it is not the preferred therapy, a leukotriene modifier (montelukast or zafirlukast) could be considered as an alternative for mild persistent asthma or as add-on therapy to inhaled glucocorticoids, especially for patients who have shown a uniquely favorable response to this class of agents prior to pregnancy. More pregnancy data are available for montelukast than zafirlukast. (See 'Leukotriene modifiers' below.)
Safety of specific medications — Experience with many of the medications used to treat asthma suggests minimal or no known adverse effects for their use during pregnancy [3,11,12,18-24]. Additional information and links to national databases for reproductive teratology are provided separately. (See "Birth defects: Approach to evaluation".)
The following sections review the safety information that is available for each of the major drug classes used in the treatment of asthma. Additional information on the fetal and neonatal risks of maternal drug ingestion during pregnancy and lactation is available from the following resources:
●Perinatology: Drugs in pregnancy and breastfeeding
●MotherToBaby: Medications and more during pregnancy and breastfeeding
Inhaled beta-adrenergic agonists — The majority of reports provide reassurance regarding the use of inhaled beta-agonists during pregnancy [25-28]. Clinical experience is greater with the older agents (eg, albuterol) than with the newer ones (eg, formoterol, salmeterol).
●Short-acting beta-adrenergic agonists — The short-acting, selective beta-2 adrenergic bronchodilators (SABAs) are used to provide quick relief of asthma symptoms and appear to be relatively safe during pregnancy. However, some case-control studies have suggested a slight increase in risk of certain infant abnormalities, as noted by the following reports:
•In a case-control study, a small increased risk of gastroschisis was reported among infants exposed in utero to bronchodilators [29].
•In a case-control study using European registry data, gastroschisis (odds ratio [OR] 1.89, 95% CI 1.12-3.20) and cleft palate (OR 1.63, 95% CI 1.05-2.52) were associated with a greater likelihood of first trimester beta-agonist exposure [30].
•An association with cardiac defects was noted in a cohort study that examined the effect of exposure to bronchodilator therapy during pregnancy [31].
•A case control study reported a 30 percent increased risk (OR 1.3, 95% CI 1.1-1.5) of autism spectrum disorder in children exposed to maternal beta-2 adrenergic receptor agonist drugs during gestation [32].
One problem with assessing the consequences of bronchodilator use in pregnancy is confounding introduced by indication; SABA use is a marker for poorly-controlled asthma and more frequent exacerbations, which may independently contribute to the development of congenital anomalies [33]. Furthermore, some studies only have access to data about prescriptions filled and not the frequency of actual use [30]. Even if the statistical associations for relative risk are valid, the anomalies mentioned above are infrequent. Therefore, the absolute increase in risk is very small and, as noted earlier, less than the risk of poorly-controlled maternal asthma.
●Long-acting beta-adrenergic agents — Clinical experience with inhalation of the long-acting, selective beta-2 adrenergic bronchodilators (LABAs) during pregnancy is less extensive than with the SABAs (table 3). Salmeterol is not expected to increase the risk of congenital anomalies, based on data from animal studies and limited human experience [34]. Animal studies are also reassuring for formoterol, although data from human pregnancies are limited [35,36]. A retrospective database study showed that salmeterol and formoterol do not increase the risk of delivering low birth weight, small for gestational age, or preterm infants [15,17]. Given these findings, continuation of a LABA during pregnancy is reasonable if a LABA has been needed (in combination with an inhaled glucocorticoid) to achieve asthma control before pregnancy [10,11].
Human safety data for newer LABAs, such as indacaterol, olodaterol, and vilanterol are lacking. Some adverse effects were noted in animal studies of olodaterol but are not reported with indacaterol or vilanterol. Of these agents, the only one that is available in an inhaled glucocorticoid combination inhaler is vilanterol, which is available with fluticasone furoate.
When comparing a combination LABA plus inhaled glucocorticoid versus monotherapy with a higher dose of the inhaled glucocorticoid, the risk of congenital malformations appears similar. In a study of 1302 pregnant patients with asthma, the odds ratio for a major congenital malformation was not increased (OR 1.1, 95% CI 0.6-1.9) when a LABA plus low dose inhaled glucocorticoid was compared with a medium dose inhaled glucocorticoid or when a LABA plus medium-dose inhaled glucocorticoid was compared with a high-dose inhaled glucocorticoid (OR 1.2, 95% CI 0.5-2.7) [37].
The indications for LABA therapy in asthma, the importance of combining LABA therapy with an inhaled glucocorticoid, and the controversy regarding the safety of LABA therapy are discussed separately. (See "Treatment of moderate persistent asthma in adolescents and adults", section on 'Medium-dose inhaled GCs plus LABA' and "Treatment of severe asthma in adolescents and adults", section on 'Combination inhaled GC/LABA' and "Beta agonists in asthma: Acute administration and prophylactic use".)
Oral/Systemic glucocorticoids — Systemic glucocorticoids have been used fairly extensively during pregnancy to treat asthma exacerbations and rarely for control of severe asthma. For each pregnant woman, the potential risks of gestational oral glucocorticoids must be balanced against the risks to the mother or infant of inadequately treated asthma. As the risks of severe uncontrolled asthma include maternal or fetal mortality, these risks are considered to be greater than the potential risk of systemic glucocorticoids. Thus, oral glucocorticoids should be used during pregnancy when indicated for the management of severe asthma [12,19].
