CME: Asthma in pregnancy: drugs to keep it under control

We sometimes forget that we graduated from medical school before we became specialists. It’s important not only that we maintain our basic knowledge of diseases such as asthma and their pathophysiology, but also keep up with new recommendations. How often does a frustrated patient tell us her primary-care physician is refusing to prescribe a medication or treat a common problem because she is pregnant? As physicians for women’s health, we need not be experts in the field of asthma, but we must be familiar enough with this and other diseases that can coexist with pregnancy to guide and encourage primary-care physicians to work with us in caring for our pregnant patients.

Asthma is one of the most common potentially serious conditions that can complicate pregnancy. Its estimated prevalence among pregnant women 18- to 44-years old is up to 9%.1,2

But it’s up to 12% in younger pregnant women aged 18 to 24.2 The chances of ever receiving a diagnosis of asthma doubled between 1998 and 2002. According to the National Health Interview Survey conducted from 1997 to 2003, 38.5% of pregnant women who carry an asthma diagnosis reported at least one asthma attack in the previous year,2 which suggests that many patients are not being adequately managed. These data, however, were based on selfreporting and were not corroborated by a physician.

Asthma has been historically linked to poor pregnancy outcomes, including hyperemesis gravidarum, gestational diabetes, preterm delivery, preeclampsia, cesarean delivery, neonatal mortality, and low birthweight, although the data supporting these claims have been inconsistent.3 The mechanisms by which these outcomes occur, while poorly understood, likely result from chronic hypoxia and the downstream deleterious effects on the pregnancy. The current literature supports this hypothesis, as those with poor control are more likely to have adverse pregnancy outcomes.

Recently, however, the Maternal Fetal Medicine Unit (MFMU) published a prospective observational study that identified few significant differences between women with and without asthma. This study evaluated preterm delivery, gestational diabetes, preeclampsia, preterm labor, chorioamnionitis, oligohydramnios, cesarean delivery, low birthweight, small-for-gestational-age, and congenital malformations in women with and without asthma. Among 2,620 women, however, the only statistically significant difference in outcome was an increased cesarean delivery rate in women with moderate-to-severe asthma.4 Although the MFMU states there are no real issues, other studies have reported pregnancy complications.5-7

When interpreting the study results of asthma in pregnancy, one must be aware of many considerations: although the results of these prospective studies are reassuring in their consensus of good pregnancy outcomes, they don’t mean that asthma should be considered benign because active asthma management was a part of these studies and may have had a positive impact on the outcomes. Similarly, women who enroll in research studies tend to be more vigilant regarding their health care and more adherent to therapy. The lack of adverse outcomes associated with severe asthma is potentially due to the small numbers of women in that category, and therefore there was likely insufficient power to detect significant results.1

Generally throughout pregnancy, asthma severity stays the same in one third of patients, improves in one third of patients, and worsens in one third.8-11 It should come as no surprise that those with severe disease before becoming pregnant are more likely to deteriorate,11 but even mild disease can cause complications. (For example, one group of researchers reported a 12.6% exacerbation rate and a 2.3% hospitalization rate with mild asthma).12,13

Often, the course of disease will be similar from one pregnancy to the next. Proper medical control should allow a woman with asthma to maintain a pregnancy with little or no increased risk to herself or her fetus.14 In fact, as ACOG and others point out, it is probably safer for a pregnant woman to be treated with asthma medications than for her pregnancy to be riddled with asthmaexacerbations.

Classifying the disease’s severity

Asthma causes chronic airway inflammation, which leads to airway hyperresponsiveness and airflow constriction, and which in turn causes cough, dyspnea, wheezing, and chest tightness. Environmental triggers can exacerbate asthma attacks, but usually a viral illness triggers them. Classically, asthma is characterized by obstructive lung disease that is reversible either spontaneously or with treatment.14,15

It’s essential to appropriately classify the pregnant woman with asthma based upon severity of disease: either mild intermittent, mild persistent, moderate persistent, or severe persistent asthma.14,15 This stratification is important to obstetricians/gynecologists,as it helps predict potential complicationsof pregnancy and provides a basis forpharmacologic intervention (Table 1).

