Conditions such as asthma and allergic rhinitis are common in women of childbearing age and can affect up to 30% of this age group. The principle of pharmacological treatment is similar to that of non-pregnant patients in the same disease group. Nevertheless, to ensure the best outcome for mother and child, treatment should be well defined, as a variety of immunologic changes occur during pregnancy that can promote type 2 reactions and exacerbate disease phenotypes.
Allergic diseases are among the most common diseases in industrialized countries, affecting 18-30% of women of childbearing age. While the risk of allergic disease is higher in males during childhood, it shifts in favor of females during adolescence. In particular, allergic rhinitis, asthma, atopic dermatitis, and food allergies are the main allergic phenotypes. Asthma in pregnancy is associated with increased perinatal risks such as preterm birth, low birth weight, and preeclampsia. Therefore, appropriate disease control and education of patients and health care providers are critical to ensure the best possible care for both mother and child.
Immunological changes
The immunological changes during pregnancy provide a coordinated balance between effective immune defense and subtle immune modulation specific to each stage of pregnancy. In this context, implantation, placentation, fetal growth and birth represent distinct processes that require a specific immune environment. Thus, implantation and placentation not only involve the creation of a local pro-inflammatory process, they also require the presence of immune cells. Natural killer cells (NK cells) play an important role. They interact with self-molecules such as HLA-C and their response patterns vary from inflammatory to regulatory. Fetal growth and development, on the other hand, require an anti-inflammatory environment. In particular, the second trimester is characterized by a shift toward type 2 immunity and the promotion of regulatory mechanisms. Regulatory T cells (Treg cells) play a central role in maintaining an anti-inflammatory milieu by controlling immune responses against paternal antigens and protecting fetal cells from rejection by the maternal immune system. In the third trimester, with the onset of labor and delivery, a switch to a more inflammatory type 1 immune state occurs. The influx of immune cells into the myometrium is critical to promote uterine contraction, delivery of the baby, and release of the placenta.
Asthma very common in pregnancy
Uncontrolled asthma poses an increased risk to both mother and child. Inadequate disease control is therefore associated with an increased risk of preeclampsia, cesarean section, preterm birth, low birth weight, and smaller gestational age infants. Compared to non-asthmatic mothers, it also increases the risk of early asthma in the offspring, which can then become more pronounced. Hormonal, immunological and physiological changes during pregnancy are responsible for the different course. Sex hormones such as estrogens, progesterone, and prostaglandin E have bronchodilator effects, whereas hormones such as prostaglandin F promote bronchoconstriction. Immunologic changes during pregnancy that exacerbate type 2 phenomena and promote airway inflammation are critical factors to consider. Adaptation of the immune response also increases susceptibility to viral respiratory infections in pregnant women, which are the most common triggers of asthma exacerbations. Because asthma in childbearing age is predominantly triggered by type 2 mechanisms, the relative type 2 shift over a prolonged period of pregnancy may contribute to worsening asthma control in a group of patients. Thus, asthma control and symptoms may change during pregnancy. In addition, pregnancy-related physiologic changes may contribute to poor disease control in pregnant patients. Thus, increased blood volume, adipose tissue, rhinitis, and edema during pregnancy may contribute to upper airway narrowing. Gastroesophageal reflux disease (GERD) is also common because of decreased esophageal sphincter tone and gastric motility in pregnant women. Approximately 65% of pregnant women with asthma also experience rhinitis, which can be allergic or non-allergic. Obstructive sleep apnea syndrome (OSAS) is also often underdiagnosed during pregnancy and may be a reason for poor asthma control.
Assessment of these comorbidities before and during pregnancy holds the potential for preventive strategies to improve maternal and fetal health. In this regard, the goals of asthma treatment in pregnancy are identical to those in the nonpregnant population: risk control and symptom reduction. A stepwise approach is recommended, as described for example in the GINA guidelines. The most commonly used medications are inhaled short-acting beta agonists (SABA), inhaled corticosteroids (ICS), inhaled long-acting beta agonists (LABA), leukotriene receptor antagonists (LTRA), inhaled tiotropium bromide, oral steroids (OCS), and biologics.
Asthma exacerbations are significant problem
Risk factors for uncontrolled asthma or exacerbations during pregnancy include nonadherence to inhaled corticosteroid medications, preexisting poor lung function, severe asthma before pregnancy, smoking, and obesity. Participation in an asthma treatment program with regular disease monitoring, activity, and reassessment of inhaler use and techniques, leads to improved medication adherence and asthma self-management. Asthma exacerbations during pregnancy are associated with an increased risk of pregnancy-related hypertension, cesarean delivery, low birth weight, and preterm birth. Most exacerbations occur in the second and early third trimesters, with asthma-related symptoms decreasing in the last weeks of pregnancy. Asthma exacerbations during labor are rare. Treatment of exacerbations requiring emergency admission is similar to that for nonpregnant asthmatics, with special attention to adequate oxygenation. Inflammation-based asthma treatment via inhaled steroids reduces exacerbations and may also improve pregnancy outcomes.
