Allergic Diseases and Asthma in Pregnancy
Posted: March 2009
Isabella Pali-Schöll, PhD, and Erika Jensen-Jarolim, MD
From the Department of Pathophysiology, Center of Physiology, Pathophysiology and Immunology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
Isabella Pali-Schöll, PhD, Department of Pathophysiology, Center of Physiology, Pathophysiology and Immunology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria; e-mail: email@example.com
Tel: +43-1-40400-5122, Fax: +43-1-40400-5130
Key words: allergy, atopy, newborn, pregnancy, prevention
Research for this manuscript was supported by Hertha Firnberg stipend T283-B13 and SFB F1808-B13 from the Austrian Science Fund (FWF).
A detailed review on this synopsis is submitted to the WAO journal.
|IP-10||interferon gamma-inducible protein 10|
|MIG||monokine induced by interferon gamma|
|PUFA||polyunsaturated fatty acids|
|PUPPP||pruritic urticarial papules and plaques of pregnancy|
|RANTES||regulated on activation, normal T cell expressed and secreted|
|Th2||T helper type 2|
Epidemiology: Prevalence of Asthma and Allergy in Pregnant Women
Allergic sensitization to common allergens can be detected in approximately 25% to 35% of the general population in industrialized countries. In the United States of America (USA) about 18-30% of woman in the childbearing age suffer from allergic diseases, especially rhinitis and asthma. Other allergic diseases which may complicate pregnancy include conjunctivitis, acute urticaria, anaphylaxis, food allergy and drug allergy. These disorders represent the most common group of medical conditions that complicate pregnancy. Optimal management of these disorders during pregnancy is vital to ensure the welfare of the mother and the baby.
Diagnosis of Allergy During Pregnancy
The diagnosis of allergy in pregnant women should focus on a detailed medical history and symptom analysis. For diagnosis, (i) a diary of allergy symptoms and (ii) avoidance of specific allergens accompanied by monitoring of changes of allergic symptoms may be helpful. However, it is important not to put the mother on a rigid elimination diet, as this could negatively influence the nutrition of both the mother and the growing infant.
In vitro diagnostic tools such as serologic testing, e.g., radioallergosorbent test (RAST) for type I allergy, or the lymphocyte transformation test for type IV allergy, are preferred to in vivo testing. Although not contraindicated, skin prick testing (SPT) should be postponed until after birth, because of possible, though rare, anaphylactic reactions. The same applies to in vivo tests such as food challenge tests and patch tests. Only in situations where in vitro diagnosis is not conclusive and the mother is at risk of developing allergy symptoms, should in vivo skin tests be used. Importantly, when performing in vivo testing such as skin tests or provocation tests, the exceptional immunologic status accompanying pregnancy should be considered when interpreting test results. Any unexpected test result and any symptoms that change over time should be re-evaluated after pregnancy. In addition, the attending physician should bear in mind that some symptoms may be a direct result of pregnancy and not allergy-related, e.g. vasomotor rhinitis in the last trimester and gestational urticaria (pruritic urticarial papules and plaques in pregnancy, PUPPP).
Non-Pharmacological Management of Allergic Diseases During Pregnancy
Mothers with diagnosed allergy should avoid exposure to and contact with specific allergens (including food allergens) and should especially avoid the inhalation of potent triggers for asthma, such as animal dander, house dust, tobacco smoke and irritating pollutants.
Hyposensitization (immunotherapy), which may be indicated selectively in certain patients with allergic rhinitis, bee venom sensitivity and asthma, should not be initiated during pregnancy because of the risk of systemic reactions. For patients who were already on immunotherapy prior to the pregnancy, maintenance treatment may be continued safely during pregnancy. However, the allergen dose should not be increased during pregnancy, but rather should be reduced if necessary.
Medication for Asthma and Allergy in Pregnancy
The ideal situation during pregnancy is "no pharmacologic therapy", especially during the first trimester. However, the reality is that medications must be considered for pregnant patients with medical disorders, based on a thorough appreciation of the potential deleterious effects of untreated disease. For instance, women with asthma or allergic diseases require drug therapy during pregnancy to prevent diseases severe enough to be life threatening to the mother or the fetus (e.g. acute severe asthma which can result in hypoxia).
