Allergic diseases and their treatment play an important role in primary care. Particularly in the case of complaints during pregnancy, the question of a tolerable therapy arises.
Atopics have a genetic predisposition to react to environmental substances that are actually harmless with an excessive response from the immune system. Diseases from the atopic group, which includes allergic asthma, atopic dermatitis [AD] and allergic rhinoconjunctivitis, are still on the rise . With internationally varying prevalence, it can be amed that in Switzerland up to 23% of adult women suffer from allergic rhinitis, 8% from asthma and 4-10% from AD [2-4]. In 2017, there were 87 381 live births in Switzerland . With the above prevalence, it can be amed that up to 20 000 women per year suffer from allergic disease during pregnancy.
Up to 50% of pregnant women take a prescription medication within the first trimester and up to 90% throughout pregnancy . Due to organogenesis, the first trimester is considered a particularly delicate period for influences on the embryo. In the first part of this paper the clinical pictures will be discussed, in the second part the common drugs.
Allergic clinical pictures
Approximately one-fifth of pregnant women develop transient, nonallergic gestational rhinitis, the etiology of which has not yet been determined. This can manifest itself at any time during pregnancy. A relationship with endogenous estrogen is suspected . In severe forms, topical vasoconstrictives can be used therapeutically, although there is a risk of medicinal rhinitis with prolonged use. Oral vasoconstrictives, such as those contained in some antiretrovirals, should be avoided because of the despotic risk of malformations (heart, ears, pyloric stenosis) . Topical corticosteroids have not been shown to be effective in this form of rhinitis .
Allergic rhinitis per se does not pose a risk to the unborn child . Nevertheless, treatment may be necessary in case of symptoms. In most cases, allergic rhinitis can be differentiated from gestational rhinitis based on the medical history.
The treatment of choice for allergic rhinitis is topical intranasal corticosteroids (Tab. 1). The use of phytotherapies during pregnancy is poorly studied. These methods should therefore be used with restraint [11-13].
Allergic asthma involves hypersensitivity/hyperresponsiveness of the bronchial mucosa due to exuberant inflammatory responses to natural environmental substances. This can lead to obstructive ventilation disorder, asthma. Nonspecific triggers, such as cold air, dust, odors, smoke, or physical exertion, can also induce asthma in the presence of bronchial hyperresponsiveness. Uncontrolled asthma during pregnancy is associated with a significantly increased risk of miscarriage, preterm delivery, or preeclampsia [14-16]. In about one third of patients, asthma aggravation is observed during pregnancy, with exacerbations occurring most frequently in the second trimester [17, 18]. Most guidelines recommend that patients with asthma be monitored monthly during pregnancy (primary care physician, pulmonologist, allergist) . In the case of well-controlled asthma, treatment should be reduced adaptiverespectively only after delivery . In principle, asthma treatment in pregnant women should be performed analogously to non-pregnant women .
AD is the most frequently observed pruritic skin disease in pregnant women. In a European study, 49% of pregnancy dermatoses were attributed to pregnancy eczema ("atopic eruption of pregnancy") . Most cases are the first manifestation of AD in the presence of pre-existing atopy or a recurrence after years of prior remission. In about 20% of cases, it is an exacerbation of an AD that has usually been known since childhood. Typical predilection sites are the crook of the elbow and the back of the knee, but the rest of the skin may also be affected.
In AD, even during pregnancy, the regular use of emollients as basic care is essential. If anti-inflammatory therapy is necessary, the use of topical corticosteroids is recommended. Studies on the use of topical calcineurin inhibitors [TCI] during pregnancy are not available. However, in the current position paper of the European Task Force onAtopic Dermatitis (ETFAD), the use of TCI in pregnant women is also considered safe . If systemic therapy is required, ciclosporin or corticosteroids (short-term) are available . Off-label medications for severe AD such as methotrexate or mycophenolate mofetil are absolutely contraindicated during pregnancy due to teratogenic effects (Tab. 2).
Urticaria is divided into acute (6 weeks) . The causes of acute urticaria are variedbut can often be easily identified (z.B. Infections, reactions to medications, hymenopteran stings, or foods). Triggers are to be avoided whenever possible. Chronic urticaria is converted into spontaneous. An inducible subdivides. In the spontaneous or idiopathic form [CSU], no cause can be determined and in the inducible form, mechanical or physical factors (prere, rubbing, temperature differences) lead to the skin manifestations . Thyroid, autoimmune diseases, or infections are occasionally associated as causes of CSU . It is estimated that CSU affects 0.5-1.0% of the population .
