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 harm that medications may cause to the fetus. Asthma attacks during pregnancy are significantly associated with adverse events such as infant death, preterm delivery and low birth weight babies. Therefore, management of asthma during pregnancy and appropriate treatment is very important. The American Asthma Education and Prevention Program (NAEPP) first developed guidelines for the treatment of asthma in pregnancy in 1993, which have been revised several times in the last decade or so, and were updated again in 2005 after summarizing the management and treatment experience of the last decade or so, providing important guidelines for the use of medications in asthma in pregnancy. This article reviews the new understanding of pharmacological treatment of asthma in pregnancy.
I. Epidemiology of asthma in pregnancy
According to the literature, the incidence of asthma during pregnancy is 3.8-8.4%, and the incidence has been found to be increasing in recent years. Pregnancy combined with asthma accounts for about 0.3-1.3% 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 varied, with 1/3 of patients experiencing an exacerbation of asthma during pregnancy, mostly between the 24th and 36th weeks of gestation, another 1/3 experiencing an improvement in asthma during pregnancy, and another 1/3 experiencing 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 are characterized by different changes during pregnancy: more severe asthma tends to worsen during pregnancy, while milder asthma tends to stabilize or improve. There is also a clear correlation between the course of rhinitis during pregnancy and the course of asthma. Factors that contribute to worsening asthma during pregnancy include changes in maternal immune function due to pregnancy, increased maternal susceptibility due to pregnancy, conception of a female child, irrational use of medication, 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 composite 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 prematurity, dysplasia, growth retardation, overdue delivery and low birth weight babies; for pregnant women, it can cause pre-eclampsia, gestational hypertension, pregnancy toxemia, 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, well-controlled asthma can significantly reduce the risk of perinatal period and delivery for pregnant women and reduce fetal complications.
Treatment of asthma in 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; avoid the use of drugs whose safety to the pregnant woman and the fetus is still uncertain; if the condition requires the use of drugs, the dose of drugs should be controlled to the lowest level possible; administer drugs by inhalation as much as possible, and reduce the use of oral or injectable drugs.
(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, active pharmacological treatment is advocated to control asthma. In the past, asthma was thought to be caused by bronchospasm, so treatment was mainly based on antispasmodic treatment. Nowadays, bronchial asthma is considered to be a manifestation of airway hyperresponsiveness based on chronic airway inflammation, and structural and functional abnormalities of bronchus can be found even in asymptomatic patients. 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. The other inhaled glucocorticoids fluticasone (Class C drug: no risk has been ruled out; these drugs can be used during pregnancy but should be used after weighing the pros and cons) and beclomethasone dipropionate (Class C) have similar efficacy to budesonide, but the FDA classifies these two 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 glucocorticoids has been shown in animal studies to cause cleft lip, cerebral edema, and craniosynostosis defects in the fetus, 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 entering the fetal circulation through the placenta, 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%, and the use of glucocorticoids throughout pregnancy may increase the incidence of fetal cleft lip and palate. The application of glucocorticoids may increase the incidence of preeclampsia, preterm birth, and low birth weight babies.
(2) Sodium cromoglycate and sodium nedolomide: These drugs have an anti-inflammatory effect 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 as prophylactic agents. 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. updated guidelines from the NAEPP have similarly confirmed the safety of β2 agonists in pregnancy through a decade of experience with a large number of animals and pregnant asthma patients, and 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 to 12ug/ml) is safe when given during pregnancy. However, it is also noted that in a double-blind controlled study comparing the effects of hormones and theophylline in pregnant women with asthma, the incidence of adverse events, discontinuation during the observation period, and the number of patients with pulmonary function FEV1 <80% of expected values were greater in the theophylline group than in the hormone group.
(3) Anticholinergic drugs: Inhaled atropine (class C drug) or ipratropium bromide (class B drug) relaxes bronchial smooth muscle by decreasing vagal tone and reducing cGMP production. Inhaled ipratropium bromide has minimal circulating absorption, no significant CNS or systemic side effects, and synergistic effects with β2 agonists, glucocorticoids, and theophylline. Currently, inhaled anticholinergic drugs are considered safe for the treatment of asthma during pregnancy.
3.Drugs harmful to the fetus are prohibited
Class X drugs are prohibited for pregnant women and are more harmful than their therapeutic value. Anti-metabolic and cytotoxic drugs (such as methotrexate, cyclosporine, etc.) are prohibited. Drugs that are used with caution on balance when necessary, such as isoprenaline and epinephrine, are mostly used in emergency situations.
In 2005, an update of the NAEPP’s “Management of Asthma in Pregnancy: Recommendations for Pharmacologic Therapy” was published, in which the following medications were highlighted for endorsement
(1) Salbutamol: a short-acting inhaled beta2 agonist used for rapid relief of asthma symptoms. This medication can be used at any time in pregnant women with asthma.
