Asthma in pregnancy

Authors

  • Michelle H Goldie RM,

    Honorary Research Associate, Former Specialist Midwife
    1. Institute for Lung Health, Department of Infection, Immunity & Inflammation, Clinical Sciences Wing, University Hospitals of Leicester, Leicester, UK
    2. Leicester Royal Infirmary, Leicester, UK
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  • Chris E Brightling PhD FRCP

    Professor of Respiratory Medicine & Honorary Consultant Physician, Corresponding author
    1. Institute for Lung Health, Department of Infection, Immunity & Inflammation, Clinical Sciences Wing, University Hospitals of Leicester, Leicester, UK
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Abstract

Key content

  • Asthma is a common condition that affects ˜10% of pregnant women.
  • Pregnancy worsens asthma control in one-third of women, improves it in one-third and has no effect on one-third.
  • Poor asthma control has adverse effects upon maternal and fetal outcomes.
  • Good asthma management to maintain control is important in line with national guidelines.
  • Standard therapy with inhaled corticosteroids with or without the addition of short and long-acting β-agonists can be used in pregnancy.

Learning objectives

  • Comprehensive overview of asthma in pregnancy.
  • Review asthma management in pregnancy.

Ethical issues

  • Are women appropriately counselled on the pregnancy risks of asthma?
  • Are doctors aware of the safety of routine asthma treatments in pregnancy?

Introduction

Asthma affects an estimated 235 million people worldwide and the burden is likely to rise substantially in the next few decades.[1-3] The condition causes about 239 000 deaths per year (0.4% of all deaths due to disease) and results in a large burden of disability. The total cost of asthma in Europe is estimated to be €17.7 billion per annum.[2]

Asthma is a chronic inflammatory disease of the airways, which is characterised by intermittent episodes of wheeze, shortness of breath, chest tightness and cough, which are often worse at night. It is a variable disease where inflammation and structural changes can occur in the airway in response to certain stimuli or triggers (Box 1).[3, 4] This causes airway hyper-responsiveness and variable airflow obstruction leading to the symptoms described. Patients suffer from flare-ups or exacerbations of their disease either in response to an acute infection, which is usually viral in origin, or due to poor control of their airway inflammation.

Box 1. Triggers for asthma

  • Allergens, such as house dust mite, pollen, etc.
  • Smoking
  • Exercise
  • Occupational exposure
  • Pollution
  • Drugs, such as aspirin, β-blockers
  • Food and drinks such as dairy produce, alcohol, peanuts and orange juice
  • Additives such as monosodium glutamate and tartrazine
  • Medical conditions, such as rhinitis and gastric reflux
  • Hormonal, such as premenstrual conditions and pregnancy

The prevalence of asthma in pregnant women is 4–12%, making it the most common chronic condition in pregnancy.[5, 6] Pregnancy can affect asthma control and conversely asthma can affect pregnancy. Importantly, the British Thoracic Society/Scottish Intercollegiate Guideline Network (BTS/SIGN) asthma guideline on the management of asthma apply in pregnancy and good asthma control during pregnancy is critical.[7]

Breathlessness in pregnancy

Breathlessness is the sensation of feeling out-of-breath or unable to catch your breath. A healthy respiratory rate is 12–20 breaths/minute at rest. A persistent respiratory rate at rest >24 breaths/minute is abnormal. Breathlessness in pregnancy is extremely common and may reflect either the normal anatomical and physiological changes that occur in pregnancy, or anxiety, or may be a consequence of an underlying pathology. Therefore, in a woman with known asthma the cause of increased breathlessness may not be due to asthma. Similarly, in a woman not diagnosed as asthmatic new incident asthma can be the cause of breathlessness, albeit rarely. The causes of breathlessness to be considered in pregnancy are shown in Box 2.

