13.5.1 Pregnancy Complications

Several studies have shown that the presence of asthma may increase the risk of comorbidities associated with pregnancy. A recent meta-analysis of studies up to 2012 showed that maternal asthma was associated with gestational diabetes, with more severe asthma conferring a slightly higher risk compared with mild asthma [28]. The Consortium on Safe Labor, which included 12 clinical centers with 19 hospitals across the United States, studied data extracted from electronic medical records from 223,512 singleton deliveries between 2005 and 2007, with 7.6% of the mothers having asthma [29]. The authors confirmed the association between maternal asthma and gestational diabetes. Moreover, they found that maternal asthma increased the risk for pulmonary embolism and ICU admissions. As with nonpregnant patients with asthma, pregnant women with asthma are at higher risk for viral respiratory infections [30]. If the viral infection is laboratory confirmed, women were at higher risk for uncontrolled asthma and preeclampsia.

Pregnancy and placental complications are also increased in pregnant mothers with asthma. Multiple studies have shown that the risks of preeclampsia [8, 29, 31], placental abruption and previa [28, 29], antepartum hemorrhage [28, 29], cesarean delivery [8, 29], premature rupture of membranes [28, 29], and spontaneous abortions[28] are increased in pregnant asthmatic women compared to non-asthmatic women. In contrast, in a study of pregnant asthmatics identified through two administrative health databases in Quebec, Canada, Blais et al. [10] did not find an association between long-acting beta-agonists and hypertensive disorders of pregnancy, including preeclampsia.

13.5.2 Offspring Outcomes

Perinatal and childhood adverse outcomes are also more common in offspring of women with asthma compared with those without asthma. This was most recently shown in a Finnish register-based cohort between the years of 1996 and 2002 [4]. The authors showed that maternal asthma is associated with the risk of perinatal mortality, 1.24 (95% confidence interval [CI], 1.05–1.46). In addition, maternal asthma was also associated with increased risks of preterm birth, low birth weight, fetal growth restriction, and asphyxia. These risks become more likely in a pregnant asthmatic with difficulty in controlling asthma. Mothers with asthma are more likely to have neonates with low birth weight [8] and who are small for gestational age (SGA) than women without asthma [29]. The risks for these adverse events appeared to increase with increasing maternal asthma severity [8]. A meta-analysis also showed that congenital malformations, cleft lip with or without cleft palate, neonatal death, and neonatal hospitalizations were increased among mothers with asthma [31].

Several studies have attempted to investigate the effects of asthma medications in pregnancy on offspring outcomes, although many have been either small or retrospective in design. There are a few large prospective studies. In a Danish register-based study, Chen et al. [32] showed that children exposed to beta-agonists in utero in the first or second trimesters had about a 33–35% increase in the risk for epilepsy. In contrast, the study from the MFMU did not find an increased risk of perinatal adverse outcomes (gestational hypertension, preterm births, low-birth-weight infants, small-for-gestational-age infants, or major malformations) with inhaled beta-agonists, inhaled corticosteroids, nor theophylline. In a study linking three administrative databases from Quebec, Canada, Eltonsy and colleagues [33] found a suggestion that the risk for any congenital malformation was increased with the use of long-acting beta-agonists during the first trimester (adjusted OR = 1.37, 95%CI = 0.92, 2.17) but not with the use of short-acting beta-agonists (adjusted OR = 1.04, 95%CI 0.92, 1.17). The study using the Swedish Medical Birth Register found an increased risk for adverse pregnancy outcomes with exposure to asthma medications in pregnancy [8]. They were unable, however, to detect a difference in adverse events in women who discontinued their medications at some point during pregnancy vs those who continued their medications. It is difficult to determine whether these adverse outcomes are due to exposure to these medications or whether they are due to the presence of asthma. Additional studies designed to tease out the effects of the medications vs control of asthma during pregnancy on perinatal outcomes are needed.

Maternal asthma is the strongest risk factor for asthma in the child [34] and has been validated in multiple epidemiologic studies. More recently, studies have investigated the effects of asthma control during pregnancy. In a case-control study, Martel and colleagues showed that children of mothers who had moderate-to-severe uncontrolled asthma had a 27% increased risk for asthma. However, this study ascertained maternal asthma control retrospectively. A large Danish study identified maternal asthma status prior to pregnancy from the Danish National Patient Register. The authors then categorized mothers as having active asthma if they filled their medication prescription or had one or more outpatient, inpatient, or emergency department visit for asthma during the index pregnancy and categorized their asthma based on data from national registries [35]. Compared with mothers with mild controlled asthma, children of mothers with uncontrolled asthma had a higher prevalence of early-onset persistent asthma.

