Asthma in Pregnancy

Dr . Nahid SherbiniConsultant IM & PulmonaryKFH ,Medina ,SA

What I Will talk about ? 1

• NORMAL PHYSIOLOGY DURING PREGNANCY

• EFFECTS OF PREGNANCY ON ASTHMA

• EFFECTS OF ASTHMA ON PREGNANCYComplications causes of adverse outcomes

What I Will talk about ? 2

• OVERVIEW OF MEDICATIONS IN PREGNANCY

• GENERAL CARE

• SAFETY OF SPECIFIC MEDICATIONS

• OVERVIEW OF ASTHMA MANAGEMENT IN PREGNANCYChronic asthmaAcute exacerbations

INTRODUCTION

• Asthma is one of the most common medical conditions encountered during pregnancy, occurring in 3 - 8 % of pregnant women.

Namazy JA, Schatz M. Pregnancy and asthma: recent developments. Curr Opin Pulm Med 2005; 11:56.Liccardi G, Cazzola M, Canonica GW, et al. General strategy for the management of bronchial asthma in pregnancy. Respir Med 2003; 97:778.Tan KS, Thomson NC. Asthma in pregnancy. Am J Med 2000; 109:727.Dombrowski MP, Schatz M, Wise R, et al. Asthma during pregnancy. Obstet Gynecol 2004; 103:5.

Normal Physiology

Pregnancy Changes Increased TV Decreased ERV and RV and FRC Intact FEV1 Less than normal PCo2 Above normal PO2

Questions about the interaction of asthma and pregnancy are raised by clinicians and patients alike:• How does pregnancy affect asthma?• How does asthma affect the outcomes of

pregnancy?

Effects of Pregnancy on Asthma

• Two prospective studies (1998) of more than 500 women

1/3 aggravate 1/3 improve 1/3 does not change

• BA severity correlated with asthma morbidity during pregnancy

• Mild asthma 13% had exacerbation• Moderate 26 % had exacerbation• Severe 50% had exacerbation

Most studies suggest that asthma severity prior to pregnancy is related to asthma severity during pregnancy.• The following additional trends have been noted :1. Asthma was generally less severe during the last 4w of

pregnancy.2. In women who improved, the improvement was gradual

as pregnancy progressed.3. In women whose asthma worsened, the increase in

symptoms was most prominent between w 29 - 36 of gestation.

4. Substantial asthma symptoms were uncommon during labor and delivery.

5. The course of asthma in successive pregnancies in an individual patient tended to be similar

Effects of Asthma on Pregnancy

• Controversial results in terms of preeclampsia, cesarean delivery, prematurity, IUGR, and perinatal mortality rate

• Generally unless there is severe disease, asthma has relatively minor effects on pregnancy outcome

Effects of Asthma on Pregnancy

• A prospective study by Dombrowski (2000), preterm delivery among pregnancies complicated by asthma compared to non-asthmatic controls. the majority of women enrolled with severe asthma showed an increase of preterm labor by two fold.

• Bracken (2003) found preterm delivery only slightly increased with asthma while IUGR increased with severity of asthma.

Complications of Asthma in Pregnancy

• Perinatal mortality • Hyperemesis• Vaginal hemorrhage• Preeclampsia• Complicated labor• Neonatal mortality• Prematurity• Hypertension• Low birthweight infants

A study of 36,985 subjects asthmatic 15 -20 % increased risk of perinatal mortality, preeclampsia, preterm deliveries, or low birth weight infants compared to non-asthmatic women

These risks are increased 30 - 100 % those with more severe asthma

Asthma is not associated with risk of congenital malformations

Use of anti-asthmatic drugs during pregnancy. Congenital malformations in the infants.Källén B, Otterblad Olausson P Eur J Clin Pharmacol. 2007;63(4):383.

Potential adverse effects of Asthma Medication

•Miscarriage•Fetal death•Congenital malformation (especially first trimester exposure)•Reduced fetal growth•Impaired function of developing organs, such as the central nervous system or kidney•Reduced uteroplacental blood flow•Increased risk of preterm delivery•Drug related side effects in the newborn

Outcomes of pregnancy in asthmatic women Schatz, M, Dombrowski, MImmunol Allergy Clin North Am. 2000; 20:715.

Possible causes of adverse outcomes

• Direct consequences impair fetal oxygenation and uteroplacental blood flow

• Diminished pulmonary function during pregnancy .

• An observational series of 2123 pregnant women with asthma demonstrated that decreased gestational maternal (FEV1) was associated with gestational hypertension and preterm birth compared to women with a normal FEV1.

