Asthma during pregnancy is a special case in the management of asthma. This special period is important both to control asthma and to enable pregnant women to pass through pregnancy to delivery, and to avoid the possible harm caused by medications to the fetus. Asthma attacks during pregnancy are significantly associated with adverse events such as infant mortality, preterm birth and low birth weight babies.
I. Epidemiology of asthma in pregnancy
According to the literature, the incidence of asthma during pregnancy ranges from 3.8 to 8.4%, and the incidence has been found to be increasing in recent years. Pregnancy combined with asthma accounts for about 0.3 to 1.3% of maternal cases. Recently, it was found that 55% of female patients with a history of asthma will experience at least one acute asthma attack during pregnancy.
II. Interaction of pregnancy and asthma
The changes in asthma during pregnancy are diverse, with 1/3 of patients experiencing an exacerbation of asthma during pregnancy, mostly between the 24th and 36th weeks of gestation; another 1/3 of patients experiencing an improvement in asthma during pregnancy, and another 1/3 of patients with no specific change in their condition. paul et al. reported that 0.2% of patients experienced persistent asthma during pregnancy, and 10% of pregnant women experienced an The majority of women with asthma have an acute asthma attack in the first 3 days after delivery. Most women with asthma return to pre-pregnancy levels by 3 months after delivery.
These patients may have a recurrence of asthma attacks in subsequent pregnancies. Asthma attacks, especially severe asthma and persistent asthma, are not only dangerous for the pregnant woman, but can also cause intrauterine hypoxia, growth retardation, distress and even death of the fetus due to severe maternal hypoxia. Therefore, improper management of asthma attacks during pregnancy will have serious effects on the pregnant woman and her fetus.
1.The effect of pregnancy on asthma
Pregnancy can cause changes in the condition of asthma. Different degrees of asthma have different characteristics during pregnancy: more severe asthma tends to worsen during pregnancy, while milder asthma tends to stabilize or improve. In addition, the course of rhinitis during pregnancy is significantly correlated with the course of asthma. Factors that contribute to the worsening of asthma during pregnancy include changes in maternal immune function due to pregnancy, increased maternal susceptibility due to pregnancy, conception of a female fetus, irrational use of medications, and being a patient with severe asthma prior to pregnancy.
The mechanisms underlying the changes in asthma status during pregnancy are not well understood. Various biochemical and physiological alterations during pregnancy may accelerate or worsen the course of asthma during pregnancy. It has been reported in the literature that the presence of the fetus and placenta during pregnancy causes changes in the maternal immune system that are very similar to those described in patients with non-eosinophilic asthma in the non-pregnant state, and studies suggest that worsening asthma during pregnancy may not be due only to pregnancy and asthma, but may be a combination of factors and events.
2. Impact of asthma on pregnancy
During pregnancy, recurrent asthma attacks can have adverse effects on pregnancy. For the fetus, recurrent asthma attacks can lead to preterm birth, dysplasia, growth retardation, overdue delivery, and low birth weight babies; for pregnant women, it can cause pre-eclampsia, gestational hypertension, toxemia of pregnancy, vaginal bleeding, and obstructed labor. Severe asthma attacks can even endanger the life of the pregnant woman and the fetus. Under close observation and effective treatment, good control of asthma can significantly reduce the risk of perinatal and delivery, and reduce fetal complications.
Treatment of asthma during pregnancy
(a) The principles of medication for asthma during pregnancy
Use non-pharmacological therapy as much as possible to reduce the damage of drugs to the fetus; try to avoid using drugs whose safety to the pregnant woman and the fetus is still uncertain; if the condition requires medication, the dose of medication should be controlled to the lowest level possible; administer medication by inhalation as much as possible, and reduce oral or injectable medication.
