National Asthma Education Program Report of the Working Group on Asthma and Pregnancy MANAGEMENT OF ASTHMA DURING PREGNANACY NATIONAL INSTITUTES OF HEALTH National Heart, Lung, and Blood Institute Report of the Working Group on Asthma and Pregnancy Management of Asthma During Pregnancy NATIONAL INSTITUTES OF HEALTH National Heart, Lung, and Blood Institute National Asthma Education Program Public Health Service U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NIH Publication No. 93-3279 September 1993 TABLE OF CONTENTS National Asthma Education Program Coordinating Committee vi Working Group on Asthma and Pregnancy vii FOREWORD ix EXECUTIVE SUMMARY 1 CHAPTER 1: OVERVIEW AND INTRODUCTION 5 CHAPTER 2: DEFINITION, PATHOGENESIS, AND DIAGNOSIS OF ASTHMA 7 Definition 7 Pathogenesis 7 Airway Inflammation 7 Epithelial Injury 7 Neural Mechanisms 7 Intrinsic Smooth Muscle Abnormalities 7 Airway Geometry 7 Pathophysiology of Exacerbations of Asthma 7 Diagnosis 8 CHAPTER 3: PHYSIOLOGY OF PREGNANCY AND INTERACTIONS WITH ASTHMA 11 Maternal Physiology and Impact on Fetal Oxygenation 11 Respiratory System Changes 11 Cardiovascular System Changes 12 Circulatory System Changes 13 Fetal Response to Maternal Critical Illness 13 Fetal Management 13 The Effect of Asthma on Mother and Fetus 14 Epidemiologic Studies 14 Mechanisms 14 Effects of Pregnancy on Asthma 14 Epidemiology 14 Other Clinical Observations 14 Mechanisms 15 CHAPTER 4: ASTHMA DRUGS IN PREGNANCY AND LACTATION 17 Physiologic Changes in Pregnancy Affecting Drug Distribution 17 Breast Feeding 18 How Drug Therapies Are Evaluated 18 Animal Data 18 Human Data 18 The FDA Categories 18 Asthma Drugs: Summaries of Findings 18 Anti-Inflammatory Agents 18 Bronchodilators 19 Antihistamines 20 Decongestants 20 Immunotherapy/Environmental Agents 20 Asthma Drugs: Human and Animal Data 21 Anti-Inflammatory Agent: Corticosteroids 21 Anti-Inflammatory Agent: Cromolyn Sodium 21 Anti-Inflammatory Agent: Nedocromil Sodium 22 Bronchodilator: Beta-Adrenergic Agonists (Beta2-Agonists) 22 Bronchodilator: Nonselective Beta-Agonists 22 Bronchodilator: Theophylline 23 Bronchodilator: Anticholinergics 23 Antihistamines 23 Decongestants 24 CHAPTER 5: FOUR COMPONENTS OF THE MANAGEMENT OF ASTHMA DURING PREGNANCY AND LACTATION 25 Introduction 25 Goals of Therapy for Pregnant Women 25 Principles of Therapy for Pregnant Women 25 Component 1: Objective Measures for Assessment and Monitoring 25 Maternal Lung Function 25 Fetal Monitoring 26 Component 2: Measures To Avoid or Control Asthma Triggers 27 Environmental Control 27 Immunotherapy 28 Vaccines 28 Component 3: Pharmacologic Therapy 28 General Principles of Pharmacologic Management 28 Preferred Medications and Selection Criteria for Pregnant Women With Asthma 29 Step-Care Pharmacologic Management of Asthma During Pregnancy 29 Management of Exercise-Induced Asthma 33 Management of Exacerbations of Asthma During Pregnancy 35 Component 4: Patient Education 46 Building a Partnership 46 The Content of Teaching 46 Psychological Support 47 CHAPTER 6: SPECIAL CONSIDERATIONS 49 Hypertension 49 Diabetes 49 Rhinitis 49 Diagnosis 49 Treatment 49 Sinusitis 50 Diagnosis 50 Treatment 50 Anaphylaxis 50 Treatment 50 REFERENCES 51 APPENDIX: PATIENT HANDOUTS 59 LIST OF TABLES Table 1. Characteristic Asthma Symptoms 8 Table 2. Common Triggers of Asthma 8 Table 3. Central Hemodynamic Changes 12 Table 4. Data Supporting a Relationship Between Poor Asthma Control and Perinatal Mortality/Morbidity 15 Table 5. Physiologic Changes During Pregnancy That May Affect the Course of Asthma 16 Table 6. Potential Fetal/Neonatal Adverse Effects of Asthma Drugs 19 Table 7. Drugs and Dosages for Asthma and Associated Conditions Preferred for Use During Pregnancy 29 Table 8. Drugs for Asthma and Associated Conditions That Generally Should Be Avoided During Pregnancy 30 Table 9. Dosages of Drugs in Acute Exacerbations of Asthma During Pregnancy 41 LIST OF FIGURES Figure 1. Respiratory Changes During Pregnancy 11 LIST OF CHARTS Chart 1. Management of Asthma During Pregnancy: Chronic Mild Asthma 31 Chart 2. Management of Asthma During Pregnancy: Chronic Moderate Asthma 32 Chart 3. Management of Asthma During Pregnancy: Chronic Severe Asthma 34 Chart 4. Acute Exacerbations of Asthma During Pregnancy: Home Management 36 Chart 5. Acute Exacerbations of Asthma During Pregnancy: Emergency Department Management 38 Chart 6. Acute Exacerbations of Asthma During Pregnancy: Hospital Management 39 Chart 7. Management of Asthma During Labor 44 Chart 8. Management of Asthma During Delivery 45 COORDINATING COMMITTEE Claude Lenfant, M.D., Chairman National Heart, Lung, and Blood Institute Lynn A. Bosco, M.D., M.P.H. Agency for Health Care Policy and Research Nancy Sander Allergy and Asthma Network/Mothers of Asthmatics Albert L. Sheffer, M.D. American Academy of Allergy and Immunology Marc L. Rivo, M.D., M.P.H. American Academy of Family Physicians Gary Rachelefsky, M.D. American Academy of Pediatrics Sheila Fitzgerald, R.N., Ph.D. American Association of Occupational Health Nurses Thomas Kallstrom, R.R.T. American Association for Respiratory Care Allan T. Luskin, M.D. American College of Allergy and Immunology Robert A. Barbee, M.D., F.C.C.P. American College of Chest Physicians Robert Rothstein, M.D. American College of Emergency Physicians Sandra Klima American Hospital Association Noreen Clark, Ph.D. American Lung Association Paul Williams, M.D. American Medical Association Barbara Santamaria, R.N., M.P.H. American Nurses' Association, Inc. Dennis Williams, Pharm.D. American Pharmaceutical Association Pamela Luna, Dr.P.H. American Public Health Association Lani Majer, M.D. American School Health Association Leslie Hendeles, Pharm.D., F.C.C.P. American Society of Hospital Pharmacists A. Sonia Buist, M.D. American Thoracic Society Barbara Hager, M.P.H., R.H.Ed., C.H.E.S. Association of State and Territorial Directors of Public Health Education Mary Worstell, M.P.H. Asthma and Allergy Foundation of America Benedict I. Truman, M.D., M.P.H. Centers for Disease Control Vivian Haines, R.N., M.S., S.N.P. National Association of School Nurses Sadako Holmes, R.N. National Black Nurses' Association, Inc. Marsha Davenport, M.D., M.P.H. National Center for Health Statistics Ruth I. Quartey, M.A., R.R.T. NHLBI Ad Hoc Committee on Minority Populations Lawrence Prograis, Jr., M.D. National Institute of Allergy and Infectious Diseases Sheila A. Newton, Ph.D. National Institute of Environmental Health Sciences Floyd Malveaux, M.D., Ph.D. National Medical Association L. Kay Bartholomew, Ed.D., M.P.H. Society for Public Health Education Joe Caliguro U.S. Department of Education Maria Segarra, M.D. U.S. Public Health Service WORKING GROUP ON ASTHMA AND PREGNANCY OF THE NATIONAL ASTHMA EDUCATION PROGRAM Allan T. Luskin, M.D., Chair Associate Professor of Medicine and Immunology/Microbiology Department of Immunology and Microbiology Rush Medical Center Chicago, Illinois Steven Clark, M.D. Professor of Obstetrics and Gynecology University of Utah Director, Intermountain Health Care Perinatal Centers Salt Lake City, Utah Marilyn Frederiksen, M.D. Associate Professor Department of Obstetrics and Gynecology Associate in Clinical Pharmacology Northwestern University Medical School Chicago, Illinois Mark Jacobs, M.D. Director, Perinatal Services Marin General Hospital Assistant Clinical Professor Department of Obstetrics, Gynecology, and Reproductive Sciences University of California San Francisco San Francisco, California Ralph Kaufman, M.D. Professor of Pediatrics and Pharmacology Wayne State University School of Medicine Director, Division of Clinical Pharmacology and Toxicology Children's Hospital of Michigan Detroit, Michigan Debra Myers, M.D. Assistant Clinical Professor of Medicine Department of Medicine, Division of Pulmonary and Critical Care Indiana University School of Medicine Indianapolis, Indiana Harold S. Nelson, M.D. Senior Staff Physician Department of Medicine National Jewish Center for Immunology and Respiratory Medicine Denver, Colorado Michael Schatz, M.D. Associate Clinical Professor of Medicine and Pediatrics University of California San Diego School of Medicine Department of Allergy Kaiser-Permanente Medical Center San Diego, California Anthony Scialli, M.D. Associate Professor of Obstetrics and Gynecology Georgetown University Medical Center Director, Reproductive Toxicology Center Columbia Hospital for Women Washington, D.C. Robert A. Wise, M.D. Associate Professor of Medicine Johns Hopkins University School of Medicine Johns Hopkins Asthma and Allergy Center Baltimore, Maryland FEDERAL LIAISON REPRESENTATIVES Donald McNellis, M.D. Special Assistant for Obstetrics Pregnancy and Perinatology Branch Center for Mothers and Children National Center for Child Health and Human Development Bethesda, Maryland Lawrence Prograis, Jr., M.D. Deputy Director Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases Bethesda, Maryland NATIONAL HEART, LUNG, AND BLOOD INSTITUTE STAFF Sydney R. Parker, Ph.D. Chief, Prevention, Education, and Research Training Branch Division of Lung Diseases Virginia Silver Taggart, M.P.H. Health Program Specialist Division of Lung Diseases Robinson Fulwood, M.S.P.H. Coordinator, National Asthma Education Program Office of Prevention, Education, and Control Suzanne Hurd, Ph.D. Director Division of Lung Diseases SUPPORT STAFF Ted Buxton, M.P.H. University Research Corporation Lisa Harris University Research Corporation Lucy Blanton Consultant, Editor The Working Group would like to thank the following consultants for their review of a draft of this report: Thomas Benedetti, M.D. Eugene R. Bleecker, M.D. Paul Greenberger, M.D. Myron Lipkowitz, M.D. Julie Graves Moy, M.D. Robert M. Ward, M.D. Nathan Wasserstrum, M.D., Ph.D. FOREWORD The many questions and uncertainties concerning the treatment of asthma during pregnancy are addressed in this report by the Working Group on Asthma and Pregnancy of the National Asthma Education Program (NAEP). The working group was made up of 12 physicians experienced in treating pregnant women with asthma and included obstetricians/gynecologists, a reproductive toxicologist, pediatric and adult pharmacologists, as well as allergists and pulmonologists. The working group met three times in the course of 18 months. This report focuses on ensuring the safety of mothers and fetuses. The working group emphasizes that the risks of uncontrolled asthma are far more dangerous to the pregnant patient with asthma and her fetus than are the risks from the medications used to control asthma. The report is designed to enable clinicians to use therapy appropriately for chronic control as well as for symptomatic relief of asthma in pregnant women. It draws heavily on the comprehensive guidelines for detecting and treating asthma that are contained in the NAEP Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma (1991). Treatment recommendations conform to those of the expert panel report but are adapted specifically for pregnant women with asthma. Topics specific to pregnant women, such as fetal monitoring, the safety of asthma drugs to the fetus, and treating asthma during labor and delivery are addressed in detail. During the development of this report, the working group recognized that the amount of empirical data available on the treatment of pregnant women with asthma is limited. The data are nevertheless sufficient to estimate the risks and benefits and to make reasonable recommendations for care. Animal data, therapeutic principles, and the expert judgment and experience of the working group were used to form the recommendations where data with human subjects were not available. The working group emphasizes that the recommendations in this report are general guidelines developed to assist clinician and patient decisions about appropriate asthma care. Specific therapeutic regimens must be tailored to individual needs and circumstances. Because the recommendations are based upon review of the scientific literature, the expert panel report of the NAEP, the expert judgment and opinion of the working group, and review and approval by all members of the NAEP Coordinating Committee, they represent a broad consensus. However, these recommendations are not to be construed either as an official regulatory document or as a document that has been endorsed by the U.S. Food and Drug Administration. This report is designed principally to provide all clinicians who care for pregnant women with new insights into asthma management. It is hoped that the report will promote the best possible asthma care for pregnant women, improve maternal health and well-being, and ensure healthy pregnancy outcomes. On behalf of the NAEP Coordinating Committee and the National Heart, Lung, and Blood Institute, I would like to acknowledge the excellent efforts of the working group and the leadership of its chair, Dr. Allan T. Luskin. Dedication, thoroughness, and a commitment to improving the care of pregnant women with asthma have characterized the development of this report. Claude Lenfant, M.D., Director National Heart, Lung, and Blood Institute Chairman, National Asthma Education Program Coordinating Committee EXECUTIVE SUMMARY Asthma is one of the most common illnesses that complicate pregnancy. Asthma may occur for the first time during pregnancy, or it may change during pregnancy; about one-third of pregnant women with asthma experience worse asthma during pregnancy, one-third remain the same, and one- third improve. In any case, pregnant women with asthma need treatment to control their asthma and thus protect their health and the health of their fetus. Asthma is a chronic, persistent disease of the airways characterized by exacerbations of coughing, wheezing, chest tightness, and difficult breathing that are usually reversible, but that can be severe and sometimes fatal. Recent studies demonstrated that inflammation is a critical factor in the pathogenesis of asthma, and therefore asthma therapy is predicated on medications to reverse and prevent this abnormality. Pregnant women with asthma require long-term management to maintain lung function and blood oxygenation to ensure the oxygen supply to the fetus. Uncontrolled asthma during pregnancy can produce serious maternal and fetal complications. Maternal complications include preeclampsia, gestational hypertension, hyperemesis gravidarum, vaginal hemorrhage, toxemia, and induced and complicated labors. Fetal complications include increased risk of perinatal mortality, intrauterine growth retardation, preterm birth, low birth weight, and neonatal hypoxia. When asthma is properly controlled, however, pregnant women with asthma can maintain a normal pregnancy with little or no increased risk to themselves or their fetuses. The goals of therapy for pregnant women with asthma are to control symptoms, including nocturnal symptoms; maintain normal or near-normal pulmonary function; maintain normal activity levels, including exercise; prevent acute exacerbations of asthma; avoid any adverse effects from asthma medications; and deliver a healthy infant. To achieve these goals, the Working Group on Asthma and Pregnancy strongly recommends that asthma be as aggressively treated in pregnant women as it is in nonpregnant women. Underestimation of asthma