Systemic effects of salbutamol and salmeterol in patients with asthma.Bennett JA, Smyth ET, Pavord ID, Wilding PJ, Tattersfield AEThorax. 1994;49(8):771

What I Will talk about ? 2• GENERAL CAREMonitoring lung function ,Smoking cessation ,Environmental control & Patient education

• SAFETY OF SPECIFIC MEDICATIONS

• OVERVIEW OF MEDICATIONS IN PREGNANCY

• OVERVIEW OF ASTHMA MANAGEMENT IN PREGNANCY

Management

The Expert Panel Report of the Working Group on Asthma and Pregnancy stressed the following four important components of effective therapy :1. Objective monitoring of maternal lung function and fetal well–

being as a guide to therapy2. Proper control of environmental and other triggers for asthma 3. Patient education4. Pharmacologic therapy

NAEPP expert panel report. Managing asthma during pregnancy: recommendations for pharmacologic treatment-2004 update.National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Asthma and Pregnancy Working GroupJ Allergy Clin Immunol. 2005;115(1):34.

GENERAL CARE

The two primary goals of asthma management:

• Prevention of acute episodes should prevent potentially harmful acute hypoxia, hypocapnia, alkalosis, and dehydration.

• Optimization of chronic maternal pulmonary function should reduce the potential for chronic hypoxia, maternal symptoms, as well as the likelihood of acute episodes.

Patient Education

• Understanding that asthma control is important to fetal well being.• Reduction of triggers.• Understanding of basic medical management including

self monitoring

Environmental control

• Avoiding exposure to allergens and to nonspecific airway irritants such as tobacco smoke, dust, and environmental pollutants.

• Particular allergens of concern are from pets and antigens from household dust mites.

Smoking cessation

It is critical for the pregnant asthmatic woman to discontinue smoking during pregnancy [2]. 1- Predispose the patient to asthma exacerbations, bronchitis or sinusitis necessitate an increased need for medication [1]. 2-Increase perinatal morbidity to the baseline risk of uncontrolled maternal asthma [3].

(1)Murphy VE, Clifton VL, Gibson PG. The effect of cigarette smoking on asthma control during exacerbations in pregnant women. Thorax 2010; 65:739.(2)Newman RB, Momirova V, Dombrowski MP, et al. The effect of active and passive household cigarette smoke exposure on pregnant women with asthma. Chest 2010; 137:601(3)Schatz M, Zeiger RS, Hoffman CP. Intrauterine growth is related to gestational pulmonary function in pregnant asthmatic women. Kaiser-Permanente Asthma and Pregnancy Study Group. Chest 1990; 98:389.

Follow-up

• By clinicians experienced in managing asthma is essential. • Regular medication at least monthly.• All pregnant patients should have access to their clinician

(effective communication exists among the clinician managing the asthma, the patient, and the obstetrician).

Objective Measures for Accurate Monitoring

• FEV1 is best single measure of pulmonary function but requires a spirometer.• PEFR is inexpensive as it is measured by peak flow ,Self-monitoring of PEFR aids in detecting early signs of deterioration in lung function.

Pharmacologic Therapy

OVERVIEW OF MEDICATIONS IN PREGNANCY

Two important considerations arise with the use of any medication in pregnancy:• Are there potential adverse effects of the medication on the

developing fetus?• Does pregnancy alter the metabolism or the bioavailability of

the medication?

SAFETY OF SPECIFIC MEDICATIONS

• Experience with many of the medications used to treat asthma suggests minimal or no known adverse effects for their use during pregnancy.• Most drugs used in the treatment of asthma fall into

categories B or C .

Overview

• Cohort studies are reassuring and show a lack of adverse effects on human pregnancy outcomes with the following drugs :

Albuterol Metaproterenol Theophylline Cromolyn sodiumBeclomethasoneBudesonide

Cont.

• Data regarding the use of oral glucocorticoids during pregnancy have not been totally reassuring.

• These include drugs with-Reassuring animal studies (formoterol , salmeterol , ipratropium , nedocromil , zafirlukast, and montelukast) -Non-reassuring animal studies (zileuton).

Inhaled beta-adrenergic agonists

• The majority of reports provide reassurance regarding the use of inhaled beta-agonists during pregnancy

• Clinical experience is greater with the older agents (eg, albuterol) than with the newer ones (eg, formoterol, salmeterol).

Short-acting beta-adrenergic agonists SABA• In animal studies, some of the SABAs have been teratogenic

when given in high doses, but there has been no clear evidence of teratogenicity in humans.

