Asthma is seen frequently in young women and therefore often complicates pregnancy. Asthma prevalence increased steadily in many countries beginning in the mid-1970s but may have plateaued in the United States, with a prevalence in adults of approximately 10 percent (Barnes, 2012; Centers for Disease Control and Prevention, 2010c). The estimated asthma prevalence during pregnancy ranges between 4 and 8 percent, and this appears to be increasing (Kwon, 2006; Namazy, 2005). Finally, evidence is accruing that fetal as well as neonatal environmental exposures may contribute to the origins of asthma in certain individuals (Harding, 2012; Henderson, 2012).
Asthma is a chronic inflammatory airway syndrome with a major hereditary component. Increased airway responsiveness and persistent subacute inflammation have been associated with genes on chromosomes 5q that include cytokine gene clusters, β-adrenergic and glucocorticoid receptor genes, and the T-cell antigen receptor gene (Barnes, 2012). Asthma is heterogeneous, and there inevitably is an environmental allergic stimulant such as influenza or cigarette smoke in susceptible individuals (Bel, 2013).
The hallmarks of asthma are reversible airway obstruction from bronchial smooth muscle contraction, vascular congestion, tenacious mucus, and mucosal edema. There is mucosal infiltration with eosinophils, mast cells, and T lymphocytes that causes airway inflammation and increased responsiveness to numerous stimuli including irritants, viral infections, aspirin, cold air, and exercise. Several inflammatory mediators produced by these and other cells include histamine, leukotrienes, prostaglandins, cytokines, and many others. IgE also plays a central role in pathophysiology (Strunk, 2006). Because F-series prostaglandins and ergonovine exacerbate asthma, these commonly used obstetrical drugs should be avoided if possible.
Asthma findings range from mild wheezing to severe bronchoconstriction, which obstructs airways and decreases airflow. These reduce the forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio and the peak expiratory flow (PEF). The work of breathing progressively increases, and patients note chest tightness, wheezing, or breathlessness. Subsequent alterations in oxygenation primarily reflect ventilation–perfusion mismatching, because the distribution of airway narrowing is uneven.
Varied manifestations of asthma have led to a simple classification that considers severity as well as onset and duration of symptoms (Table 51-1). With persistent or worsening bronchial obstruction, stages progress as shown in Figure 51-1. Hypoxia initially is well augmented by hyperventilation, which maintains arterial Po2 within a normal range while causing the Pco2 to decrease with resultant respiratory alkalosis. As airway narrowing worsens, ventilation–perfusion defects increase, and arterial hypoxemia ensues. With severe obstruction, ventilation becomes impaired as fatigue causes early CO2 retention. Because of hyperventilation, this may only be seen initially as an arterial pco2 returning to the normal range. With continuing obstruction, respiratory failure follows from fatigue.
Clinical stages of asthma. FEV1 = forced expiratory volume in 1 second.
TABLE 51-1Classification of Asthma Severity ||Download (.pdf) TABLE 51-1 Classification of Asthma Severity
| ||Severity |
| || ||Persistent |
|Component ||Intermittent ||Mild ||Moderate ||Severe |
|Symptoms ||≤ 2 day/wk ||> 2 day/wk, not daily ||Daily ||Throughout day |
|Nocturnal awakenings ||≤ 2×/mo ||3–4×/mo ||> 1/wk, not nightly ||Often 7×/wk |
|Short-acting β-agonist for symptoms ||≤ 2 day/wk ||≥ 2 day/wk, but not > 1×/day ||Daily ||Several times daily |
|Interference with normal activity ||None ||Minor limitation ||Some limitation ||Extremely limited |
|Lung function ||Normal between exacerbations || || || |
| • FEV1 ||> 80% predicted ||≥ 80% predicted ||60–80% predicted ||< 60% predicted |
| • FEV1/FVC ||Normal ||Normal ||Reduced 5% ||Reduced > 5% |
Although these changes are generally reversible and well tolerated by the healthy nonpregnant individual, even early asthma stages may be dangerous for the pregnant woman and her fetus. This is because smaller functional residual capacity and increased pulmary shunting render the woman more susceptible to hypoxia and hypoxemia.