severity and undertreatment of exacerbations are two common errors that may lead to adverse maternal and fetal outcomes. Asthma care should be integrated with obstetric care. Effective management of asthma includes ongoing management to prevent asthma exacerbations and control chronic symptoms, and early intervention to relieve acute exacerbations. There are four integral components of effective asthma management: 1. Use objective measures for assessment and monitoring. Maternal lung function. Objective measures of lung volumes or flow rates are essential for assessing and monitoring the severity of asthma in order to make appropriate therapeutic recommendations. Using an office spirometer in the initial assessment of all pregnant patients being evaluated for asthma, and periodically thereafter as appropriate, is recommended. The single best measure of pulmonary function for assessing severity is forced expiratory volume in 1 second (FEV1). Peak expiratory flow rate (PEFR), which can be measured reliably with inexpensive portable peak flow meters, correlates well with FEV1. Home peak expiratory flow monitoring should be considered for patients who take medications daily. Regular monitoring can help detect early signs of deterioration, indicate when asthma therapy might be changed, and assess response to therapy. Women with asthma may have minimal symptoms but still have abnormal pulmonary function tests and potentially impaired fetal oxygenation. Peak flow measurement will also help differentiate asthma from other causes of dyspnea during pregnancy. Fetal monitoring. Fetal evaluation is based on objective measurements made by different techniques used according to gestational age and risk factors. Early (12 to 20 weeks) sonography provides a benchmark for progressive fetal growth. Sequential sonographic evaluations of fetal growth are indicated in second and third trimesters if asthma is moderate or severe or if growth retardation is suspected. Electronic fetal heart rate monitoring and ultrasonic determinations of fetal behavior in the third trimester should be used as needed to ensure fetal well-being. For many third-trimester patients weekly fetal assessment is sufficient, but frequency should increase if fetal problems are suspected. Daily maternal recording of fetal activity, or "kick counts," should be encouraged. Immediate antepartum fetal assessment is indicated in asthma exacerbations with an incomplete or poor response to therapy or with significant maternal hypoxemia. One reasonable approach to antepartum fetal assessment is continuous electronic fetal heart rate monitoring. When women with asthma are admitted in labor, careful fetal monitoring is essential. Intensive fetal monitoring (either continuous electronic tent auscultation) is recommended for those patients who enter labor with uncontrolled or severe asthma and with a nonreassuring admission test of fetal assessment or other risk factors. 2. Avoid or control asthma triggers. The identification and control of triggers--factors that induce airway inflammation or precipitate asthma exacerbations--are important in controlling asthma during pregnancy. Avoiding exposure to identified allergens and irritants can reduce asthma symptoms, airway hyperresponsiveness, and the need for medication. In addition, eliminating all exposure to tobacco smoke is important for pregnant women with asthma. Although immunotherapy should not be started during pregnancy, ongoing immunotherapy may be continued to reduce the response to a specifically identified allergen. 3. Establish medication plans for chronic management of asthma and for managing exacerbations using preferred medications. Chronic management of asthma. Asthma is a disease that varies among patients, and the degree of severity may change for individual patients from 1 month or season to the next or during pregnancy. Therefore, specific therapeutic regimens must be tailored to individual needs and circumstances. A stepwise approach to pharmacological therapy, in which the number and frequency of medications are increased with increasing asthma severity, permits this flexibility. Once control of asthma is sustained for several weeks or months, a reduction in therapy--a step down--can be carefully considered because the aim of pharmacotherapy is to use the least medication to maintain control. The stepwise approach presented with detailed recommendations in this report emphasizes that anything more than mild occasional asthma requires daily therapy with inhaled anti-inflammatory agents, either cromolyn sodium or beclomethasone. Further, all patients must have inhaled beta2-agonists to relieve symptoms, but it is essential that patients should not rely on frequent use of bronchodilator agents to control their asthma. An increased need for inhaled beta2-agonist is an indication that the asthma is deteriorating and anti- inflammatory therapy should be instituted or increased. An extensive review (discussed in the report) of the animal and human studies on the effects of asthma medications found few risks of adverse effects to the fetus. The known risks of uncontrolled asthma are far greater than the known risks to the mother or fetus from asthma medications. Managing exacerbations. Anticipatory or early intervention is important in treating acute exacerbations. This reduces the likelihood of an episode progressing to severe airway obstruction with impaired maternal/fetal oxygenation. Every patient needs to have a written action plan for recognizing and responding early to signs of worsening asthma. The action plan indicates how to increase medications in response to decreased PEFR or increased symptoms and how to obtain medical advice at any time. Patients should not delay seeking medical help in the emergency department or hospital if any of the following occur: therapy does not provide rapid improvement, the improvement is not sustained, there is further deterioration, the asthma exacerbation is severe, or the fetal kick count decreases. Treatment in the emergency department or hospital emphasizes intensified administration of inhaled beta2-agonists, oxygen supplementation, and the early introduction of systemic corticosteroids. Monitoring is essential because, in the presence of a moderate to severe exacerbation, deterioration can be rapid and a decrease in maternal PaO2 (especially below 60 mmHg) and fetal PaO2 can result in profoundly decreased fetal oxygen saturation and fetal hypoxia. Furthermore, fetal distress can occur even in the absence of maternal hypotension or hypoxia. Aggressive monitoring of fetal well- being is essential during critical maternal illness. Managing asthma during labor and delivery. The patient's regularly scheduled asthma medications should be continued during labor and delivery. The patient's PEFR should be taken upon admission to labor and delivery and, subsequently, every 12 hours. Asthma is often quiescent during labor and delivery. However, if asthma symptoms develop, PEFR should be monitored after asthma treatments. The patients should be kept well hydrated and be provided adequate analgesia to limit the risk of bronchospasm. Patients who have required chronic systemic corticosteroids during pregnancy should be given hydrocortisone to treat for possible adrenal suppression. Narcotic analgesics that cause histamine release should be avoided; fentanyl is a preferred agent. Lumbar epidural analgesia reduces oxygen consumption and minute ventilation during first and second stages of labor, which offers patients with asthma considerable benefit. If a general anesthetic is necessary, preanesthetic use of atropine and glycopyrrolate may provide bronchodilatory effect. For induction of anesthesia, ketamine is the agent of choice. Low concentrations of halogenated anesthetics can provide bronchodilation to the patient with asthma. For labor induction, oxytocin is the drug of choice. Prior to term, the use of 15 methyl prostaglandin F2-alpha should be avoided because it may cause bronchospasm; use of prostaglandin E2 suppositories or gel has not been reported to cause bronchospasm. For postpartum hemorrhage, oxytocin is the recommended agent. If additional agents are required, methylergonovine as well as ergonovine should be avoided if possible because they may cause bronchospasm. If their use is unavoidable, pretreatment with methylprednisolone is recommended. If prostaglandin treatment is necessary, the safest analog is E2, which is less likely to cause bronchospasm. The treatment of preterm labor in a patient already receiving asthma medication creates the risk of dangerous drug interactions. During an asthma exacerbation, uterine contractions are common and usually do not progress to preterm labor. Successful treatment of the exacerbation will usually abate the contractions. If tocolytic therapy is necessary, care should be taken to avoid the use of more than one type of beta2-agonist. Magnesium sulfate is recommended to treat uterine contractions if the patient is already taking a systemic beta2-agonist for her asthma. 4. Educate pregnant patients to develop a partnership in asthma management. It is of the greatest importance for pregnant women with asthma to understand that they are "breathing for two." These women need information on how to properly control and manage their asthma during pregnancy to reduce the risk to the fetus. Concerns of pregnant women need to be elicited and addressed. Open communication, joint development of a treatment plan by the clinician and patient, and encouragement of the family's efforts to improve prevention and treatment of the patient's symptoms will assist in promoting maternal and fetal safety and well-being. Providing support to pregnant women with asthma during this potentially anxious time is important. This report elaborates on these four components of effective asthma management for pregnant patients. It provides more detailed recommendations with supporting documentation from the scientific literature. 1 OVERVIEW AND INTRODUCTION Asthma is one of the most common illnesses that complicate pregnancy. Recent studies have shown that approximately 4 percent of pregnancies are complicated by bronchial asthma. The true prevalence may be even higher; at least 10 percent of the population appears to have nonspecific airway hyperreactivity, a hallmark of asthma. Furthermore, during the 1980's, the prevalence, morbidity, and mortality of asthma increased; specifically, from 1980 to 1989, the prevalence of asthma increased by 60 percent. This major national health problem stimulated the launching of the National Asthma Education Program; this report is one of its endeavors to alter these trends and to help persons with asthma live normal lives. Uncontrolled asthma has serious maternal and fetal complications. With uncontrolled asthma there is an increased risk of perinatal mortality, premature and/or low birth weight infants, and preeclampsia. Asthma may begin or be exacerbated during pregnancy, and pregnancy may adversely affect the course of asthma in about one-third of the pregnant women with asthma. Therapy for medical conditions complicating pregnancy may affect the control of asthma, and therapy for asthma may influence the pregnancy or complicating conditions such as diabetes and hypertension. Nevertheless, most pregnant women with asthma can successfully control their asthma and have a healthy baby. Proper control of asthma should allow a woman with asthma to maintain a normal pregnancy with little or no increased risk to herself or her fetus. A number of myths have complicated the delivery of appropriate asthma care during pregnancy. On one hand are notions that asthma is uncommon, mild, or only a minimally inconvenient illness, or that asthma is a psychological problem. On the other hand are beliefs that asthma necessitates severe limitations on activities or that asthma requires potentially dangerous medicine for control. There is a perception among the lay population that all medicine is harmful during pregnancy. However, concerns about pharmacotherapy must be balanced by an understanding of the significant adverse effects of uncontrolled asthma. Women with asthma may have minimal symptoms but still have abnormal pulmonary function tests and potentially impaired fetal oxygenation. Patients will often be more receptive to taking appropriate medication if they understand the importance of maintaining fetal oxygenation--that the pregnant woman is "breathing for two." Traditionally, asthma therapy was characterized by reliance on symptomatic therapy with bronchodilators. This reflects the view of asthma as an intermittent acute illness that is primarily a bronchospastic event. However, recent pathophysiological insights more clearly define the dominant role of chronic airway inflammation in contributing to bronchial hyperreactivity and exacerbations of reversible airway obstruction. Thus asthma is now viewed as a chronic disease characterized by acute exacerbations. Therapy should focus on treating the underlying chronic inflammation with specific anti-inflammatory therapy. Control of inflammation should minimize or eliminate the acute exacerbations and dramatically decrease the morbidity and mortality of the illness. Patients with asthma who are pregnant need asthma treatment. Therefore, pregnant women and women attempting to become pregnant should receive pharmacologic and nonpharmacologic treatments to safely treat asthma and help them reach realistic goals for their health and the health of their children. Asthma therapy for pregnant women has clear-cut goals. These include control of symptoms, with no nocturnal awakenings due to asthma, no limitation of activities including exercise, normal or near-normal maternal pulmonary function tests and oxygenation, prevention of exacerbations of asthma, no emergency department visits or hospitalizations, and use of convenient therapy with minimum side effects for mother and fetus. This report emphasizes the importance of a good working relationship among the patient, her family, and her clinician(s). It also provides assistance to the clinician in providing the necessary education to the mother so that she will understand the goals of therapy, appropriately monitor her condition, and optimally use the various therapeutic options. The National Asthma Education Program has previously published a comprehensive Expert Panel Report: Guidelines for Diagnosis and Management of Asthma. The report of the Working Group on Asthma and Pregnancy draws heavily on this original report. More detailed information and references concerning many aspects of the pathophysiology, diagnosis, and treatment of asthma may be found in the expert panel report. The report of the Working Group on Asthma and Pregnancy is designed to enable the clinician to use therapy appropriately for chronic control of asthma as well as symptomatic improvement. The report discusses the pathophysiology of asthma that underlies the therapeutic recommendations. Monitoring of pulmonary function and appropriate prenatal care will assist in assessing severity of asthma and response to therapy, predicting impending exacerbations, and detecting a fetus at risk. During the development of this report on asthma and pregnancy, the working group recognized that there is a limited amount of empirical data available on the treatment of pregnant women with asthma. However, there are sufficient data to assess risks and benefits and to make reasonable recommendations for care. Where empirical human data were not available, animal data, therapeutic principles, and the expert judgment and experience of the working group were used to form the recommendations. Treatment recommendations in general conform to those of the Expert Panel on the Management of Asthma, as adapted for pregnant women. The Working Group on Asthma and Pregnancy believes that the implementation of the recommendations in this report will increase maternal health and well-being and significantly diminish perinatal morbidity and mortality. 