Asthma is the most common serious illness during pregnancy, with significant effects on both the mother and the fetus, and several studies have shown that asthma symptoms may worsen during pregnancy.
Also, the incidence of pre-eclampsia, preterm birth, low birth rate, low birth weight, and perinatal mortality may be increased. The reasons for this include hypoxia, other pathophysiology due to uncontrolled asthma, medications and other related factors.
Therefore, the management of asthma in pregnancy and the rational use of medications are very important. The ultimate goal of asthma treatment in pregnancy: to ensure fetal oxygen supply and reduce maternal hypoxia time.
1.Inhaled glucocorticoids
In 2005, the American Asthma Education and Prevention Program (NAEPP) adopted inhaled glucocorticosteroids as the first-line medication for the treatment of asthma during pregnancy.
Studies have demonstrated that inhaled glucocorticoids are safe in patients with asthma during pregnancy at low to moderate doses (low doses: beclomethasone propionate 200-500 μg/d, budesonide 200-400 μg/d, fluticasone 100-250 μg/d; moderate doses: beclomethasone propionate 500-1000 μg/d, budesonide 400-800 μg/d, fluticasone 250-500 μg/d), but the safety of high doses (beclomethasone propionate >1000 μg/d, budesonide >800 μg/d, fluticasone >500 μg/d) remains to be studied. d) still needs to be further tested for safety.
Currently, among all inhaled glucocorticoids, only budesonide, the safest and most commonly used class B drug, is safe for the fetus at regular therapeutic doses (0.1-0.8 mg/d), while inhaled doses of 1.4-1.8 mg/d may cause suppression of hypothalamic-pituitary-adrenocortical axis function in pregnant women. Fluticasone and beclomethasone propionate have the same efficacy as budesonide, but are metabolized more slowly than budesonide for intrahepatic inactivation and are classified as Class C drugs by the FDA.
It is generally accepted that less than 20% of adults with inhaled beclomethasone propionate <1.0 mg >1.5 mg/d experience suppression of the thalamus-pituitary-adrenocortical axis; with inhaled doses >2.0 mg/d, almost all patients experience suppression of this hormonal axis. In addition, trimethoprim, flunisolide, and mometasone furoate are all class C drugs. Therefore, budesonide is the first choice for inhaled glucocorticoids in asthma during pregnancy.
2.Systemic glucocorticosteroids
Systemic glucocorticosteroids have adverse effects in the perinatal period, but the adverse consequences of severe asthma attacks should also be considered. One study showed that systemic glucocorticoids increased the incidence of preeclampsia, preterm birth, and low birth weight, and reduced gestational age by an average of 2.2 weeks.
In addition, in 2005, the NAEPP noted that oral glucocorticoids in the first trimester increased the incidence of cleft lip and cleft palate in the fetus. In the literature, the incidence of fetal malformations in pregnant women taking oral glucocorticoids in early pregnancy was 0.3% compared to 0.1% in the general cohort.
Among the systemic glucocorticoids, prednisone and prednisolone are class B drugs, and methylprednisolone, dexamethasone and beclomethasone propionate are class C drugs.
Prednisone is the most commonly used oral glucocorticosteroid, and 87% of the drugs are inactivated by the placental enzyme 11-dehydrogenase before entering the fetal circulation through the placenta, with little effect on the fetus. At present, it is believed that taking prednisone ≤ 10 mg/d has little effect on pregnant women and fetuses.
3.Allergic mediator blocking drugs
Sodium cromoglycate and sodium nedolomide are allergen-blocking agents for the prophylactic treatment of asthma attacks. Studies have been conducted to evaluate the effects of inhaled sodium cromoglycate during pregnancy on perinatal outcomes.
It was found that the use of sodium cromoglycate in pregnant women did not increase their incidence of preterm birth or congenital malformations.
Studies on inhaled sodium nedolomide in pregnant women have not been reported, and animal studies have shown no teratogenic or other toxic effects of sodium nedolomide in animals.
The AEPP states that both sodium cromoglycate and nedolomide are Class B drugs and are safe for use during pregnancy. These drugs have limited efficacy compared to inhaled glucocorticoids and may be used as an option for patients with mild persistent asthma during pregnancy, but are not the drug of choice.