Although most of the existing data regarding asthma and allergy medications during pregnancy have not demonstrated adverse effects (Box 1), data regarding the use of oral corticosteroids have not been totally reassuring: in infants of corticosteroid-treated mothers an increased risk of oral clefts, preeclampsia, preterm birth, and lower birth weight have been reported. However, the potential side effects of any drug must be balanced against the risks to the mother or the infant of suffering from inadequately treated disease; the risk of severe uncontrolled asthma would usually be the greater risk, suggesting that oral corticosteroids must still be used when indicated for the management of gestational severe asthma.
BOX 1. Recommendations for treatment of asthma and allergies in pregnancy
DRUGS PREFERRED FOR USE DURING PREGNANCY
Antiinflammatory: cromolyn, beclomethasone, prednisone
DRUGS THAT GENERALLY SHOULD BE AVOIDED DURING PREGNANCY
α-Adrenergic compounds (other than pseudoephedrine)
From National Asthma Education Program Working Group on Asthma and Pregnancy: Management of asthma during pregnancy, NIH Pub No 93-3279A, Bethesda, MD, 1993, National Institutes of Health.
Treatment of asthma
Certain physiological changes occur normally during pregnancy, like increased tidal volume and minute ventilation, and decreased residual volume, functional residual capacity and diffusion capacity. These alterations are primarily the result of hormonal effects. The physiologically elevated position of the diaphragm and hyperventilation occurring in pregnancy further increase the risk of hypoxia. Preexisting asthma symptoms may worsen, improve, or remain unchanged during pregnancy. Each of these three possibilities is observed in about one third of cases. Optimal asthma treatment is crucial, as the risk of pre-eclampsia, premature birth, low birth weight, and maternal and neonatal hypoxia and morbidity posed by undertreated asthma may be greater than that from the use of oral steroids for the treatment of asthma.
Treatment of acute asthma is similar to that recommended for non-pregnant patients including inhaled beta2 agonists, oxygen (essential), and corticosteroids (oral or parenteral). It is also reasonable to add nebulized ipratropium bromide in patients who do not respond to beta2 agonists. Intravenous aminophylline is not generally recommended in the emergency management of acute asthma (because of its potentially harmful effects) but may be used in pregnant patients hospitalized for acute asthma (theophylline levels should be monitored). Intravenous magnesium sulfate may be beneficial in acute severe asthma as an adjunct to inhaled beta2 agonists and corticosteroids.
The goals of management of chronic asthma are the same as those for asthma in general, including prevention of severe exacerbations, improvement of quality of life (no interference with sleep or daily activities) and maintenance of normal lung function. The recommendations for medical treatment have been summarized by a Working Group of the National Asthma Education and Prevention Program (NAEPP) in a report on managing asthma during pregnancy. A step-wise approach is suggested for medical treatment. Inhaled salbutamol is the preferred short-acting beta-agonist, with an outstanding safety profile, and inhaled corticosteroids (e.g., budesonide) should be used confidently as long-term control medications. Salmeterol is the preferred agent when long-acting beta2 agonists are indicated in a pregnant woman as add-on treatment for persistent asthma. Leukotriene modifiers may be used as alternative add-on treatment: montelukast and zafirlukast are the preferred anti-leukotriene drugs. Zileuton in contrast, being the only leukotriene synthesis inhibitor, is not recommended in pregnancy due to its potential to cause abnormal liver function (FDA pregnancy category C).
Patients whose asthma is not controlled with maximal doses of bronchodilators and anti-inflammatory agents may need systemic corticosteroids. The lowest possible effective dose (alternate-day or single daily dose) should be used. Patients must be monitored closely for potential adverse effects of corticosteroids, especially gestational diabetes, preeclampsia, and intrauterine growth retardation.