Allergic and chronic rhinitis
Both allergic rhinitis due to hyperemia and edema of the nasal mucosa and chronic rhinosinusitis with nasal polyps (CRSwNP) may worsen during pregnancy. Therefore, careful management is critical to avoid asthma exacerbations. Basically, the treatment during pregnancy is similar to the treatment of the non-pregnant population. The most important steps are avoidance of triggers and treatment with appropriate medications: Nasal corticosteroids and antihistamines and combinations thereof and oral antihistamines. Furthermore, for CRSwNP, adjunctive therapy with biologics may be considered.
Antiallergic treatment during pregnancy
Antihistamines are commonly prescribed for various indications during pregnancy. Second-generation non-sedating antihistamines are recommended for treatment. First-generation antihistamines (H1 antihistamines) such as chlorpheniramine, diphenhydramine, hydroxyzine, and ketotifen are not suitable for the treatment of allergic rhinitis because of their pregnancy-independent safety profile. However, if prescribed, no increased rate of congenital malformations was reported. Among first-generation antihistamines, chlorpheniramine was recommended as the first-line agent. The agents of choice for second-generation H1 antihistamines, with less sedating properties, are cetirizine and loratadine.
The leukotriene receptor antagonists (LTRAs) montelukast and zafirlukast are prescribed for asthma control and maintenance therapy. Studies showed no association with major congenital malformations or adverse perinatal outcomes. However, given the limited data, LTRAs should be considered as second-line therapy during pregnancy only if better-tested treatment options fail.
According to ESR/TSANZ Task Force Statement 2020, theophylline is compatible with pregnancy. However, it is only an alternative and should not be a preferred add-on treatment for asthma in pregnancy.
A randomized controlled trial of the safety of sublingual immunotherapy in pregnancy and several retrospective studies have shown that maintenance therapy during pregnancy does not lead to unfavorable outcomes. However, due to lack of data and the existing, albeit very rare, risk of treatment-associated anaphylaxis, initiation of allergen-specific immunotherapies or dose escalation steps should be avoided during pregnancy. In the case of hymenopteran allergy, an individual decision must be made and the risk-benefit ratio discussed with the patient. If well tolerated and effective, allergen immunotherapy can be continued during pregnancy.
If conventional asthma treatment approaches are poorly tolerated or ineffective, biologics may be considered for moderate to severe asthma phenotypes. The currently approved biologics for the treatment of allergic diseases are IgG1 (omalizumab, benralizumab, and mepolizumab) or IgG4 (dupilumab and reslizumab) isotypes. Due to placental transport, maternal IgG levels of the respective isotype increase in the fetal circulation after week 13. Concentrations reach 50% at weeks 28-32 and may exceed maternal levels after week 35. The exact IgG levels of a fetus depend on the IgG levels of the mother. For this reason, continuation or discontinuation of biologics during pregnancy should be made by weighing the risk-benefit ratio of maternal and fetal well-being.
In addition to asthma type 2, dupilumab is approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for atopic dermatitis and chronic rhinosinusitis with nasal polyps. Dupilumab is an IgG4 isotype antibody and targets the anti-IL-4Ralpha antibody. The EMA emphasizes that women must be advised that the potential benefits of biological exposure during pregnancy must be weighed against the risks to the fetus.
Immunosuppressants
Cyclosporine may be considered as first-line therapy when long-term treatment is required for disease control. Studies have not shown an increased rate of congenital malformations. Adverse pregnancy outcomes such as fetal growth retardation, prematurity, or preeclampsia are likely related to the mother’s underlying disease rather than drug therapy. Nevertheless, it is recommended to monitor the mother’s blood pressure and kidney function. Azathioprine can be continued if started before pregnancy, according to ETFAD. Based on available data, there is no evidence that azathioprine exposure is associated with an increased incidence of congenital malformations. However, it should be noted that most reports of azathioprine involve women with underlying autoimmune/chronic inflammatory diseases that may affect pregnancy outcomes.
Corticosteroids are used for a variety of chronic conditions during pregnancy, including allergic diseases. In general, corticosteroids cross the placenta; the extent of concentrations in the fetus may vary depending on maternal metabolism and in the placenta. Both human and animal studies suggest increased rates of cleft palate, preterm birth, low birth weight, stillbirth, preeclampsia, and gestational diabetes. The severity of the underlying maternal disease and inflammation are important confounding factors that must be considered when interpreting these results. A meta-analysis conducted examined the association between maternal corticosteroid use and orofacial clefts. The results showed that even if corticosteroid use during the first trimester is indeed associated with cleft lip without or with cleft palate, the absolute risk remains very low (baseline risk 1/1000, exposed pregnancies 1.2/1000). Since palate formation is complete by the 12th week of fetal life, there is no risk of abnormalities with subsequent therapy.