Box 2. Main differential diagnoses in pregnant women with dyspnoea

  • Anxiety
  • Hyperventilation
  • Dysfunctional breathing
  • Respiratory disease:
    • asthma
    • chest infection and/or pneumonia
    • thromboembolic disease
    • interstitial lung disease, e.g. sarcoid or secondary to a connective tissue disorder
    • pneumothorax
    • amniotic fluid embolism
  • Cardiac disease:
    • arrhythmias
    • ischaemic heart disease
    • cardiomyopathy
  • Endocrine disease:
    • diabetes mellitus leading to hyperventilation in the setting of acute ketoacidosis
    • acute thyrotoxicosis
  • Haematological:
    • chronic anaemia
    • acute haemorrhage
  • Renal disease:
    • hyperventilation to compensate for metabolic acidosis secondary to acute renal failure

The effects of pregnancy on asthma

The severity of asthma during pregnancy remains unchanged, worsens or improves in equal proportions.[8] Box 3 describes physiological factors that affect asthma during pregnancy. In severe disease, asthma control is more likely to deteriorate (~60%) than in mild disease (~10%).[9, 10] Exacerbations are most common between 24 and 36 weeks of pregnancy.[9, 11] Respiratory viral infections were the most frequent triggers of exacerbations (34%), followed by poor adherence to inhaled corticosteroid therapy (29%).[9] Therefore, during pregnancy women with asthma need to be closely reviewed throughout pregnancy, irrespective of disease severity.

Box 3. Physiological factors affecting asthma in pregnancy

  • Increase in free cortisol levels may protect against inflammatory triggers.
  • Increase in bronchodilating substances (such as progesterone) may improve airway responsiveness.
  • Increase in bronchoconstricting substances (such as prostaglandin F) may promote airway constriction.
  • Placental 11β-hydroxysteroid dehydrogenase type 2 decreased activity is associated with an increase in placental cortisol concentration and low birthweight.
  • Placental gene expression of inflammatory cytokines may promote low birthweight.
  • Modification of cell-mediated immunity may influence maternal response to infection and inflammation.

The effects of asthma on pregnancy

Where risks have been reported the data on the effects of asthma on pregnancy outcomes is conflicting.[12-14] This is probably due to differences in study designs, asthma severity and its management in different studies and inadequate consideration of potential confounders. There are limited data on how asthma control prior to pregnancy influences pregnancy outcomes, although in one case–controlled study of two-thousand women, poor asthma control and disease severity prior to pregnancy were associated with an elevated risk of hypertension in pregnancy.[15] This is consistent with previous studies that have demonstrated an association between asthma and hypertension during pregnancy,[8] and two large, multicentre, prospective studies that found in women with daily asthma symptoms[16] or impaired lung function[17] there was an increase in hypertension. In contrast, a systematic review that included nearly one thousand women found that asthma exacerbations were not associated with an increased risk of pre-eclampsia.[8, 13] Recent evidence suggests that airway hyper-responsiveness – a hallmark of asthma – may be a predictor of pre-eclampsia and points to a mechanistic common pathway of mast cell–airway smooth muscle cell interactions.[18]

Retrospective and prospective studies have demonstrated that women with asthma have a higher frequency of caesarean section than women without asthma.[8] Intrauterine growth restriction or low birthweight were observed in retrospective studies but this has not been replicated in large prospective studies. However, low birthweight is associated with measures of poor asthma control such as persistent daily symptoms or poor lung function.[16, 17] and in women not using inhaled corticosteroids.[12] Similarly in a systematic review, of nearly one thousand women, asthma exacerbations during pregnancy increased the risk of low birthweight compared to women with asthma without exacerbations and women without asthma.[13]

Taken together these data do support the view that asthma severity and poor asthma control are associated with adverse outcomes in pregnancy, although it is important to note that in most women with well-controlled asthma there are no or minimal additional risks.