Once the patient’s asthma is classified,you must take into account how thepathophysiologic changes of pregnancyaffect her asthmatic symptoms. For example:alterations in progesterone levels may bea factor in both improving and worseningsymptoms at night. The smooth musclerelaxation associated with progesteronemay lead to less bronchial smooth muscleconstriction and overall improvement ofsymptoms. The concomitant relaxationof the lower esophageal sphincter, however,can lead to more frequent esophageal refluxsymptoms: a known trigger of bronchospasm. Gastroesophageal reflux disease (GERD) may likely be the cause if patients report worsening nocturnal symptoms, when ref lux most commonly occurs.16

Fetal gender has also been correlated with maternal asthma exacerbations, with increased severity in women carrying female fetuses and improved symptoms in patients with male fetuses. It’s thought this is due to the androgenic surge in male fetuses that may increase the relaxation of ß-adrenergicmediated bronchial tissue and further inhibit tissue response to histamine.16,17 While this effect is most often seen at 12 to 16 weeks’ gestation, it may confer protection until the early third trimester.

Anatomic a l ly, we know the diaphragm is elevated about 4 cm with advancing pregnancy, which leads to a drop in functional residual capacity. This translates into increased sensitivity to the effects of hypoxia. Exploring how pregnancy affects basic spirometry, a group of researchers showed the effect of gestational age and position on peak expiratory flow rate (PEFR) in a longitudinal study of nonasthmatic patients.18 They noted a gradual but significant decrease (0.65L/min per week) in PEFR with advancing gestation.18 This knowledge may be especially helpful in appropriately managingasthma in the third trimester.

Antenatal care of the gravida with asthma

Prepregnancy and prenatal counseling are integral to the appropriate care of a patient with asthma. Emphasize that most drugs prescribed for asthma are not considered teratogenic. A patient must understand that she should not decrease or discontinue any drug without consulting with her physician. Obstetrican/ gynecologists should also communicate the same message to primary-care physicians and medical specialists. Furthermore, all concerned must understand that severe asthma exacerbations can be disastrous for both mother and fetus.

Make sure, as recommended in the ACOG bulletin and elsewhere, that patients understand the differences between maintenance and rescue medications, know how to use inhalers correctly, are able to perform PEFR readings twice daily, know the asthma triggers (allergens and irritants-especially tobacco smoke and fireplaces) and how to avoid them, and have a written plan to adjust medications based on measurement of peak expiratory flow.3

The PEFR value in pregnancy should be between 380–550 L/min while standing, and the patient should establish her “personal best.” It’s common in asthma management to determine individualized zones: green zone being greater than 80% of her personal best; yellow zone is between 50% and 80% of personal best; and red zone is less than 50% of her personal best.13 Were she to fall in the yellow zone, “step up” therapy would be indicated, whereas red zone readings would send her to the emergency room.

The goal of asthma therapy in pregnancy is to use the least amount of medication necessary to control the severity of a patient’s asthma. And the ultimate goal of asthma therapy in pregnancy is to maintain “adequate oxygenation of the fetus by preventing hypoxic episodes in the mother” (as recommended in the ACOG bulletin and elsewhere), 1 avoid asthma exacerbations, and continue to successfully accomplish activities of daily living. This is perhaps best achieved via collaborative care: you as an obstetrician/ gynecologist coordinating with the primary- care/pulmonologist who manages your patient’s asthma outside of pregnancy.

Drugs are far safer than exacerbations

Historically, medications in pregnancy have sparked fear of congenital malformations, leading some women to stop taking asthma drugs at the beginning of their pregnancies to avoid such events. But we now know that it’s safer for women with asthma to continue their treatment than to endure increasing symptoms and exacerbations while pregnant. Stepwise pharmacologic therapy is advocated in pregnancy and outlined in Table 1.

