Two factors were demonstrated to have significant and profound effects on the course of asthma: 1) prepregnancy asthma severity; and 2) use of asthma medication according to Global Initiative for Asthma guidelines. Although a number of other factors were analyzed (race, age, atopic status, BMI, parity, fetal sex, and smoking), none were significant risk factors for changes in asthma severity, measured in a clinically important way as a one-step change in Global Initiative for Asthma category. Women with mild asthma received the most benefit from appropriate treatment, a 60% decrease in risk for worsening asthma among those with intermittent asthma and a 50% decreased risk among women with mild persistent asthma. There was little indication that month or trimester of gestation were themselves associated with changes in asthma severity.
Strengths of this study include women being recruited from prenatal care providers and may represent the range of asthma severity usually seen in obstetric practice (57.4% intermittent and 20.1% mild persistent). Data were collected prospectively and the study was able to examine effects of medication use, controlling for severity of asthma. Asthma severity was measured using Global Initiative for Asthma categories, an accepted classification that allowed measurement of severity for each month of gestation. A limitation of the Global Initiative for Asthma scale (and all similar scales) is that when women are classified as severe (category 4) a worsening of their condition cannot be demonstrated; also, lung function was not directly measured. Symptom and medication data were collected by interview, and errors in recall may have occurred. Follow-up interviews were conducted at 8-week intervals to minimize this error.
Schatz et al7
reported the importance of predicting asthma morbidity during pregnancy by asthma severity classification using NAEPP guidelines,15
a precursor of the Global Initiative for Asthma. Women were classified based on asthma status at enrollment, usually the second trimester of pregnancy. This classification was associated with risk for hospitalization, unscheduled physician visits and oral corticosteroid use during pregnancy. Similar results were found in our study where asthma was classified based on severity in the year before pregnancy. Hospitalization, emergency department visits, and higher Global Initiative for Asthma scores during pregnancy were all associated with asthma severity in the year before pregnancy.
Murphy et al16
studied the incidence of asthma exacerbations during pregnancy among women classified as having mild, moderate or severe asthma using Australian asthma management guidelines (similar to the National Asthma Education and Prevention Program). Severe exacerbations (defined as hospitalization, emergency department visit, unscheduled doctor visit, or oral corticosteroid use) occurred in 8% of those with mild asthma, 47% of those with moderate asthma, and 65% of those with severe asthma during pregnancy. They reported 29% of severe exacerbations were associated with nonadherence to inhaled corticosteroid medication.
Women may discontinue asthma medication when realizing they are pregnant, fearing negative effects on the fetus. Enriquez et al17
used the Tennessee Medicaid database to examine the likelihood that asthmatic women discontinue medication. The study used pharmacy claims data, which included the number of prescriptions filled and the number of days supplied. Each asthmatic woman was classified as a user or nonuser of medication for each week of pregnancy. Between week 5 and week 13 of pregnancy, there was a decrease of 13.2% (95% CI 9.0–17.2) in the use of short-acting β
agonists and a decline of 22.9% (95% CI 13.9–31.0) in the use of inhaled corticosteroids.
Physicians advising women about medication use during pregnancy must consider the effect of medication on the fetus balanced by any effect of worsening maternal asthma on the fetus. Previously, we reported an increased risk of fetal growth restriction associated with higher average Global Initiative for Asthma scores (test for trend 1.24, 95% CI 1.05–1.47). No increased fetal risks were associated with bronchodilator or inhaled steroid use. Increased risks of preterm delivery were associated with average dose of oral steroid (OR 1.11, 95% CI 1.03–1.18) and average dose of theophylline (OR 1.05, 95% CI 1.01–1.09).12
Similar results were reported by Schatz et al18
in a prospective study conducted by the Eunice Kennedy Shriver
National Institute of Child Health and Human Development Maternal–Fetal Network. No association was found between exposure to β
agonists, inhaled steroids, or theophylline and gestational hypertension, preterm delivery, low birth weight, or weight for gestational age. Controlling for asthma severity, use of oral steroids was associated with preterm delivery less than 37 weeks of gestation (OR 1.54, 95% CI 1.02–2.33) and low birth weight (OR 1.80, 95% CI 1.13–2.88). Olesen et al19
investigated associations between asthma medication use and perinatal outcomes in the Birth Registry of North Jutland, Denmark. No associations were found between receipt of prescriptions for β
agonists or inhaled steroids and gestational age, birth weight, or birth length. Women receiving prescriptions for theophylline or inhaled steroids were more likely to have neonates with low birth weight or who were small for gestational age. In addition, women who discontinued inhaled steroid therapy had term birth weights that were lower than women who did not purchase any prescription drugs during pregnancy (−219.6 g, 95% CI −417.6 to −21.7).
Several studies have specifically investigated the risks of congenital malformations with asthma medication and asthma exacerbations. Kallen and Otterblad Olausson20
observed a 9% increased risk of any congenital malformation but no consistent pattern of specific defect, and many comparisons were made. The authors recognized that residual confounding could have produced this result. Tata et al21
reported a small increase in risk of any malformation among women diagnosed with asthma (OR 1.10, 95% CI 1.01–1.20) compared with nonasthmatic women. No association was found for women receiving asthma treatment (OR 1.06, 95% CI 0.94–1.20) or for any specific medication. Blais and Forget22
investigated the association of asthma exacerbations with congenital malformations. Among women who had an asthma exacerbation during the first trimester, there was an increased risk of any malformation (OR 1.48, 95% CI 1.04–2.09). Among women who did not fill a prescription for oral steroids, women who experienced an exacerbation in the first trimester had an increased risk of a major malformation (OR 1.95, 95% CI 1.03–3.72). This suggests that it was the exacerbation of asthma, not the treatment, that may be causally related to the malformation. A case–control study23
specifically investigating risks of asthma medication in relation to gastroschisis reported an increased risk of bronchodilator use (OR 2.06, 95% CI 1.19–3.59). No adverse effect was found for antiinflammatory medication or bronchodilators used with antiinflammatory drugs. This study did not assess asthma severity, so it cannot distinguish the effect of asthma from the effect of treatment. Lin et al23
reported an increased risk of cardiac defects but concluded that uncontrolled asthma, severe asthma, or bronchodilators may increase risk. In summary, the risk, if any, for congenital malformation among the children of asthmatic women is inconclusive. The few reported risks are small, there is no consistency for specific defect, and the bias that can follow from highly selected study populations, from differences in recall or ascertainment of a malformation, or from multiple comparisons and indication (whether the drug or asthma is associated) frustrate any conclusion from this limited body of literature.
We found no support for the notion of thirds in change of asthma severity in pregnancy; rather asthma during pregnancy is likely to be similar in severity to asthma in the year before pregnancy, provided patients continue to use prescribed medication. If women discontinue medication, even mild asthma is likely to become significantly more severe. Recent research indicates that the fetus may experience significant risk from exacerbations of asthma in the mother. The American College of Obstetricians and Gynecologists (the College)24
recommends continuation of medication for the health of both mother and fetus. The current paper provides empirical support for the College guidelines: exacerbations during pregnancy are best prevented when the mother uses asthma medication appropriate to her level of symptoms.