13.6.1 Overview of Gestational Asthma Management

A 2011 double-blind, parallel group, controlled study by Powell et al. [38] tested the measurement of FeNO to guide the management of pregnant asthmatics. FeNO concentration was used to adjust the dose of inhaled corticosteroids (budesonide), and the asthma control questionnaire (ACQ) was used to adjust inhaled long-acting beta-agonist therapy (formoterol). The cutoff for dose increase was FeNO 16 ppb and ACQ > 1.5, respectively. The primary outcome was total asthma exacerbations. The authors found that the exacerbation rate was lower in the group using FeNO to adjust asthma therapies during pregnancy (0.288 exacerbations per pregnancy) compared with the control group (0.615 exacerbations per pregnancy). Short-acting beta-agonist use was significantly less in the FeNO group. Overall, 68% of women in the FeNO group were being treated with inhaled corticosteroids at the end of the study compared with 42% in the control group. The mean daily inhaled corticosteroid dose was lower in the FeNO group than in the control group. More women received long-acting beta-agonists in the FeNO group than in the control group. A follow-up study reported on the effect of the FeNO-guided management on asthma incidence in the offspring and reported a significant reduction of doctor-diagnosed asthma (OR = 0.46, 95%CI = 0.22, 0.96) in the offspring at 4–6 years of age [39]. Other outcomes such as frequent wheeze, use of short-acting beta-agonists, and emergency department visits for asthma were also reduced in the children born to mothers in the FeNO-guided treatment arm. Further studies will be necessary to confirm the generalizability of these findings.

13.6.2 Non-pharmacological Management

The available data suggest that control of maternal asthma is essential to reduce the risk of asthma exacerbations and perinatal complications. There are several factors that remain barriers to asthma control in this group of patients. They include psychological state, smoking, obesity, adherence, physician undertreatment, and viral infections.

Pregnancy represents a time of psychological vulnerability, even for healthy women. Many women feel emotionally labile and ambivalent due to pregnancy. Changes in body image, the physical symptoms accompanying normal pregnancy, and various fears regarding the pregnancy and the developing infant cause additional stress. In the pregnant woman with asthma or allergic disease, psychological stresses may be especially important. First, in women whose symptoms tend to worsen with stress, the stress of normal pregnancy may exacerbate symptoms. Furthermore, the morbidity associated with asthma or allergic symptoms, especially if the symptoms interfere with sleep, may add substantially to the stress of normal pregnancy. The following principles of optimal psychological management during pregnancy can help the asthmatic or allergic patient.

It comes as no surprise that pregnant women are hesitant about continuing asthma medications during pregnancy for the fear of causing untoward effects on their unborn baby. A retrospective nationwide database study of 115,169 pregnant asthmatics in South Korea reported that women tended to rapidly reduce their asthma medication use during the beginning of their pregnancy [40]. While the overall number of exacerbations was small, there was a significant increase in subgroups of women. Another study found that about one-third of pregnant asthmatics discontinued asthma medications during pregnancy, often without consulting their physicians [7]. Reasons for nonadherence to treatment was examined by Lim et al. [41]. Data were obtained from interviews with pregnant asthmatic women. Concerns about medication use, specifically steroid use, overshadowed concerns about the potential risk of uncontrolled asthma. Nonadherence with inhaled corticosteroids has been shown to be a major contributor to exacerbations during pregnancy [42, 43].

Uninformed decisions by pregnant asthmatic patients or those managing their asthma may lead to exacerbations of asthma during pregnancy and potentially adverse perinatal outcomes. In fact, 25% of general practitioners surveyed in one study would stop treatment with controller medication in pregnant women with well-controlled asthma [44]. Therefore, asthma education is a critical non-pharmacologic component in the management of the pregnant asthmatic. One successful approach was recently reported in the Multidisciplinary Approach to Management of Maternal Asthma (MAMMA) study. Subjects were randomized to either receive a pharmacist led intervention (consisting of self-management strategies, such as proper inhaler technique, adherence support, monthly Asthma Control Questionnaire (ACQ) assessments, FEV1, and action plans) or usual care. There was communication between the pharmacist, family physician, midwife, and patient. At the end of 6 months, there was a significant reduction in ACQ (improved asthma control) compared to the group that received usual care. [45].

Obesity has been shown to be an inflammatory state that may play an important role in asthma initiation and control. Obesity during pregnancy has been associated with adverse perinatal outcomes including gestational diabetes, preeclampsia, thromboembolic disorders, postpartum hemorrhage, large for gestational age, fetal death, and congenital anomalies. Higher BMI and gestational weight gain have been associated with an increased risk for asthma exacerbations in pregnant women [20, 46]. The mechanisms leading to these outcomes are thought to be due to a heightened inflammatory response [47]. These data suggest that obesity should ideally be addressed in asthmatic women who are contemplating pregnancy and that gestational weight gain should be carefully monitored in women with severe asthma to reduce any added risk due to excessive weight gain.