Effects of Pregnancy on Asthma
There is no evidence that pregnancy has a predictable effect on underlying asthma. In their review of six prospective studies of more than 2000 pregnant women, Gluck and Gluck (2006) reported that approximately a third each improved, remained unchanged, or clearly worsened. Exacerbations are more common with severe disease (Ali, 2013). In a study by Schatz and associates (2003), baseline severity correlated with asthma morbidity during pregnancy. With mild disease, 13 percent of women had an exacerbation and 2.3 percent required admission; with moderate disease, these numbers were 26 and 7 percent; and for severe asthma, 52 and 27 percent. Others have reported similar observations (Charlton, 2013; Hendler, 2006; Murphy, 2005). Carroll and colleagues (2005) reported disparate morbidity in black compared with white women.
Some women have asthma exacerbations during labor and delivery. Up to 20 percent of women with mild or moderate asthma have been reported to have an intrapartum exacerbation (Schatz, 2003). Conversely, Wendel and associates (1996) reported exacerbations at the time of delivery in only 1 percent of women. Mabie and coworkers (1992) reported an 18-fold increased exacerbation risk following cesarean versus vaginal delivery.
Women with asthma have had improved pregnancy outcomes during the past 20 years. From his review, Dombrowski (2006) concluded that, unless disease is severe, pregnancy outcomes are generally excellent. The incidence of spontaneous abortion in women with asthma may be slightly increased (Blais, 2013). Maternal and perinatal outcomes for nearly 30,000 pregnancies in asthmatic women are shown in Table 51-2. Findings are not consistent among these studies. For example, in some, but not all, incidences of preeclampsia, preterm labor, growth-restricted infants, and perinatal mortality are slightly increased (Murphy, 2011). Another report cited a small rise in the incidence of placental abruption and in preterm rupture of membranes (Getahun, 2006, 2007). But, in a European report of 37,585 pregnancies of women with asthma, the risks for most obstetrical complications were not increased (Tata, 2007). In the Canadian study in which inhaled-corticosteroid dosage was quantified, Cossette and coworkers (2013) found a nonsignificant trend between perinatal complications and increasing dosage. They concluded that low to moderate doses were not associated with perinatal risks and noted that more data were needed regarding higher doses.
TABLE 51-2Maternal and Perinatal Outcomes in Pregnancies Complicated by Asthma ||Download (.pdf) TABLE 51-2 Maternal and Perinatal Outcomes in Pregnancies Complicated by Asthma
Thus, there appears to be significantly increased morbidity linked to severe disease, poor control, or both. In the study by the Maternal-Fetal Medicine Units (MFMU) Network, delivery before 37 weeks’ gestation was not increased among the 1687 pregnancies of asthmatics compared with those of 881 controls (Dombrowski, 2004a). But for women with severe asthma, the rate was increased approximately twofold. In a prospective evaluation of 656 asthmatic pregnant women and 1052 pregnant controls, Triche and coworkers (2004) found that women with moderate to severe asthma, regardless of treatment, are at increased risk of preeclampsia. Finally, the MFMU Network study suggests a direct relationship of baseline pregnancy forced expiratory volume at 1 second (FEV1) with birthweight and an inverse relationship with rates of gestational hypertension and preterm delivery (Schatz, 2006).
Life-threatening complications from status asthmaticus include muscle fatigue with respiratory arrest, pneumothorax, pneumomediastinum, acute cor pulmonale, and cardiac arrhythmias. Maternal and perinatal mortality rates are substantively increased when mechanical ventilation is required.
With reasonable asthma control, perinatal outcomes are generally good. For example, in the MFMU Network study cited above, there were no significant adverse neonatal sequelae from asthma (Dombrowski, 2004a). The caveat is that severe asthma was uncommon in this closely monitored group. When respiratory alkalosis develops, both animal and human studies suggest that fetal hypoxemia develops well before the alkalosis compromises maternal oxygenation (Rolston, 1974). It is hypothesized that the fetus is jeopardized by decreased uterine blood flow, decreased maternal venous return, and an alkaline-induced leftward shift of the oxyhemoglobin dissociation curve.
The fetal response to maternal hypoxemia is decreased umbilical blood flow, increased systemic and pulmonary vascular resistance, and decreased cardiac output. Observations by Bracken and colleagues (2003) confirm that the incidence of fetal-growth restriction increases with asthma severity. The realization that the fetus may be seriously compromised as asthma severity increases underscores the need for aggressive management. Monitoring the fetal response is, in effect, an indicator of maternal status.
