Managing asthma in pregnancy

Over the past 50-60 years views on asthma in pregnancy have been changed dramatically – from consideration of it as a very benign condition with no effect on pregnancy and its outcomes¹ to acceptance that it represents a significant public health issue.²

Asthma prevalence in pregnant women

Asthma is the most common chronic disease in pregnant women, complicating up to 12.4% of pregnancies almost 10 years ago (from 3.2% in early 1990s), and its rates continue to rise.^3,4

This most likely reflects the steady increase in asthma prevalence in the general population over the past few decades, from 9.5 million adults being affected by this disease in 1995 to 17.5 million in 2009 (based on US data).⁵

If studies included not only patients with physician-confirmed diagnosis of asthma but also those with symptoms over the previous year, prevalence rates would be even higher. Ireland has the fourth-highest prevalence of asthma in the world; 470,000 had a diagnosis of this condition in 2006.⁶

Maternal asthma effects on pregnancy outcomes

Studies assessing the effects of asthma on pregnancy are mostly cohort studies, more commonly retrospective. Advantages and disadvantages for both are summarised in Table 1. Less frequently, cross-sectional surveys, case series and case-control studies are conducted.

Although the data to date have been conflicting to some extent, overall the literature suggests that asthma in pregnant females:

• Affects both the foetus and mother
• Complicates delivery as well as the pregnancy course
• Is associated with adverse pregnancy outcomes.

The most recent and largest retrospective cohort study⁷ is based on US data from 12 centres providing electronic medical records and International Classification of Diseases, ninth revision (ICD-9) discharge codes from the intrapartum admissions for 228,562 pregnancies among 208,695 women from 2002 through 2008 (the majority of the cohort [87%] delivered from 2005 through 2007). 

This study demonstrated a number of very important findings. It confirmed the known fact that females with asthma are at higher risk of having low birth weight babies (by 16%) and pre-term delivery (by 17%), and Caesarean section (by 16%). 

Their risk of developing superimposed pre-eclampsia and eclampsia was found to be higher than for non-asthma patients by 34% and 41%, respectively. The odds for other severe complications were also significantly higher in the presence of asthma: for placental abruption it was 1.22 (95% CI, 1.09-1.36), for haemorrhage 1.09 (95% CI, 1.03-1.16), for pulmonary embolism 1.71 (95% CI, 1.05-2.79) and for maternal ICU admission 1.34 (95% CI, 1.04-1.72). 

Interestingly, women with asthma in this study were more likely to be obese (9% versus 6.9%) or severely obese (9.4% versus 5.1%). They were more likely to have other chronic condition (8.2% versus 6.2%); almost twice as likely to have pre-existing diabetes (2.2% versus 1.4%); and twice more likely to smoke (12.2% versus 6.2%). 

However, even after adjustment for these and other risk factors, asthma was independently associated with higher odds for nearly all complications of pregnancy and delivery. 

There was no difference in postpartum fever and maternal death observed. Increased risk for Caesarean delivery and maternal haemorrhage in asthma patients were also reported in earlier review by Dombrowski.⁸

Another large recent population-based cohort study from Canada⁹ based on data from 40,788 pregnancies (13,007 asthmatics) between 1990 and 2002 also showed that the odds for low birth weight (OR 1.41: 95% CI 1.22-1.63) and pre-term delivery (OR 1.64: 95% CI 1.46-1.83) were significantly higher among asthmatic women, as well as for small-for-gestational-age (OR 1.27, 95% CI 1.14-1.41). 

The proportions of women with mild, moderate and severe asthma in this study were 82.5%, 12.5% and 5.0%, respectively. The risk of small-for-gestational-age was associated with severe (OR 1.48, 95%CI: 1.15-1.91) and moderate-severity asthma (OR 1.30, 95%CI:1.10-1.55) but not mild. 

Interestingly, there were no significant associations found between asthma severity, and pre-term birth and low-birth-weight, indicating that asthma regardless of its severity poses significant risk for adverse pregnancy outcomes.