Treatment of rhinitis
Significant nasal symptoms occur in approximately 30% of pregnant women. Pregnancy-associated hormones have direct and indirect effects on nasal blood flow and mucous glands. The most common causes of nasal symptoms necessitating treatment during pregnancy are allergic rhinitis, rhinitis medicamentosa, sinusitis, and (non-allergic) vasomotor rhinitis. "Vasomotor rhinitis of pregnancy" is a syndrome of nasal congestion and vasomotor instability limited to the gestational period. Allergic rhinitis is often pre-existing but may occur or be recognized for the first time during pregnancy. Allergic rhinitis commonly co-exists with asthma. As with asthma, pre-existing allergic rhinitis can worsen, improve, or remain unchanged during pregnancy. Furthermore, during pregnancy nasal congestion can worsen, although the exact mechanism for this is not defined.
The general principles of treatment for pregnant women with asthma and allergic rhinitis do not differ from the step-wise approach recommended for treatment of non-pregnant women. Of the available medications for allergic rhinitis, chlorpheniramine is recommended as the first-generation antihistamine of choice for use during pregnancy. Based on the information available (Box 1), loratadine or cetirizine may be considered the second-generation antihistamines of choice. The decision whether to use a first-generation or second-generation antihistamine for a particular patient must be individualized.
Adjunctive treatment for rhinitis, which is permitted in pregnancy, includes oxymetazoline drops or spray (for nasal congestion), pseudoephedrine (after the first trimester) for persistent nasal congestion, and buffered saline sprays (for nasal dryness, nasal bleeding and vascular congestion associated with pregnancy).
Treatment of anaphylaxis
The management of anaphylaxis during pregnancy is the same as for non-pregnant patients. Of the routine anti-anaphylaxis medications, epinephrine and diphenhydramine have been implicated in causing fetal malformations. However, the tentative nature of these data and the lack of equally effective substitutes justify their use in pregnancy for this life-threatening emergency. Adequate intravascular volume repletion and oxygenation are particularly important in the management of anaphylaxis during pregnancy to prevent both maternal and fetal complications. The pregnant hypotensive patient should be placed on her left side to prevent added positional hypotension resulting from compression of the inferior vena cava by the gravid uterus. Intravenous epinephrine may be required, despite its potential to cause decreased uteroplacental blood flow. Glucocorticoids should be administered early to patients with severe anaphylaxis. For laryngeal spasm, intubation and in rare cases tracheotomy may be necessary.
Treatment of atopic eczema (dermatitis)
Gestational itchy dermatoses are relatively common, with eczema being diagnosed in 30% to 50% of all cases. Treatment of atopic dermatitis during pregnancy should emphasize avoidance of triggering factors and reliance on topical treatment in an attempt to reduce dryness and pruritus, modulate inflammation, and treat secondary infections. Oral antihistamines should be avoided during the first trimester, unless definitely clinically indicated, and then should be used at the lowest effective dose, starting with chlorpheniramine, loratadine, or cetirizine. Topical steroids should be selected based on potency considerations, given the potential for systemic absorption and increased skin surface area of pregnancy. Topical corticosteroid treatment should be initiated when clinically indicated, with the least potent preparations such as hydrocortisone (0.5% to 1%). The recently introduced topical calcineurin inhibitors (pimecrolimus and tacrolimus), though effective in the treatment of atopic eczema, are not recommended for use in pregnant patients because of the lack of safety data.
Treatment of urticaria and angioedema
The pattern and causes of urticaria and angioedema in pregnancy are similar to those in non-pregnant patients. A unique form of urticaria associated with pregnancy, which tends to recur in subsequent pregnancies ("pregnancy urticaria"), has been reported. The pathogenesis of this condition is unknown, although there is speculation that it may be due to allergic sensitization to endogenous hormones. The first step in treatment of urticaria and angioedema in pregnancy is identification and avoidance of causative factors. Antihistamines should be avoided if possible, but if required, chlorpheniramine, loratadine, or cetirizine may be used. Rarely, systemic corticoids may be used for severe, recalcitrant urticaria and angioedema during pregnancy.
Environmental Risk Factors for Atopy
The degree of risk for atopy/allergy appears to be directly related to the family history of allergy and especially to maternal atopy. If neither parent is allergic, the chance for allergies in the child is about 15%. If one parent is allergic, the risk increases to 30%, and if both are allergic, the risk is greater than 60%, especially for developing the same organ-specific symptoms.