In 1993, the National Asthma Education and Prevention Program Expert Panel Report (NAEPP) published the “Report of the Working Group on Asthma and Pregnancy,” which was subsequently updated in 2004. The purpose of this publication was to present recommendations for the pharmacologic management of asthma in pregnancy.19,20

The report stresses behavioral modification to avoid environmental triggers for asthma exacerbations, such as using allergenimpermeable mattress and pillow covers, weekly washing of bedding in hot water, avoiding tobacco smoke and fireplaces, decreasing the humidity in the house, and leaving the house while it’s being vacuumed.

In addition, it recommends six pharmacologic interventions: inhaled corticosteroids, inhaled ß2 agonists, cromolyn, theophylline, leukotriene inhibitors, and systemic corticosteroids. Each compound has a well-studied safety profile, and the risk-benefit profile clearly supports their use in pregnancy to avoid the complications of asthma exacerbation.

(1) Inhaled corticosteroids. The backbone of treatment for any form of persistent asthma, these compounds directly address the underlying inf lammation. Inhaled steroids don’t appear to be linked with disorders of fetal growth, fetal malformations, or preterm delivery.21-23 Beclomethasone and budesonide are the most commonly used. Recently upgraded to pregnancy Category B, budesonide is the preferred inhaled steroid in pregnancy.2,15,20,24 The ACOG bulletin also states, though, that any inhaled steroid with proven effectiveness can be continued and there’s no evidence indicating that other inhaled corticosteroids are unsafe.1

(2) Inhaled short-acting ß2 agonists. These are recommended as rescue therapy for all asthmatics. Currently, the only available metered-dose inhaler is albuterol, and there are no risks of congenital malformation or adverse pregnancy outcomes associated with it. Short-acting ß2 mimetic drugs have a good track record during pregnancy, as terbutaline has been used for many years to treat preterm labor and the safety of this class of drugs in late pregnancy has been well-documented.

Conversely, the effects upon pregnancy of the long-acting ß2 agonists salmeterol and formoterol are less understood. Although data are limited, experience with salmeterol is more prevalent than with formoterol.25 The ACOG Bulletin recommends carefully assessing risk: benefit prior to continuing their use in pregnancy. Because long-acting and short acting ß2 agonists have similar pharmacology and toxicology, long-acting ß2 agonists are expected to have a safety profile similar to albuterol.1 Optimal control of asthma during pregnancy is imperative. If long-acting ß2 agonists are needed, use them.

(3) Cromolyn sodium. Once considered an excellent controller drug in persistent asthmatics, cromolyn’s role has been essentially replaced by inhaled corticosteroids. Nonetheless, it is considered to be safe inpregnancy without known adverse effects to the fetus. Given its safety profile, this is a medication that could be continued in pregnancy if the drug has been shown to control mild persistent asthma prior to conception.24

(4) Theophylline. For many years the mainstay drug for treating asthma, theophylline is rarely used today. This drug is indicated as add-on therapy for pregnant patients with moderate persistent asthma not controlled by inhaled corticosteroids alone. There doesn’t appear to be any increased risk of congenital malformations or adverse pregnancy outcome associated with theophylline. But pregnant patients may find it difficult to tolerate because of its many possible side effects, including insomnia, heartburn, palpitations, and nausea. In addition, the latest recommendations for theophylline dosing require achieving a therapeutic window of 5-12 ?g/mL. Higher doses can cause jitteriness, tachycardia, and vomiting in mothers and neonates. This therapeutic window may be difficult to achieve, given the potential for significant drug interactions associated with theophylline and the normal physiologic changes of pregnancy.11,24

