Hospital Medicine

Asthma in pregnancy

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Asthma in pregnancy

I. What every physician needs to know.

Asthma is one of the most common potentially serious medical problems that occur during pregnancy, with an estimated prevalence of 3% to 12% of all pregnancies being affected without regard to ethnicity or socioeconomics. It is defined as a chronic inflammatory disorder of the airways, and characterized by variable and recurring symptoms, airflow obstruction that is partially or completely reversible, bronchial hyperresponsiveness, and an underlying inflammation.

Acute exacerbations requiring medical intervention have been reported in up to 20% of pregnant women with asthma and nearly 6% requiring hospitalization.

II. Diagnostic Confirmation: Are you sure your patient has asthma in pregnancy?

The diagnosis of asthma in pregnancy is usually straightforward since most patients enter pregnancy with a known history of asthma. However, diagnostic confirmation is required in those with new respiratory symptoms without a preceding asthma diagnosis, or those in whom the clinical picture or response to therapy is atypical. Diagnostic confirmation is the same as in non-pregnant patients - reduced forced expiratory volume in one second (FEV1) that improves by at least 12% with the administration of a bronchodilator (albuterol).

Methacholine testing is contraindicated during pregnancy because of the lack of safety data on such testing in pregnant patients and the theoretical risks of provoking a hypoxic asthma exacerbation. Allergen testing is also contraindicated because of the risk of triggering an anaphylactic reaction, endangering mother and fetus.

A. History Part I: Pattern Recognition.

Typical symptoms of asthma include wheezing, cough, shortness of breath, and chest tightness. Symptoms may worsen at night and are of fluctuating intensity. On exam, wheezing is heard on auscultation of the lungs, although its absence does not exclude the diagnosis. A key aspect of asthma is that the airway hyperresponsiveness is reversible, and there is normal lung function when not having an exacerbation.

The most common precipitant of an exacerbation is a respiratory viral infection, so signs and symptoms of a viral upper respiratory infection (URI) may be present on presentation.

B. History Part 2: Prevalence.

There are both host and environmental factors that influence the development of asthma, which typically first appears in childhood. Early on, cytokine imbalance is thought to influence the inflammatory response critical in the development of asthma. Later, two major environmental factors affecting the development and possible severity of asthma include airborne allergens (pollution, tobacco, dust mites, cockroaches, dog and cat dander) and viral respiratory infections.

The role that pregnancy has on a patient's asthma is unpredictable, as is clear from the rule of thirds - one-third of patients with asthma in pregnancy improve, one-third worsen, and one-third experience no change. However, rates of asthma exacerbation and hospitalization in pregnant patients with asthma directly correlate to the severity of symptoms in the asthma classification schema. In addition, many patients follow the same course with their asthma symptoms in successive pregnancies, so a history of asthma severity in previous pregnancies can be very predictive.

C. History Part 3: Competing diagnoses that can mimic asthma in pregnancy.

The most common alternative diagnosis confused with asthma is physiologic dyspnea of pregnancy. Pregnancy results in a 20% increase in oxygen consumption to support an increased maternal metabolic rate. This is accomplished by increasing minute ventilation by 40-50%, not with an increase in respiratory rate, but from an increase in tidal volume. These changes are secondary to a progesterone-mediated stimulation of the respiratory center to a set point that accepts a lower partial pressure of carbon dioxide. There is no change in FEV1 or peak expiratory flow rate (PEFR) with pregnancy, which is why testing for asthma is the same for pregnant versus non-pregnant women.

The rate of pulmonary embolism in pregnancy is five times greater than that for non-pregnant women of the same age and occurs in about 1 in 1500 deliveries. Pulmonary embolism typically presents with an acute respiratory distress, with or without tachycardia, cough, chest pain, and hemoptysis. Signs of deep vein thrombosis may be present, including unilateral (usually left) leg swelling.

Clinical exclusion of further testing with a low pre-test probability and normal d-dimer is recommended first. Although Well's criteria was not validated in pregnant women and a d-dimer may be falsely elevated in second and third trimester pregnancy especially in the setting of comorbidities such as pre-eclampsia, it is advised to start with these tests to minimize further risks to mother and fetus. All remaining patients should undergo bilateral leg Doppler assessment. Starting with Doppler ultrasound as the initial test reduces the need for radiation exposure since if positive, treatment is unchanged.

If the Doppler ultrasound test is positive, the patient should be treated for pulmonary embolism; if negative, all patients should be referred for computed tomography (CT) pulmonary angiography after informed consent is obtained. All neonates exposed to iodinated contrast in utero should have their thyroid function tested in the first week of life due to the theoretical risk of contrast-induced hypothyroidism.

Pneumonia can present with shortness of breath in the setting of productive cough, pleuritic chest pain and fever. For patients with asthma, pneumonia can trigger an exacerbation. Its presence can be distinguished by an elevated white blood cell count and infiltrate on chest x-ray.

Pulmonary edema can cause acute or progressive respiratory distress in the presence of heart disease, hypertension, embolic disease, aggressive fluid replacement, or sepsis. Diagnosis is confirmed by chest x-ray. Chest x-ray is low dose radiation and in the setting of probable serious threat to mother and fetus, benefit outweighs risk.

Dyspnea caused by a dilated cardiomyopathy occurring during the final month of pregnancy or in the 6 months after delivery may be peripartum cardiomyopathy. These patients have signs and symptoms of heart failure, and the diagnosis can be confirmed by cardiac echocardiography.

If the shortness of breath occurs during delivery, consider amniotic fluid embolism. Unlike asthma, this may be complicated by hypotension, seizure, disseminated intravascular coagulation, and cardiac arrest.