The causes of allergy in general and of specific sensitization in newborns in particular have not yet been completely determined. Besides the role of genetic predisposition, some factors have been identified that may either contribute to sensitization of the mother and to the subsequent transfer of a predisposition for allergy to the offspring, or that directly induce sensitization in the offspring, that manifests shortly after birth or at a young age.
Exposure to tobacco smoke
One of the most frequently discussed risk factors for induction of sensitization in all populations and age groups is tobacco smoke (active smoking or passive environmental exposure). In a recent mouse study, exposure to smoke in utero induced a higher risk of sensitization against allergens in adult age in the offspring. In human blood samples, Th2 cytokines responsible for a predisposition toward allergy were elevated in the neonates only of mothers who had smoked during pregnancy. In addition, total and specific IgE levels, total eosinophil counts, incidence of airway disease and positive results on skin prick tests were also increased in children who were exposed to smoke either during pregnancy or in early childhood.
Alcohol consumption by the mother during pregnancy is associated with higher total IgE levels in cord blood. Alcohol consumption in adults is also a risk factor for elevated specific IgE levels against food antigens.
The food that the mother consumes during pregnancy may contribute to the immunologic profile of the child. A diet higher in n-6 polyunsaturated fatty acids (PUFAs)-as present, for example, in margarine and vegetable oils-seems to be more likely to induce eczema than n-3 PUFAs, which are found in fish. However, it may not be the absolute content but the ratio of n-6 to n-3 PUFAs that may influence the development of either tolerance or sensitization to food; in a mouse study, a high ratio of 9 of n-6/n-3 in the diet of the mother prevented the induction of oral tolerance to ovalbumin in the offspring. Celery and citrus fruits seem to increase the risk of food sensitization, while vegetable oils, raw sweet pepper and again citrus fruit increase sensitization to respiratory antigens. Interestingly, apples consumed during pregnancy were able to decrease wheezing in children.
According to a directive of the Commission of European Communities from 2005, the most allergenic foods have to be labeled due to their potency for eliciting severe allergic reactions: these are crustaceans, fish, nuts, milk, egg, wheat/gluten, peanuts, soy, sesame, mustard and celery. It has long been proposed that the mother should avoid such foods containing potential allergens during pregnancy and lactation to prevent food sensitization in the child. However, recent studies suggest that allergen exposure may be necessary to induce tolerance, and moreover, a balanced diet prevents malnutrition of both mother and child. Furthermore, alterations of the maternal diet, i.e., avoidance of milk and egg consumption during pregnancy, did not appear to lower the risk of sensitization against these foods in the child.
Use of anti-acid medication
Changes of hormone levels during pregnancy and the growing volume of the fetus often lead to heartburn, reflux and abdominal pain in the mother. About 70% of pregnant women are affected by these symptoms during their last trimester and 50% of them are likely to take acid-suppressing medication. However, recent animal and human studies indicate that acid suppression and the resulting elevated pH in the stomach may lead to an increased risk of sensitization to food. This sensitization of the mother was shown to lead to an increased risk of food allergy in the newborn in a BALB/c mouse model. An allergic status of the mother has the potential to affect the immune response of the offspring by numerous factors transferable via placenta or breast milk and even via the transamniotic route, for instance, intact maternal IgE in amniotic fluid; maternal DNA in cord blood; leukocytes; and chemokines like IL-8, RANTES, IP-10, or MIG; allergens as well as antibodies. Furthermore, the offspring of sensitized mothers are prone to experience suppression and a later onset of normal levels of the Th1-cytokine IFN-γ due to a lower frequency of IFN-γ-producing cells, and therefore a further bias towards a Th2 immune response is given.
Reduced breastfeeding and early introduction of solid food have been discussed as confounders to allergy development. However, a randomized trial revealed quite to the contrary that prolonged (exclusive) breastfeeding is not able to prevent development of allergy or asthma in children at the age of about 6 years. Also, a systematic review of several studies found no clear negative association between early solid food introduction and the development of asthma, food allergy, allergic rhinitis, or animal dander allergy.