(5) Leukotriene modulators. The most recent addition to asthma management, leukotriene modulators reverse the bronchospasm induced by the arachidonic acid metabolites, leukotrienes, by blocking, their formation. So far, there are minimal data on human pregnancy and exposures to this drug class, but zafirlukast (Accolate), and montelukast are considered pregnancy Category B. A third leukotriene modulator, zileuton (Zyf lo), has questionable animal data and should be avoided in pregnancy.3 Merck maintains a pregnancy registry (www.merckpregnancyregistries.com) of those exposed to Singulair (montelukast). As of the 9th Annual Report on Exposure During Pregnancy for Singulair covering the period February 20, 1998 through July 31, 2007, 215 live births were followed prospectively and resulted in seven congenital anomalies. Notably, there was a single case of absent left hand secondary to amniotic bands, and a case of polydactyly. These cases, combined with three retrospective reports of possible limb reduction defects have caused Merck to modify their pregnancy label to note limb reduction defects among infants exposed to montelukast, although no obvious mechanism for limb reduction exists. Interpret the pregnancy warning with caution, though, given the many methodologic f laws in data collection for Merck’s registry,13,25,26 as well as the fact that in evaluating over 1,000 health insurance claims, no limb abnormalities were noted in pregnancies exposed to montelukast. The current recommendation for use is to limit it to those women who have had a favorable response to the drug prior to becoming pregnant.

(6) Systemic corticosteroids. These drugs do carry some potential risk to the fetus. Unfortunately, given that they are indicated only for those with severe asthma, this exposure is often not optional or replaceable. First-trimester exposure to oral corticosteroids is associated with a statistically significant increase in facial clefting (OR=3.35; CI 1.97, 5.69),27 although the attributable risk is still quite low (0.2%–0.3%). Similarly, oral steroids are linked to more cases of preeclampsia, preterm delivery, and low birthweight. The MFMU prospective cohort revealed that oral steroids were significantly associated with preterm birth and birthweight less than 2,500 g.23 The amount of intravenous methylprednisolone or oral prednisone that actually reaches the fetus is quite small. These medications are metabolized by placental 11 ß-ol dehydrogenase to an inactive 11-keto-metabolite, which makes one wonder if these outcomes are due to the drug’s effect or to the severity of the asthma. The current recommendation for oral corticosteroids is for the treatment of chronic severe asthma, and intuition would support the goal of giving the lowest effective dose to achieve control. For a severe acute asthma exacerbation, IV methylprednisolone should be rapidly administered without hesitation.28

Treating asthma emergencies during pregnancy

Prospective data indicate that asthma exacerbations during pregnancy occur in about 20% of women, with 6% requiring hospitalizations.29 The most common triggers are viral infection or noncompliance with medications.29 Women with severe asthma exacerbations during pregnancy are at risk for poor pregnancy outcome, and therefore require aggressive treatment (Figure 1). Furthermore, they’re at risk for disease deterioration requiring intensive care and mechanical ventilation.

When a pregnant asthmatic arrives atthe ER with an asthma exacerbation, theemergency physician must immediatelyrealize that he or she is caring for twopat ients-a mother and a fetus-and establish the well-being of both. Continuous fetal heart rate monitoring is recommended if the fetus is viable. In determining how severely compromised PEFR has become, the treating physician should be aware of the gradual decline normally seen as pregnancy progresses. Oxygen saturation should be maintained at a level greater than 95%, with initial treatment consisting of bronchodilator therapy and IV f luids. Fluids are important, as insensible fluid loss increases with the increased respiratory rate that accompanies these exacerbations. As dehydration develops, it causes respiratory secretions to become more viscous, making the asthma worse. If bronchodilators fail to achieve a rapid response, the clinician shouldn’t hesitate to give concomitant IV corticosteroids.

Albuterol may be dosed every 20 minutes in the first hour and inhaled ipratropium bromide (500 mg) may be used as an adjunct. If the rapid treatment has resolved maternalsymptoms, PEFR is greater than 70%personal best, fetal monitoring is reassuring,and the patient remains stable 1 hour afterthe last treatment, the woman may go home.30Further, ACOG recommends that outpatientfollow-up should be arranged within 5days of the acute visit.1 The ER physicianshould watch the patient closely for signs ofimpending respiratory failure, which includematernal fatigue, fetal distress, or PaCO2greater than 35.30 This situation warrants aconsultation with an intensivist.