2 DEFINITION, PATHOGENESIS, AND DIAGNOSIS OF ASTHMA DEFINITION Although the typical clinical syndrome of asthma--episodic cough, wheezing, and dyspnea with reversible airflow obstruction--is not difficult to recognize, asthma may present with atypical symptoms such as isolated cough, chest discomfort, or exertional dyspnea. A widely accepted definition remains elusive (American Thoracic Society, 1987). The definition of asthma may overlap other related disorders such as asthmatic bronchitis and infectious bronchitis. One generally agreed-upon, working definition of asthma is as follows: Asthma is a lung disease with the following characteristics: (1) airway obstruction that is partially or completely reversible either spontaneously or with treatment; (2) airway inflammation; and (3) increased airway responsiveness to a variety of stimuli. PATHOGENESIS Asthma is characterized by airway hyperresponsiveness with exaggerated bronchoconstriction in response to many physical, chemical, and pharmacologic agents. Airflow obstruction with wheezing can occur after exposure to allergens, environmental irritants, viral respiratory infections, cold air, or exercise. Virtually all people with asthma have airway hyperresponsiveness, which often correlates with the clinical severity of the disease. Many individuals without overt symptoms of asthma can exhibit airway hyperresponsiveness, but they usually show less response to provoking agents. Several mechanisms have been proposed to explain airway hyperresponsiveness in asthma, including airway inflammation, abnormalities in bronchial epithelial integrity, alterations in autonomic neural control of airways, changes in intrinsic bronchial smooth muscle function, alterations in the volume and composition of the airway liquid lining layer, defects in control of bronchial blood flow, and abnormal airway geometry (Widdicombe, 1991). Airway Inflammation Airway inflammation is thought to be a key factor in airway hyperresponsiveness, given the evidence suggesting the presence of airway inflammation in individuals with even mild asthma. Cellular infiltrates of eosinophils, neutrophils, lymphocytes, mast cells, and macrophages are present. The release of inflammatory mediators is thought to lead to the migration and activation of more inflammatory cells, destruction of the epithelial cell layer integrity, abnormalities of autonomic neural control of airway tone, changes in mucociliary function, and increased airway smooth muscle responsiveness. Epithelial Injury Desquamation of epithelial cells and alteration of their barrier function as a consequence of the airway inflammatory process can lead to increased permeability to inhaled allergens and other provoking agents, impaired mucociliary clearance, impaired metabolism of peptide hormones, impaired regulation of the bronchial fluid lining layer, and increased response to cholinergic stimulation. Neural Mechanisms People with asthma have increased airway responsiveness to cholinergic stimulation. Nonspecific irritants induce bronchospasm, at least in part through stimulation of vagal pathways. It has also been postulated that there is abnormal local release of neuropeptides that leads to defective smooth muscle relaxation, mucosal vascular congestion, and edema. Intrinsic Smooth Muscle Abnormalities Although airway smooth muscle is clearly hypertrophied in asthma, in vitro studies have failed to show increased constriction to pharmacologic stimulation. There may, however, be impaired relaxation characteristics of the airway smooth muscle or failure of normal control mechanisms in vivo. Airway Geometry Narrowing of the airway lumen by bronchial mucosal edema, inflammatory cellular infiltrates, excess mucus and fluid, and smooth muscle hypertrophy or constriction may contribute to airway hyperresponsiveness. The tendency for the airway to close and to increase airway resistance with shortening of the surrounding smooth muscle is enhanced by the narrowed airway lumen. Normally, inflation of the lung leads to forces that tend to open airways through peribronchial attachments to alveolar septa. Peribronchial edema and inflammatory infiltration reduce the effectiveness of these alveolar septal attachments to maintain airway patency. Pathophysiology of Exacerbations of Asthma Exacerbations of asthma are acute or subacute episodes of progressively worsening shortness of breath, cough, wheezing, chest tightness, or some combination of these symptoms. Exacerbations are characterized by decreases in expiratory airflow. Airway smooth muscle contraction that results in airway obstruction is a primary abnormality in asthma. Other physiological changes also contribute to the clinical findings characteristic of asthma exacerbations.  Airways narrow because of bronchospasm, mucosal edema, and mucus plugging. Air is trapped behind peripheral small airways that become closed.  Functional residual capacity rises because of airway closure and tonic contraction of inspiratory muscles. Hyperinflation helps keep airways open, but breathing requires more effort.  Accessory muscles of respiration are used to maintain ventilation.  Hypoxemia occurs during severe exacerbations because of mismatching of ventilation and perfusion.  Hypercapnia may occur during life-threatening exacerbations because of respiratory muscle failure. Respiratory muscle failure is the consequence of increased work of breathing and the impaired mechanical advantage of the respiratory muscles in the hyperinflated condition.  Pulmonary vascular resistance may increase due to hypoxemia and hyperinflation.  Negative pleural pressures become more negative as lung hyperinflation occurs; this is manifested by pulsus paradoxus. DIAGNOSIS Asthma may present for the first time during pregnancy, and the diagnosis may be confused with the physiologic dyspnea of pregnancy. The diagnosis of asthma is based on a compatible medical history, physical examination, and laboratory test results. Other disorders with similar clinical presentations may need to be excluded when the diagnosis is in question. Diagnosis of asthma focuses on establishing episodic airway obstruction and the reversibility of the obstruction. People with asthma typically have a history of episodic cough, chest tightness, wheezing, and dyspnea. Asthma may also present with atypical symptoms such as an isolated cough, chest pain, recurrent bronchitis, or exertional dyspnea. Characteristic chest symptoms that support the diagnosis of asthma are listed in table 1. Common triggers of asthma symptoms are listed in table 2. The history is frequently also positive for rhinitis, sinusitis, or flexural eczema. Often there is a family member with asthma or allergies. During an acute exacerbation, the physical examination may reveal hyperinflation, prolonged duration of expiration, wheezing, and use of accessory respiratory muscles. The physical examination may be normal between exacerbations. Diagnostic pulmonary function findings include airflow obstruction on spirometry that is reversible. The failure to respond immediately to an inhaled bronchodilator does not exclude the diagnosis. Repeat spirometry after several weeks of treatment may show improvement. Home measurement of peak expiratory airflow (see Component 1: Objective Measures for Assessment and Monitoring in chapter 5) may show increased variability or decreased peak flow in association with symptoms. Methacholine challenge testing can establish the presence of airway hyperreactivity but is rarely needed to establish the diagnosis of asthma. When performed with proper monitoring, methacholine challenge testing poses no excess risk to pregnant patients. Additional studies may also be considered. No one test is appropriate for every patient. Procedures to consider are:  Complete blood count (CBC).  Chest x-ray. (This can rule out other causes of airway obstruction.)  Sputum examination and stain for eosinophilia. (Sputum eosinophilia is highly characteristic of asthma; neutrophils predominate in bronchitic sputum.)  Nasal secretion stain for eosinophils. (Neutrophilic nasal discharge is characteristic of sinusitis.)  Complete pulmonary function studies, including inspiratory and expiratory flow volume curve. (These may reveal upper airway problems that simulate asthma.)  In certain circumstances, selected skin (in vivo) or in vitro tests to determine specific IgE antibodies to common inhalant allergens (useful for establishing the role of allergy in a pregnant patient's asthma and for guiding advice on specific environmental control measures).  Rhinoscopy.  Sinus x-rays.  Monitoring of esophageal pH for gastroesophageal reflux. Although recurrent episodes of cough and wheezing are almost always due to asthma, the clinician needs to be aware of other causes of airway obstruction leading to wheezing. These include:  Upper airway mechanical obstruction  Laryngeal dysfunction  Chronic bronchitis  Emphysema  Pulmonary edema (cardiac or noncardiac)  Pulmonary infiltrates with eosinophilia  Infectious bronchitis and bronchiectasis  Cystic fibrosis  Antibody deficiency obstruction. In addition, there are such conditions as pulmonary embolism, hyperventilation syndrome, and physiologic dyspnea of pregnancy that may mimic symptoms of asthma. When the diagnosis of asthma is in question, it is appropriate to refer the patient to a specialist in asthma care (usually an allergist or pulmonologist). 3 PHYSIOLOGY OF PREGNANCY AND INTERACTIONS WITH ASTHMA This chapter focuses on the impact of maternal physiology on fetal oxygenation, on the effect of asthma on mother and fetus, and, finally, on the effect of pregnancy on asthma. Maternal Physiology and Impact on Fetal Oxygenation Changes in maternal respiratory, cardiovascular, and circulatory systems during pregnancy influence fetal oxygenation and acid base status. This section looks at these physiological alterations and their clinical implications. Respiratory System Changes A relative hyperventilation during pregnancy is seen beginning in the first trimester, with minute ventilation increasing up to 48 percent by term. This change is due to an increase in tidal volume; respiratory rate is relatively unchanged during pregnancy, so tachypnea in pregnancy (respirations more than 20 per minute) is an abnormal finding that must be investigated. Increased tidal volume change is due principally to increased placental progesterone production, which also accounts for a sensation of shortness of breath ("dyspnea of pregnancy") that is common in pregnancy. The hyperventilation of pregnancy is associated with significant changes in arterial blood gas with a resting arterial carbon dioxide tension (PCO2) below 35 mmHg. This chronic respiratory alkalosis is partially compensated for by increased renal bicarbonate excretion. Total oxygen consumption and basal metabolic rate also increase by 20 percent and 15 percent, respectively, accounting for increased maternal oxygen tension, which is also common in normal pregnancy. Normal values of PO2 range from 106 to 108 mmHg during the first trimester and decrease slightly in the third trimester (Prowse & Gaensler, 1965; Templeton & Kelman, 1976). Oxygenization is significantly influenced by postural effects. Twenty-five percent of pregnant women experience arterial oxygen tensions of less than 90 mmHg in the supine position, and there is also an increased likelihood of developing increased alveolar-arterial oxygen gradients in the supine, compared to the upright, position. In terms of pulmonary function, the following are seen by term: a decrease in residual volume, functional residual capacity, expiratory reserve volume, and total lung capacity; an increase in inspiratory capacity; and no change in vital capacity or forced expiratory volume in 1 second (FEV1) (Bonica, 1972; see figure 1). All the changes just discussed have the potential for profound impact upon the clinical interpretation of pulmonary function studies and blood gas measurements in the pregnant woman with asthma and must be clearly kept in mind in the clinical interpretation of such data. In general, however, those measurements of pulmonary function in common clinical use (such as respiratory rate or FEV1) do not change with pregnancy, so any changes in these measures should be considered abnormalities and treated as such. Recent information suggests that during painful labor there is relative hypoventilation between contractions resulting in decreased maternal PO2. With normal pulmonary function, the fetal implications of this phenomenon are negligible. However, this information forms a rationale for the liberal use of oxygen in laboring patients with any degree of respiratory impairment. Maternal oxygen saturation must remain greater than 95 percent to assure adequate fetal oxygenation (Clark, 1990). Cardiovascular System Changes During normal pregnancy, resting cardiac output is significantly increased by 6 weeks gestation, peaking at 30 to 50 percent over nonpregnant values by the early part of the third trimester (Clark et al., 1989). This increase is a result of increases in both heart rate and stroke volume and is sustained throughout the pregnancy (see table 3). In the third trimester, cardiac output is significantly decreased in either the supine or standing positions. Up to 10 percent of women may experience the "supine hypotensive syndrome," a marked drop in blood pressure resulting from venacaval occlusion in the supine position (Holmes, 1960). Supine hypotension can have important maternal hemodynamic consequences and, because of decreased uterine perfusion, may result in fetal hypoxia and bradycardia. Thus recumbent pregnant women should avoid the supine position and favor the lateral decubitus or lateral tilt position. Further significant increases in cardiac output are seen in the peripartum period. Labor is associated with an additional 1 to 2 liters per minute by the second stage (Ueland & Hansen, 1969). This increase may be minimized by having the patient labor in the lateral recumbent position with epidural anesthesia (Clark et al., 1991). In the immediate postpartum period, cardiac output is increased further, by up to 40 to 50 percent (Ueland et al., 1969), as a result of the "autotransfusion" phenomenon--the release of venacaval obstruction and expulsion of blood from the utero/placental bed into the central circulation. Thus the period of maximum risk for patients with compromised cardiovascular function is during the peripartum period. Cesarean section does not appear to reduce