• In a study of 259 pregnant asthmatic women, for example, no adverse effects on the fetus were noted with the use of an inhaled SABA (primarily metaproterenol) when compared with control subjects, even though 180 of the women used these agents during the first trimester .

Schatz M, Zeiger RS, Harden KM, et al. The safety of inhaled beta-agonist bronchodilators during pregnancy. J Allergy Clin Immunol 1988; 82:686.

• Cardiac defects was noted in a cohort study that examined the effect of exposure to bronchodilator therapy during pregnancy [1].

• SABA use is a marker for poorly-controlled asthma and more frequent exacerbations, which may independently contribute to the development of congenital anomalies [2].

1 Otterblad Olausson P. Use of anti-asthmatic drugs during pregnancy. 3. Congenital malformations in the infants. Eur J Clin Pharmacol 2007; 63:383.2 Blais L, Forget A. Asthma exacerbations during the first trimester of pregnancy and the risk of congenital malformations among asthmatic women. J Allergy Clin Immunol 2008; 121:1379.

LABA

These findings are preliminary; clinicians should continue with the goal of minimizing use of SABAs in both pregnant and non-pregnant patients.

Long-acting beta-adrenergic agents LABA

• Clinical experience with LABAs during pregnancy is less extensive than with SABAs.

• Salmeterol is not expected to increase the risk of congenital anomalies, based on data from animal studies and limited human experience .

• Animal studies are also reassuring for formoterol, although data from human pregnancies is very limited .

Wilton LV, Shakir SA. A post-marketing surveillance study of formoterol (Foradil): its use in general practice in England. Drug Saf 2002; 25:213.The use of newer asthma and allergy medications during pregnancy. The American College of Obstetricians and Gynecologists (ACOG) and The American College of Allergy, Asthma and Immunology (ACAAI). Ann Allergy Asthma Immunol 2000; 84:475.

LABA

• Given these findings, continuation of a LABA during pregnancy is reasonable if a LABA has been needed to achieve asthma control before pregnancy .

Schatz M, Dombrowski MP. Clinical practice. Asthma in pregnancy. N Engl J Med 2009; 360:1862.

Epinephrine

• May cause vasoconstriction in the uteroplacental circulation.

• Working Group on Pregnancy and Asthma recommended that epinephrine generally be avoided during pregnancy except in the setting of anaphylaxis .

National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Asthma and Pregnancy Working Group. NAEPP expert panel report. Managing asthma during pregnancy: recommendations for pharmacologic treatment-2004 update. J Allergy Clin Immunol 2005; 115:34.

Systemic Glucocorticoids• Several potential areas of concern have been raised

Congenital malformations (primarily cleft palate),Preeclampsia, Gestational diabetes, Low birth weight, & neonatal adrenal insufficiency.

Glucocorticoids

A few studies exist in which systemic glucocorticoids were used for the management of asthma during pregnancy . Some showed a slightly increased risk of prematurity and a slightly higher risk of low birth weight (less than 2500 g).

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.Schatz M, Dombrowski MP, Wise R, Momirova V, Landon M, Mabie W, Newman RB, Hauth JC, ay DL, Maternal-Fetal Medicine Units Network, The National Institute of Child Health and Development, National Heart, Lung and Blood InstituteJ Allergy Clin Immunol. 2004;113(6):1040.

Systemic glucocorticoids • Congenital malformations

Data from animal studies in several species suggest that high dose may lead to cleft palate.

Meta-analysis of the four case-control studies revealed an association of oral clefts in infants of mothers used oral glucocorticoid.

Pregnancy outcome after first trimester exposure to corticosteroids:Gur C, Diav-Citrin O, Shechtman S, Arnon J, Ornoy AReprod Toxicol. 2004;18(1):93

In a cohort study, 311 pregnancies with systemic glucocorticoid use for various indications during 1st trimester compared with those of 790 controls without teratogenic exposure; the rate of major anomalies did not differ significantly between the groups .No oral cleft abnormalities were noted in the glucocorticoid group.

Gur C, Diav-Citrin O, Shechtman S, et al. Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study.

Reprod Toxicol 2004; 18:93.

Preterm birth and low birth weight • A large, prospective, cohort study of 2123 pregnant

women with asthma recruited from 16 centers in the USA (12-1994 – 02- 2000 ) oral glucocorticoid use was significantly associated with preterm birth (odds ratio 1.54, 95% CI of 1.02 to 2.33) and low birth weight (odds ratio 1.80, 95% CI of 1.13 to 2.88) . • The authors did not evaluate the relationship between

these effects and the dose or duration of therapy.