Possible teratogenic or adverse fetal effects of drugs given to control asthma have been a concern. Fortunately, considerable data have accrued with no evidence that commonly used antiasthmatic drugs are harmful (Blais, 2007; Källén, 2007; Namazy, 2006). Thus, it is worrisome that Enriquez and coworkers (2006) reported a 13- to 54-percent patient-generated decrease in β-agonist and corticosteroid use between 5 and 13 weeks’ gestation.
The subjective severity of asthma frequently does not correlate with objective measures of airway function or ventilation. Although clinical examination can also be an inaccurate predictor, useful clinical signs include labored breathing, tachycardia, pulsus paradoxus, prolonged expiration, and use of accessory muscles. Signs of a potentially fatal attack include central cyanosis and altered consciousness.
Arterial blood gas analysis provides objective assessment of maternal oxygenation, ventilation, and acid-base status. With this information, the severity of an acute attack can be assessed (see Fig. 51-1). That said, in a prospective evaluation, Wendel and associates (1996) found that routine arterial blood gas analysis did not help to manage most pregnant women who required admission for asthma control. If used, the results must be interpreted in relation to normal values for pregnancy. For example, a pco2 > 35 mm Hg with a pH < 7.35 is consistent with hyperventilation and CO2 retention in a pregnant woman.
Pulmonary function testing should be routine in the management of chronic and acute asthma. Sequential measurement of the FEV1 or the peak expiratory flow rate—PEFR—are the best measures of severity. An FEV1 less than 1 L, or less than 20 percent of predicted value, correlates with severe disease defined by hypoxia, poor response to therapy, and a high relapse rate. The PEFR correlates well with the FEV1, and it can be measured reliably with inexpensive portable meters. Each woman determines her own baseline when asymptomatic—personal best—to compare with values when symptomatic. The PEFR does not change during the course of normal pregnancy (Brancazio, 1997).
Management of Chronic Asthma
The management guidelines of the Working Group on Asthma and Pregnancy include:
Patient education—general asthma management and its effect on pregnancy
Environmental precipitating factors—avoidance or control. Viral infections—including the common cold—are frequent triggering events (Murphy, 2013).
Objective assessment of pulmonary function and fetal well-being—monitor with PEFR or FEV1
Pharmacological therapy—in appropriate combinations and doses to provide baseline control and treat exacerbations. Compliance may be a problem, and periodic medication reviews are helpful (Sawicki, 2012).
In general, women with moderate to severe asthma should measure and record either their FEV1 or PEFR twice daily. The FEV1 ideally is > 80 percent of predicted. For PEFR, predicted values range from 380 to 550 L/min. Each woman has her own baseline value, and therapeutic adjustments can be made using this (American College of Obstetricians and Gynecologists, 2012; Rey, 2007).
Treatment depends on disease severity. Although β-agonists help to abate bronchospasm, corticosteroids treat the inflammatory component. Regimens recommended for outpatient management are listed in Figure 51-2. For mild asthma, inhaled β-agonists as needed are usually sufficient. For persistent asthma, inhaled corticosteroids are administered every 3 to 4 hours. The goal is to reduce the use of β-agonists for symptomatic relief. A case-control study from Canada with a cohort of more than 15,600 nonpregnant women with asthma showed that inhaled corticosteroids reduced hospitalizations by 80 percent (Blais, 1998). And Wendel and colleagues (1996) achieved a 55-percent reduction in readmissions for severe exacerbations in pregnant asthmatics given maintenance inhaled corticosteroids along with β-agonist therapy.
Stepwise approach to asthma treatment. ICS = inhaled corticosteroids; LABA = long-acting β-agonists; OCS = oral corticosteroids. (Modified from Barnes, 2012.)
Theophylline is a methylxanthine, and its various salts are bronchodilators and possibly antiinflammatory agents. They have been used less frequently since inhaled corticosteroids became available. Some theophylline derivatives are considered useful for oral maintenance therapy if the initial response to inhaled corticosteroids and β-agonists is not optimal. Dombrowski and associates (2004b) conducted a randomized trial with nearly 400 pregnant women with moderate asthma. Oral theophylline was compared with inhaled beclomethasone for maintenance. In both groups, approximately 20 percent had exacerbations. Women taking theophylline had a significantly higher discontinuation rate because of side effects. Pregnancy outcomes were similar in the two groups.