Other monitoring considerations

Consider the pregnant patient with asthma at risk for adverse perinatal outcomes, letting the severity of asthma determine the need for fetal heart rate monitoring in the third trimester. If excellent control is present throughout pregnancy, daily fetal movement counts may be sufficient. If the patient exhibits poor control or there’s evidence of intrauterine growth restriction or fetal compromise, initiate nonstress testing.14 Because of the possibility of fetal growth restriction, we advise serial sonograms for fetal growth in the late second and third trimesters. The severity of the asthma should dictate the frequency of these sonographic studies.

Also, when using systemic corticosteroids, pay close attention to maternal glycemia throughout pregnancy, as the drugs may exacerbate insulin resistance. Finally, if the patient is taking chronic steroids, screen for diabetes earlier than usual.

Managing the asthmatic patient on L&D

Continue asthma medications throughout labor, even though only 10% to 20% of women have a f lare-up during labor and delivery.19 In conjunction with her primarycare physician, consider “stress dose” steroids (e.g., 100 mg of hydrocortisone every 8 hours during labor and 24 hours postpartum) if the patient has received systemic steroids in the previous month or is taking chronic oral glucocorticoids. Avoid those medications that can induce bronchospasm, such as drugs often used totreat postpartum hemorrhage like Hemabate(prostaglandin F2ß) and methergine(methylergonovine). However, prostaglandinE2 and magnesium can be safely used.31Finally, regional anesthesia is preferredfor avoiding the obvious complication ofbronchospasm associated with intubationshould a patient need an urgent cesareandelivery. The degree of sedation appropriatefor intubation during pregnancy is differentfrom that used during general surgery fornonpregnant patients.32

To reiterate, asthma is the most commonpotentially life-threatening condition thatcan affect pregnancy. Without adequatecontrol, this disease can predispose a patientto a variety of poor obstetric outcomes.Fortunately, there are many ef fectivemedications that are safe to use in pregnancy.Proactive and aggressive use of medication,in conjunction with patient education and astepwise approach to asthma management,offers the patient the best opportunity fora symptom-free pregnancy and optimalobstetric outcome.

DR. PRASAD is Assistant Professor and DR. SAMUELS is Program Director,Obstetrics and Gynecology Residency, and Associate Professor, Division ofMaternal-Fetal Medicine, Department of Obstetrics and Gynecology, The OhioState University School of Medicine, Columbus, OH.

REFERENCES

1. Dombrowski MP, Schatz M; ACOG Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin: cl inical management guidel ines for obstetriciangynecologists number 90, February 2008: asthma in pregnancy. Obstet Gynecol. 2008;111(2 Pt 1):457-464.

2. Kwon HL, Triche EW, Belanger K, et al. The epidemiology of asthma in pregnancy: prevalence, diagosis and symptoms. Immunol Al lergy Clin N Am. 2006;26:29-62.

3. Powrie RO, Larson L, Miller M. Managing asthma in expectant mothers. Treat Respir Med. 2006;5:1-10.

4. Dombrowski MP, Schatz M, Wise R, et al. Asthma during pregnancy. Obstet Gynecol. 2004;103:5-12.

5. Wen SW, Demissie K, Liu S. Adverse outcomes in pregnancies of asthmatic women: results from a Canadian population. Ann Epidemiol. 2001;11:7-12.

6. Kallen B, Rydhstroem H, Aberg A. Asthma during pregnancy-a population based study. Eur J Epidemiol. 2000;16:167-171.

7. Liu S, Wen SW, Demissie K, et al. Maternal asthma and pregnancy outcomes: a retrospective cohort study. Am J Obstet Gynecol. 2001;184:90-96.

8. Tan KS, Thompson NC. Asthma in pregnancy. Am J Med. 2000;109:727-733.

9. Gluck JC, Gluck PA. The effects of pregnancy on asthma: a prospective study. Ann Allergy. 1976;37:164- 168.

10. White RJ, Couts II, Gibbs CJ, et al. A prospective study of asthma during pregnancy and the puerperium. Respir Med. 1989;83:103-106.

