Evidence Based Approach for The Management of Asthma in Pregnancy

Picture of a pregnant woman using an inhaler taken from science library photo taken at this link [here]

Asthma is an increasingly common chronic illness in pregnancy with the prevalence may reach up to  8%. [Holland & Thomson, 2006]. Pregnancy is characterized by a physiological immunosuppression, an immunological tolerance that protects the fetus from maternal immune response against paternal antigens expressed by the fetus.  [Lilla Tamasi et al, 2011]

Physiological pregnancy has been described as a Th2-dominated state, and current studies show that a trimester dependent, pregnancy-induced increase in regulatory T cell (Tregs) number has a key role in the maintenance of maternal tolerance to paternal antigens during pregnancy, exerting an inhibition on the activation of effector T lymphocytes and NK cells. [Lilla Tamasi et al, 2011] Absence of trimester dependent regulatory T cell elevation in asthmatic pregnancy leads to impaired inhibition of T lymphocyte and NK cell activation and proliferation. Elevated numbers of activated effector T lymphocytes and NK cells may cause immune mediated alteration of fetal growth and enhancement of allergic/asthmatic response. [Lilla Tamasi et al, 2011]

Pregnancy may alter the natural course of asthma. Asthma improves during pregnancy in about one-third, remains the same in another one-third, and worsens in one-third of pregnant women. More severe asthma before pregnancy increases the risk of worsening during pregnancy, and there is a concordance between the courses of asthma during subsequent pregnancies [Lilla Tamasi et al, 2011]. Lung inflammation, smoking, obesity , altered placental function [Ross E. Rocklin, 2011] and female fetuses are also recognized risk factor for asthma exacerbation. [Lilla Tamasi et al, 2011] and poor pregnancy outcomes.

Patient may also suffers from co- morbid condition such as obesity, pregnancy-induced hypertension and gastro-oesophageal reflux. [Holland & Thomson, 2006] Asthma represents a risk factor for several maternal and fetal complications, such as asthma exacerbations, use of oral corticosteroids, hospitalizations due to asthma attacks, preeclampsia, gestational hypertension, preterm delivery, cesarean delivery, low birth weight, intrauterine growth restriction, and fetal death [Lilla Tamasi et al, 2011].

Most of the asthma exacerbation are usually mild and self limiting and rarely causing severe attack. However, if severe exacerbation occur, it will cause significant morbidity and mortality to the patient as well as the fetus.  Major risk of asthma to the mother and fetus are due to under treatment or poorly controlled disease and may be compounded by poor maternal compliance with treatment due to fears of side-effects on the unborn child [Holland & Thomson, 2006] Apart from that, Jennifer W. Mc Callister et al, has found out that there is a disparities of treatment for acute exacerbation of asthma in emergency department especially in term of systemic steroid administration.  This should not happen and pregnancy should be considered an indication for maximizing therapy during an exacerbation, rather than withholding it.

Congenital malformation may complicate maternal asthmatic exacerbation in early trimester as maternal hypoxia together with respiratory alkalosis may decrease the placental blood flow. Decreased fetal blood oxygen could result in abnormal growth and development of the fetus. Furthermore, maternal hypoxia has been found to be associated with an increased risk of cleft lip and palate in mice.[ Lucie Blais & Amelie Forget, 2008]

Short acting beta 2 agonist (SABA) is safe eventhough it is previously being said that the usage of this agent will increase the risk of developing pregnancy induced hypertension. The explaination laid behind this hypothesis was that the inhaled SABA will enter the systemic circulation and cause vasodilation of the blood vessel. This will then cause reduction in diastolic blood pressure and cause reflex tachycardia. Study by Marie-Jose´e Martel et al however shows that inhaled SABA actually reduced the risk of PIH and the use of this medication is safe throughout pregnancy. The reasons for the previous hypothesis of relation between SABA-PIH could be due to some reason including  smoking and masking effect of SABA that reduce the diastolic blood pressure, hence lead to under diagnosed of PIH. The usage of SABA alone is safe, however, it should be pointed out that all patients with persistent asthma require a controller medication such as an inhaled steroid [R.E. Rocklin et al, 2011]

Long-acting Beta 2 agonists are now recommended to be used in conjunction with inhaled steroids. The use of these long-acting bronchodilators as monotherapy was reported in one study that did not find any evidence of an effect on fetal growth in humans [R.E. Rocklin et al, 2011]

The usage of high dose ICS may increase the risk of congenital malformation if use in the first trimester. Lucie Blais et al in her study observed that women who took high doses of ICSs during the first trimester of pregnancy were 63% more likely to have a baby with a congenital malformation than women taking low to moderate doses of ICSs. However, low to moderate dose of ICS is safe. Furthermore, current asthma guidelines recommend ICSs for the management of all levels of persistent asthma during pregnancy and recommend that pregnant women be treated as aggressively as nonpregnant women to achieve and maintain control of asthma.  [Marie-Claude Breton et al, 2010] The risk of perinatal mortality was not found to be significantly associated with ICS use during pregnancy. The result associated with higher doses of ICSs is limited due to a lack of statistical power and a possibility of residual confounding by asthma severity and  control. [Marie-Claude Breton et al, 2010] Furthermore, a trend towards higher Treg cell prevalence was observed compared to those with inadequate adherence to ICS treatment. [Lilla Tamasi et al, 2011] Therefore, asthmatic pregnant women should be managed with the minimum effective ICS dose. But if higher doses of ICSs are needed to control asthma, their benefits outweigh their risks. [Marie-Claude Breton et al, 2010]