Several potential areas of concern have been raised with systemic glucocorticoids: congenital malformations (primarily cleft palate), preeclampsia, gestational diabetes, low birth weight, and neonatal adrenal insufficiency. Among the studies in which systemic glucocorticoids were used for the management of asthma during pregnancy [25,26,38-41], some showed a slightly increased risk of prematurity and a slightly higher risk of low birth weight (<2500 grams) [25,26,40].
●Congenital malformations – Data from animal studies in several species suggest that high dose systemic glucocorticoids may lead to cleft palate. Human studies are less concerning but a possible effect cannot be dismissed. Palatal closure is usually complete by the 12th week of pregnancy, so potential risk would be limited to administration during the first trimester. The risk of cleft lip/palate with systemic glucocorticoid use is discussed separately. (See "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate", section on 'Genetic factors'.)
●Preterm birth and low birth weight – A large, prospective, cohort study of 2123 pregnant patients with asthma recruited from 16 centers in the United States in the period from December 1994 to February 2000 found that oral glucocorticoid use was significantly associated with preterm birth (before 37 weeks of gestation, OR 1.54, 95% CI 1.02-2.33) and low birth weight (<2500 grams, OR 1.80, 95% CI 1.13-2.88) [25]. Increased prematurity and/or lower birth weights have been noted in other studies as well [26,39,40,42-46]. The authors did not evaluate the relationship between these effects and the dose or duration of therapy.
●Other adverse outcomes – An increased risk of preeclampsia has been associated with oral glucocorticoid use in several studies [38,47,48]. Neonatal adrenal insufficiency following maternal administration of glucocorticoids is distinctly unusual, probably because the nonhalogenated glucocorticoids are largely metabolized to inactive metabolites by the placenta [49]. Gestational diabetes and hypertension are additional potential maternal complications of systemic glucocorticoid administration [44].
However, it remains possible that the consequences of severe uncontrolled asthma caused some or all of these reported adverse effects, given that asthma symptoms were severe enough to require oral glucocorticoids.
Inhaled glucocorticoids — In contrast with oral/systemic glucocorticoids, the safety data on inhaled glucocorticoids are reassuring [2,10,13,25,27,38,39,48,50-60]. Budesonide, beclomethasone, and fluticasone are preferred among the inhaled glucocorticoids as more safety information is available for these agents [3,10]. However, if the patient’s asthma was already well-controlled on an alternate agent (eg, ciclesonide, mometasone) prior to pregnancy, there is no need to change therapy.
Examples of studies assessing the safety of inhaled glucocorticoids include the following population based studies:
●In a meta-analysis of data on 519,242 pregnancies from three cohort studies, inhaled glucocorticoids were associated with an odds ratio for anal atresia of 3.4 (99% CI 1.15-10.04) [24]. However, no increased risk of inhaled glucocorticoids was found in relationship to 35 other specific anomalies, and chance (multiple comparisons) or residual confounding cannot be excluded as an explanation for this relationship. Moreover, anal atresia is rare and the absolute risk remains low.
●Use of inhaled budesonide during early pregnancy was assessed in a registry-based cohort study of 2014 Swedish pregnancies [13]. The rate of congenital malformations was not different from that of the general population (3.8 versus 3.5 percent). Additional data from the Swedish Medical Birth Registry reported no clinically significant effects of inhaled budesonide on fetal mortality, gestational age, or fetal growth [51].
●In a population-based study using the United Kingdom's Clinical Practice Research Datalink, the risk of major congenital malformation (MCM) was assessed among 5362 pregnancies with inhaled glucocorticoid exposure during the first trimester and known fetal outcomes at one year of age [16]. Eighty-nine MCMs were identified following exposure to non-fluticasone inhaled glucocorticoids, and 42 following exposure to fluticasone propionate (overall 2.4 percent). When fluticasone was compared with other inhaled glucocorticoids, the adjusted odds ratio for MCM was 1.1 (95% CI 0.5-2.3), suggesting no increase in risk with fluticasone.
●In a retrospective database study, the odds ratios of low birth weight, preterm, or small for gestational age was not significantly different in infants from 3190 mothers exposed to fluticasone propionate compared with 608 mothers exposed to budesonide [15].
●In addition, a separate study of 13,280 pregnancies in patients with asthma confirmed that low to moderate doses of inhaled glucocorticoids were NOT associated with an increased risk of congenital malformations. However, the use of high doses (>1000 mcg/day) during the first trimester was associated with a 63 percent increase in risk of all congenital malformations [57]. The strength of this observation is limited because the study was underpowered to assess the risk of specific malformations, such as cleft palate, which has been associated with maternal use of systemic glucocorticoids. In addition, the authors could not exclude the possibility that greater asthma severity contributed to the overall increased risk of malformations. Benefit-risk considerations favor the use of high dose inhaled glucocorticoids over a lower dose when needed for asthma control to avoid the use of systemic oral glucocorticoids, with the potential risks listed above. (See 'Oral/Systemic glucocorticoids' above.)