Population-based studies have shown a relationship between smoking and airway hyperresponsiveness [48, 49], implying that smoking is a risk factor for asthma. Asthma exacerbations during pregnancy are more common and more severe in current and former smokers than in never smokers [50]. The potential for maternal smoking to both increase the risk of uncontrolled asthma and to directly adversely affect pregnancy suggests that discontinuation of smoking should be a high priority goal during pregnancy.

Infections during pregnancy can certainly affect the course of gestational asthma and be a barrier to asthma control. Some degree of decrease in cell-mediated immunity may make the pregnant patient more susceptible to viral infection, and upper respiratory tract infections have been reported to be the most common precipitants of asthma exacerbations during pregnancy [42]. Sinusitis, a known asthma trigger, has been reported to be six times more common in pregnant compared with nonpregnant women [51]. In addition, pneumonia has been reported to be greater than five times more common in asthmatic than non-asthmatic women during pregnancy [52].

Pregnant women with asthma have been shown to have more common colds during pregnancy than pregnant women without asthma. In one study, the severity of cold symptoms was also increased in women with asthma [30]. In addition, among women with asthma, having a laboratory-confirmed viral infection was associated with poorer maternal health, with 60% of infections associated with uncontrolled asthma and a higher likelihood of preeclampsia. Viral infections may be complicated by bronchitis, bacterial pneumonia, and bacterial sinusitis, all of which having adverse effects on both the mother and baby. More research is needed on the prevention of viral-induced asthma exacerbations during pregnancy. Pregnant women are at increased risk of severe influenza during pregnancy, which may also lead to asthma exacerbations. Therefore, vaccination for influenza for the pregnant asthmatic is an important part of management.

A recent study tried to determine whether a diagnosis of upper respiratory infection or sinusitis was more common during pregnancy and whether pregnant women were more likely to receive a prescription for antibiotics. This study did not confirm the prior finding that sinusitis or antibiotic use for upper respiratory infections is increased in pregnancy. The report did find that respiratory comorbidities, such as asthma, increased the risk of antibiotic use during pregnancy [53].

More clinical trials are needed addressing the non-medication aspects of gestational asthma management, including assessment and monitoring, self-management education, and adherence. The study by Powell et al. [38] discussed above suggests that the use of FeNO to guide inhaled corticosteroid is a promising addition to the clinicians’ armamentarium. Related to adherence, one of the most important needs for the future is the availability of additional safety information for asthma medications used during pregnancy that can also account for asthma control.

Another priority for future research is developing methods for overcoming barriers to asthma control during pregnancy. As discussed above, these barriers include major modifiable risk factors such as cigarette smoking, clinician undertreatment, patient nonadherence, and viral infections which have been shown to be associated with asthma exacerbations. Optimal smoking cessation strategies, clinician education, effective patient education and support, and means of preventing viral infections or at least reducing their adverse effect on asthma should increase the likelihood of adequately controlled gestational asthma.

13.6.3 Pharmacologic Therapy

The medical management of asthma during pregnancy is not unlike that of the nonpregnant asthmatic. Therapy is divided into long-term control medications and rescue therapy. Long-term control medications are used for maintenance therapy to prevent asthma manifestations and include inhaled corticosteroids, cromolyn, long-acting beta-agonists, leukotriene receptor antagonists, and theophylline. Controller therapy should be increased in steps (Table 13.3) until adequate control is achieved. Rescue therapy, most commonly inhaled short-acting beta-agonists, provides immediate relief of symptoms. Oral corticosteroids can either be used as a form of rescue therapy or as chronic therapy for severe persistent asthma.

Because pregnant women are generally excluded from clinical trials, there is a lack of adequate prospective efficacy or safety information for most medications taken during pregnancy, especially newer medications, as well as biologics and sublingual immunotherapy. Current knowledge regarding the safety data on these medications on the fetus and offspring are presented below and summarized in Table 13.4. Moreover, the existing observational data are often limited by the lack of information regarding asthma control as mentioned above. Thus, more studies are needed to better define the effect of asthma severity and control on perinatal outcomes in general and as a potential confounder in the medication data.

Table 13.4

Human pregnancy summary safety data for selected asthma and allergy medications^a