Low-dose antihistamines should be selected as first-line therapy for CSU during pregnancy (10 mg cetirizine or loratadine 1× daily). If there is an inadequate response to antihistamines, omalizumab is the best alternative, and therapy should be continued but not reinitiated during pregnancy .
The lifetime prevalence for a severe, life-threatening general reaction, whether immunologic or nonimmunologic, is between 0.05 and 2.0% . The etiology of anaphylactic events is the same in pregnant and non-pregnant women and the general population. In adults, insect stings and medications followed by food are the most common causes of anaphylactic reaction. Peripartum, antibiotic prophylaxis for cesarean section or when the pregnant woman is colonized with group B streptococci is a common cause [30, 31].
Therapy of anaphylactic shock in pregnancy is managed in the same way as in the nonpregnant woman. Here, epinephrine (0.3-0.5 mg i.m.), for which there are no absolute contraindications, in the emergency situation as the most important and effective drug . Further emergency therapy for anaphylaxis includes venous access, volume and O2 administration, antihistamines i.v. (z.B. Clemastine 2 mg) as well as corticosteroids i.v. (z.B. Methylprednisolone 125 mg). Furthermore, care should be taken to position the pregnant woman on her left side so that the uterus does not block venous blood flow back to the heart.
Allergen-specific immunotherapy is a procedure in which tolerance is induced in the immune system by repeated administration of small amounts of allergens. If pregnancy is present, allergen-specific immunotherapy should not be initiated or the dose increased because of the risk of severe allergic side effects. However, if pregnancy is known, the previously used dose can be continued if tolerance is good, after weighing the risk-benefit ratio . Particular attention should be paid to the education of pregnant women. Congenital malformations, miscarriages, or premature births related to allergen-specific immunotherapy have not been identified .
Classification of medications
A risk classification of drugs is no longer performed in Switzerland since 2003 . Instead, the professional information will point out any risks associated with administering medication during pregnancy and breastfeeding. For the assessment of pregnancy tolerance, Swissmedic takes into account available clinical safety data as well as clinical experience with the drugs. In the absence of sufficient clinical experience, evaluation is based on data from animal studies of reproductive toxicity . If the marketing authorization application for a drug is based on a marketing authorization that has already been granted abroad, this documentation is also taken into account for the assessment . Due to misinterpretation and unclear interpretation, the Food and Drug Administration (FDA) has also stopped using pregnancy categories since 2015 .
In Switzerland, there are a large number of different dosage forms for antihistamines. Since many preparations are available without prescription, it can be amed that a not insignificant number of pregnancies are carried to term under medication with antihistamines. But no antihistamine can be classified as safe for the growing child based on existing studies . Some meta-analyses failed to find an association between the use of antihistamines during pregnancy and a teratogenic effect . Of theantihistamines, cetirizine is considered to be. Loratadine as the drug of choice in pregnancy. No teratogenic effects have been observed in a high number of exposed pregnant women taking once daily . There are no studies on higher-dose antihistamines during pregnancy. Because fexofenadine administration has been associated with decreased birth weight in animal studies, fexofenadine should tend not to be prescribed during pregnancy . Clemastine, a sedating first-generation antihistamine that has been on the market for decades, is the only antihistamine approved in Switzerland that can be administered parenterally. Clemastine is injected primarily in emergency situations, such as anaphylactic shock. According to the Swiss technical information, clemastine is supposed to have potentially harmful pharmacological effects on the fetus or the newborn, which is why the drug should not be administered during pregnancy and lactation, at least not over a long period of time . However, clemastine should be used immediately in the event of a severe, anaphylactic general reaction.
There are no studies on the tolerability of topicalantihistamines such as levocabastine or azelastine during pregnancy. These active substances should therefore only be used with restraint. Cromoglicic acid is a mast cell stabilizer. Prevents the release of histamine from sensitized cells. The agent has not been associated with teratogenic effects in several studies and thus has an excellent risk profile . In particular, it is used for mild symptoms. Cromoglicic acid is short-acting, acts locally and is hardly absorbed systemically.
Most studies have failed to find an association between the use of inhaled corticosteroids [ICS] and fetal malformations [44-46]. Only one European meta-analysis discussed an increased risk of anal atresia with ICS use . Since inhaled asthma therapy uses a higher ICS dose than intranasal application, theexperiential values of asthma therapy are used for the evaluation of topical nasal sprays. Only triamcinolone administered in the first trimester was suspected of promoting respiratory tract abnormalities such as choanal atresia, laryngeal malformations, or tracheal abnormalities. Therefore, triamcinolone should not be prescribed or administered in the first trimester . Budesonide is considered the drug of choice worldwide for any indication of pregnancy . To date, no teratogenicrisks have been demonstrated .