(B) Pharmacological treatment of asthma during pregnancy
Pregnant women are special individuals, and the treatment of asthma during pregnancy should take into account the safety of the pregnant woman and the fetus. The choice of asthma medication depends on whether the risk to the pregnant woman or the fetus is greater or lesser than that of the asthma attack. Because asthma itself has adverse effects on both the fetus and the pregnant woman, aggressive pharmacological treatment is recommended to control asthma.
In the past, asthma was thought to be caused by bronchospasm, so treatment was mainly based on antispasmodic treatment. Nowadays, it is believed that bronchial asthma is a manifestation of airway hyperresponsiveness based on chronic airway inflammation, and even asymptomatic patients can be found to have structural and functional abnormalities of the bronchi. Currently, inhaled glucocorticoids are preferred in patients with asthma during pregnancy, along with bronchodilators such as theophylline and β2 agonists, to provide anti-inflammatory treatment along with wheezing.
Uncontrolled asthma is very harmful to the pregnant woman and the fetus. This is because uncontrolled asthma increases the complications of pregnancy (low birth weight newborns and preterm infants), a risk that is much higher than that posed by asthma treatment medications for pregnancy. Therefore, it is essential to use medications to control asthma during pregnancy. The following medications are commonly used for asthma during pregnancy.
1.Anti-inflammatory drugs
(1) Glucocorticosteroids: mainly administered by inhalation, inhaled glucocorticosteroids can effectively inhibit the number of inflammatory cells and their activity in the airways, and because they work locally in the airways, they can significantly reduce the side effects of systemic medication. Among them, budesonide (Class B drug: no significant harm to humans, and this type of drug is safe for use during pregnancy) is the most common and safe inhaled drug used during pregnancy. Regular therapeutic doses have no adverse effects on the fetus, but hypothalamic-pituitary-adrenal axis suppression may occur at inhalation doses of 1.4 to 1.8 mg/d.
Other inhaled glucocorticosteroids fluticasone (class C drugs: risk not excluded, these drugs can be used during pregnancy but should be used on balance) and beclomethasone dipropionate (class C) have similar efficacy to budesonide, but the FDA classifies these drugs as class C drugs. Therefore, budesonide should be preferred for inhaled glucocorticoids during pregnancy. The NIH document states that inhalation therapy with sodium cromoglycate or budesonide given to pregnant women with persistent asthma is considered the first-line agent. Some studies have shown that inhaled hormones improve lung function and reduce acute asthma attacks during pregnancy; numerous other prospective studies have found no association between inhaled hormones and fetal congenital abnormalities or other adverse events during pregnancy.
Approximately 5% of patients with asthma during pregnancy require oral glucocorticosteroids, and both short-term and long-term oral regimens are available, with short-term use being less likely to result in systemic side effects. The use of high doses of glucocorticosteroids has been shown to cause cleft lip, cerebral edema, and craniosynostosis in fetuses in animal studies, but has not been demonstrated in humans. Prednisone is the most common oral glucocorticosteroid, and 87% of the blood drug is inactivated by the action of 11-dehydrogenase in the placenta before it enters the fetal circulation, with little effect on the fetus. At present, it is believed that if prednisone is taken ≤10mg daily during pregnancy, there are few adverse effects on pregnant women and fetuses.
In severe cases, prednisone can be taken 30-40mg daily for 3-7 days, then gradually reduced to every other day or once daily, and gradually overtaken by inhaled glucocorticoid therapy. The NAEPP states that the use of glucocorticoids in the first trimester of pregnancy increases the incidence of fetal cleft lip and palate, with the incidence of fetal cleft lip and palate in the general population being 0.1%, while the incidence of fetal cleft lip and palate in pregnant women taking oral hormones in the early stages of pregnancy is 0.3%. The incidence of preeclampsia, preterm birth, and low birth weight babies may be increased by the use of glucocorticoids throughout pregnancy.