When other treatment options fail, systemic corticosteroids are used as maintenance therapy to treat severe asthma in pregnancy. Short cycles are indicated to treat exacerbations during pregnancy. The increased risk of untreated disease, recurrent exacerbations, and associated maternal and fetal mortality should be weighed against the potentially increased risks of the drugs to the mother and fetus.
Inhaled beta-agonists and inhaled corticosteroids.
Treatment with albuterol/salbutamol is considered safe in light of current data. Few studies suggested an increased risk of malformations associated with exposure to beta-agonists. Reported associations may also result from the severity of maternal asthma and associated fetal hypoxia or chance alone, rather than from respective drug use. Long-acting beta agonists are expected to have a similar safety profile to albuterol/salbutamol due to similar pharmacology and toxicology.
Nasal corticosteroids
Safety data on corticosteroid nasal sprays (ICS) do not indicate an increased risk to mother and child, especially for budesonide, which can be considered the first-line agent for nasal use. Also, the overall limited data on the safety of intranasal corticosteroids do not suggest an increased risk of congenital malformations, particularly oral clefts, during pregnancy. Budesonide, ciclesonide, fluticasone, and mometasone are thus considered probably safe. Based on animal data, the use of nasal antihistamines such as olopatadine or azelastine is not expected to increase the risk of congenital anomalies; however, no human data are currently available.
Topical treatment
Systemic absorption occurs after topical application of corticosteroids, especially when applied to larger areas of inflamed or injured skin. A Cochrane review evaluated the safety of exposure to topical corticosteroids during pregnancy and reported no increased risk of malformations. Therefore, if stronger topical corticosteroids are required, exposure should be limited to a short period of time. The current recommendation is that mild to moderate topical corticosteroids are the first choice over strong to very strong corticosteroids.
No studies are available on the use of topical calcineurin inhibitors (CNIs) in pregnant women. Published data on oral tacrolimus do not indicate an increased risk of serious congenital malformations beyond the baseline risk in the general population. The bioavailability of topical tacrolimus is low, and due to the large size of tacrolimus, systemic absorption is very low (0/1-0.03%). Therefore, topical dosage forms are expected to have low absorption, which should not affect the fetus. The ETFAD recommends justifying the use of topical CNIs during pregnancy based on the known results after oral administration. Similar to tacrolimus, systemic absorption is also low with pimecrolimus. Data on exposure to pimecrolimus during pregnancy are too limited to assess the safety of use during pregnancy. And data on the topical phosphodiesterase-4 inhibitor (PDE-4 inhibitor) crisaborole are also too limited, so its use before conception or during pregnancy is not recommended.
Contraindicated drugs in pregnancy
Methotrexate is a folic acid antagonist and inhibits dihydrofolate reductase. It is associated with congenital malformations in children. Craniofacial anomalies (hydrocephaly, meningoencephalocele, anencephaly, parietal craniostenosis, cleft lip and/or palate, hypo- or retrognathia), limb defects (syndactyly, clubfeet), intrauterine growth retardation, and mental retardation have been reported after the use of methotrexate. Data on contraception after accidental exposure at low doses revealed variable risk; therefore, a shared, informed decision should be made. Methotrexate is contraindicated during pregnancy, and several contraceptive recommendations have been proposed. In summary, ETFAD states, “EFTAD recognizes the discrepancy between the EULAR/EADV/EDF recommendations (1 to 3 months prior to desired date of conception) and the EMA label (6-month waiting period) and recommends discontinuation of therapy 6 months prior to desired date of conception in the absence of local/national guidance.”
Mycophenolate mofetil is a purine synthesis inhibitor. The most common malformations described in association with mycophenolate are: Abnormal ear development, facial clefts, eye, skeletal and heart defects. Increased rates of spontaneous abortion and preterm birth have also been reported in women exposed to mycophenolate mofetil. Mycophenolate mofetil is teratogenic, strictly contraindicated in pregnancy, and treatment must be discontinued at least three months prior to planned conception. Therefore, women of childbearing age must be informed about the teratogenicity of the drug. Therefore, if women are planning to become pregnant, mycophenolate mofetil should not be prescribed by healthcare providers.
Literature:
- Pfaller B, et al: Management of allergic diseases in pregnancy. European Journal of Allergy and Clinical Immunology 2021; https://doi.org/10.1111/all.15063.
InFo PNEUMOLOGY & ALLERGOLOGY 2022; 4(2): 26-28.