Antileukotrienes inhibit leukotriene synthesis and include zileuton, zafirlukast, and montelukast. These drugs are given orally or by inhalation for prevention, but they are not effective for acute disease. For maintenance, they are used in conjunction with inhaled corticosteroids to allow minimal dosing. Approximately half of asthmatics will improve with these drugs (McFadden, 2005). They are not as effective as inhaled corticosteroids (Fanta, 2009). Finally, there is little experience with their use in pregnancy (Bakhireva, 2007).
Cromones include cromolyn and nedocromil, which inhibit mast cell degranulation. They are ineffective for acute asthma and are taken chronically for prevention. They are not as effective as inhaled corticosteroids and are used primarily to treat childhood asthma.
Management of Acute Asthma
Treatment of acute asthma during pregnancy is similar to that for the nonpregnant asthmatic (Barnes, 2012). However, the threshold for hospitalization is significantly lowered. Intravenous hydration may help clear pulmonary secretions, and supplemental oxygen is given by mask. The therapeutic aim is to maintain the po2 > 60 mm Hg, and preferably normal, along with 95-percent oxygen saturation. Baseline pulmonary function testing includes FEV1 or PEFR. Continuous pulse oximetry and electronic fetal monitoring, depending on gestational age, may provide useful information.
First-line therapy for acute asthma includes a β-adrenergic agonist, such as terbutaline, albuterol, isoetharine, epinephrine, isoproterenol, or metaproterenol, which is given subcutaneously, taken orally, or inhaled. These drugs bind to specific cell-surface receptors and activate adenylyl cyclase to increase intracellular cyclic AMP and modulate bronchial smooth muscle relaxation. Long-acting preparations are used for outpatient therapy.
If not previously given for maintenance, inhaled corticosteroids are commenced along with intensive β-agonist therapy. For severe exacerbations, magnesium sulfate may prove efficacious. Corticosteroids should be given early to all patients with severe acute asthma. Unless there is a timely response to bronchodilator and inhaled corticosteroid therapy, oral or parenteral corticosteroids are given (Lazarus, 2010). Intravenous methylprednisolone, 40 to 60 mg, every 6 hours for four doses is commonly used. Equipotent doses of hydrocortisone by infusion or prednisone orally can be given instead. Because their onset of action is several hours, corticosteroids are given initially along with β-agonists for acute asthma.
Further management depends on the response to therapy. If initial therapy with β-agonists is associated with improvement of FEV1 or PEFR to above 70 percent of baseline, then discharge can be considered. Some women may benefit from observation. Alternatively, for the woman with obvious respiratory distress, or if the FEV1 or PEFR is < 70 percent of predicted after three doses of β-agonist, admission is likely advisable (Lazarus, 2010). Intensive therapy includes inhaled β-agonists, intravenous corticosteroids, and close observation for worsening respiratory distress or fatigue in breathing (Wendel, 1996). The woman is cared for in the delivery unit or an intermediate or intensive care unit (ICU) (Dombrowski, 2006; Zeeman, 2003).
Status Asthmaticus and Respiratory Failure
Severe asthma of any type not responding after 30 to 60 minutes of intensive therapy is termed status asthmaticus. Braman and Kaemmerlen (1990) have shown that management of nonpregnant patients with status asthmaticus in an intensive care setting results in a good outcome in most cases. Consideration should be given to early intubation when maternal respiratory status worsens despite aggressive treatment (see Fig. 51-1). Fatigue, carbon dioxide retention, and hypoxemia are indications for mechanical ventilation. Lo and colleagues (2013) have described a woman with status asthmaticus in whom cesarean delivery was necessary to effect ventilation. Andrews (2013) cautioned that such clinical situations are uncommon.
For the laboring asthmatic, maintenance medications are continued through delivery. Stress-dose corticosteroids are administered to any woman given systemic corticosteroid therapy within the preceding 4 weeks. The usual dose is 100 mg of hydrocortisone given intravenously every 8 hours during labor and for 24 hours after delivery. The PEFR or FEV1 should be determined on admission, and serial measurements are taken if symptoms develop.
Oxytocin or prostaglandins E1 or E2 are used for cervical ripening and induction. A nonhistamine-releasing narcotic such as fentanyl may be preferable to meperidine for labor, and epidural analgesia is ideal. For surgical delivery, conduction analgesia is preferred because tracheal intubation can trigger severe bronchospasm. Postpartum hemorrhage is treated with oxytocin or prostaglandin E2. Prostaglandin F2a or ergotamine derivatives are contraindicated because they may cause significant bronchospasm.