Two randomized trials support the efficacy and safety of inhaled glucocorticoids during pregnancy. One study assessed 84 pregnant patients who were managed with or without inhaled beclomethasone after discharge following an asthma hospitalization during pregnancy [61]. Use of this medication significantly decreased the rate of readmission for asthma (12 versus 33 percent), and no adverse events or outcomes were reported. A subsequent study compared inhaled beclomethasone to theophylline in the management of moderate asthma during pregnancy [54]. Although exacerbation rates were similar in the two groups, pulmonary function was better in the beclomethasone group and fewer patients in the beclomethasone group discontinued therapy due to side effects.
Muscarinic antagonists — Muscarinic antagonists (also known as anticholinergic agents), such as ipratropium, glycopyrrolate, and tiotropium, are not generally used as a primary form of therapy for asthma. However, questions may arise about their safety during pregnancy.
The minimal chronotropic effect of inhaled ipratropium in the mother suggests that the inhaled preparation should have negligible chronotropic effects on the fetus. Gestational animal studies are also reassuring for ipratropium [49]. Consequently, inhaled ipratropium, which is sometimes used for quick relief of asthma symptoms during an exacerbation, is felt to be safe for intermittent use during pregnancy [12,62].
The inhaled long-acting muscarinic antagonist (LAMA), tiotropium, is approved by the US Food and Drug Administration (FDA) for use in asthma, but is usually reserved for patients with moderate-to-severe asthma that is not controlled with a LABA-inhaled glucocorticoid combination (table 3). The safety of inhaled tiotropium during pregnancy is uncertain as adverse effects were reported with high doses in animal studies and human fetal outcomes have not been reported [10]. Other LAMAs (eg, aclidinium, glycopyrrolate, and umeclidinium) are not approved for use in asthma, although it is reasonable to assume that they would have similar effects.
Leukotriene modifiers — Montelukast and zafirlukast (leukotriene receptor antagonists) and zileuton (a 5-lipoxygenase inhibitor) are agents that affect leukotriene synthesis or action. We suggest use of montelukast or zafirlukast, in preference to zileuton, and would reserve these agents for add-on therapy to inhaled glucocorticoids, especially in patients who had a good response to this medication prior to pregnancy [12]. (See "Antileukotriene agents in the management of asthma".)
Accumulating evidence for montelukast and zafirlukast is reassuring, although limited.
●The first prospective, controlled study of the use of leukotriene receptor antagonists in pregnancy followed 96 women taking these medications, 122 women taking SABAs only, and 346 women without asthma. No increase in major congenital anomalies or adverse outcomes was detected in the offspring of patients receiving these medications [63]. A subsequent study with similar design described 180 montelukast-exposed pregnancies compared to 180 disease matched controls and 180 pregnancies in non-asthmatic women. In this study, montelukast did not appear to increase the baseline rate of major malformations, although lower birth weights were seen in both asthmatic groups [64]. Larger studies are needed to detect small increases in adverse pregnancy outcomes or rare congenital anomalies.
A large retrospective insurance claims cohort analysis compared the incidences of selected congenital malformations in infants of mothers exposed to montelukast (n = 1535), inhaled corticosteroids (n = 3918), other asthma medications (n = 8834), and controls with no asthma medications or asthma diagnoses (n = 38,828) [65]. No significant differences between groups were observed.
No teratogenicity was observed with montelukast given to rats or rabbits at doses greater than 300 times the maximum human daily oral dose on an mg/m2 basis [66].
●Animal data on zafirlukast have shown no teratogenicity at oral doses up to 160 times the maximum human daily oral dose on a mg/m2 basis [67]. Human studies are reassuring, although the numbers of pregnancies included are small [63].
In contrast, adverse events were noted in animal reproduction studies of zileuton, and adequate studies of zileuton in pregnancy are lacking [68].
Immunotherapy for allergic asthma — The initiation of subcutaneous or sublingual allergen immunotherapy is not recommended during pregnancy due to the potential harm to the fetus should a systemic allergic reaction occur [25,69]. However, patients who are tolerating maintenance immunotherapy and deriving benefit may continue it. Immunotherapy during pregnancy is discussed in more detail separately. (See "Recognition and management of allergic disease during pregnancy", section on 'Allergen immunotherapy'.)
Biologics
Anti-immunoglobulin E — Omalizumab is a humanized, recombinant IgG1, monoclonal anti-immunoglobulin E antibody approved for add-on therapy in patients with moderate to severe asthma that is inadequately controlled despite appropriate use of inhaled glucocorticoids. Studies of the safety of omalizumab in pregnancy are limited, although available data are reassuring. Immunoglobulin G molecules, such as omalizumab, are known to cross the placenta. (See "Anti-IgE therapy".)
A prospective observational registry study reported pregnancy outcomes of 250 pregnant patients exposed to omalizumab [70]. The incidences of prematurity (15 percent), small for gestational age (9.7 percent), and major congenital malformations were not substantially different from outcomes reported in other studies of patients with more severe asthma. The initiation of omalizumab during pregnancy is not recommended, although if a woman becomes pregnant while receiving omalizumab, it is suggested that therapy can be continued if the benefits are estimated to outweigh the potential harms. (See "Anti-IgE therapy", section on 'Safety in pregnancy and lactation'.)