this risk. Circulatory System Changes Blood volume. Blood volume increases markedly in pregnancy, with an increase in plasma volume at term averaging 40 to 50 percent over nonpregnant values (Clark et al., 1989). This increase, due to estrogen stimulation of aldosterone, begins as early as 4 to 6 weeks gestation, plateaus at approximately 32 to 34 weeks gestation, and then remains unchanged until delivery. There is a concomitant increase in red cell mass, erythropoiesis being stimulated by chorionic somatomammotrophin, progesterone, and possibly prolactin. Because red cell mass is increased 20 to 25 percent as opposed to the greater increase in plasma volume, a "physiologic anemia" of pregnancy may be produced. In absolute terms, it is estimated that blood volume in single pregnancies is increased 1,600 cc, with an average 2,000-cc increase observed by 32 weeks in twin gestations. Blood pressure. Systolic and diastolic arterial blood pressure decrease until midpregnancy and gradually return to nonpregnant values by term (Wilson et al., 1980). These changes appear to be secondary to hormonally mediated decreases in systemic vascular resistance. Thus blood pressures that might be considered frankly hypotensive in the adult male may be normal in the pregnant female, especially during the second trimester of pregnancy. In evaluating blood pressure in the seriously ill pregnant patient with asthma, a comparison of prenatal blood pressure records is important. Other hemodynamic changes. Systemic vascular resistance falls by the second trimester, rising toward normal by late third trimester. However, even in the late third trimester, systemic vascular resistance is decreased by 20 percent compared to nonpregnant controls (Clark et al., 1989). Similarly, pulmonary vascular resistance falls 35 percent by late pregnancy compared to nonpregnant values. Left ventricular stroke work index, pulmonary capillary wedge pressure, and central venous pressure all remain unchanged. The pulmonary-capillary-wedge pressure/colloid-oncotic pressure gradient decreases significantly, however, by the third trimester of pregnancy. This predisposes the pregnant woman to pulmonary edema, either because of increased intravascular pressure (i.e., increased fluid overload) or increased pulmonary capillary permeability. Fetal Response to Maternal Critical Illness In the presence of maternal critical illness, such as an acute exacerbation of asthma, the maternal arterial PO2 may fall from its normal value of near 106 mmHg. Because the fetus operates on the steep portion of the oxygen dissociation curve (normal fetal venous PO2 is close to 33 mmHg), decreases in maternal and fetal PaO2 (especially below 60 mmHg) can result in profoundly decreased fetal oxygen saturation and fetal hypoxia. Administration of oxygen to the mother produces only small increases in fetal PaO2. For example, as the maternal PaO2 increases from 91 to 583 mmHg, fetal PaO2 rises only from 11 to 16 mmHg. However, because the fetus is on the steep portion of the hemoglobin oxygen dissociation curve, a small change in fetal PaO2 produces significantly increased fetal oxygen saturation and may be of benefit to the marginally hypoxic fetus (Motoyama et al., 1967; Sobrevilla et al., 1971). This may be especially true if there are problems with fetal-placental function such as intrauterine growth retardation. Thus, aggressive monitoring of fetal well-being is essential during critical maternal illness. Adequacy of uterine blood flow is another important consideration for the fetus of a seriously ill mother. Near term, uterine blood flow approaches 500 cc per minute, accounting for approximately 10 percent of total maternal cardiac output. Circulation to the placental cotyledons accounts for 85 to 90 percent of uterine blood flow at term. The uterine arteries exhibit remarkably little capacity for autoregulation. Thus as systemic arterial pressure falls, so does uterine and placental blood flow. In addition, maternal hyperventilation and hypocarbia may cause uterine vasospasm, decreasing uterine blood flow. In the hypotensive or hypoxic mother, compensatory vasodilation aimed at maintaining circulation to vital organs such as the heart and brain will decrease uterine blood flow even further. It is therefore not surprising that maternal hypotension or significant hypoxia of any etiology may be first brought to the clinician's attention by an abnormal fetal heart rate pattern indicating fetal distress. Because maternal compensatory mechanisms will tend to maintain systemic arterial pressure and oxygenation of vital maternal organs at the expense of uterine blood flow, fetal distress can occur even in the absence of maternal hypotension or hypoxia. Thus the fetus acts as a built-in oximeter; in the absence of fetal heart rate abnormalities, clinically significant maternal hypoxia or hypotension are highly unlikely (Clark, 1990). Aggressive monitoring of fetal well-being is essential during critical maternal illness. Although abrupt and profound maternal cardiopulmonary decompensation, manifested as fetal bradycardia, should be readily apparent, more subtle deterioration of maternal condition may produce only diminished beat-to-beat fetal heart rate variability and/or subtle hypoxic decelerations. Thus even in a medical or surgical intensive care unit setting, continuous electronic monitoring of the fetal heart rate, along with appropriate interpretation, is important after the beginning of the third trimester. Fetal Management Intrauterine growth retardation and adverse perinatal outcome have been associated with asthma during pregnancy. For this reason, all patients with moderate or severe asthma or uncontrolled asthma during pregnancy should have serial ultrasound assessment of fetal growth as well as antepartum fetal heart rate assessment during the late third trimester of pregnancy. The Effect of Asthma on Mother and Fetus Epidemiologic Studies Two large epidemiologic studies published in the early 1970's most clearly define the potential adverse effects of maternal asthma on pregnancy and the infant. One study (Bahna & Bjerkedal, 1972) described pregnancy outcomes in 381 women with asthma compared to a control population of 112,530 pregnant women with no medical illness. There was a statistically significant increase in preterm births and low birth weight infants, decreased mean birth weight, increased neonatal mortality, and increased neonatal hypoxia in the pregnancies of women with asthma compared to control pregnancies. The study also found a statistically significant increase in hyperemesis gravidarum, vaginal hemorrhage, and toxemia as well as a significant increase in induced and complicated labors in pregnant women with asthma versus control pregnant women. The study did not find an increased incidence of congenital malformations. The second study (Gordon et al., 1970) compared the pregnancy outcome of 277 women with asthma to the pregnancy outcome of the entire cohort population of 30,861 women. This study found a statistically significant increase in perinatal mortality in pregnant women with asthma versus pregnant women without asthma. Neonatal mortality was not specifically reported in this series. Maternal "chronic hypertensive disease" was present in three of the eight cases of fetal death. The data also suggested that pregnant women with severe asthma were at particularly high risk. Subsequent controlled studies have reported increases in low birth weight infants (Lao & Huengsburg, 1990), chronic hypertension (Dombrowski et al., 1986), and preeclampsia (Stenius-Aamiala et al., 1988) in pregnant women with asthma compared to pregnant women without asthma. In addition to fetal morbidity and mortality, severe asthma during pregnancy may be a cause of maternal mortality (Gordon et al., 1970; Schaefer & Silverman, 1961; Williams, 1967). These epidemiological studies have found that pregnant women with asthma have increased risk of perinatal mortality, prematurity, intrauterine growth retardation, gestational hypertension, and other adverse effects. These studies, however, do not define the mechanisms of the increased risk. Mechanisms Definition of the mechanisms of asthma's adverse effects on pregnancy would allow institution of optimal intervention strategy. Potential explanations for the adverse effects of maternal asthma on pregnancy and the neonate include: (1) poor asthma control, (2) asthma medications (see chapter 4), (3) increased prevalence of cigarette smoking among pregnant women with asthma versus pregnant women without asthma (Dombrowski et al., 1986), (4) extrapulmonary autonomic nervous system abnormalities, such as uterine muscle hyperreactivity (Bertrand et al., 1985), and (5) an increased proportion of African Americans among asthma patients (Centers for Disease Control, 1990a) with associated excess perinatal morbidity (Centers for Disease Control, 1990b). The published data do not fully define the mechanism(s) of maternal asthma's potential adverse effects on pregnancy and the infant. However, available information does suggest that poor asthma control may be the most important factor (see table 4). The information available also supports the important generalization that adequate asthma control during pregnancy is important in improving maternal/fetal outcome. Effects of Pregnancy on Asthma Epidemiology A number of studies suggest that the course of asthma may change during pregnancy. In a combined series of 1,087 patients from the literature, the course of asthma was reported to improve in 36 percent, worsen in 23 percent, and remain unchanged in 41 percent (Gluck & Gluck, 1976). However, individual studies differed substantially in their results (Gluck & Gluck, 1976). This pattern is maintained in recent studies (Gluck & Gluck, 1976; Juniper et al., 1989; Schatz et al., 1988a; Stenius-Aamiala et al., 1988; White et al., 1989), in which 18 to 69 percent of patients improved while 6 to 42 percent worsened. There are at least two reasons for this variability: (1) the method by which the course of asthma was assessed and (2) the asthma severity of the population studied. Review of the data suggests that women with severe asthma prior to pregnancy are more likely to deteriorate during pregnancy (Gluck & Gluck, 1976; White et al., 1989). The variable effect of pregnancy on the course of asthma appears to be more than random fluctuations in the natural history of the disease because the changes generally revert toward the prepregnancy level of severity within 3 months postpartum (Schatz et al., 1988a). It is also of interest that asthma severity is often consistent among successive pregnancies in individual women (Schatz et al., 1988a; Williams, 1967). Other Clinical Observations A study that prospectively evaluated methacholine sensitivity in 16 pregnant women with asthma (Juniper et al., 1989) found a twofold improvement (decrease) in airway responsiveness during pregnancy compared to preconception and postpartum. An associated improvement in clinical asthma severity, as indicated by a reduction in minimum medication requirements, was also observed. Individually, 11 of 16 subjects demonstrated improved airway responsiveness. Change in responsiveness was not closely related to serum concentrations of progesterone or estriol. Additional observations have identified factors contributing to worsening asthma during pregnancy. Upper respiratory tract infections appear to be the most common precipitants of asthma exacerbations during pregnancy (Williams, 1967). Patient noncompliance with medical regimens may also be associated with poor asthma control during pregnancy, especially among adolescents (Apter et al., 1989). The peak incidence of exacerbations appears to be between the 24th and 36th weeks of gestation (Gluck & Gluck, 1976), particularly in women whose asthma worsens with pregnancy (Schatz et al., 1988a). In contrast, women with asthma, in general, tend to experience fewer symptoms during weeks 37 to 40 of pregnancy than during any prior 4-week gestational period (Schatz et al., 1988a). Finally, asthma generally remains quiescent during labor and delivery. Ninety percent of 360 women with asthma in one study had no symptoms of asthma at all during labor and delivery (Schatz et al., 1988a). Of those who did, approximately half required no acute treatment, some used inhaled bronchodilators, and only two required intravenous aminophylline. Mechanisms The mechanisms responsible for the altered course of asthma during pregnancy are unknown and represent a fertile area for additional research. There are multiple biochemical, physiological, and psychological factors that could potentially ameliorate or exacerbate asthma during pregnancy (see table 5). It seems probable that the importance of individual factors varies from individual to individual, and presumably a combination of these factors determines what effect, if any, pregnancy will have on the course of asthma. 4 Asthma Drugs in Pregnancy and Lactation The effects of drugs used for asthma on fetal development and on infants who are breast fed are discussed in this chapter. When considering the possible effects of drugs and disease on pregnancy, it is important to keep in mind the background incidence of adverse pregnancy outcome in the general population. For example, congenital anomalies are recognized in 3 to 8 percent of live-born infants, miscarriage occurs in 20 to 25 percent of clinically diagnosed pregnancies, and severe mental retardation occurs in 1 to 2 percent of births. In addition, although birth defects are the most dramatic evidence of embryogenesis gone amiss, other endpoints of abnormal development are equally significant. These include spontaneous abortion (miscarriage), fetal death (stillbirth), and functional abnormalities such as impairments in the nervous or immune systems. Growth retardation, preterm labor, and other obstetric complications are also developmental problems of clinical importance. The challenge is to determine whether a drug or disease exposure increases the incidence of adverse outcome over the background incidence. It is also important to remember that drug-induced birth defects are unusual: Of the 3 to 8 percent of newborns with congenital anomalies, only 1 percent or fewer of these are attributable to drug exposures (Czeizel & Racz, 1990). PHYSIOLOGIC CHANGES IN PREGNANCY AFFECTING DRUG DISTRIBUTION With the profound physiologic changes that occur during pregnancy, it is reasonable to suppose that these changes affect the manner in which drugs are handled by the body. Pharmacokinetics is the study of drug absorption, distribution, metabolism, and elimination in the body. Although few therapeutic agents have been completely studied as to the effect of pregnancy on the drug's pharmacokinetics, the following changes have been shown to occur during pregnancy and are clinically relevant:  Reduction in plasma proteins. This is largely caused by a decrease in serum albumin concentration (Dean et al., 1980). During pregnancy, drugs bound to serum albumin show a reduction in protein binding and a corresponding increase in the available free fraction of the drug (Connelly et al., 1990; Frederiksen et al., 1986; Gardner et al., 1987). This change in protein binding implies that for certain drugs plasma concentrations should be reduced or kept at the lower end of the therapeutic range during pregnancy (Connelly et al., 1990). For example, the protein binding of theophylline decreases by 10 to 15 percent during pregnancy; therefore, the therapeutic range for theophylline needs to be modified to account for the corresponding increase in the free fraction of theophylline. During pregnancy, theophylline plasma concentrations between 8 and 12 g/mL are therapeutically equivalent to concentrations of 10 to 15 g/mL in the nonpregnant patient.  