4. Leukotriene receptor modulators
These drugs mainly include leukotriene receptor antagonists (montelukast, zalust) and leukotriene synthesis inhibitors (zileuton).
Currently, the FDA has only approved the results of animal studies of leukotriene receptor modulators, so these drugs are not recommended as the first choice for patients with asthma during pregnancy, but only for patients who have been treated with these drugs before pregnancy with significant results, or as an alternative to inhaled glucocorticoids.
The FDA classifies montelukast and zalutost as Class B drugs and zileuton as Class C drugs.
5. Theophylline
Theophylline has bronchodilator and anti-inflammatory effects and is a Class C drug. It should be noted that its therapeutic concentration is close to the toxic concentration. As the ability of pregnant women’s liver to metabolize theophylline is reduced, theophylline concentration in blood or urine should be monitored frequently and the dose should be adjusted in time to avoid serious adverse reactions.
Theophylline can pass the placental barrier, making no significant difference between maternal and umbilical cord serum theophylline concentrations. The NAEPP states that the recommended dose of theophylline (6-10 mg/(kg.d) at a blood concentration of 5-12 μg/ml) is safe for use during pregnancy.
A study comparing the efficacy and safety of theophylline and inhaled beclomethasone propionate suggested that there was no significant difference in the effectiveness of the two drugs in controlling asthma, but the incidence of adverse effects was higher and compliance was poorer with theophylline.
Currently, low-dose theophylline is an option for patients with mild persistent asthma in pregnancy, but blood levels must be monitored during treatment and is not the preferred treatment option. In patients with moderate to severe asthma in pregnancy, the combination of long-acting β2 agonists and theophylline should be considered only when inhaled glucocorticoids are not controlled.
6.Long-acting β2 agonists
Currently, the combination of long-acting β2 agonists with inhaled glucocorticoids is recommended for patients with moderate to severe asthma during pregnancy, while monotherapy with long-acting β2 agonists is not recommended.
In combination with glucocorticoids, long-acting β2 agonists are potentially less toxic and more effective than theophylline and leukotriene receptor modulators in treatment regimens.
Currently, the American College of Obstetricians and Gynecologists and the American Academy of Allergy, Asthma and Immunology use long-acting β2 agonists as the preferred combination of inhaled glucocorticoids, and commonly used combination regimens include salmeterol in combination with fluticasone and formoterol in combination with budesonide.
7.Short-acting β2 agonists
Short-acting β2 agonists have strong bronchodilator effect, which can rapidly release bronchospasm, reduce airway resistance, and attenuate airway hyperresponsiveness, and are now mostly used for quantitative inhaler or solution nebulizer treatment.
This class of drugs includes salbutamol (class C), levosalbutamol (class C), terbutaline (class B), oxybutynin (class C) and pirbuterol (class C). Short-acting β2 agonists are the first-line agents for the treatment of acute exacerbations of bronchial asthma and are relatively safe for use during pregnancy.
In recent years, several clinical studies have demonstrated the safety of salbutamol, and both the American College of Obstetricians and Gynecologists and the NAEPP have recommended it as the preferred inhaled short-acting β2 agonist. However, because the drug may induce palpitations, tremors, arrhythmias and myocardial ischemia, it should be used with caution in asthmatic patients with heart disease; at the same time, long-term use of large amounts may reduce the number or sensitivity of the body’s beta receptors, leading to drug tolerance and reduced efficacy, so it is recommended for short-term use as needed.
8.Anti-cholinergic drugs
Anticholinergic drugs have weaker bronchodilatory effects than β2 agonists, with slower onset of action, but longer duration of action, and long-term use is not easily tolerated, with fewer adverse reactions in the cardiovascular system. For asthma patients who cannot tolerate β2 agonists, these drugs can be used. Anticholinergic drugs mainly include atropine (class C) and ipratropium bromide (class B).
Among them, inhaled atropine inhibits glandular secretion, causes thick respiratory secretions and is not easily excreted, and should not be used in critically ill asthmatic patients during pregnancy. Ipratropium bromide is mostly administered by inhalation and is mainly used to relieve the symptoms of mild to moderate asthma in the acute phase, especially for asthma patients with heart disease.
Inhaled anticholinergics are currently considered safe for patients with asthma during pregnancy.