(2) Sodium cromoglycate and sodium nedolomide: These drugs have anti-inflammatory effects by inhibiting mast cell degranulation, as well as attenuating respiratory neuronal reflexes and inhibiting the accumulation of eosinophils and neutrophils in the lung epithelium. These drugs have no bronchodilator effect and can be used prophylactically. Inhalation of their powder before exercise or exposure to allergens can prevent asthma attacks. These drugs have no toxic side effects except for a slight irritation when inhaled. Sodium cromoglycate is a class B drug that can be used as a mast cell stabilizer during pregnancy with less than 10% systemic absorption and does not cross the placenta. NAEPP also states that cromoglycate is a safe drug to use during pregnancy.
(3) Leukotriene modulators: This class of drugs includes leukotriene receptor antagonists (montelukast and zalutostat) and 5-lipoxygenase inhibitors (zileuton). Given this information from a recently completed clinical study that looked at 2205 pregnant women with 873 asthma patients, 9 of whom used leukotriene receptor antagonists, the NAEPP notes that there is only very little evidence to support the use of leukotriene modulators for asthma during pregnancy. The US FDA has only approved the results of animal studies of leukotriene receptor antagonists.
2. Bronchodilators
(1) β2 agonists: These drugs are suitable for patients with various degrees of asthma during pregnancy. The biggest advantage of these drugs is that they can rapidly relieve bronchospasm, among which the commonly used drugs are salbutamol, terbutaline and pirbuterol, but their effect can only be maintained for 4-6 hours. Inhalation of β2 agonists in early pregnancy is still safe for mother and child, except for terbutaline which belongs to class B drugs, all other drugs belong to class C. Its side effects mainly include tremor and tachycardia.
β2 agonists can be used as first-line drugs for mild asthma. However, long-term use can lead to serious adverse effects such as hypertension and increased mortality, and long-term, heavy use of β2 agonists can reduce the number or sensitivity of the body’s β2 receptors, so short-term use on an as-needed basis is recommended. The updated NAEPP guidelines, which have confirmed the safety of β2 agonists in pregnancy through a large number of animal and pregnant asthma patients over a decade of experience with the drugs, also confirmed that two long-acting β2 agonists (salmeterol and formoterol) are also available for use during pregnancy and that their pharmacology and toxicology are similar to those of short-acting β2 agonists (salbutamol), except that their deposition time in the lungs is prolonged.
(2) Theophylline drugs: These drugs exert drug effects by relaxing bronchial smooth muscle, stimulating respiratory center, enhancing diaphragm movement, and anti-inflammation, etc. The main mechanisms of action are: inhibition of phosphodiesterase activity; antagonism of adenosine receptors; reduction of intracellular calcium ion concentration; increase of endogenous catecholamine concentration; and inhibition of inflammatory mediators released from mast cells.
As a second-line drug, this class of drugs has a limited therapeutic concentration range, and because of decreased hepatic metabolism during pregnancy, theophylline concentrations in blood or urine must be monitored and doses adjusted to avoid serious side effects. Theophylline crosses the placental barrier and there is no significant difference between maternal and umbilical cord serum theophylline concentrations. When the blood concentration is greater than 10ug/ml, transient neonatal vomiting, tremor and tachycardia can occur; the blood concentration should be maintained at 5-15ug/ml in non-pregnant asthmatic patients, and theophylline blood concentration should be maintained at 5-12ug/ml in pregnant women; when the blood concentration is >30ug/ml it can cause severe toxicity. In the second trimester, the clearance of aminophylline may decrease by 20%-35%, so the blood concentration should be closely monitored.
The use of aminophylline in pregnant women may reduce the incidence of preterm birth, gestational hypertension syndrome and low birth weight babies, but may increase the incidence of pre-eclampsia. The updated NAEPP guidelines state that a large number of studies and experience confirm that extended-release theophylline (blood levels of 5-12ug/ml) is safe when given during pregnancy. However, it also notes that in a double-blind controlled study comparing the effects of hormones and theophylline in pregnant women with asthma, the incidence of adverse events, observation period discontinuation rate, and pulmonary function FEV130% were preferred in the theophylline group.