Increased total body water and plasma volume. Several studies, however, have shown that this change does not affect the volume of distribution for drugs if the weight of the patient is taken into consideration (Aldridge et al., 1981; Frederiksen et al., 1986; Gardner et al., 1987; Philipson, 1977; Philipson & Stiernstedt, 1982). Therefore, to achieve the therapeutic drug concentration usually recommended, the mg/kg dose should be calculated using the actual weight of the patient. For example, to calculate a loading dose of aminophylline or theophylline for a pregnant patient not previously receiving a methylxanthine, use the recommended 6-mg/kg regimen and the actual weight of the patient at the time therapy is instituted.  Decreased gastrointestinal motility. This change does not affect the overall absorption of even poorly absorbed drugs, such as ampicillin (Philipson, 1977); however, the time to peak drug concentration is prolonged, and the peak concentration is lower (Philipson, 1977). This may in part explain the observation that an oral dose of 500 mg of ampicillin during pregnancy gives a plasma peak concentration 40 percent lower than in a nonpregnant patient, and the peak concentration occurs approximately 1 hour later.  Altered drug elimination. Pregnancy can alter the manner in which drugs are eliminated from the body, with the greatest effect occurring in the last trimester of pregnancy. Renal elimination of drugs may increase for such drugs as theophylline, ampicillin, and cefuroxime due to the increase in glomerular filtration rate that occurs during pregnancy (Frederiksen et al., 1986; Philipson, 1977; Philipson & Stiernstedt, 1982). Metabolic elimination of drugs is less predictable; some drugs, such as methadone, have an increase in metabolic clearance (Pond et al., 1985) and others, including theophylline, have a decrease in metabolic clearance (Frederiksen et al., 1986; Gardner et al., 1987). Therefore, the elimination route and characteristics of each drug must be considered, and frequent use of therapeutic drug monitoring is indicated. Thus, because the overall elimination rate of intravenous methylxanthine decreases by 30 percent in the last trimester of pregnancy, the recommended dose for intravenously administered methylxanthine is a continuous infusion rate of 0.4 mg/kg/hr theophylline (or 0.5 mg/kg/hr aminophylline) in order to maintain serum theophylline concentrations within the range of 8-12 g/mL. As a general rule most medications administered to pregnant women will cross the placenta and can be detected in fetal blood. However, extremely large molecular weight drugs, or highly polar compounds, such as heparin, do not effectively cross the placenta in measurable amounts. Breast Feeding Nearly all medications enter breast milk by diffusion from plasma. Milk concentrations are typically very low, and it is unusual for infants to receive a dose sufficient to produce toxic effects. Recommendations concerning drugs and breast feeding have been made by the American Academy of Pediatrics Committee on Drugs (1989) and by the World Health Organization (Bennett, 1988). HOW DRUG THERAPIES ARE EVALUATED Animal Data Experimental animals differ from humans in a number of ways, including drug handling, sensitivities to drug effects, and embryonic timetables. These differences notwithstanding, animal teratology experiments can be useful in evaluating human drug risks. Animal studies are designed to maximize the response of the system to potential toxic effects of test agents. This is accomplished by using large doses; the highest dose customarily chosen is one that induces maternal toxicity. It is believed that positive results in a testing scheme using appropriate doses in at least two species, one of which is not a rodent, is sufficient to raise suspicion of human developmental risk. There are no known human developmental toxicants that would not be identified by this scheme. It follows that if an agent is appropriately tested in animals and found not to be a developmental toxicant, its potential for developmental toxicity in humans is low. Thalidomide is often given as an example for which animal testing was inadequate to identify human developmental risk. In fact, thalidomide was tested before the development of modern protocols and is not a reflection on the adequacy of current testing methods, which would have detected thalidomide's risk. Positive data in animal studies are not completely informative because it may not be possible to know whether the high doses used, maternal toxicity, or species differences were responsible for the effects on the offspring. Human Data Case reports, in which an exposure and an outcome are presented, are the most common human data available, but they cannot be used to imply cause and effect. Controlled human studies include two general designs: the cohort, in which exposed and nonexposed populations are evaluated prospectively to determine outcome, and the case control, in which affected and nonaffected subjects are evaluated retrospectively for whether or not they were exposed. Cohort studies require large numbers of exposed women to detect unusual outcomes and are often impractical and expensive. Case control studies identify outcomes of interest; however, accurate ascertainment of exposure may be difficult. With both cohort and case control studies, controlling for confounding factors, such as other exposures, ethnicity, and socioeconomic factors, is important. Human reports, when available, can be reassuring supplements to negative animal data. By themselves, human studies rarely include sufficient numbers of exposed individuals to rule out a low order increase in adverse pregnancy outcome. One of the largest human cohort drug studies during pregnancy was the National Collaborative Perinatal Project (Heinonen et al., 1977). In this investigation, women were enrolled as early as possible during pregnancy. Histories were taken for exposure to medications and other agents. As the pregnancies progressed, exposure histories were updated. The outcomes for more than 50,000 children were evaluated, and associations between exposures and birth defects were identified. As the investigators of this study noted, the large number of different exposures and the large number of different adverse outcomes made it likely that some exposures and outcomes would be associated by chance alone. Therefore, all data suggesting impact of drugs on pregnancy outcome from the National Collaborative Perinatal Project should be viewed as preliminary until independently confirmed. The FDA Categories In an effort to summarize the availability of animal and/or human developmental data on a drug, the Food and Drug Administration (FDA) uses a letter-based code (A, B, C, D, or X). A large amount of information of varying quality may not be adequately represented by a single letter designation, and the FDA category scheme is not considered very useful for making specific therapeutic decisions. ASTHMA DRUGS: SUMMARIES OF FINDINGS This section and table 6 contain summaries of the findings of studies evaluating the various asthma drugs. Information about the specific studies on which these summaries are based may be found in the subsequent section, Asthma Drugs: Human and Animal Data. Anti-Inflammatory Agents Corticosteroids. Among the most effective anti- inflammatory drugs for the treatment of asthma are corticosteroids. The primary mechanisms of action are interference with arachidonic acid metabolism and synthesis of leukotrienes and prostaglandins, prevention of directed migration and activation of inflammatory cells, and increased responsiveness of beta- receptors of airway smooth muscle. Corticosteroids can be administered parenterally (e.g., methylprednisolone, hydrocortisone), orally (e.g., prednisone, prednisolone, methylprednisolone), or as aerosols (beclomethasone, flunisolide, and triamcinolone). Chronic maternal administration of oral or parenteral (systemic) corticosteroids have been associated with decreased birth weight. Animal studies show palatal clefting in species very sensitive to this anomaly, but no increase in birth defects has appeared in humans. Three agents are available for inhalation: beclomethasone, triamcinolone, and flunisolide. Of these, the largest experience in pregnancy is with beclomethasone. Triamcinolone and flunisolide use during pregnancy has not been studied. Because of its reassuring clinical experience, beclomethasone is the preferred inhaled corticosteroid during pregnancy. Although systemic absorption of inhaled corticosteroids can occur, the low plasma levels achieved by inhalation make it unlikely that fetal effects will be seen. Neither systemic nor inhaled corticosteroid use by the mother is a contraindication to breast feeding. Cromolyn sodium. This drug is a nonsteroidal anti- inflammatory agent for the chronic management of asthma. Administered prophylactically, cromolyn sodium inhibits early- and late-phase allergen-induced airway narrowing as well as acute airway narrowing after exercise and after exposure to cold dry air and sulfur dioxide. Its mechanism of action is not fully understood, but it is thought that cromolyn sodium stabilizes and prevents mediator release from mast cells. Acceptable animal studies and human experience suggest little potential for fetal harm from cromolyn sodium. Nedocromil sodium. This is a new anti-inflammatory pyranoquinalone that appears similar in action to cromolyn sodium. Although preclinical animal data are reassuring, there is no reported experience with this agent during human pregnancy. Bronchodilators Beta2-adrenergic agonists (beta2-agonists). Beta2- agonists relax airway smooth muscle and may modulate mediator release from mast cells and basophils. Inhaled beta2- agonists are the medications of choice for initial treatment of acute exacerbations of asthma and for the prevention of exercise-induced asthma. Beta2-agonists have also been used chronically to aid in the control of persistent airway narrowing, although recent reports suggest that regularly scheduled use of beta2-agonists (as opposed to as-needed or prn use) is associated with diminished control of asthma (Sears et al., 1990). Because well-controlled asthma requires minimal use of inhaled beta2-agonist, increased use is an indication of deteriorating control. Metaproterenol (orciprenaline), albuterol (salbutamol), pirbuterol, bitolterol, and terbutaline are commonly used selective beta2-agonists. Animal studies with beta2-agonists are generally negative, although some of these agents produce anomalies at high doses. Human experience is extensive, but generally restricted to the latter part of pregnancy. There is no evidence of fetal injury from the use of these drugs systemically or by inhalation, and there is no contraindication to the use of these agents during lactation. Nonselective beta-agonists. Beta-agonists that activate both beta1 and beta2 receptors include epinephrine (adrenaline) and its isopropyl analog, isoproterenol. Epinephrine given subcutaneously in severe acute exacerbations may be considered, although other therapies are initiated first. Epinephrine is also present in some over- the-counter asthma inhalers, although its use in this manner is not recommended. Concern has been raised about uterine vasoconstriction due to the alpha-adrenergic effects of epinephrine (Briggs et al., 1990). The effects of nonselective beta2-agonists on experimental animals may be of concern; however, the occasional, episodic use of epinephrine for severe acute exacerbations is unlikely to produce chronic hemodynamic changes such as were seen in the animal studies. The positive findings of the National Collaborative Perinatal Project require confirmation before they can be considered sufficient evidence of epinephrine toxicity. Theophylline. Theophylline is the principal methylxanthine used in asthma therapy. Although its precise mechanism is not known, theophylline serves as a mild-to-moderate bronchodilator, depending upon serum concentration. When given in a sustained-release preparation, it has long duration of action and is thus particularly useful in the control of nocturnal asthma. When used in combination with usual doses of inhaled beta2-agonists, theophylline may produce additional bronchodilation. In addition, theophylline may also reduce respiratory muscle fatigue and possess some degree of anti- inflammatory activity. Theophylline use during pregnancy has been extensive and without evidence of adverse effects to the neonate when doses are guided by appropriate serum levels (not exceeding 12 g/mL). Approximately 1 percent or less of the maternal theophylline dose reaches the nursing infant; this is usually not clinically significant. Anticholinergics. Inhaled anticholinergic agents produce bronchodilation by reducing intrinsic vagal tone to the airways. Such agents also block reflex bronchoconstriction caused by inhaled irritants. Atropine, a belladonna alkaloid, is the prototype anticholinergic, but it has local and systemic adverse effects for the patient with asthma. Ipratropium, a quaternary derivative given by inhalation, lacks atropine's adverse effects. It has been shown to be effective in treating acute exacerbations when used in nebulized form. The role of ipratropium in day-to-day management of asthma has not been established. Anticholinergic agents have been used during pregnancy without adverse effects. Ipratropium produces less systemic effect than atropine and is not contraindicated in pregnancy, although it is generally not used except for patients with severe asthma. Antihistamines Antihistamines are used to block the action of histamine released during a mast cell activation in response to an allergen or other stimulus. Antihistamines are present in many over-the-counter cold and allergy remedies. Newer H1- blockers such as terfenadine and astemizole have significantly less sedative properties than older "first generation" medications. Antihistamines have not been shown to be harmful during early pregnancy, and the animal and human experience suggest little, if any, potential for human teratogenicity. It seems reasonable to choose older antihistamines for which reassuring human data exist for use during pregnancy. Although concerns have been raised about antihistamine effects on young children, there are no data establishing adverse effects due to late pregnancy or lactational use of these drugs. Antihistamines are considered compatible with breast feeding (American Academy of Pediatrics Committee on Drugs, 1989). Decongestants Decongestants are alpha-adrenergic drugs used to constrict blood vessels in the nasal mucosa. Agents in this class include