Schatz M, Dombrowski MP, Wise R, Momirova V, Landon M, Mabie W, Newman RB, Hauth JC, ay DL, Maternal-Fetal Medicine Units Network, The National Institute of Child Health and Development, National Heart, Lung and Blood InstituteJ Allergy Clin Immunol. 2004;113(6):1040.

Inhaled Steroid

• The safety of these medicines was best assessed in a registry-based cohort study of 2014 Swedish women who used inhaled budesonide during early pregnancy . • Based largely upon these findings, budesonide is

currently the only inhaled glucocorticoid with a pregnancy category B rating.

Källén B, Rydhstroem H, Aberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol 1999; 93:392.National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Asthma and Pregnancy Working Group. NAEPP expert panel report. Managing asthma during pregnancy: recommendations for pharmacologic treatment-2004 update. J Allergy Clin Immunol 2005; 115:34

Inhaled Steroid

• The rate of congenital malformations was not different from that of the general population (3.8 Vs 3.5 %). Additional data from the Swedish Medical Birth Registry reported no clinically significant effects of inhaled budesonide on fetal mortality, gestational age, or fetal growth .

Norjavaara E, de Verdier MG. Normal pregnancy outcomes in a population-based study including 2,968 pregnant women exposed to budesonide. J Allergy Clin Immunol 2003; 111:736

Inhaled Steroid

• A study of 13,280 pregnancies in women with asthma confirmed that low to moderate doses of inhaled glucocorticoids were NOT associated with an increased risk of congenital malformations.

butthe use of high doses (>1000 mcg/day) during the 1st trimester 63 % increase in risk of all congenital malformations .

Blais L, Beauchesne MF, Lemière C, Elftouh N. High doses of inhaled corticosteroids during the first trimester of pregnancy and congenital malformations. J Allergy Clin Immunol 2009; 124:1229.

Inhaled Steroid

Two randomized controlled trials support the efficacy of inhaled glucocorticoids during pregnancy.

• One study - 84 pregnant women who were managed with or without inhaled beclomethasone after discharge following an asthma hospitalization Use of this medication significantly decreased the rate of readmission for asthma (12 Vs 33 %), and no adverse events or outcomes were reported.

Wendel PJ, Ramin SM, Barnett-Hamm C, et al. Asthma treatment in pregnancy: a randomized controlled study. Am J Obstet Gynecol 1996; 175:150.

Inhaled Steroid

• A more recent study compared inhaled beclomethasone to theophylline in the management of moderate asthma during pregnancy .

• Although exacerbation rates were similar in the two groups, pulmonary function was better in the beclomethasone group and fewer patients in the beclomethasone group discontinued therapy due to side effects.

Dombrowski MP, Schatz M, Wise R, et al. Randomized trial of inhaled beclomethasone dipropionate versus theophylline for moderate asthma during pregnancy. Am J Obstet Gynecol 2004; 190:737.

Anticholinergic agents

• Fetal tachycardia can occur with the systemic administration of atropine to the mother. But the minimal chronotropic effect of inhaled ipratropium in the mother suggests that the inhaled preparation should have negligible chronotropic effects on the fetus.

• Gestational animal studies are also reassuring for ipratropium. • Inhaled ipratropium, the most commonly used drug in this

category, is felt to be safe during pregnancy .

National Asthma Education and Prevention Program Expert Panel Executive Summary Report: Guidelines for the Diagnosis and Management of Asthma - Update on Selected Topics 2002. National Institutes of Health, National Heart, Lung, and Blood Institute, Publication No. 02-5075, 2002. www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf (Accessed on March 1, 2006).

Methylxanthines

• Extensive clinical experience suggests that theophylline

and its ethylenediamine complex, aminophylline, do not increase the risk of adverse effects during pregnancy .

Stenius-Aarniala B, Riikonen S, Teramo K. Slow-release theophylline in pregnant asthmatics. Chest 1995; 107:642.Neff RK, Leviton A. Maternal theophylline consumption and the risk of stillbirth. Chest 1990; 97:1266.

Methylxanthines

• Inhaled glucocorticoids have been shown to be more effective than theophylline for persistent asthma in non-pregnant patients and at least as effective as theophylline with fewer side effects in pregnant patients .

• Theophylline could be considered as an add-on therapy to inhaled glucocorticoids for pregnant women if needed .