Prematurity and low birth weight
Prematurity and low birth weight are not associated with an increased risk for development of food allergy in childhood. The impact of these factors for sensitization to other allergens, such as aeroallergens, has not been investigated. However, one study showed that adolescents who had been born prematurely had a substantially decreased expiratory volume and increased bronchial hyperresponsiveness, making them potential candidates for developing asthma.
Insufficient exposure to environmental bacteria
The "hygiene hypothesis" states that low exposure of the mother during pregnancy and of the newborn in early life to environmental bacteria contributes to a Th2-biased immune response. This hypothesis has been confirmed by several experimental animal and epidemiological human studies.
Preventive Measures for Mother and Child
Strategies for prevention of atopic diseases may be categorized as primary, secondary and tertiary. Primary prevention addresses symptom-free children at risk (i.e. without the established disease). Secondary prevention addresses individuals with early indicators of atopic disease. Tertiary prevention is directed at patients with a chronic disease to prevent additional problems related to the disease.
Based on currently available evidence, guidelines for primary and secondary prevention of allergic disease can be summarized as follows;
- Smoking and alcohol:
Smoking and passive exposure to cigarette smoke as well as alcohol consumption should be strictly avoided.
There should be no special diet for the mother during pregnancy and lactation, unless the mother or child has a diagnosed food sensitization. In infants with risk of allergy, introduction of solid foods in general should be postponed until 6 months of age, milk products until 12 months, hen's egg until 24 months, and peanut, tree nuts, fish, and seafood until at least 36 months.
- Other allergens:
Avoidance of allergens (pets, house dust, contact allergens, drugs) is not recommended except when sensitization has already been diagnosed.
- Reflux treatment:
Pregnancy-associated reflux should be treated by non-pharmacological measures first (avoidance of large meals, sleeping with elevated upper body, not lying down after a meal, avoiding sweet and fatty food as well as alcohol and smoking).
For newborns at suspected risk for atopy, i.e., with a history of atopy/allergy in a first degree relative (parents, siblings), exposure to irritating air pollutants and airborne allergens like molds should be minimized.
Infants should be breastfed for at least 4 months but no longer than 9 months. Special hypoallergenic formula (extensively hydrolyzed, not soy-based) should be used only if the child is diagnosed with atopy.
All non-prescription drugs (e.g., anti-acids) should be avoided during pregnancy and lactation unless recommended by a physician; patients should avoid intake of any medication including over-the-counter substances without consulting their physician.
For more information on primary, secondary and tertiary prevention of allergy, readers are referred to the document, "Prevention of Allergy and Allergic Asthma," a document based on findings presented at the World Health Organization/World Allergy Organization meeting in January 2002. This document also includes a summary of evidence-based guidelines and strength of recommendations.
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- World Health Organization. Prevention of allergy and allergic asthma. Document based on the WHO/WAO Meeting on the Prevention of Allergy and Allergic Asthma; Geneva, Switzerland; January 8-9, 2002. Available at http://www.worldallergy.org/professional/who_paa2003.pdf. Accessed 31 October 2007.
- Auckland Allergy Clinic. Allergic diseases in pregnancy. Available at http://www.allergyclinic.co.nz/guides/28.html. Accessed 31 October 2007.
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- Schöll I, Ackermann U, Ozdemir C, Blümer N, Dicke T, Sel S, Wegmann M, Szalai K, Knittelfelder R, Untersmayr E, Scheiner O, Garn H, Jensen-Jarolim E, and Renz H. Anti-ulcer treatment during pregnancy induces food allergy in mouse mothers and a Th2-bias in their offspring. Faseb J. 2007;21:1264-1270.
- Schöll I, Untersmayr E, Bakos N, Roth-Walter F, Gleiss A, Boltz-Nitulescu G, Scheiner O, and Jensen-Jarolim E. Antiulcer drugs promote oral sensitization and hypersensitivity to hazelnut allergens in BALB/c mice and humans. Am J Clin Nutr. 2005;81:154-160.