The relationship between asthma severity and pregnancy outcomes was addressed in more detail in a recent systematic review and meta-analysis by Namazy et al.¹⁰

This meta-analysis was based on nine cohort studies published between 1975 and March 2012. In that analysis maternal asthma exacerbations and oral corticosteroid use were associated with low birth weight (RR 3.02, 95% CI 1.87-4.89 and RR 1.41, 95% CI 1.04-1.93, respectively) and pre-term delivery (RR 1.54, 95% CI 0.89-2.69 and RR 1.51, 95% CI 1.15-1.98, respectively). 

Moderate-to-severe asthma during pregnancy was shown to increase the risk of small-for-gestational-age (RR 1.24, 95% CI 1.15-1.35) and low birth weight (RR 1.15, 95% CI 1.05-1.26) infants. 

This highlights the importance of achieving adequate asthma control during pregnancy. Interestingly, an earlier study by the same group of researchers demonstrated that not using inhaled corticosteroids during pregnancy increased the relative risk for low-birth weight by up to 55%.2

Intra-uterine growth restriction associated with asthma severity was also demonstrated in a prospective study from the US (more than 2,200 pregnant women enrolled|).¹¹ This association may reflect an effect of hypoxia on the foetus. 

During this same systematic review of publications dated between 1975 and March 2012, 21 cohort studies¹² were identified that assessed other perinatal outcomes, including congenital malformations, neonatal complications and perinatal mortality. 

They found that maternal asthma was associated with a significantly increased risk of congenital malformations (relative risk [RR] 1.11, 95% CI 1.02-1.21, I2 = 59.5%), cleft lip with or without cleft palate (RR 1.30, 95% CI 1.01-1.68, I2 = 65.6%), neonatal death (RR 1.49, 95% CI 1.11-2.00, I2 = 0%), and neonatal hospitalisation (RR 1.50, 95% CI 1.03-2.20, I2 = 64.5%). 

Importantly, use of bronchodilators and inhaled corticosteroids were not associated with congenital malformation risk.

Table 1(click to enlarge)

Possible mechanisms of maternal asthma on pregnancy outcomes

The proposed mechanisms for poorer pregnancy outcomes in females with asthma include:²

• Maternal hypoxia
• Inflammation with release of bioactive mediators 
• Increased ratio of T-helper cell Th2:Th1 cytokines in the placenta
• Hyperactivity of the smooth muscle in both the bronchioles and the myometrium
• Altered placental blood flow with reduced supply of nutrients to the foetus 
• Decreased enzyme activity of 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2), which protects the foetus from excess maternal glucocorticoids. 

Maternal hypoxia is considered to play a particularly important role in reducing intra-uterine foetal growth in women who have been hospitalised with an asthma exacerbation.¹³

Effects of pregnancy on asthma

As a general rule, the course of an individual subject’s asthma during pregnancy remains unpredictable and could differ in different trimesters of gestation. 

Most subjects who felt their asthma worsened during pregnancy improved postpartum; conversely, most subjects who felt their asthma improved during pregnancy worsened after pregnancy.¹⁴ 

Lao et al reported in 1990¹⁵ that among treated asthmatics, 39% had no change, 30% had an increase and 31% had a decrease in the frequency and severity of symptoms or attacks during pregnancy; this generally reflects the consensus that has remained for many years. 

Most studies, however, were based on subjective questionnaires and relatively few had examined objective measures, such as lung function by peak flow meter or spirometry, or airway hyper-responsiveness.

Of concern is the fact that 8% of subjects who stated that their asthma improved still had an emergency department presentation for asthma during pregnancy.¹⁴

On average, 9-15% of pregnant women with asthma experience an acute asthma attack,^16,17 more commonly around 21-24 weeks of gestation. Severe exacerbations including status asthmaticus were found to be positively associated with IgE levels.¹⁷ 

Possible mechanisms for the effects of pregnancy on asthma course

These mechanisms are not fully understood, although increases in maternal circulating hormones (cortisol, oestradiol, progesterone), alteration in beta 2-adrenoreceptor responsiveness, altered immune system (successful pregnancy has been described as a Th2 phenomenon – similar to asthma itself) and foetal sex may be involved.