Dombrowski MP, Schatz M, Wise R, et al. Randomized trial of inhaled beclomethasone dipropionate versus theophylline for moderate asthma during pregnancy. Am J Obstet Gynecol 2004; 190:737.National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Asthma and Pregnancy Working Group. NAEPP expert panel report. Managing asthma during pregnancy: recommendations for pharmacologic treatment-2004 update. J Allergy Clin Immunol 2005; 115:34.

Alterations in drug metabolism

Two changes of potential clinical importance in the bioavailability and metabolism of theophylline during pregnancy.:

1. Decreased binding to albumin results in an increased proportion of free drug in the circulation the total (free plus bound) theophylline concentration falls target plasma levels during pregnancy are 8 to 12 rather than 10 to 15 micrograms/mL.

2. Clearance of theophylline appears to decrease during the 3rd trimester, reduction in the maintenance dose .

With an IV aminophylline infusion during the 3rd trimester, for example, the loading dose of 5 to 6 mg/kg is unchanged, but the maintenance infusion rate is decreased from 0.9 mg/kg/hr to approximately 0.5 mg/kg/hr; the dose is then adjusted to maintain the desired plasma level of 8 to 12 micrograms/mL.

Connelly TJ, Ruo TI, Frederiksen MC, Atkinson AJ Jr. Characterization of theophylline binding to serum proteins in pregnant and nonpregnant women. Clin Pharmacol Ther 1990; 47:68.Carter BL, Driscoll CE, Smith GD. Theophylline clearance during pregnancy. Obstet Gynecol 1986; 68:555.

• Like SABA&LABA, theophylline can also inhibit uterine muscle contraction in vitro. • This effect is presumably mediated by an inhibitory

action of increased c AMP (due to theophylline-induced phosphodiesterase inhibition) on uterine smooth muscle, but has not been shown to be clinically important.

Leukotriene Modifiers

• Little experience with use in pregnancy

• Given orally for maintence not effective in acute setting• Often used in conjunction with oral corticosteroids to

obtain minimal steroid dose.• Ducharme in 2002 reviewed all randomized trials

conducted through 2001• Concluded these agents only slightly improved control

Leukotriene modifiers • The first prospective, controlled study of the use of

leukotriene receptor antagonists in pregnancy followed 96 women taking these medications

122 women taking SABAs only, and 346 women without asthma

No increase in major birth defects or adverse outcomes was detected in the offspring of patients receiving these medications.

Bakhireva LN, Jones KL, Schatz M, et al. Safety of leukotriene receptor antagonists in pregnancy. J Allergy Clin Immunol 2007; 119:618..

Leukotriene modifiers • A subsequent study with similar design described 180

montelukast-exposed pregnancies compared to 180 disease matched controls and 180 pregnancies in non-asthmatic women.

did not appear to increase the baseline rate of major malformations.

• Larger studies are needed to detect small increases in adverse pregnancy outcomes or rare birth defects.

Sarkar M, Koren G, Kalra S, et al. Montelukast use during pregnancy: a multicentre, prospective, comparative study of infant outcomes. Eur J Clin Pharmacol 2009; 65:1259

Leukotriene Modifiers

1. Animal data on zafirlukast have shown no teratogenicity .2. No adequate and well–controlled studies of zileuton

animal studies have not been reassuring .3. Use of montelukast In preference to the other leukotriene

modifiers, and would reserve this agent for add-on therapy to inhaled glucocorticoids, especially in patients who had a good response to this medication prior to pregnancy .

National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Asthma and Pregnancy Working Group. NAEPP expert panel report. Managing asthma during pregnancy: recommendations for pharmacologic treatment-2004 update. J Allergy Clin Immunol 2005; 115:34.

Immunotherapy

• The initiation of allergen immunotherapy is not recommended during pregnancy based upon risk-benefit considerations . The risk of systemic reactions.

• Allergen immunotherapy can be continued during pregnancy in patients already receiving it .

Breathing for Two. A Guide to Asthma During Pregnancy. Asthma & Allergy Network Mothers of Asthmatics (AANMA), 2003.

Management

Acute Exacerbation

The most common cause of asthma exacerbation Discontinuation of drugs Viral infections

SUMMARY

• BA worsens during pregnancy in a third of patients, improves in a third, and is unchanged in a third.

• Severity prior to pregnancy is related to asthma severity during pregnancy.

• Asthma exacerbations affect 20 to 36 % of pregnant asthmatic patients and tend to occur during the middle trimester.

• Gestational asthma is associated with a relatively small but statistically significant increase in pregnancy complications, such as perinatal mortality, preeclampsia, and preterm delivery.

• Appropriate therapy and good asthma control probably minimize these complications.

Thank You