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Antiasthmatic and cough medication
Bronchial asthma affects 4–12% of pregnant women worldwide. During pregnancy, asthma should be adequately treated not only for the benefit of the mother but also to safeguard proper fetal oxygenation. Severe, poorly treated asthma is associated with adverse perinatal outcomes ( ), such as a higher risk of prematurity ( ), lower birth weight ( ) or small for gestational age (SGA) children ( ), preeclampsia ( ), and other complications ( ). There is a debate about the possibility of a slight increase of some malformations ( ), and also if the fetal gender can influence the course of asthma during pregnancy. Results are contradictory ( ). In a recently published meta-analysis, maternal asthma was associated with an increased risk of cleft lip but not with other major malformations ( ). Maternal asthma can be associated with an increased offspring risk of infectious and parasitic diseases, diseases of the nervous system, ear, respiratory system, and skin ( ).
The traditional classification of asthma based on symptoms with four categories (intermittent, persistent to a minor degree, medium degree, and severe degree) is only useful for untreated patients. It does not consider the impact of therapy, and is thus not able to help adjust treatment in the course of the disease. Three stages of asthma control have been defined:
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Controlled asthma
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Partially controlled asthma
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Uncontrolled asthma.
The aim of asthma treatment is to obtain freedom from symptoms as much as possible (“controlled asthma”), with the least number of antiasthmatic drugs at the lowest possible dose. Outside pregnancy it is recommended to try to reduce asthma medication after 3 months of stabilization. This approach, however, should be very carefully applied in pregnant women ( ). Pregnant women using long-term therapy should be seen monthly by their physician/specialist, or even more frequently if the asthma exacerbates or is inadequately controlled during pregnancy ( ).
Pharmacotherapy and drug-free interventions (such as cessation of smoking and weight loss) are building blocks of asthma management. The step-wise approach for asthma therapy for adults applies, in principle, for pregnant women as well (see specific medication groups), starting with a rapidly effective β 2 -adrenergic drug, and a short-acting beta agonist (SABA) used as inhaler when necessary. When this is inadequate, low-dose inhaled corticoids (ICS) or leukotriene modifiers are added as long-term medication. At the third level of therapy low dose ICSs are combined with LABA, leukotriene modifier or sustained release theophylline. The next level consists of ICSs at medium or high dose plus a long-acting beta agonist. Theophylline and/or leukotriene modifiers may become necessary. If all this fails, oral prednisolone or anti-IgE treatment should be used ( ). Other treatment options are of lesser importance in the outpatient care of adults, but will be presented here briefly.
2.3.1
Selective β 2 -adrenergic agonists
β 2 -adrenergic agonists induce a relaxation of the smooth muscle of blood vessels (vasodilatation), bronchi (bronchodilatation), and uterus as well as a rise in the blood levels of glucose, lipids, and ketones. An exclusively acting β 2 -agonistic drug is not available; those listed here act primarily as β 2 -agonists.
Because of rapid onset of action, good effectiveness, and low side-effect profile inhalative β 2 -agonists should be chosen as medications on demand. They include: fenoterol , albuterol , salbutamol , and terbutaline , levalbuterol , pirbuterol and reproterol . About 10% of inhalative SABAs reach the bronchi directly, while the rest is swallowed and absorbed by the gastrointestinal tract ( ).
Albuterol is the best investigated drug for use during pregnancy ( ) and it was well tolerated in most studies. A case-control study with 4,593 asthmatic pregnant women even detected a protective effect of SABA in pregnancy-induced hypertension ( ).
However, there are also results with converse outcomes. For instance, retrospective case-control studies found an association with gastroschisis ( ) and with heart defects ( ). An additional publication reported a slightly increased risk of cardiac defects ( ). In a large population based study, some association was found between bronchodilator and inhaled steroid use on omphalocele, esophageal atresia and anorectal atresia, although possibly due to the level of asthma severity (hypoxia) and not the asthma medications ( ). In another large database study, SABAs during the first trimester were not associated with an increased risk of congenital malformations ( ). Terbutalin exposure has been associated with autism spectrum disorders of the offspring if used for more than 2 days in the third trimester, although larger studies are required to confirm this observation ( ).
Long-term acting β 2 -adrenergic agonists or long-acting beta agonists (LABAs) should be applied exclusively in combination with corticoids; they include formoterol with its rapid onset, salmeterol and the new indacaterol . Experiences with these are limited; it can be assumed that they do not differ in their compatibility from SABAs, although some studies have found an association with first trimester exposure to LABA and cardiac malformations ( ).
Oral and parenteral administration of beta agonists is limited to special situations. Currently available are salbutamol, terbutaline, bambuterol , tulobuterol , reproterol, and clenbuterol .