11. Schatz M, Harden K, Forsythe A, et al. The course of asthma during pregnancy, postpartum, and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol. 1988;81:509-517.

12. Schatz M, Dombrowski MP, Wise R, et al. Asthmamorbidity during pregnancy can be predicted byseveri ty classi f icat ion. J Al lergy Cl i n Immunol.2003;112:283-288

13. Dombrowski MP. Asthma and pregnancy. ObstetGynecol. 2006;108: 667-681.

14. National Institutes of Health, National Heart, Lungand Blood Institute. Report of the Working Groupon Asthma and Pregnancy: management of asthmaduring pregnancy. 1993. Avai lable at http://www.nhlbi.nih.gov/health/prof/lung/asthma/astpreg.txt.Accessed 1/26/2008.

15. National Heart, Lung and Blood Institute, NationalAsthma Education and Prevention Program. Expertpanel report 3. Guidelines for the diagnosis and managementof asthma. Full Report 2007. Available at Accessed 11/01/2008.http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf..

16. Ostrom NK. Women with asthma: a review ofpotential variables and preferred medical management.Ann Allergy Asthma Immunol. 2006;96:655-665.

17. Kwon HL, Belanger K, Holford TR et al. Effect offetal sex on airway lability in pregnant women withasthma. Am J Epidemiol. 2006;163:217-221.

18. Harirah HM, Donia SE, Nasralleh FK, et al. Effectof gestational age and position on peak expiratoryflow rate: a longitudinal study. Obstet Gynecol.2005;105:372-376.

19. Namazy JA, Schatz M. Current guidelines for themanagement of asthma during pregnancy. ImmunolAllergy Clin N Am. 2006;26:93-102.

20. National Asthma Education Prevention Program.Working Group Report on Managing Asthma DuringPregnancy. Recommendations for PharmacologicTreatment-Update 2004. NIH publication No. -05-5236. Rockvi l le, MD, U.S. Depar tment of Healthand Human Services, National Institutes of Health.Avai lable at: ht tp://www.nhlbi.nih.gov/health/prof/lung/asthma/astpreg.htm Accessed 11/01/2008.

21. Rahimi R, Nikfar S, Abdollahi M. Meta-analysisfinds use of inhaled corticosteroids during pregnancysafe: a systematic meta-analysis review. Hum ExpToxicol. 2006;25:447-452.

22. Bakhireva LN, Jones Kl, Schatz M, et al. Asthmamedication use in pregnancy and fetal growth.J Allergy Clin Immunol. 2005;116:503-509.

23. Schatz M, Dombrowski MP, Wise R, et al. Therelationship of asthma medication use to perinataloutcomes. J Al lergy Cl in Immunol. 2004:113:1040-1045.

24. Namazy JA, Schatz M. Update in the treatment ofasthma during pregnancy. Clin Rev Allergy Immunol.2004;26:139-148.25. Reprotox.org. Accessed 1/26/2008.

26. Bakhireva LN, Jones Kl, Schatz M, et al. Safetyof leukotriene receptor antagonists in pregnancy.J Allergy Clin Immunol. 2007;119:618-625.

27. Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birthdefects after maternal exposure to corticosteroids:prospective cohort study and meta-analysis of epidemiologicalstudies. Teratology. 2000;62:385-392.

28. Hanania NA, Belfort MA. Acute asthma in pregnancy.Crit Care Med. 2005;33[suppl]:S319-S324.

29. Murphy VE, Clifton VL, Gibson PG. Asthma exacerbationsduring pregnancy: incidence and associationwith adverse pregnancy outcomes. Thorax.2006:61:169-176.

30. Cydulka RK. Acute asthma during pregnancy.Immunol Allergy Clin N Am. 2006;26:103-117.31. Towers CV, Briggs GG, Rojas JA. The use of prostaglandinE2 in pregnant patients with asthma. Am JObstet Gyneocol. 2004;190:1777-1780.

32. Kuczkowski KM. Labor analgesia for the parturientwith respiratory disease: what does anobstetrician need to know. Arch Gynecol Obstet.2005;272:160-166.