Anti-interleukin 5 — The anti-interleukin (IL)-5 antibody preparations, benralizumab, mepolizumab and reslizumab, are approved by the FDA for add-on maintenance therapy in patients with severe eosinophilic asthma. The use of these agents in severe asthma is discussed separately. (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-IL-5 therapy'.)
Monoclonal antibodies, including benralizumab, mepolizumab and reslizumab, are likely to cross the placenta in increasing amounts as pregnancy progresses [71,72].
●No evidence of fetal harm due to benralizumab was noted in monkeys at doses approximately 310 times the human dose [73]. One case report of its use during pregnancy for hypereosinophilic syndrome reported transient infant eosinopenia up to seven months of age but no other adverse effects [74].
●No evidence of fetal harm was noted in monkeys treated with intravenous mepolizumab in doses up to 30 times the human dose [75]. There is a case report of a patient who became pregnant while on mepolizumab for severe asthma [76]. She had received two doses and discontinued it when she found out she was pregnant. She delivered a healthy child at term without congenital malformations. Information about a pregnancy exposure registry is provided in the package insert [72].
●Adverse events were not noted with reslizumab in animal studies (mice and rabbits), but human studies are not available [71].
Anti-interleukin 4/13 — Dupilumab binds to the IL-4 receptor alpha subunit, which is also part of the IL-13 receptor. It is approved in the United States for the treatment of moderate to severe eosinophilic asthma or oral corticosteroid-dependent asthma. No adverse developmental effects were observed in offspring born to pregnant monkeys after subcutaneous dupilumab at doses up to ten times the maximum recommended human dose [77]. There are no reports regarding its use for asthma during pregnancy, but there are reports of seven patients who received dupilumab during pregnancy for atopic dermatitis (n = 6) or pemphigoid gestationis (n = 1) [78]. All seven pregnancies led to live births with one premature birth and one low birth weight infant.
Anti-thymic stromal lymphopoietin (TSLP) — Tezepelumab inhibits the action of TSLP, an epithelial cell-derived cytokine involved in the pathogenesis of asthma. There was no evidence of fetal harm following intravenous administration throughout pregnancy in monkeys [79], but there are no human data available.
Rarely used medications — Methylxanthines and cromoglycates are rarely used in the management of asthma due to the availability of alternative agents with greater effectiveness and ease of use.
●Methylxanthines – The clinical use of methylxanthines (theophylline, aminophylline) during pregnancy is limited because of the potential for altered metabolism during pregnancy, the need for drug level monitoring, and the potential for fetal tachycardia and irritability at the time of delivery. Moreover, inhaled glucocorticoids have been shown to be more effective than theophylline for persistent asthma in non-pregnant patients and at least as effective as theophylline with fewer side effects during pregnancy [12,54]. Extensive clinical experience suggests that theophylline does not increase the risk of fetal anomalies [3,21].
Methylxanthine binding to albumin and hepatic clearance are altered during pregnancy, necessitating careful assessment of serum levels and adjustments to dosing over the course of pregnancy. (See "Theophylline use in asthma".)
Like the beta-2 adrenergic agonists, theophylline can inhibit uterine muscle contraction in vitro, but this effect has not been shown to be clinically important. Methylxanthines are transferred across the placenta, leading to theophylline concentrations in neonatal and cord blood that are similar to those in maternal blood [80]. Transient tachycardia and irritability have been reported in some neonates of mothers receiving methylxanthines.
●Cromoglycates – The availability of cromolyn sodium and nedocromil is limited and varies from one country to another. (See "The use of chromones (cromoglycates) in the treatment of asthma", section on 'Limitations on availability'.)
Animal and limited human data on use during pregnancy (n = 318) have not demonstrated an increase in fetal malformations or other adverse effects with cromolyn sodium [38,62]. The one study that reported an increase in musculoskeletal abnormalities with maternal use of chromones had a very small number of exposures (n = 5), limiting the strength of the observation [18]. (See "The use of chromones (cromoglycates) in the treatment of asthma".)
Nonpharmacologic treatments — The main nonpharmacologic interventions to maintain asthma control during pregnancy are patient education, avoidance of irritants (eg, cigarette smoke) and control of allergenic triggers of asthma.
●Patient education – The principles of patient education are generally similar for the pregnant and nonpregnant patient with asthma. Important issues include early recognition of signs and symptoms of an asthma exacerbation, avoidance of precipitating factors, correct use of medications, and development of a treatment plan for acute exacerbations. (See "Asthma education and self-management" and "Patient education: Asthma and pregnancy (Beyond the Basics)".)
The primary issues that are specific for pregnancy are education about the interrelationships between asthma and pregnancy and the safety of asthma medications during pregnancy. The clinician should clearly explain that it is safer for pregnant patients with asthma to take asthma medications than to have ongoing symptoms or exacerbations of asthma [11,33,81]. Patients should be reassured that safe and adequate asthma treatment is possible during pregnancy and that good asthma control can help to minimize the risk of complications [3].
●Smoking cessation – It is critical for the pregnant asthmatic mother to discontinue smoking during pregnancy [82]. First, smoking may predispose the patient to asthma exacerbations, bronchitis or sinusitis, and therefore necessitate an increased need for medication [83]. Second, cigarette smoking is associated with numerous adverse pregnancy outcomes, including spontaneous pregnancy loss, placental abruption, preterm premature rupture of membranes (PPROM), placenta previa, preterm labor and delivery, low birth weight, and ectopic pregnancy. The risks associated with maternal smoking during pregnancy and methods to enable smoking cessation are discussed separately. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate", section on 'Adverse outcomes'.)