The usage of oral corticosteroid previously being said to be associated with increase risk of congenital malformation particularly cleft lip, cleft palate or both. However, observation by Lucie Blais & Amelie Forget in their study shows that women who had an asthma exacerbation but who did not fill a prescription for oral corticosteroids were 2 times more likely to have a baby with a major congenital malformation than women who did not have an exacerbation. It is found that the hypothesis that link between the usage of oral corticosteroid and congenital malformation are weak. Study by Ludmila N. Bakhireva et al, demonstrate that the usage of systemic corticosteroid may resulting in deficit of about 200 g in birthweight compared with controls and exclusive B2-agonist users. However, the result is not significant to suggest that the usage of this agent impair fetal growth and it use should be weighed against the necessity to control severe asthma.

Chromones such as cromolyn and nedocromil have an anti inflammatory activity but due to their relatively limited efficacy, it should only be used in mild persistent asthma and recommended as alternative medication only.

Leukotriane modifiers such as leukotriene receptor antagonists (montelukast and zirfirlukast) and 5-lipoxygenase pathway inhibitors (zileuton) are not preferred as treatment option in mild persistent asthma in pregnancy.

Theophylline that has bronchodilating activity and mild anti inflammatory properties are safe to be used in pregnancy but it is considered as alternative treatment and not the preferred therapy

In managing severe acute asthma, Oral corticosteroid should not be witheld. The British Thoracic society guidelines has clearly stated that the medical management of asthma in pregnant and non pregnant mother are same. Volume resuscitation should be considered as there would be a volume deplition due to combination of hyperventilation and intercurrent sepsis despite of difficulty in accessing the fluid balance. Central venous access is impractical and potentially dangerous in severe asthmatic. Regional anesthesia especially epidural is more preferred than general anesthesia  if patient required operative delivery or as pain management as it reduce hyperventilation and stress response to the pain. However, judgement should be made clearly as regional anesthesia would be impractical in patient who are severely breathless and precipitate deterioration of lung function due to loss of intercostal muscle function

Apart from that, education about asthma, life style modification and smoking cessation should be encourage to the patient. Main education topic should includes information about the disease, use of inhaler devices, adherence to treatment and importance of regular visit, environmental control measure to reduce exposure to allergens and irritants and self treatment action plan. [Lilla Tamasi et al, 2011].

Reference:

1)         Faranak Firoozi, Catherine Lemiere, Francine M. Ducharme et al, "Effect of maternal moderate to severe asthma on perinatal outcomes", Respiratory Medicine (2010) 104, 1278- 1287

2)         Jennifer W. McCallister, Cathy G. Benninger, Heather A. Frey, et al, "Pregnancy related treatment disparities of acute asthma exacerbations in the emergency department", Respiratory Medicine (2011) 105, 1434-1440

3)         Lilla Tamasi, Ildiko´ Horvath, Aniko Bohacs et al, " Asthma in pregnancy e Immunological changes and clinical management", Respiratory Medicine (2011) 105, 159-164, Elsevier

4)         Lucie Blais & Amelie Forget, "Asthma exacerbations during the first trimester of pregnancy and the risk of congenital malformations among asthmatic women", J Allergy Clin Immunol 2008;121:1379-84

5)         Lucie Blais, Marie-France Beauchesne, Catherine Lemie` & Naoual Elftouh, "High doses of inhaled corticosteroids during the first trimester of pregnancy and congenital malformations", J Allergy Clin Immunol 2009;124:1229-34.

6)         Ludmila N. Bakhireva, Kenneth Lyons Jones, Michael Schatz et al, "Asthma medication use in pregnancy and fetal growth", J Allergy Clin Immunol 2005;116:503-9.)

7)         Marie-Claude Breton,, Marie-France Beauchesne, Catherine Lemie, et al, "Risk of perinatal mortality associated with inhaled corticosteroid use for the treatment of asthma during pregnancy", J Allergy Clin Immunol 2010;126:772-7.

8)         Marie-Jose´e Martel, E´ velyne Rey, Marie-France Beauchesne, et al "Use of short-acting b2-agonists during pregnancy and the risk of pregnancy-induced hypertension", J Allergy Clin Immunol 2007;119:576-82

9)         Ross E. Rocklin, "Asthma, asthma medications and their effects on maternal/fetal outcomes during pregnancy", Reproductive Toxicology 32 (2011) 189–197

10)       S. M. Holland, K. D. Thomson, "Acute severe asthma presenting in late pregnancy", International Journal of Obstetric Anesthesia (2006) 15, 75–78

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