(2) Inhaled hormone: a drug recommended for use in pregnant women with persistent asthma to control lower airway inflammation. This updated guideline states that there are many data confirming the safety of inhaled budesonide over other inhaled hormones for use in pregnant women. However, there are no data to confirm that other inhaled hormones are unsafe for use during pregnancy. Inhaled hormones can be used continuously if they control the patient’s asthma. Alternatively, daily leukotriene antagonists, sodium cromoglycate, or theophylline may be options.
(3) For patients with persistent asthma whose symptoms are not well controlled by inhaled low-dose hormones, the updated guidelines recommend increasing the dose of inhaled hormones or adding another drug, an inhaled long-acting beta2 agonist. The expert panel discussed that the evidence for recommending one of these combination regimens over several others is not yet strong.
(4) Oral hormones can be used in patients with severe asthma. The updated guidelines also present some data that contradict the view that oral hormones are safe during pregnancy. However, severe, uncontrolled asthma in pregnancy shows clear risks to the mother and fetus, and it is correct to give oral hormone therapy to such patients.
5. Pharmacological treatment of acute asthma attacks during pregnancy
(1) Active oxygen inhalation, adjust oxygen concentration to maintain arterial blood gas index at PaO2≥70mmHg or SaO2≥95%.
(2) Nebulized inhalation of short-acting β2 agonists, starting with 3 consecutive inhalations within 60-90 minutes, and then, 1 inhalation every 1 to 2 hours.
(3) Intravenous administration of methylprednisolone (methylprednisolone) 1mg/kg every 6-8 hours, and gradually reduce the dose after the symptoms improve.
(4) Intravenous administration of aminophylline: the loading dose is 6mg/kg, the maintenance dose is 0.5mg/kg/h. Adjust the dose to maintain theophylline blood concentration at 5-12ug/ml.
(5) If the above treatment is not effective, terbutaline 0.25mg can be injected subcutaneously.
(6) After active treatment, if the pregnant woman’s symptoms do not improve significantly, especially those with PaO2 <70mmhg should be closely monitored for blood gas changes, and for patients with severe asthma and life-threatening conditions, tracheal intubation and assisted ventilation are required. < p="">
6. Medication for lactating asthma patients
Prednisone, beta2 agonists, beclomethasone, sodium cromoglycate, and anticholinergics and theophylline are not contraindicated in patients with asthma in general therapeutic doses during breastfeeding, and can be breastfed if the condition is relatively stable.
Terbutaline can be secreted through breast milk, and the concentration of the drug in breast milk peaks 4 hours after administration in breastfeeding asthma patients, and the infant absorbs about 0.7% of the maternal blood concentration after breastfeeding, and no symptoms of adrenergic excitation have been found in infants so far. Theophylline can also be secreted from breast milk, although only 1% of theophylline can be absorbed by newborns, but due to individual differences, toxic side effects may still occur in newborns, when the level of aminophylline in breast milk accounts for 10% of maternal blood concentration, it can cause infant irritation and insomnia, and should be reduced or discontinued.
In addition, it should be noted that antihistamines can cause drowsiness in infants when they reach a certain concentration in breast milk.
Management of asthma during pregnancy
The management of asthma during pregnancy is firstly to avoid the influence of environmental factors, and then to give appropriate medication and specific immunotherapy. The management of asthma in pregnancy is similar to that of ordinary asthma patients. Medication is the main method to control asthma, and effective avoidance of exposure to harmful irritants and allergenic substances such as cigarettes, dust mites and pollen can effectively prevent asthma attacks in pregnancy and reduce the medication used for asthma treatment. Patients with asthma who have started atopic immunotherapy before pregnancy and are on maintenance therapy can continue atopic immunotherapy during pregnancy, which can reduce acute asthma attacks and asthma maintenance medication. However, specific immunotherapy should not be initiated during pregnancy.
Patient education is the first item in the asthma management plan. Asthma during pregnancy is a special time for asthma patients, and whether pregnant women with asthma and their families are educated about asthma directly affects the outcome of asthma patients. Through education, patients and their families learn to understand the nature and pathogenesis of asthma; learn to monitor, self-assess, and self-manage changes in their condition; prevent and reduce acute asthma attacks; properly use asthma medications and control environmental causative factors; and provide psychotherapy for pregnancy and delivery.
In pregnancy and delivery, patients with asthma should be given oxygen, correction of water-electrolyte acid-base balance, necessary anti-infection and good psychological preparation for the delivery period should not be neglected. Pregnancy is a period of relative psychological stress, and this stressful and anxious psychological state of pregnant women with asthma in pregnancy may trigger asthma attacks or aggravate asthma symptoms, so active education and psychological guidance and medication guidance are extremely important for pregnant women with asthma in pregnancy.