●Control of environmental triggers – Control of environmental triggers is a particularly important component of the management of asthma during pregnancy as it helps to reduce the need for pharmacologic intervention. This includes avoiding exposure to allergens and to nonspecific airway irritants, such as tobacco smoke, dust, and environmental pollutants. Particular allergens of concern are dander from pets and antigens from household dust mites. (See "Allergen avoidance in the treatment of asthma and allergic rhinitis" and "Trigger control to enhance asthma management".)
Monitoring — Careful follow-up by clinicians experienced in managing asthma is essential. The optimal frequency of asthma evaluations is not known; generally, the frequency is determined based on the prepregnancy degree of asthma control. In an observational study, visits every four weeks improved adherence to controller medication and asthma control [84]. All pregnant patients should have ready access to their clinician should their symptoms change or increase. It is also important that effective communication exists among the clinician managing the asthma, the patient, and the obstetrician.
Diminished pulmonary function during pregnancy is associated with adverse perinatal outcomes [81,85]; it is therefore important to monitor pulmonary function in patients with asthma. Normal pregnancy-related changes in pulmonary function are discussed separately. (See "Maternal adaptations to pregnancy: Dyspnea and other physiologic respiratory changes", section on 'Physiologic cardiopulmonary changes in pregnancy'.)
Although monitoring pulmonary function using spirometry can be useful, measurement of peak expiratory flow (PEF) or forced expiratory volume in one second (FEV1) using a portable device offers the advantages of less expense and greater ease of serial measurements at home. The frequency of measurement should be individualized; patients with more severe asthma may need to measure their PEF twice a day: upon awakening and approximately 12 hours later. Measurement of PEF during times of worsening symptoms can also provide a real-time assessment of the patient’s condition and guide the need for more intensive therapy. (See "Peak expiratory flow monitoring in asthma".)
An additional issue for pregnant patients with asthma is the difficulty differentiating symptoms due to an exacerbation of asthma from the normal sensation of dyspnea experienced during pregnancy. The presence of cough and wheezing suggests asthma. Objective information can also be obtained by measurement of the PEF or FEV1; reductions in either suggest an asthma exacerbation. (See "Maternal adaptations to pregnancy: Dyspnea and other physiologic respiratory changes" and "Asthma in adolescents and adults: Evaluation and diagnosis", section on 'Pulmonary function testing'.)
A parallel group, randomized trial in 220 pregnant patients with asthma demonstrated reduced exacerbations in patients managed based on an algorithm that included fractional exhaled nitric oxide (FENO) and the Asthma Control Questionnaire (ACQ) compared with an algorithm based on the ACQ alone [86]. Further evaluation of FENO-guided management in other populations of pregnant patients with asthma is needed. (See "Exhaled nitric oxide analysis and applications", section on 'Clinical use of FENO in asthma'.)
ACUTE EXACERBATIONS — Acute asthma exacerbations are common during pregnancy and increase the risk of preeclampsia, gestational diabetes, placental abruption and placenta previa [46,87,88]. The recommended pharmacotherapy of acute asthma during pregnancy does not differ substantially from the management in non-pregnant patients (table 4) [89]. Intensive monitoring of both mother and fetus is essential. (See "Overview of antepartum fetal assessment".)
Maternal and fetal monitoring — For acute asthma exacerbations that require emergency department management or hospitalization, fetal monitoring may be indicated in addition to routine monitoring for asthma [90]. Early consultation with the obstetrics service for co-management is appropriate.
●Maternal monitoring – Continuous measurement of oxygen saturation by pulse oximetry (SpO2) is prudent, aiming for a SpO2 ≥95 percent. Measurement of expiratory airflow with a peak flow meter (or spirometer) is the best method for objective assessment of the severity of an asthma attack. Peak flow measurements can also be used to monitor a patient's response to treatment and as a predictive marker for the possibility of hypercapnia. Normal values for peak expiratory flow are not significantly altered by pregnancy.
The changes in blood gases that occur secondary to acute asthma during pregnancy are superimposed on the "normal" respiratory alkalosis of pregnancy. Thus, an arterial carbon dioxide tension (PaCO2) >35 mmHg or an arterial oxygen tension (PaO2) <70 mmHg associated with acute asthma can represent more severe compromise during pregnancy than in the nongravid state. (See "Asthma in pregnancy: Clinical course and physiologic changes".)
A chest radiograph is not indicated for the majority of asthma exacerbations and is reserved for patients with suspected pneumonia, pneumothorax, or impending or actual respiratory failure.
●Fetal monitoring – Fetal heart rate monitoring is the best available method for determining whether the fetus is adequately oxygenated. After 23 to 24 weeks of gestation, noninvasive fetal heart rate monitoring is appropriate during asthma exacerbations requiring emergency department treatment or hospitalization. The fetal heart rate tracing should be evaluated by a clinician experienced in fetal heart rate assessment. (See "Nonstress test and contraction stress test".)