At sufficient dose all adrenergic agents can trigger tachycardia and arrhythmias, not only in the mother but also in the fetus. They can also increase glucose intolerance – an effect that needs to be taken into consideration in pregnant women with a diabetogenic metabolism. Terbutalin has been associated with autism spectrum disorders among the offspring ( ).
Experience in pregnancy with indacaterol have not been reported, and for bambuterol, clenbuterol, and tulobuterol they are inadequate. Yet, there are no indications that these drugs have teratogenic effects in humans.
Recommendation
Adrenergic drugs are also part of asthma management in pregnancy. Inhalative drug of choice is the well-investigated short-acting albuterol as medication on demand. If the severity of asthma makes it necessary, the administration of the long-acting formoterol (together with an ICS) is the treatment of choice in pregnancy. The treatment steps outlined above should be observed. At the end of pregnancy, inhibition of uterine contractions and β 2 -specific effects need to be taken into consideration.
2.3.2
Inhaled corticosteroids (ICSs)
Inhaled corticosteroids (ICSs) are part of any long-term treatment of asthma and should not be discontinued in pregnancy.
ICSs have anti-inflammatory, antiallergenic, and immunosuppressive activities and enhance the response of bronchial β-receptors. Available treatments are budesonide , an agent well-studied in pregnancy, as well as the following halogenated ICSs: beclomethasone , fluticasone , mometasone , and ciclesonide and triamcinolone .
Theoretical concerns about use of ICSs during pregnancy are based on the results of some studies of systemic use ( Chapter 2.15 ). Studies of ICSs in thousands of pregnant women have been able to remove these doubts ( ). In a large population based study some association was found between bronchodilator and inhaled steroid use on omphalocele, esophageal atresia and anorectal atresia, although possibly due to the degree of asthma severity (hypoxia), and not the asthma medications ( ). Low to moderate doses of ICSs were not associated with an increased prevalence of perinatal outcomes such as low birth weight, preterm birth and small for gestational age ( ), although there is still concern regarding high dose ICS therapy ( ). ICS therapy is known to have an inhibitory effect upon the maternal cortisol feedback regulation only when the fetus was female ( n = 38) ( ); this needs to be explored in future studies. ICS therapy has been associated with offspring endocrine, metabolic, and nutritional disorders ( ).
Most experiences have been reported with budesonide ( ), followed by beclometasone and fluticasone. At this point there is no evidence that the minimally investigated mometasone or ciclesonide would lead to different results.
In cases of severe asthma, or for the treatment of an asthma attack, glucocorticoids may also be used systemically ( Chapter 2.15 ).
Recommendation
According to the International Asthma Guidelines, ICS is the preferred treatment of choice for long-term therapy in pregnancy ( ). More thoroughly investigated substances such as budesonide are to be preferred.
2.3.3
Theophylline
Theophylline is a strong bronchial dilatator. Aside from theophylline, the related aminophylline is also available.
The plasma concentration of theophylline correlates closely with a bronchodilatative effect, but also has undesirable side effects. When the bronchial obstruction is less pronounced, theophylline is a less effective dilatator than β 2 -agonists.
Theophylline has a mildly positive cardiac effect, and stimulates different parts of the central nervous system. It enhances the sensitivity of the breathing center for CO 2 and thus increases frequency and depth of breathing. This effect is used to prevent threatening apnea in premature infants; in these premature children the half-life is prolonged to more than 24 hours. There are no observations of negative sequelae on later childhood development.
Theophylline crosses the placenta. Because protein binding and clearance decrease during pregnancy and, despite an increase in the distribution volume, a reduction in the dose may become necessary in order to avoid side effects for both the mother and the child. Maternal serum concentrations of 8–12 μg/ml should not be exceeded during treatment.
Although theophylline has been shown to be teratogenic at high concentrations in the animal model, no embryotoxic effects have been observed in humans ( ). Significant differences regarding birth parameters have not been noted when comparing inhalable β 2 -adrenergic agonists, inhalable corticoids, and theophylline. The rate of side effects increased with the use of theophylline in pregnant women ( ), consisting primarily of tremors, tachycardia, and vomiting. Such symptoms can also be exhibited by newborns exposed to theophylline in utero . For that reason, pregnant women should be treated with the lowest possible dose. Newborns need to be monitored for effects of theophylline therapy. Moreover, if treatment with theophylline continues until the end of pregnancy, uterine contractions may be inhibited.
Recommendation
Theophylline may be used for the treatment of asthma throughout pregnancy. The therapeutic steps outlined by the Asthma Guidelines ( ) should be observed. To minimize maternal and neonatal side effects, treatment should aim for the lowest possible but still effective dose.
2.3.4
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