oxymetazoline, phenylephrine, phenylpropanolamine, ephedrine, and pseudoephedrine. Because these drugs have alpha-adrenergic activity, there is concern about their potential to constrict the vascular supply involved in maternal-fetal gas and nutrient exchange (Smith & Corbascio, 1970); however, pseudoephedrine appears not to produce this effect at therapeutic doses. Human experience with decongestants has not produced a consistent picture of birth defects, although the National Collaborative Perinatal Project has raised questions about phenylephrine and phenylpronolomine. Immunotherapy/Environmental Agents A number of reports have appeared describing immunotherapy without apparent adverse effect on human pregnancy (Chester, 1950; Derbes & Sodeman, 1946; Heinonen et al., 1977; Jensen, 1953; Maietta, 1955; Metzger et al., 1978; Schaefer & Silverman, 1961). Anaphylaxis following immunotherapy is a potential risk to mother and fetus. Patients already receiving immunotherapy may be maintained at their current or somewhat reduced dose during pregnancy; however, it is generally advisable not to begin immunotherapy during pregnancy. The influenza vaccine is a killed virus vaccine. There have been two reports that together include 245 women vaccinated just before or during pregnancy. No adverse outcomes were attributable to the vaccine (Deinard & Ogburn, 1981; Sumaya & Gibbs, 1979). Tannic acid may be used to denature environmental cat or dust mite antigen. There are no published studies on exposure to this agent during pregnancy. Benzyl benzoate is an ascaricide used to clear dust mites from an environment. Teratogenicity tests have been negative in rats (Morita et al., 1981) and mice (Eibs et al., 1982). Boric acid is useful as an insecticide in eliminating cockroaches. Feeding boric acid to pregnant rats does not increase the incidence of adverse pregnancy outcome (Weir & Fisher, 1972). An evaluation of 253 pregnancies with early exposure to boric acid was unable to identify a significant increase in the incidence of birth defects in the offspring (Heinonen et al., 1977). ASTHMA DRUGS: HUMAN AND ANIMAL DATA Anti-Inflammatory Agent: Corticosteroids Developmental Toxicity-- Animal Data High doses of corticosteroids characteristically cause cleft palate in developing mice, rats, and rabbits, although not all steroids produce this effect in all species (Pinsky & DiGeorge, 1965; Walker, 1967, 1971). The developmental toxicity of beclomethasone in mice and rabbits is similar to that associated with other corticosteroids, consisting of increased fetal resorptions and cleft lip/palate (Esaki et al., 1976; Ohguro et al., 1970). High-dose inhalation studies in pregnant monkeys and feeding studies in rats demonstrate that a decrease in fetal survival and weight is associated with the maternal toxicity of this agent, but without an observable increase in fetal malformations in these species (Furuhashi et al., 1979; Hasegawa et al., 1979; Sumaya & Gibbs, 1979; Tanioka, 1976). Triamcinolone has been associated with cleft palate in offspring when given to pregnant mice, rats, rabbits, and hamsters (Shah & Kilistoff, 1976; Walker, 1965, 1967, 1969). It also caused central nervous system, craniofacial, and other abnormalities in the offspring of three different nonhuman primates (Hendricks et al., 1975, 1980; Jerome & Hendricks, 1988; Parker & Hendricks, 1983; Tarara et al., 1988). It has been noted that triamcinolone is 200 times more potent in producing palatal clefts in mice than is cortisone (Walker, 1965). In avian experiments, triamcinolone produces inhibition of scale and feather development, as do other corticosteroids; however, triamcinolone is 10,000 times more potent a teratogen in this model than is hydrocortisone (Fischer & Sawyer, 1986). Developmental Toxicity-- Human Data A large experience with humans has failed to suggest any increase in facial clefts or other birth defects from the use of corticosteriods (Bongiovanni & McPadden, 1960; Briggs et al., 1990; Serment & Ruf, 1968). Clinical observations suggest prenatal exposure to systemic corticosteroids is associated with a 300- to 400-gram decrease in birth weight and a small increase in "small-for- dates" babies (Pirson et al., 1985; Reinisch et al., 1978; Scott, 1977). This effect on growth has been seen in women, without other known causes of fetal growth impairment, who took 10 mg of prednisone throughout their pregnancies (Reinisch et al., 1978). Severe fetal growth retardation has been described in a single case in which a woman used extremely high doses of topical (not inhaled) triamcinolone in the middle trimester of pregnancy (Katz et al., 1990). There have also been concerns that some of the toxicity associated with corticosteroids in adults may be seen in offspring. Cataracts are occasionally observed in adults receiving corticosteroids, and congenital cataracts were reported in one infant exposed to prednisone throughout pregnancy (Kraus, 1975). Suppression of the immune system may be seen with high-dose corticosteroids. Although immunosuppression lasting 15 weeks after birth was observed in one infant born of a woman receiving high doses of prednisone and azathioprine (Cote et al., 1974), lymphopenia and reduced immunoglobin levels have not been commonly observed in similarly exposed infants (Cederqvist et al., 1977). Two clinical studies have investigated the outcome of 101 pregnancies in which women received beclomethasone and/or prednisone for severe asthma (Fitzsimmons et al., 1986; Greenberger & Patterson, 1983). The prevalence of congenital malformations in this population was within the normal range for all births, although the incidence of premature deliveries and low birth weight infants was slightly increased (Fitzsimmons et al., 1986). In general, nonhalogenated corticosteroids do not cross the placenta well, and there is no reason to believe that fetal or neonatal adrenal suppression will occur with maternal therapy. High-dose systemic corticosteroids have been used to accelerate lung maturity in pregnancies at risk for premature delivery. Although a number of reports raised concerns about effects of such therapy on brain development, followup of treated human pregnancies has shown no adverse effects of steroid treatment on neurodevelopmental testing at age 5 (Doyle et al., 1989). Breast Feeding Small amounts of prednisone and its active metabolite, prednisolone, will enter breast milk (Katz & Duncan, 1975; McKenzie et al., 1975; Ost et al., 1985). Even at 80 mg per day, however, the amount secreted in breast milk would be equivalent to less than 10 percent of a nursing infant's endogenous cortisol production, and it is unlikely that such a dose could produce clinically significant effects (Ost et al., 1985). Prednisone and prednisolone are considered compatible with breast feeding (American Academy of Pediatrics Committee on Drugs, 1989). Anti-Inflammatory Agent: Cromolyn Sodium Developmental Toxicity--Animal Data Intravenous and subcutaneous injections of cromolyn or closely related compounds did not produce fetal malformations in mice, rats, or rabbits (Cox et al., 1970). Developmental Toxicity--Human Data A report on 296 pregnancies during which cromolyn was used did not suggest an increase in fetal abnormalities associated with this drug (Wilson, 1982). Anti-Inflammatory Agent: Nedocromil Sodium Developmental Toxicity-- Animal Data Adverse reproductive effects were not seen in preclinical reproductive studies in rats and rabbits using 800 times the human therapeutic dose (Clark et al., 1986). Insufficient detail was presented in the report to evaluate the teratologic methods used. Developmental Toxicity-- Human Data None available. Bronchodilator: Beta-Adrenergic Agonists (Beta2- Agonists) Developmental Toxicity-- Animal Data Experiments using mice, rats, rabbits, and rhesus monkeys have not associated metaproterenol with teratogenic activity (Banerjee & Woodard, 1971; Hollingsworth et al., 1971; Matsuo et al., 1982). In a preliminary study published in abstract, albuterol (salbutamol) produced an increase in cleft palate in mice but no increase in anomalies in rats and rabbits (Szabo et al., 1975). Unpublished reports from the manufacturer also show cleft palate induction in mice, which are very susceptible to this defect, and cranioschisis in rabbits. The latter effect was produced with 78 times the maximum human dose. Pirbuterol, an analog of albuterol, did not result in increased congenital anomalies in the offspring of rats and rabbits treated during pregnancy (Sakai et al., 1989). Unpublished studies by the manufacturer reported no adverse pregnancy effects in mice, rats, or rabbits given up to 1,500 times the recommended human dose of terbutaline. Similar reports for pirbuterol noted no adverse effects at very high doses (300 mg/kg) in rats. In rabbits, this high dose produced abortion and fetal mortality. No information was given on maternal toxicity, a possible contributor to fetal death at such high doses. Developmental Toxicity-- Human Data Experience with beta2-adrenergic agonists as tocolytics has shown that these drugs can produce tachycardia, hypoglycemia, and tremor in prenatally exposed neonates (Baillie et al., 1970; Zilianti & Aller, 1971). The effects are treatable and reversible and do not constitute contraindications to the use of these medications. Terbutaline treatment of pregnant women has been shown to produce either no change or an increase in uterine blood flow (Akerlund et al., 1975; Cs k ny et al., 1982; Soares de Moura, 1981). Inhaled beta2- agonist therapy did not produce an increase in adverse pregnancy outcome in 259 women, 180 of whom used these agents during the first trimester (Schatz et al., 1988b). Breast Feeding Terbutaline is considered compatible based on the very low levels appearing in milk (Bennett, 1988). Presumably, the same considerations apply to other agents in this group. Bronchodilator: Nonselective Beta-Agonists Developmental Toxicity-- Animal Data Anomalies have been produced by direct epinephrine injection of rat and rabbit fetuses (Jost, 1953; Jost et al., 1969). The injection of pregnant mice with epinephrine produced a 14-percent frequency of cleft palate (Loevy & Roth, 1968). Epinephrine-induced malformations are also produced in the chick embryo (Hodach et al., 1974). Epinephrine impairs uteroplacental perfusion in sheep and monkeys (Adamsons et al., 1971; Misenheimer et al., 1972; Rosenfeld et al., 1976). Data on isoproterenol are instructive in isolating the role of hemodynamic changes in producing developmental toxicity. Injection of isoproterenol into incubating chick eggs results in abnormalities in the embryo (Cheung et al., 1977; Dusek & Ostadal, 1985; Janatova et al., 1986; Kuhlmann et al., 1983; Ostadal et al., 1987). The developmental toxicity of isoproterenol in the chick can be antagonized by pretreatment with beta-blocking agents (Janatova et al., 1986; Kuhlmann et al., 1983; Ostadal et al., 1987). It is believed that catecholamine-induced alterations in blood flow in the embryonic cardiovascular system are responsible for isoproterenol-associated toxicity (Cheung et al., 1977; Clark et al., 1985). This agent has also been found to cause hepatotoxicity (Dusek & Ostadal, 1984) and limb malformations in a small percentage of chick embryos (Bruyere et al., 1983). Teratogenic effects have also been noted after administration of isoproterenol to mice (Robson et al., 1965) and hamsters (Geber, 1969). Experiments in rats (Jones-Price et al., 1983; Vogin et al., 1970) and rabbits (Hollingsworth et al., 1971; Vogin et al., 1970) have not shown teratogenic effects, although hemodynamic effects of the drug are evident in a number of experimental animals (Macdonald et al., 1984; Robkin et al., 1976; Tweed et al., 1987; van de Walle & Martin, 1985). Developmental Toxicity-- Human Data There is only one report that suggests epinephrine might be associated with human teratogenesis. The National Collaborative Perinatal Project found an association between first trimester exposure to epinephrine and an increased risk of major and minor malformations as a group (Heinonen et al., 1977). Inguinal hernia was the only specific anomaly that was associated with epinephrine both after first trimester exposures or anytime during pregnancy. The National Collaborative Perinatal Project included 31 women who used isoproterenol during the first trimester. No increase in birth defects was shown (Heinonen et al., 1977). Bronchodilator: Theophylline Developmental Toxicity-- Animal Data Theophylline administration to pregnant mice at up to 600 mg/kg produced cleft palate and digit defects (Tucci & Skalko, 1978). Teratogenic effects were not observed, however, in rat experiments (Fujii et al., 1972; Maren & Ellison, 1972). Developmental Toxicity-- Human Data The National Collaborative Perinatal Project included 193 pregnant women with exposure to theophylline or to aminophylline, a complex of theophylline and ethylenediamine. No increase in adverse pregnancy outcome was identified. In addition, there is a large experience with the use of theophylline in pregnant women, with the consequent impression that this agent does not pose risks to development (Greenberger & Patterson, 1978). Case reports have appeared of children with heart defects born after maternal theophylline use; however, a large collaborative case-control study did not associate congenital heart disease with use of theophylline during pregnancy (Rubin et al., 1991). Theophylline crosses the placenta easily, and theophylline concentrations in the fetus are likely to be equal to or slightly higher than those in the mother. Newborns who were exposed to theophylline in utero have shown signs of theophylline intoxication, including jitteriness, tachycardia, and vomiting (Arwood et al., 1979; Yeh & Pildes, 1977). Generally, these symptoms have been observed in neonates with blood theophylline levels of more than 12 g/mL (Horowitz et al., 1982; Ron et al., 1984). Because therapeutic levels in the pregnant woman should not exceed 12 g/mL, appropriate dosing should not result in toxicity in the newborn. Breast Feeding Theophylline is excreted into breast milk, and a milk-to- plasma ratio of 0.73 has been reported (Berlin, 1981). Although less than 1 percent of the maternal dose of theophylline may be transferred to the neonate (Stec et al., 1980; Yurchak & Jusko, 1976), increased sensitivity to this drug may produce toxic effects in the newborn, including vomiting, feeding difficulties, jitteriness, and cardiac arrhythmias. Bronchodilator: Anticholinergics Developmental Toxicity-- Animal Data Relatively high doses of atropine did not cause developmental abnormalities in rats, chicks, or dogs (Back et al., 1961; Bueker & Platner, 1956; Maeda & Yasuda, 1979). Skeletal abnormalities detected after atropine was administered to pregnant mice may have resulted from the maternal toxicity of the atropine, and not from selective teratogenic effects (Arcuri & Gautieri, 1973). The adverse findings in mice could not be reproduced (Zellers, 1979). Teratology studies on ipratropium have been negative in rats and rabbits (Niggeschulze & Palmer, 1976; Nishimura et al., 1978). When tested in mice and rats, glycopyrrolate was not associated with an increased incidence