Management of stable asthma in pregnancy

The management and treatment of asthma are generally the same in pregnant women as in non-pregnant women and in men.[7] The intensity of antenatal maternal and fetal surveillance should be based on the severity of asthma, i.e. current need for therapy, symptom control, exacerbation frequency including high-dose corticosteroid usage and hospitalisation and lung function, for example, peak flow and spirometry together with the risk of fetal complications. The general principles of asthma management in pregnancy are summarised in Box 4. Women with moderate to severe asthma treatment step 3 or above (Figure 1) need to be managed by both a respiratory physician and obstetrician to optimise asthma control.

Box 4. Pregnancy issues

  • Poorly controlled asthma confers an increased risk to the mother and fetus.
  • Asthmatic women are more at risk of low birthweight neonates, preterm delivery and complications such as pre-eclampsia, especially in the absence of actively managed asthma treated with inhaled corticosteroids, although the increased risk is very small in women with well-controlled asthma.
  • There is no contraindication to most first-line treatments for asthma when used in pregnancy.
  • Smoking cessation is an important part of general obstetric advice, but is important in asthma to reduce symptoms and the efficacy of inhaled corticosteroids is reduced in asthmatics who smoke.
  • Exacerbations of asthma should be managed in line with current guidelines from British Thoracic Society/Scottish Intercollegiate Guidelines Network.
Figure 1.

Guidelines from British Thoracic Society/Scottish Intercollegiate Guidelines Network for asthma treatment steps. SR=slow releasing; BDP = beclomethasone dipropionate equivalent. Reprinted from BTS/SIGN British Guideline on the Management of Asthma, 2008, revised 2012 with permission from The British Thoracic Society

Nonpharmacological management

Education is the cornerstone of asthma management and needs to include understanding of the condition and its management, trigger avoidance, asthma control, adequate use of devices, and the importance of adherence to medication together with the construction of personal action plans. Systematic reviews have reported that education and action plans lead to improvements in asthma control and reduction in the need to seek emergency medical help and hospital admissions.

Pharmacological treatment

There are concerns held by mothers and their healthcare providers about the potential adverse effects of asthma drugs on their babies and themselves. In pregnancy women reduce their use of inhaled corticosteroids by 23% and short-acting β2-agonists by 13% for stable therapy and oral corticosteroids for exacerbations by 54%.[19] This change in adherence by women is mirrored by doctors who are more reluctant to prescribe corticosteroids both initially and on discharge to pregnant women than to nonpregnant women.[20]

It should be emphasised that it is safer for women to use asthma therapy in pregnancy to achieve and maintain good control than to have uncontrolled asthma.[16] Systematic reviews report consistently that inhaled corticosteroids, short or long-acting β2-agonists and theophylline do not increase the risk of maternal or neonatal outcomes such as pre-eclampsia, fetal congenital malformations, low birthweight or preterm delivery.[21] Therefore, good asthma control remains the aim throughout pregnancy.

Pregnancy may modify the pharmacodynamics and pharmacokinetics of some medications, but this effect is small and the dose and regimen of asthma medications rarely need to be changed in pregnancy. Inhaled corticosteroids are the standard anti-inflammatory therapy for asthma. They are safe in pregnancy,[21] and importantly, several studies have reported that inhaled corticosteroids reduce the risk of asthma exacerbations during pregnancy.[21]

Likewise, prospective, observational, and case–control studies have shown that short-acting β2-agonists are safe during pregnancy.[21] By contrast, few data exist on long-acting β2-agonists used alone or in combination with inhaled corticosteroids during pregnancy. However, in the limited studies to date, salmeterol and formoterol did not cause fetal malformations, preterm delivery, or low birthweight.[16] The safety of long-acting β2-agonists prescribed alone in the absence of inhaled corticosteroids has been questioned with respect to asthma control and thus they should always be used together with an inhaled corticosteroid, ideally in a combination product.[7]

Theophylline is safe in pregnancy at recommended doses.[22] Importantly, serum theophylline levels need to be monitored throughout pregnancy both as part of routine care and because pregnancy might affect the pharmacokinetics of theophylline. Theophylline usage has decreased in asthma due to alternative therapies but still has a place in asthma management.