Supportive care
●Maternal positioning – In general, pregnant patients with acute asthma should rest in a seated or lateral position, rather than supine, particularly in the third trimester, to avoid aortocaval compression by the gravid uterus.
●Hydration – Intravenous fluids are not necessary unless the patient is unable to maintain oral hydration.
Supplemental oxygen — Supplemental oxygen (initially 3 to 4 L/min by nasal cannula) should be administered, adjusting the fraction of inspired oxygen (FiO2) to maintain a PaO2 of at least 70 mmHg and/or oxygen saturation by pulse oximetry of 95 percent or greater [12].
Medications — The recommended agents for management of acute asthma exacerbations in pregnant patients are the same as for asthma exacerbations in nonpregnant adults and adolescents. These agents include inhaled short-acting beta agonists, inhaled ipratropium, oral or intravenous glucocorticoids, and, if appropriate, intravenous magnesium sulfate (table 4). (See 'Safety of specific medications' above and "Acute exacerbations of asthma in adults: Home and office management" and "Acute exacerbations of asthma in adults: Emergency department and inpatient management".)
Additional points regarding pharmacotherapy include the following:
●Systemic glucocorticoids – The indications for systemic glucocorticoids are the same for pregnant patients experiencing an asthma exacerbation as for nonpregnant patients. Patients should be reassured that the benefits of oral glucocorticoids in preventing exacerbations from becoming life-threatening asthma outweigh any risk to the mother or fetus [11,91]. Doses of systemic glucocorticoids for acute asthma exacerbations in pregnancy are not different than those recommended for non-pregnant patients, as glucocorticoid bioavailability does not appear to be affected by pregnancy [92]. (See 'Oral/Systemic glucocorticoids' above and "Acute exacerbations of asthma in adults: Emergency department and inpatient management", section on 'Systemic glucocorticoids'.)
●Ipratropium – The muscarinic antagonist, ipratropium, is often used to treat severe acute asthma exacerbations. As noted above, inhaled ipratropium is felt to be safe during pregnancy [12,62]. (See 'Muscarinic antagonists' above.)
●Intravenous magnesium sulfate – Intravenous magnesium sulfate may be beneficial in acute severe asthma as an adjunct to inhaled beta agonists and intravenous glucocorticoids [92]. Magnesium sulfate is among the most extensively studied medications in pregnancy. It is routinely given to prevent eclamptic seizures and appears to have neuroprotective effects for the neonate if administered prior to preterm birth. It also may decrease the frequency of uterine contractions. (See "Neuroprotective effects of in utero exposure to magnesium sulfate" and "Acute exacerbations of asthma in adults: Emergency department and inpatient management", section on 'Magnesium sulfate'.)
●Parenteral beta-agonists – Parenteral beta-agonists are rarely needed for asthma exacerbations. Due to theoretic concerns that the alpha–adrenergic effects of epinephrine might cause vasoconstriction in the uteroplacental circulation, the Working Group on Pregnancy and Asthma recommended that epinephrine generally be avoided during pregnancy except in the setting of anaphylaxis [12]. For the rare patient who requires use of a systemic beta-agonist to treat asthma, subcutaneous administration of terbutaline is a reasonable choice (table 4).
The safety of terbutaline is suggested by its use as a tocolytic agent (ie, as inhibitors of uterine contraction) in the setting of premature labor. When given for tocolysis, the major maternal adverse effects are hyperglycemia, hypokalemia, and, less commonly, noncardiogenic pulmonary edema. Prenatally exposed neonates have been found to have tachycardia, hypoglycemia, and tremor. However, these effects in the neonate are treatable, reversible, and not considered a contraindication to use. (See "Inhibition of acute preterm labor", section on 'Beta-agonists (eg, terbutaline)'.)
●Intravenous aminophylline/theophylline is NOT generally recommended for use in the emergency management of acute gestational asthma because aminophylline/theophylline provides no additional benefit to optimal inhaled beta agonist and intravenous glucocorticoid therapy [12,61]. In addition, when used in combination with intensive inhaled beta-agonist therapy, intravenous aminophylline causes increased adverse side effects [12].
More detailed discussions of the treatment of acute exacerbations of asthma and acute respiratory failure due to asthma exacerbation are provided separately. (See "Acute respiratory failure during pregnancy and the peripartum period", section on 'Asthma exacerbation' and "Invasive mechanical ventilation in adults with acute exacerbations of asthma" and "Acute exacerbations of asthma in adults: Emergency department and inpatient management".)
Respiratory infections — Most respiratory infections that trigger an exacerbation of asthma are viral rather than bacterial and do not require antibiotic therapy [9]. However, testing for and treatment of influenza and COVID-19 may be appropriate, depending on the time of year and symptom pattern. The treatment of respiratory infections during pregnancy is discussed separately. (See "Approach to the pregnant patient with a respiratory infection".)
PREVENTION OF ASTHMA/WHEEZE IN NEXT GENERATION — Parents with asthma are more likely to have children with asthma due to a complex mixture of genetic and environmental contributors. Among risk factors for asthma or early childhood wheeze, a few are potentially modifiable, such as maternal cigarette smoking during pregnancy, poorly-controlled maternal asthma, and maternal vitamin D insufficiency. To mitigate these risk factors, we advise mothers with asthma to avoid cigarette smoking to protect their own and their child’s respiratory health (see 'Nonpharmacologic treatments' above); we aim for optimal asthma control, stepping asthma therapy up or down, as needed (see 'Maintaining asthma control' above); and we suggest maternal vitamin D supplementation based on the evidence described below (see 'High-dose vitamin D' below). Numerous other risk factors for asthma are discussed separately. (See "Risk factors for asthma".)