of birth defects (Kagiwada et al., 1983). Developmental Toxicity-- Human Data Although atropine readily crosses the human placenta (Kanto et al., 1981; Kivalo & Saarikoski, 1977) and may alter fetal heart rate (Onnen et al., 1979) or inhibit fetal breathing (Roodenburg et al., 1979), fetal exposure to this drug has not been associated with adverse developmental effects or significant fetotoxicity, whether exposure occurred early in pregnancy (Heinonen et al., 1977; Mellin, 1964) or shortly before delivery (Abboud et al., 1983; Diaz et al., 1980; Janz & Fuchs, 1964). Glycopyrrolate use in pregnant women near term has not been associated with adverse effects (Abboud et al., 1981, 1983). Breast Feeding Although the elimination of atropine is reduced in children below 2 years of age, atropine exposures through breast milk have not been widely associated with neonatal toxicity (Stewart, 1981). Atropine is considered compatible with breast feeding (American Academy of Pediatrics Committee on Drugs, 1989). Antihistamines Developmental Toxicity--Animal Data Teratogenicity testing in rats, mice, and rabbits has not suggested an association between diphenhydramine and congenital malformations (Naranjo & de Naranjo, 1968; Schardein et al., 1971). Astemizole was not teratogenic in rats and rabbits at 200 times the recommended human dose in unpublished premarketing studies by the manufacturer. Embryolethality was seen at maternally toxic doses in the rats in this study. Terfenadine was reported by its manufacturer to produce a decrease in pup survival in rats given 63 times the human dose during pregnancy. Developmental Toxicity--Human Data The National Collaborative Perinatal Project suggested a possible association between the use of brompheniramine and chlorpheniramine during pregnancy and an increase in the incidence of birth defects (Heinonen et al., 1977). Because of the small numbers of affected children and the miscellaneous nature of the defects, these findings cannot be accepted as showing causation. Confirmation of these associations has not appeared in spite of the widespread use of these agents. Antihistamines are not considered to be teratogenic (Aselton et al., 1985; Greenberger & Patterson, 1978), although some antihistamines have been associated with birth defects in retrospective studies. For example, one study (Saxen, 1974) found that first trimester use of diphenhydramine was more common among 599 children born with oral clefts (20 exposures) than among 590 controls without clefts (6 exposures). The manufacturer of astemizole has on record 63 exposed pregnancies through February 1988 with no birth defects. Since that time, four reports of congenital anomalies have been brought to the manufacturer's attention; however, there is no indication whether this exceeds the number to be expected by chance alone. The most convincing data set for an antihistamine is that concerning doxylamine, a drug once used as an antinauseant during pregnancy and now used in over-the-counter sleep aids. A number of human studies have confirmed the lack of teratogenicity of this agent, confirmed by a meta-analysis (Einarson et al., 1988). Third trimester use of antihistamines has rarely been described in association with a withdrawal syndrome in the neonate. The reports do not permit conclusion of a cause- and-effect relationship. Breast Feeding Antihistamines are said to inhibit lactation, although this effect appears largely to be a theoretical concern. These drugs are often withheld during nursing; however, milk concentrations of these agents are extremely low, and there are no data establishing adverse effects on the neonate. Decongestants Developmental Toxicity-- Animal Data A dose of phenylephrine equivalent to the content of one "cold" tablet has been shown to decrease uterine blood flow by 40 percent in pregnant sheep (Cottle et al., 1982). Another investigation, also performed on pregnant sheep, indicated that the uterine vascular bed is substantially more responsive to the vasoconstrictive effects of alpha- adrenergic agonists than is the systemic vasculature (Magness & Rosenfeld, 1986). Ephedrine was associated with cardiovascular anomalies in the chick, even when very small doses were used (Nishikawa et al., 1985). Developmental Toxicity-- Human Data Pseudoephedrine normally will not produce hypertensive effects until more than four times its therapeutic dose is consumed (Pentel, 1984). Because of its favorable therapeutic index, pseudoephedrine appears to be the preferred decongestant for use during pregnancy. When ingested by healthy pregnant subjects in the third trimester, a single 60-mg dose of pseudoephedrine did not significantly alter blood pressure or blood flow velocities in the uterine or fetal circulation (Smith et al., 1990). The National Collaborative Perinatal Project included more than 4,000 women exposed to phenylephrine during pregnancy, 1,249 of whom were exposed during the first 4 lunar months (Heinonen et al., 1977). Possible associations were found between first trimester exposure and ear and eye defects, syndactyly, and clubfoot, and between pregnancy use in general and hip dislocation, musculoskeletal deformities, and umbilical hernia. It is important to recognize, however, that these associations are based on the appearance of small numbers of children with malformations. For example, for abnormalities associated with first trimester exposure to phenylephrine, the largest group consisted of eight children with eye and ear defects. Critical statistical analysis of these data has not been performed, and it is not currently known whether, in fact, phenylephrine increases the incidence of any birth defect. The National Collaborative Perinatal Project also found a possible association between use of phenylpropanolamine during the first 4 months of pregnancy and hypospadias, eye and ear malformations, polydactyly, and pectus excavatum (Heinonen et al., 1977). The number of malformations in this study was small (seven cases in the largest of the groups), and the observational design does not permit the conclusion that phenylpropanolamine was the causative agent in these abnormalities. The National Collaborative Perinatal Project was unable to identify an association between ephedrine exposure in the first trimester and an increase in any kind of birth defect (Heinonen et al., 1977). This report included 373 exposed pregnancies. Near term, ephedrine may be given to treat or avoid hypotension associated with epidural analgesia or with anaphylactic reactions. No adverse effects of such therapy have been documented, and ephedrine has been found not to alter intervillous blood flow (Hollmen et al., 1984). When studied in 12 uncomplicated pregnancies, a single dose of a 0.05-percent oxymetazoline nasal spray did not significantly alter blood flow velocity in the uterine arcuate artery, fetal aorta, or umbilical artery (Rayburn et al., 1990). A single dose such as this may not be representative of usual patterns of use. In one case report, the excessive use of an oxymetazoline nasal spray by a woman in her 41st week of pregnancy was associated with a nonreactive nonstress test and late decelerations in fetal heart rate, suggesting that uterine perfusion may have been impaired (Baxi et al., 1985). Breast Feeding Pseudoephedrine is excreted in breast milk. The reported milk-to-plasma ratio for this agent was approximately 3.0. A nursing neonate may ingest about 0.6 percent of the maternal dose (Findlay et al., 1984). The use of this drug during lactation has not been associated with adverse effects in exposed newborns, and it is categorized as compatible with breast feeding (American Academy of Pediatrics Committee on Drugs, 1989). 5 FOUR COMPONENTS OF THE MANAGEMENT OF ASTHMA DURING PREGNANCY AND LACTATION* Introduction Effective management of asthma for pregnant women relies on four integral components:  Objective measures for assessing and monitoring maternal lung function and fetal well-being in order to make appropriate therapeutic recommendations  Measures to avoid or control asthma triggers in the patient's environment  Pharmacologic therapy  Patient education. Goals of Therapy for Pregnant Women Goals for the management of asthma in pregnant women--as for all asthma patients--are:  Maintain (near) normal pulmonary function rates  Control symptoms, including nocturnal symptoms  Maintain normal activity levels, including exercise  Prevent acute exacerbations of asthma  Avoid adverse effects from asthma medications. An important additional goal for the management of asthma in pregnant women is:  Give birth to a healthy baby. Principles of Therapy for Pregnant Women Asthma is a chronic condition with acute exacerbations. Continuing attention is required to control symptoms, prevent exacerbations, and reduce chronic airway inflammation. Prevention of exacerbations is particularly important. This includes avoidance of triggers, and for allergic patients the avoidance of allergens, especially in the indoor environment. It also includes regular (daily) and aggressive use of anti-inflammatory medication for many patients. Anticipatory or early intervention in treating acute exacerbations of asthma reduces the likelihood of the episode progressing to severe airway obstruction and impaired maternal/fetal oxygenation. Both nonpharmacologic and pharmacologic therapies should be considered. Optimal use of nonpharmacologic measures is important because they may reduce the requirement for medication. Therefore, patients, if allergic, should avoid exposure to house-dust mites, animal dander, pollen, and mold spores. Patients should avoid irritant triggers, especially active and passive exposure to tobacco smoke. Using as few medications as possible is generally desirable. Inhaled medications are preferred; however, systemic drugs should be employed when inhaled medications are not sufficient to control symptoms and normalize pulmonary function. Although some not yet fully defined risk may be associated with the use of asthma medications during pregnancy, it is well recognized that the greater risk to the fetus is uncontrolled asthma. The Working Group on Asthma and Pregnancy strongly recommends that asthma should be aggressively treated in pregnant women just as it should be in nonpregnant patients. Studies to date have identified few risks to the fetus from drugs employed in treating asthma. The known risk of uncontrolled asthma, which causes morbidity in the mother and hypoxemia in the fetus, is far greater than any known risks to the mother or fetus from asthma medications. Striving to maintain the mother's normal lung function and blood oxygenation is essential to ensure normal oxygen supply to the fetus. Treating associated conditions is an important adjunct to asthma therapy. Such conditions as sinusitis, rhinitis, and gastroesophageal reflux can aggravate asthma; treatment can lead to more effective asthma control. (See chapter 6, Special Considerations.) Component 1: Objective Measures for Assessment and Monitoring; Maternal Lung Function Pulmonary function tests are essential for assessing the severity of asthma in order to make appropriate therapeutic recommendations. Asthma is characterized by variable airflow obstruction that is often at its worst at night or on arising. Measurements of pulmonary function performed during the day in the physician's office may offer incomplete insight into the course of the asthma throughout the 24-hour day. Home measurement of pulmonary function is important for assessing circadian variation in pulmonary function and for documenting that asthma is the cause of nocturnal awakening. Patients' and physicians' perceptions of the severity of asthma are often insensitive, making a quantitaive assessment of airflow obstruction highly desirable. Further, it can be extremely difficult for the patient and her physician to differentiate breathlessness associated with pregnancy, anxiety, or asthma without objective measures of lung function. Pulmonary function has traditionally been assessed by spirometry. FEV1 (the volume of air expired in 1 second from maximum inspiration) is the single best measure of pulmonary function for assessing severity. Therefore, it is recommended that office spirometry be conducted in the initial assessment of all pregnant patients being evaluated for asthma, and periodically thereafter as appropriate. The peak expiratory flow rate (PEFR) is the greatest flow velocity that can be obtained during a forced expiration starting with fully inflated lungs, and it correlates well with FEV1. PEFR can be measured reliably with inexpensive, portable peak flow meters. Because PEFR only measures large airway function, however, PEFR is not the most sensitive measurement of airflow obstruction. Thus PEFR measurements may not be sufficient to make a diagnosis or to fully evaluate the physiologic impairment associated with asthma. Nevertheless, home PEFR monitoring is extremely useful in assessing circadian variation in pulmonary function (an indication of airway hyperresponsiveness) and in following both the course of asthma and a patient's response to therapy. PEFR measurements can also help differentiate asthma from other causes of dyspnea during pregnancy. Use PEFR to assess symptoms and predict exacerbations of asthma. It is recommended that PEFR be used as the objective parameter to follow in assessing symptoms and making therapeutic recommendations when such recommendations depend on the severity of airflow obstruction. PEFR monitoring is especially valuable for detecting deterioration of asthma, predicting acute exacerbations, and assessing response to therapy. Availability of PEFR measurements not only allows formulation of a management plan with criteria for both intensification of therapy and recourse to medical assistance but also facilitates telephone communication with health care providers. Maintenance of as near normal pulmonary function as possible is desirable during pregnancy; patients for whom there is any concern in this regard should be supplied with a home peak flow meter device. In general this includes all women with moderate to severe asthma. These patients should record PEFR in the morning, upon arising, and approximately 12 hours later, and should bring PEFR records to each prenatal visit. Use PEFR to adjust asthma therapy. Predicted values of PEFR are in the range of 380 to 550 liters per minute for women and do not change during the course of pregnancy. Rather than employing the predicted value, it is often better to establish a personal best PEFR for each patient at a time when asthma is well controlled. Recommendations for changes in asthma therapy may then be based on deviations from this personal best level. For more complete discussion, see the National Asthma Education Program's Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma. Fetal Monitoring The goal of managing the pregnant woman with asthma is to optimize maternal pulmonary function and to identify those fetuses at risk for intrauterine growth retardation and adverse outcome. In the absence of maternal or fetal decompensation, an additional goal should be to provide a normal family-centered birthing experience. Prevention of adverse fetal outcome is complicated. Ill-informed concern about adverse fetal outcomes associated with medications used early in pregnancy may defer appropriate drug therapy (see chapter 4). Further, in the third trimester, monitoring of the fetus is sometimes overlooked during an asthma exacerbation. Finally, there are multiple methods available for fetal evaluation; more research is needed to determine which method correlates best with good fetal outcome. Therefore, principles for management of the fetus during a pregnancy complicated by asthma are:  There is little additional risk from mild or well- controlled asthma.  