In some asthmatics disease control can only be achieved with oral corticosteroids and systemic therapy are required to manage acute severe or life-threatening exacerbations. In epidemiological studies oral corticosteroids have been shown to increase the risk of fetal cleft lip or palate in the first trimester.[23] However, this increased risk is small (<0.3%). Therefore, oral corticosteroids should still be prescribed when required but should be used with caution and only when there is a clear clinical need.

Leucotriene modifiers are increasingly used in mild to moderate asthma and have a good safety profile. Animal studies show no teratogenicity with montelukast.[5] However, there is a paucity of data in pregnancy. Therefore, due to lack of data in pregnancy it is prudent to substitute leucotriene modifiers with an inhaled corticosteroid prior to conception or at the beginning of pregnancy alone or in combination with a long acting β2-agonist.

Anti-IgE is the only biological therapy available for asthma.[24] Its effects on pregnancy are unknown. This therapy should only be prescribed in specialist tertiary asthma centres and although it is not recommended during pregnancy, it needs to be considered in light of the risk–benefit ratio on an individual patient basis, as with all therapies in those with very severe disease. Immunosuppressant therapy such as methotrexate and cyclosporine are contraindicated in pregnancy, but in non-pregnant individuals are sometimes used particularly as oral corticosteroid sparing agents in severe asthmatics.

Management of asthma exacerbations in pregnancy

Asthma exacerbations are managed as per the BTS/SIGN guidelines,[7] which include the use of oral corticosteroids, nebulised β2-agonists and oxygen as well as other additional supportive care dependent upon severity.

Asthma: labour and delivery

Asthma does not usually affect labour or delivery with less than a fifth of women experiencing an exacerbation during labour,[8] and severe or life-threatening exacerbations are very rare. Prostaglandin F (for example, Hemabate®, Pfizer Ltd., Sandwich, UK) can cause bronchospasm and needs to be used with caution, whereas prostaglandin E2 (for example, Prostin®, Pharmacia Ltd., Sandwich, UK) is not associated with bronchospasm. Box 5 outlines the key points for women with asthma during labour.

Box 5. Peripartum issues

  • Acute, severe or life-threatening exacerbations of asthma during labour are extremely rare.
  • Women who have been on regular oral steroids may require hydrocortisone during labour.
  • Ergometrine, Syntometrine and prostaglandin may cause bronchoconstriction and should be used with caution.

Asthma: postpartum and breastfeeding

In the postpartum period there is not an increased risk of asthma exacerbations and within a few months after delivery a woman's asthma severity typically reverts to its pre-pregnancy level.[5] Few data are available on the safety of asthma drugs in breastfed neonates, but in general the same medications deemed safe in pregnancy can be continued and those with a negative or an uncertain safety profile should be avoided. Non-steroidal anti-inflammatory drugs (NSAIDs) for analgesia are to some degree contraindicated in asthma and may cause bronchospasm but in women without intolerance to NSAIDs they can be used.

Primary care physicians can manage most women with asthma, but women with severe disease, particularly if systemic corticosteroids are considered, need to be managed by respiratory physicians.

The World Health Organization recommends that women should exclusively breastfeed for at least 6 months.[25] Whether breastfed children have a reduced risk of developing allergic disease including asthma is unproven, but this does not detract from the overwhelming benefit of breastfeeding.

Conclusion

Asthma is a widespread condition that affects ~10% of pregnant women. Poor asthma control has adverse effects upon maternal and fetal outcomes. Good asthma management to maintain control is therefore important and standard therapy with inhaled corticosteroids with or without the addition of short- and long-acting β-agonists may be used in pregnancy.

Disclosure of interests

MG has no conflicts of interest. CEB receives grant income and consultancy fees via his Institution from GlaxoSmithKline, AstraZeneca, MedImmune, Novartis, Chiesi and Roche/Genentech.