In principle, the use of cutaneous topical corticosteroids of all potencies is considered safe. However, there is a possible association between intrauterine growth retardation and maternal use of potent and highly potent topical corticosteroids, especially at high cumulative doses during pregnancy . The current European Guidelines recommend the use of topical corticosteroids class II and III . Due to the good benefit-risk profile, newer, double-esterified corticosteroids are preferred.
Systemic corticosteroids are rarely used for the treatment of allergic disease. Nevertheless, it is a cost-effective substance group that is being increasingly promoted again, for example for the treatment of pollen allergies. Whether there is an increased risk of cleft palate withuse, especially in the first trimester, is subject to controversy [52, 53]. If the use of systemic corticosteroids is necessary, the dose should be chosen as low as possible but as high as necessary. Prednisone or prednisolone are the agents of choice .
β-2 receptors are found particularly on smooth muscle cells (bronchi, uterus, gastrointestinal tract, heart). Activation of the receptor leads to smooth muscle relaxation. Short-acting β-sympathomimetics are commonly used for rapid relief of asthmatic symptoms. Salbutamol, a short-acting β-sympathomimetic, has not been shown to have teratogenic effects in the long time it has been available . As for long-acting β-sympathomimetics during pregnancy, fewer study results are available. However, use is not associated with a specific, increased birth defect . Salmeterol and formoterol are considered similarly safe for the fetus .
The xanthine derivative is still used in asthma in some countries, but no longer has a place in modern asthma therapy, and so also in pregnancy . Montelukast is used as an add-on preparation for allergic rhinitis. Used in allergic asthma. In a case-control study, no increased risk regarding pregnancy complications or congenital anomalies was found with the use of leukotriene receptor antagonists compared with treatment with short-acting β-agonists during pregnancy . Because of the overall limited safety data, initiation of therapy with montelukast during pregnancy is not recommended.
Since IgG antibodies are placental and excreted in breast milk, the child is exposed to the agents during both pregnancy and lactation.
Omalizumab, a humanized monoclonal antibody, has been approved in Switzerland since 2006 for severe allergic asthma in patients six years of age and older. Since 2014, anti-IgE antibody can also be used in CSU aged twelve years and older if treatment with antihistamines (high-dose) is not effective . The indication for treatment with omalizumab in severe asthma should be made by the specialist in allergology or pneumology, and in CSU by the specialist in allergology or dermatology. Omalizumab reduces the amount of free circulating IgE. In a prospective study of 188 patients, there was no evidence of increased malformations in the newborns. Increased preterm births, decreased birth weight, or decreased size have also not been observed . Whether to continue omalizumab during pregnancy should be decided based on current knowledge after individual risk-benefit assessment. However, due to the potential risk of anaphylaxis, it should not be re-prescribed in pregnancy.
Mepolizumab, reslizumab and benralizumab are humanized monoclonal antibodies that can be used in patients with severe eosinophilic asthma 18 years of age and older. Interleukin-(IL-)5 leads to proliferation, activation, recruitment, and maturation of eosinophils and plays an important role in the pathogenesis of eosinophilic asthma . InMepolizumab and Reslizumab, the antibodies target IL-5, preventing it from binding to its target receptor. In benralizumab, the antibody targets the α-subunit of the IL-5 receptor while binding with high affinity to immune effector cells, leading to apoptosis of eosinophils. The indication of these biologics can be made by the specialist in allergology or pneumology. Mepolizumab has been approved in Switzerland since April 2016, reslizumab since November 2017, and benralizumab since June 2018 . The first prospective cohort studies investigating pregnancy outcomes in humans are underway .
Dupilumab is a humanized monoclonal antibody that inhibits the IL-4 and IL-13 signaling pathways. Dupilumab has been approved in the U.S. and Europe since 2017 for the treatment of moderate-to-severe AD that responds inadequately to topical therapy. Dupilumab has also been approved for the treatment of moderate to severe asthma in the United States since 2018 [64, 65]. In Switzerland, the active ingredient has been approved for AD since April 2019 . The indication for the treatment is subject to different regulations depending on the organ and is set by allergologists, pneumologists as well as dermatologists. There are still no studies on tolerance during pregnancy. Therefore, they should not be consumed during pregnancy for the time being.