In multiple studies since the early 1960s it has been shown that significantly more mothers pregnant with a female foetus reported shortness of breath, nocturnal waking and a worsening of cough and asthma in general, while mothers pregnant with a male foetus were more likely to report an improvement in asthma.¹⁸

Treatment of asthma during pregnancy

Asthma control goals for pregnant patients are the same as for the non-pregnant state or males (GINA):

• Achieve and maintain control of symptoms
• Maintain pulmonary function as close to normal as possible
• Maintain normal activity levels including exercise
• Prevent asthma exacerbations
• Avoid adverse events
• Prevent asthma mortality.

Inhaled corticosteroids (ICS) are the most effective therapy in asthma and have an excellent safety profile in pregnancy^19,20 at the doses usually required in asthma. Adverse effects appear mostly at higher doses. Budesonide remains the best-studied ICS in pregnancy.²¹

In relation to systemic effect of ICS, recent studies suggest that patients with asthma (as opposed to patients with chronic obstructive pulmonary disease) do not have an excess risk of pneumonia, tuberculosis or glaucoma while using ICS in low doses.²²

High doses of ICS, however, increase the risk of clinically overt diabetes and the progression to insulin therapy. Reassuringly, even use of high doses of ICS during pregnancy does not appear to affect foetal adrenal function.²²

Should patients with mild, persistent asthma use inhaled steroids?

Yes, the evidence of benefit (better asthma control, reduced number of exacerbations) was demonstrated in several trials which included patients with mild or early asthma:

• The START study²³ (budesonide)
• The IMPACT study²⁴ (budesonide).

There are not enough data to support use of the long-acting beta2-agonists (such as salmeterol and formoterol) either alone or in combination with ICS in asthma patients during pregnancy, as well as use of leukotriene-modifying drugs (the leukotriene receptor antagonists montelukast and zafirlukast; and the 5-lipoxygenase inhibitor zileuton).²⁵

Is there any advantage to intravenous corticosteroids versus oral corticosteroids in patients with acute exacerbation of asthma?

No, there was no difference in the rate of pulmonary function improvement demonstrated, as well as no difference in the length of stay.²⁶ Intravenous steroids should be reserved for those patients who cannot take oral medications. The optimal dose of steroids in this scenario remains controversial. 

Tailoring asthma treatment

A useful algorithm to consider in the care of the pregnant patient with poor asthma control is ABCD:

• A – is it Asthma? Consider differential diagnosis: pulmonary embolism, amniotic fluid embolism, pulmonary oedema, peripartum cardiomyopathy, chest infection, physiological dyspnoea of pregnancy
• B – are Bronchial triggers known?
• C – is Compliance optimal; have patient’s concerns and fears been addressed?
• D – can patient use Device correctly?

Management principles²

• A stepwise approach to therapy is recommended based on asthma severity (initial assessment) and level of control during subsequent evaluations
• While assessing the risk/benefit ratio of asthma medication, consider that the benefits of well controlled maternal asthma currently outweigh any potential risks
• Spirometry and peak expiratory flow rate (PEFR) are useful objective tools for monitoring pulmonary function during pregnancy as they are essentially unaffected by gestation, and routine measurement is recommended
• The development of individualised self-management plans 
• Education is essential and has been shown to improve patients’ adherence with medications.²⁷

Conclusions

Asthma in pregnant patients is common, can be potentially harmful to both baby and mother when inadequately controlled, and requires treatment with inhaled corticosteroids, even if mild. Its management could be challenging due to poor treatment adherence in pregnancy.