Other coexistent conditions such as hypertension or diabetes increase risk.  Patients with severe or uncontrolled asthma warrant increased surveillance.  Consultation with a perinatologist is recommended when serious fetal problems are suspected.  The most common errors leading to adverse outcome are underestimation of asthma severity and undertreatment of exacerbations. Fetal evaluation during the pregnancy of a woman with asthma is longitudinal and uses different techniques according to gestational age and risk factors. Because accurate determination of gestational age is crucial in making obstetric decisions, early (12 to 20 weeks) sonography should be performed for most patients, especially when accurate clinical dating is not possible or if asthma is moderate or severe. Early obstetric sonography will provide a benchmark against which fetal growth can be measured. Monitoring of pregnant patients with asthma starts with an evaluation of progressive fetal growth. Growth during the second and third trimesters is determined by careful serial measurements of fundal height. Confirmation with sequential sonographic evaluations of fetal growth is indicated if the patient's asthma is uncontrolled or if growth retardation is suspected. In the third trimester electronic fetal heart rate monitoring (nonstress test or contraction stress test) and ultrasonic determinations of fetal behavior (biophysical assessment) should be used, if needed, to assure fetal well-being. Indications for antepartum fetal assessment include growth retardation, moderate to severe asthma, asthma exacerbation, and decreased fetal movements. The type of monitoring chosen and its frequency depend on many factors. For many third trimester patients, weekly fetal assessment is sufficient; if fetal problems are suspected the frequency increases. Daily maternal recording of fetal activity, or "kick counts," should be encouraged. Several methods are used and appear to improve perinatal outcome in both low- and high-risk pregnancies. If there is serious maternal illness, as in an acute exacerbation of asthma with an incomplete or poor response to therapy or with significant maternal hypoxemia, previous fetal monitoring is irrelevant, and intensive fetal monitoring should begin and continue until maternal status is stable. One reasonable approach to antepartum fetal assessment is continuous electronic fetal heart rate monitoring. It is rarely necessary to deliver a fetus by emergency cesarean section for acute asthma complicated by respiratory failure. In most cases, fetal distress can be successfully treated by aggressive ventilation and medical management. When women with asthma are admitted in labor, careful fetal monitoring is essential. In low-risk patients, continuous electronic fetal monitoring may not be necessary. Fetal assessment can be accomplished by 20 minutes of electronic monitoring--the so-called admission test. Subsequently, for patients with mild or moderate asthma that is well controlled and with a reassuring admission test, intermittent auscultation, peak expiratory flow rate measurements, or electronic fetal heart rate monitoring may be sufficient. Intensive fetal monitoring is recommended for those patients who enter labor with uncontrolled or severe asthma and have a nonreassuring admission test or other risk factors. This may be performed by either continuous electronic fetal heart rate monitoring or intermittent auscultation (every 15 minutes in the first stage of labor; every 5 minutes in the second stage of labor). During the course of labor, intensive fetal monitoring may be considered to guide appropriate obstetrical and asthma management decisions. (See charts 7 and 8.) COMPONENT 2: MEASURES TO AVOID OR CONTROL ASTHMA TRIGGERS Environmental Control Eliminating adverse environmental exposures is critically important in controlling asthma during pregnancy. Irritants and allergens that provoke acute symptoms may also increase airway hyperresponsiveness, which in turn may increase vulnerability to further irritant or allergen exposure. Nonspecific irritants include tobacco smoke, dusts, strong odors, and environmental air pollutants. Certainly if the patient herself is smoking she should be strongly encouraged to quit and referred to an appropriate smoking cessation program. If allergy plays a role in an individual patient's asthma, environmental control measures to avoid these specific allergens are paramount. All warm-blooded pets, including small rodents and birds, produce dander, urine, and saliva that can cause allergic reactions. To eliminate exposure to animal dander, the animal should be removed from the house. Removal of the pet may not afford immediate relief even when followed by vigorous cleaning because dander has been shown to remain in the home for many months. Recent studies indicate that the residual allergen can be rendered nonallergenic by application of a 3-percent tannic acid spray, which is commercially available. If the pet cannot be removed from the house, it should at the very least be kept out of the pregnant woman's bedroom at all times. If there is forced-air heating in a home where a pet resides, the air ducts into the bedroom should be sealed. An electric baseboard heater can be used if necessary. Weekly washing of the pet may reduce exposure somewhat by decreasing the amount of dander and dried saliva deposited on carpets and furnishings. House-dust mites appear to play a major role in the causation of allergic asthma. Because they are dependent for survival on moisture from the atmosphere, they occur in environments where the relative humidity is usually greater than 50 percent. Mite allergen is found throughout the home: in mattresses, pillows, carpets, upholstered furniture, bed covers, clothes, and soft toys. Mite antigen is easily found in the air during house cleaning, but it is present in only very small amounts in undisturbed air. Mite antigen control involves encasing mattresses in airtight, plastic covers; either encasing pillows or washing them weekly; and washing bedding weekly in water that is 130ø F. If allergic to house-dust mites, a pregnant woman should not vacuum and should remain away from home for about 1 hour following house cleaning. If this is not possible, wearing a mask while vacuuming may be helpful. Additional measures that may be indicated include use of an acaracide (mite killer) on the carpets and avoidance of lying on upholstered furniture. In areas of very high humidity, she should consider using a dehumidifier or air conditioner. The use of humidifiers is discouraged because they provide moisture that may encourage mite growth. Home humidity levels should be maintained at less than 50 percent. Indoor exposure to mold and cockroach allergens may be important in homes with specific problems with dampness (molds) or infestation (cockroaches). Outdoor allergen exposure can be reduced by avoiding outdoor activities during the warmer months from midmorning until dusk, the period of highest prevalence for pollens and some mold spores. The use of an air conditioner during these same months will allow the woman to keep her doors and windows closed, effectively preventing outdoor pollen and mold spores from entering the home. Immunotherapy Immunotherapy may prevent allergic inflammation and has been shown to reduce asthma symptoms provoked by such allergens as house-dust mites, cat dander, grass pollen, and Alternaria. Immunotherapy may be considered for patients when avoiding allergens and irritants is not possible and when appropriate medication fails to control asthma symptoms. The principal concern with the use of immunotherapy during pregnancy has been the occurrence of systemic reactions (anaphylaxis). Induction of uterine contractions following anaphylaxis and resulting in abortion has been reported, although rarely. Patients at increased risk of anaphylaxis include those who are receiving increasing doses of antigen, have extreme sensitivity, and/or are exposed to high levels of ambient allergens. Accordingly, the general recommendation is that immunotherapy should not be started during pregnancy, but that ongoing immunotherapy may be continued at the current dose. Exceptions would be if immunotherapy has only recently been started or if the patient is experiencing frequent reactions that have prevented her from reaching an effective dose. Further, patients who have demonstrated a tendency to have systemic reactions should have their treatment discontinued. Extra caution is required during the patient's pollen season, when she may be at greater risk of experiencing a systemic reaction; therefore a reduction in dose during this period should be considered. Vaccines It is generally recommended that an influenza vaccine be given each year to patients with moderate and severe asthma. Influenza is a killed vaccine, and there is no evidence suggesting that it is associated with any maternal or fetal risk, although it has been recommended that it should be given after the first trimester as an extra precaution. Component 3: Pharmacologic Therapy Discussion of this component opens with a statement of the general principles of pharmacologic management and a listing of preferred medications and selection criteria for pregnant women with asthma. Following are the protocols for managing asthma during pregnancy, the exacerbations of asthma during pregnancy, and asthma during labor and delivery. There are no randomized prospective human studies of asthma pharmacotherapy during pregnancy. The following recommendations are based on the published safety and efficacy data and the experience of the working group members. General Principles of Pharmacologic Management  Tailor general therapy guidelines to individual patient needs. Asthma is a disease that varies among patients. Further, the degree of severity for any woman may change from one month or season to the next or during pregnancy. Therefore, specific pharmacologic regimens must be tailored to individual needs and circumstances and integrated with recommendations for nonpharmacologic management strategies.  Integrate asthma care with obstetrics care. The obstetrical care provider must be involved in asthma care. Consultation with an asthma specialist is appropriate as indicated for evaluation of the role of allergy and irritants, complete pulmonary function studies, or evaluation of the medication plan if there are complications in achieving the goals of therapy. A team approach is required if there is more than one clinician managing the asthma and the pregnancy.  Obtain information on asthma status during prenatal visits. Collect the following information: 1. Day and nighttime symptoms 2. Peak flow measures or spirometry reading 3. Medication usage.  Use step-care pharmacologic therapy. An aim of therapy is to use the minimum medication needed to maintain control with the least risk of adverse effects. The step- care approach in which the number of medications and frequency of administration are increased as necessary to establish control (step up) and reduced when possible to maintain control (step down) is used to achieve this aim. - In general, every asthma patient must have an inhaled beta2-agonist available for rescue treatment of acute symptoms. This rescue treatment also has a step-care pattern. Medications are added as necessary to control symptoms. The increase is often temporary and depends on the severity and duration of the asthma exacerbation as well as the patient's response. (Note, however, that increasing use of rescue treatment by the patient is an indication to review the medication plan and possibly to increase preventive therapy.) - Maintenance therapy, or chronic management of asthma, also uses a step-care approach and is based on the severity of disease: mild, moderate, or severe.  Monitor continually. Continual monitoring, which includes objective measures of lung function, is necessary to ensure that therapeutic goals are met. - While the patient is achieving control of asthma, PEFR variability greater than 10 to 20 percent and continued presence of chronic symptoms indicate a need to reevaluate the patient's technique in using medication, any environmental aggravators and the patient's efforts to control them, the pressure of concomitant upper respiratory disease, and finally, the possibility that medications need to be increased. - Once asthma control is established, regular followup visits in conjunction with prenatal visits continue to be essential. Clinicians need to monitor and review the treatment plans, the medications, and the patient's management techniques (i.e., for using medicines and peak flow meters, for controlling the environment). Preferred Medications and Selection Criteria for Pregnant Women With Asthma The choice of a specific medication plan during pregnancy is based on the following considerations: 1. Available animal and human gestational data (see chapter 4). 2. Efficacy. 3. Preference for drugs administered by inhalation. (Asthma is a disease of the airways and therefore treatment by inhalation is generally preferable to systemic therapy. Aerosolized medications for asthma deliver the drug directly to the airways in higher concentrations and systemic effects are usually avoided.) 4. Preference for older medications with a long history of use during pregnancy and documented clinical investigation. Based on these considerations, the specific drugs listed in table 7 are currently preferred by the Working Group on Asthma and Pregnancy for the management of asthma and associated conditions during pregnancy. However, it should be noted that lack of inclusion of a specific medication on this list does not necessarily imply that it is inappropriate for use during pregnancy. Table 8 lists drugs for asthma and associated conditions that generally should be avoided during pregnancy. Step-Care Pharmacologic Management of Asthma During Pregnancy Treatment plans for asthma during pregnancy are based on the goals of therapy, the general principles for managing asthma, and information on the use of medications during pregnancy. This section and its accompanying charts present application of these principles to the development of treatment protocols based on the severity of disease. Specific therapeutic regimens must be tailored to the needs and circumstances of the individual patient. The step-care approach recommends increasing the number and frequency of medications with increasing asthma severity. Once control of asthma is established and sustained for several weeks, a reduction in therapy, or step down, is carefully considered in order to identify the minimum therapy required to maintain control. Chronic Mild Asthma (Ch