Medication	Major birth defects	Other birth outcomes
Systemic corticosteroids	Meta-analysis of cohort studies showed no overall increased risk of major birth defects in pooled 535 exposed pregnancies; meta-analysis of four case-control studies showed an increased risk of ~ threefold for oral clefts [82]. However, most recent and largest case-control study from US National Birth Defects Prevention Study showed no increased risk for oral clefts with first-trimester systemic steroid use for any indication in 2372 cases and 5922 controls [83]	Preterm delivery, low birth weight or reduced birth weight, preeclampsia, and gestational diabetes have all been reported to occur more frequently in women treated with systemic steroids in pregnancy; however, studies that attempted to control underlying maternal disease and disease activity typically find the associated risks for these outcomes reduced or eliminated [86]
Any inhaled corticosteroids (ICS) including beclomethasone, budesonide, flunisolide, fluticasone, and triamcinolone	No increased risk for major birth defects in 396 exposed pregnancies compared with the general population [87]. A meta-analysis of studies of inhaled steroids did not find increased risk of major birth defects overall [88]	No increased risks for preterm delivery, low birth weight, or pregnancy-induced hypertension in 396 exposed pregnancies or in meta-analysis [87, 88]
Budesonide	No overall increased risk for major birth defects or oral clefts among 2014 exposed pregnancies in population-based Scandinavian register [58]	No increased risks for preterm birth, reduced birth weight or length, or stillbirths in 2968 exposed pregnancies in population-based Scandinavian register [55]
Fluticasone	No overall increased risk of major congenital malformations in a cohort study of 1602 mother-infant pairs exposed to fluticasone compared to 3678 exposed to other ICS, stratified by severity [72]	No increased risk of low birth weight, preterm birth, or small for gestational age in retrospective database study of infants of 3190 mothers exposed to fluticasone compared to 608 mothers exposed to budesonide [71]
Cromolyn Nedocromil	No overall increase in major birth defects in 296 pregnancies exposed throughout pregnancy [89] No overall increase in major birth defects in 151 exposed pregnancies [54]. No overall increase in major birth defects in case-control study of 5124 malformed controls compared to the other 30,053 controls, nine cases exposed to cromones, some suggestion of an increased risk for musculoskeletal malformations among the nine cases but no specific pattern noted [90]	No increased risk for premature delivery or spontaneous abortion/stillbirth in 296 pregnancies exposed throughout pregnancy [89]. No increased risk for premature delivery, preeclampsia, or low birth weight in 243 women exposed anytime in pregnancy [54]
Montelukast	No overall increased risk of major birth defects in 74 and 180 exposed pregnancies [79, 91]. No overall increased risk in major birth defects or specific birth defects in 1164 exposed pregnancies in claims study [80]. No increased risk in major birth defects in 1827 exposed pregnancies in Danish register study [92]	No increased risk for reduced birth weight or shortened gestational age in 180 exposed pregnancies when compared to other asthmatics [79] No increased risk for preterm delivery, low birth weight, or preeclampsia in 1827 exposed pregnancies compared to other treated asthmatics [92]
Omalizumab	No overall increased risk compared to general population for major birth defects in 169 exposed pregnancies (156 live births) enrolled in a registry [85]
Short-acting beta-agonists (primarily albuterol)	No increase in major birth defects over expected 1090 albuterol-exposed pregnancies in a claims database [93] No increase in major birth defects in 1753 albuterol-exposed pregnancies compared to other asthmatic pregnancies [9] Modest increased risk in isolated cleft lip or cleft palate (odds ratios from 1.65 to 1.79) in albuterol-exposed pregnancies in case-control study of 2711 cases of oral clefts and 6482 controls [94] Several additional studies have suggested modest increased risks (odds ratios <3) for specific birth defects such as any cardiac or gastroschisis, esophageal atresia, and omphalocele [73, 76, 95]	No increase in preterm delivery, low birth weight, or small-for-gestational-age infants in 1828 pregnancies exposed to short-acting beta-agonists compared to other asthmatic pregnancies [9]
Short-acting beta-agonists (others)	Ephedrine: No increased risk in major birth defects in 373 exposed pregnancies [96]
	Epinephrine: Increased overall risk for major and minor birth defects and specifically for inguinal hernia in 189 exposed [96]
	Metaproterenol: No excess in major birth defects noted in 361 exposed pregnancies from a database [93]
	Terbutaline: No increased risk for major birth defects in 149 exposed pregnancies [93]
Long-acting beta-agonists	No evidence of increased risk in major birth defects in 65 salmeterol-exposed pregnancies [97]. In one analysis of a database, increased risks for major cardiac and major “other” birth defects were seen with first-trimester exposure in 165 pregnancies [33]. However, in a later study from the same database, 841 pregnancies exposed to long-acting beta-agonists with low- or medium-dose inhaled corticosteroids showed no overall increased risk of major birth defects compared to pregnancies exposed to medium- to high-dose inhaled corticosteroids alone [98]	No difference in low birth weight, preterm birth, or small for gestational age was noted in infants of mothers exposed to salmeterol versus formoterol in a retrospective database study [71]
Theophylline	No overall increase in major birth defects in 212, 292, and 273 pregnancies [9, 54, 99]. Three case reports of severe cardiac defects in exposed pregnancies [100]

aThis table is modified from Namazy, J and Schatz, M, Eds. Asthma, Allergic and Immunologic Diseases during Pregnancy: A Guide to Management

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