References 

1. Schaefer G, Silverman F. Pregnancy complicated by asthma. Am J Obstet Gynecol 1961; 82: 182-191
2. Murphy VE, Gibson PG, Smith R, Clifton VL. Asthma during pregnancy: mechanisms and treatment implications. Eur Respir J 2005; 25: 731-750
3. Kwon HL, Triche EW, Belanger K, Bracken MB. The epidemiology of asthma during pregnancy: prevalence, diagnosis, and symptoms. Immunol Allergy Clin North Am 2006; 26: 29-62
4. Kurinczuk JJ, Parsons DE, Dawes V, Burton PR. The relationship between asthma and smoking during pregnancy. Women Health 1999; 29: 31-47
5. Akinbami LJ, Moorman JE, Liu X. Asthma prevalence, health care use, and mortality: United States, 2005-2009. Natl Health Stat Report 2011: 1-14
6. McGowan B, Bennett K, Barry M et al. An analysis of the utilisation and expenditure of medicines dispensed for the management of severe asthma. Ir Med J 2009; 102: 73-76
7. Mendola P, Laughon SK, Mannisto TI et al. Obstetric complications among US women with asthma. Am J Obstet Gynecol 2013; 208: 127 e1-8
8. Dombrowski MP. Outcomes of pregnancy in asthmatic women. Immunol Allergy Clin North Am 2006; 26: 81-92
9. Firoozi F, Lemiere C, Beauchesne MFet al. Impact of maternal asthma on perinatal outcomes: a two-stage sampling cohort study. Eur J Epidemiol 2012; 27: 205-214
10. Namazy JA, Murphy VE, Powell H et al. Effects of asthma severity, exacerbations and oral corticosteroids on perinatal outcomes. Eur Respir J 2013; 41: 1082-1090
11. Bracken MB, Triche EW, Belanger K et al. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies. Obstet Gynecol 2003; 102: 739-752
12. Murphy V, Wang G, Namazy J et al. The risk of congenital malformations, perinatal mortality and neonatal hospitalisation among pregnant women with asthma: a systematic review and meta-analysis. BJOG 2013
13. Jana N, Vasishta K, Saha SC, Khunnu B. Effect of bronchial asthma on the course of pregnancy, labour and perinatal outcome. J Obstet Gynaecol (Tokyo 1995) 1995; 21: 227-232
14. Schatz M, Harden K, Forsythe A et al. The course of asthma during pregnancy, post partum, and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol 1988; 81: 509-517
15. 15. Lao TT, Huengsburg M. Labour and delivery in mothers with asthma. Eur J Obstet Gynecol Reprod Biol 1990; 35: 183-190
16. Stenius-Aarniala BS, Hedman J, Teramo KA. Acute asthma during pregnancy. Thorax 1996; 51:411-414
17. Henderson CE, Ownby DR, Trumble A, DerSimonian R, Kellner LH. Predicting asthma severity from allergic sensitivity to cockroaches in pregnant inner city women. J Reprod Med 2000; 45: 341-344
18. Beecroft N, Cochrane GM, Milburn HJ. Effect of sex of fetus on asthma during pregnancy: blind prospective study. BMJ 1998; 317: 856-857
19. Schatz M, Zeiger RS, Harden K et al. The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol 1997; 100: 301-306
20. Namazy J, Schatz M, Long L et al. Use of inhaled steroids by pregnant asthmatic women does not reduce intrauterine growth. J Allergy Clin Immunol 2004; 113: 427-32
21. Breton MC, Martel MJ, Vilain A, Blais L. Inhaled corticosteroids during pregnancy: a review of methodologic issues. Respir Med 2008; 102: 862-875
22. Ernst P, Suissa S. Systemic effects of inhaled corticosteroids. Curr Opin Pulm Med 2012; 18: 85-89
23. Busse WW, Pedersen S, Pauwels RA et al. The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early intervention with budesonide in mild persistent asthma. J Allergy Clin Immunol 2008; 121: 1167-1174
24. Boushey HA, Sorkness CA, King TS et al. Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005;352: 1519-1528
25. Rey E, Boulet LP. Asthma in pregnancy. BMJ 2007; 334: 582-585
26. Ratto D, Alfaro C, Sipsey J et al.Are intravenous corticosteroids required in status asthmaticus? JAMA 1988; 260: 527-529
27. Schatz M. Asthma during pregnancy: interrelationships and management. Ann Allergy 1992; 68: 123-133