High-dose vitamin D — Accumulating evidence suggests that high-dose maternal vitamin D supplementation during pregnancy might reduce the risk of early life asthma/wheeze in the offspring [93,94]. For pregnant patients whose children are at high risk of asthma (eg, one or both parents have asthma), we suggest high-dose vitamin D supplementation (eg, 2000 to 4000 IU/day, preferably D3) in addition to the Recommended Dietary Allowance (RDA) of vitamin D 600 IU/day (in prenatal vitamins). Serum 25-hydroxyvitamin D levels may be helpful to guide high-dose supplementation. (See "Risk factors for asthma", section on 'Vitamin D' and "Risk factors for asthma", section on 'Vitamin D in infancy' and "Nutrition in pregnancy: Dietary requirements and supplements", section on 'Calcium and vitamin D'.)
Evidence in favor of high dose vitamin D supplementation to reduce the risk of wheeze or asthma (up to age three) comes from a meta-analysis of two randomized trials, the Vitamin D Antenatal Asthma Reduction Trial (VDAART; 4400 IU versus 400 IU) and the Copenhagen Prospective Studies on Asthma in Childhood trial (COPSAC2010; 2800 IU versus 400 IU), which are described separately (see "Risk factors for asthma", section on 'Vitamin D') [93,95,96].
Briefly, the meta-analysis found that maternal vitamin D intake was protective for the occurrence of wheeze or asthma in the offspring up to age three (adjusted OR 0.74, 95% CI, 0.57-0.96) [93]. An important point is that these trials only performed vitamin D supplementation during the prenatal phase, and analysis of the participants at age six suggests a loss of benefit [97,98]. No supplementation was undertaken after birth, and it remains to be seen whether additional post-natal supplementation will sustain the protective effect seen in early life. (See "Risk factors for asthma", section on 'Vitamin D in infancy'.)
High-dose vitamin D supplementation during pregnancy appears safe; it is associated with a lower risk of small-for-gestational-age and no increase in risk of fetal or neonatal mortality or congenital abnormality [99]. In addition, no adverse events attributable to vitamin D intake were reported in the VDAART and COPSAC2010 trials [95,96].
PERIPARTUM CARE — A few issues are relevant to the peripartum management of the asthmatic patient and her baby [12]:
●Oxytocin is the drug of choice for induction of labor and control of postpartum hemorrhage [100]. (See "Postpartum hemorrhage: Management approaches requiring laparotomy", section on 'Evaluation of the abdomen' and "Postpartum hemorrhage: Medical and minimally invasive management", section on 'Administer additional uterotonic medications' and "Induction of labor with oxytocin".)
●Analogs of prostaglandin F2-alpha (eg, carboprost) can cause bronchoconstriction [101,102] and should not be used for termination of pregnancy, cervical ripening, induction of labor, or control of uterine hemorrhage [103]. (See "Postpartum hemorrhage: Medical and minimally invasive management", section on 'Administer additional uterotonic medications'.)
●Prostaglandin E2 (dinoprostone, in gel or suppository form) and prostaglandin E1 (misoprostol) are considered safer analogs, if prostaglandin treatment is required, due to their bronchodilatory effects [104].
●For peripartum pain control, morphine and meperidine should be avoided, if possible, since they can induce histamine release, especially from skin mast cells; however, evidence of acute bronchoconstriction caused by these agents is lacking. Butorphanol or fentanyl may be appropriate alternatives.
●Epidural anesthesia is preferred for the asthmatic patient who opts for pain control during labor because it reduces oxygen consumption and minute ventilation in the first and second stages of labor and usually can provide adequate anesthesia if cesarean delivery becomes necessary.
●If general anesthesia is required, ketamine and halogenated anesthetics are preferred, because they may have a bronchodilatory effect. (See "Anesthesia for adult patients with asthma".)
●Isolated case reports have described bronchoconstriction following use of ergot derivatives (eg, ergonovine) in the peripartum care of patients with asthma [12]; this may be an idiosyncratic reaction.
●If high doses of SABA have been given during labor and delivery, blood glucose levels should be monitored in the baby (especially if preterm) for the first 24 hours.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Asthma in adolescents and adults" and "Society guideline links: Respiratory disease in pregnancy".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Asthma and pregnancy (The Basics)")
●Beyond the Basics topics (see "Patient education: Asthma treatment in adolescents and adults (Beyond the Basics)" and "Patient education: Asthma and pregnancy (Beyond the Basics)" and "Patient education: Trigger avoidance in asthma (Beyond the Basics)" and "Patient education: How to use a peak flow meter (Beyond the Basics)" and "Patient education: Inhaler techniques in adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Principles of asthma control during pregnancy
•Asthma may improve, worsen, or remain unchanged in severity during pregnancy. The potential mechanisms involved and clinical implications of these findings are discussed separately. (See "Asthma in pregnancy: Clinical course and physiologic changes".)
•The two primary goals of asthma therapy during pregnancy are preventing acute exacerbations and minimizing impairment (as reflected by symptoms, interference with sleep or activity, and reduced pulmonary function).
•The four important components of effective asthma therapy during pregnancy are:
-Objective monitoring of maternal lung function and fetal well-being as a guide to therapy (see "Overview of antepartum fetal assessment" and "An overview of asthma management", section on 'Follow-up monitoring')
-Proper control of environmental and other triggers for asthma (eg, cigarette smoking, animal allergen exposure) (see 'Nonpharmacologic treatments' above and "Trigger control to enhance asthma management")
-Patient education (see "Asthma education and self-management")
-Pharmacologic therapy (see 'Adjustments to pharmacologic therapy in pregnancy' above)
●Pharmacologic control of asthma during pregnancy
•Studies are reassuring regarding the rarity of adverse effects on human pregnancy outcomes with albuterol and inhaled glucocorticoids (especially budesonide, beclomethasone, and fluticasone). Reassuring animal studies have been reported with ipratropium, nedocromil, zafirlukast, montelukast, and omalizumab, but published experience in human pregnancy with these agents is more limited. Some reassuring human gestational data exist for formoterol and salmeterol. (See 'Safety of specific medications' above and "Anti-IgE therapy", section on 'Safety in pregnancy and lactation'.)
•The general principles of pharmacologic therapy for asthma during pregnancy are similar to those in nonpregnant patients and involve a step-wise approach, as recommended by national and international guidelines (table 2 and table 5). (See 'Maintaining asthma control' above and "An overview of asthma management".)
•We do not initiate allergen immunotherapy during pregnancy due to risk of fetal harm from systemic allergic reactions. However, allergen immunotherapy can be continued during pregnancy in patients already receiving it who appear to be deriving benefit, who are not prone to systemic reactions, and who are receiving a maintenance concentration. (See 'Immunotherapy for allergic asthma' above.)
•A few medication preferences have been identified for asthma management during pregnancy based on greater experience in treating patients with these medications (see 'Adjustments to pharmacologic therapy in pregnancy' above):
•For relief of acute asthma symptoms, we suggest using the short-acting beta-agonist (SABA) albuterol, rather than other SABAs (Grade 2C). An alternative recommended in current international guidelines is to use a combination inhaler with formoterol and a low-dose inhaled glucocorticoid (eg, formoterol-budesonide) for quick relief (and maintenance if maintenance therapy is indicated), although more safety data exist for albuterol than for formoterol. This approach has not been specifically studied in pregnancy.
•For patients who require a long-term controller for asthma, we suggest using budesonide, beclomethasone, or fluticasone as the preferred inhaled glucocorticoid (Grade 2C). However, other inhaled glucocorticoids can be continued if the patient was well-controlled on one of these medications prior to pregnancy.
●Management of asthma exacerbations during pregnancy
•The management of acute asthma exacerbations during pregnancy does not differ substantially from that of nonpregnant patients and includes treatment with inhaled short-acting beta-agonist albuterol, inhaled ipratropium, oral or intravenous glucocorticoids, and, if necessary, intravenous magnesium sulfate (table 4). Intensive monitoring of both mother and fetus is essential. (See 'Acute exacerbations' above.)
•Potential areas of concern have been raised with the use of systemic glucocorticoids, including slightly increased risks of congenital malformations (primarily cleft palate), preeclampsia, low birth weight, and neonatal adrenal insufficiency. However, these potential risks of systemic glucocorticoids are small compared with the substantial risk to the mother and fetus of severe, uncontrolled asthma. Dosages of glucocorticoids for treatment of acute asthma exacerbations in pregnancy are not different than those for non-pregnant patients. (See 'Oral/Systemic glucocorticoids' above.)
•For the rare patient who requires use of a systemic beta-agonist to treat asthma, we suggest subcutaneous administration of terbutaline rather than epinephrine (table 4) (Grade 2C). This is based on a concern about potential uterine artery vasoconstriction with systemic administration of epinephrine (table 4). (See 'Medications' above.)
●Asthma prevention in offspring
•For pregnancies where the resulting child has at least one parent with asthma, we suggest maternal supplementation with high-dose vitamin D (eg, 2000 to 4000 IU/day, preferably vitamin D3) to reduce early childhood respiratory symptoms (Grade 2C). Serum 25-hydroxyvitamin D levels may be helpful to guide supplementation. (See 'High-dose vitamin D' above.)
●Peripartum care of patients with asthma
•For pharmacologic induction of labor and control of postpartum hemorrhage in patients with asthma, oxytocin appears to be safe in pregnancy. (See 'Peripartum care' above and "Induction of labor with oxytocin", section on 'Oxytocin administration' and "Postpartum hemorrhage: Medical and minimally invasive management", section on 'Administer additional uterotonic medications'.)
•For patients with asthma who require prostaglandin treatment for termination of pregnancy, cervical ripening, induction of labor, or control of uterine hemorrhage, we recommend using prostaglandin E1 or E2, rather than analogs of prostaglandin F2-alpha (Grade 1B). This recommendation is based on the risk of bronchoconstriction associated with the latter agent. (See 'Peripartum care' above.)