D. Physical Examination Findings.

During an asthma exacerbation, there is tachypnea, use of accessory muscles and paradoxical movement of the abdomen with respiration. On lung exam, there is a prolonged expiratory phase and wheezing during exhalation. Nasal exam might reveal increased nasal secretion, mucosal swelling and nasal polyps. The presence of atopic dermatitis or other allergic skin conditions increases the likelihood that shortness of breath is related to asthma.

E. What diagnostic tests should be performed?

Because the physiologic respiratory changes of pregnancy do not affect FEV1 or PEFR, and these are negatively affected by asthma symptoms and exacerbations, they are both an ideal method of monitoring asthma severity in pregnancy.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The natural hyperventilation of pregnancy causes a normal respiratory alkalosis that is compensated for by a metabolic acidosis. Typical arterial blood gas when pregnant shows a potential hydrogen (pH) of 7.40 to 7.45 and a carbon dioxide partial pressure (pCO2) of 28 to 32 mmHg. There is a mild increase in oxygen partial pressure (pO2) of 106 to 110 mmHg.

Keeping this in mind, an arterial blood gas (ABG) should be checked during an asthma exacerbation when pregnant and interpreted within the realm of what is expected with the acid-base balance of pregnancy. Although a pCO2 of 40 would be considered normal in the non-pregnant state, in pregnancy this level actually reflects a degree of carbon dioxide retention and possible impending respiratory failure. In addition, the pO2 in the umbilical veins is lower than in the placenta, therefore maternal hypoxemia will quickly result in a decreased oxygen content supplied to the fetus.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

With an acute exacerbation, chest x-ray can be used to rule out any pulmonary process (e.g. pneumonia) that may be precipitating symptoms. One chest x-ray has the equivalent radiation exposure of the background radiation all people at sea level are exposed to in 10 days. Therefore, radiation exposure is minimal and in the setting of illness, benefit outweighs risk. As is commonly done during pregnancy, the uterus should be shielded for non-pelvic procedures.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

N/A

III. Default Management.

The main goal of treatment with asthma is to prevent hypoxic episodes to preserve adequate fetal oxygenation. Medical therapy should follow a stepwise approach balancing the use of the least amount of medication with control of symptoms. Goals of therapy include having normal or near normal pulmonary function and minimal or no symptoms. Overall, the risks associated with asthma medication in pregnancy are considered to be definitely lower than the risks associated with uncontrolled asthma and under treatment must be avoided.

Inhaled corticosteroids (ICS) have been shown to be the most effective treatment for the airway inflammation of asthma and are preferred for the management of all levels of persistent asthma in pregnancy. They reduce exacerbations by more than threefold as compared to those who do not use ICS, reduce the risk of readmission following an exacerbation, and multiple studies have confirmed their safety in pregnancy.

There is more data on budesonide than any other ICS, so it is the preferred medication to begin with (pregnancy category B; all other ICS category C), unless symptoms are already under control with the use of another ICS. ICS should be started at low dose and titrated up as indicated by disease control. High-dose ICS have raised some safety concerns (fetal malformations) but risk of uncontrolled disease continues to outweigh the risk of treatment.

Inhaled short acting beta-2 agonists (SABAs) are recommended for treatment with all classes of severity. Albuterol is the first line rescue inhaler for symptoms with acute bronchospasm. No association has been found between the use of SABAs and adverse fetal or maternal outcomes when symptoms are adequately controlled.

Long-acting beta-agonists (LABAs) have been shown to be more effective than leukotriene receptor antagonists or theophylline as add-on therapy to inhaled corticosteroids. Salmeterol is preferred over formoterol due to longer history of use. Combination agents (moderate strength ICS and LABA) are also an option.

Leukotriene receptor antagonists are an alternative treatment for mild persistent asthma, and can be used as an adjunct in moderate to severe asthma. Both zafirlukast and montelukast are pregnancy category B. Cromolyn and theophylline are also alternative options in mild asthma and adjunctive therapy in moderate to severe asthma, but are not preferred given the need for drug level monitoring with theophylline.

Women who are on systemic steroids, or who have received several short courses of them during pregnancy, should receive stress dose steroids (hydrocortisone 100 mg every 8 hours or an equivalent dosing) during labor and for 24 hours post-delivery to prevent adrenal crisis.

Medications that can potentially worsen asthma should not be used during labor and delivery. Carboprost (induces contractions) and ergonovine (causes vasoconstriction, used to reduce postpartum bleeding) are non-selective beta-blockers that can trigger bronchospasm. Indomethacin (closes patent ductus arteriosus) can also trigger bronchospasm in patients who are sensitive to aspirin.

For women who plan on breastfeeding, only small amounts of asthma medications pass into breast milk, and none are a contraindication to breastfeeding.

The medication recommendations for asthma in pregnancy follow the recommended stepwise pharmacological approach of the NHLBI published in 2007. The same, tiered approach to increasing asthma medication use based on symptoms should be used in pregnant and breast-feeding women as in patients who are not pregnant. Most medications are FDA-pregnancy class C (risk cannot be ruled out) because there are no controlled studies in pregnant women. There is no asthma medication that is class 'X'. Inhaled route is preferred over per os due to more localized effect.

A. Immediate management.

Immediate evaluation and management should be the same in pregnancy as it is in the non-pregnant state.

  1. Measurement of the PEFR and comparison with predicted or previously recorded best.

  2. Give supplemental inhaled oxygen to keep oxygen saturation greater than 94%.

  3. Administer inhaled albuterol via nebulizer with oxygen every 20 minutes, up to 3 doses in the first hour.

  4. If no improvement seen, or if severe exacerbation, give intravenous (IV) or PO corticosteroids.

  5. Continuous external fetal monitoring for those greater than 24 weeks gestation.

  6. Provide ample hydration with IV fluids if PO intake is not possible.

Hospitalization is indicated if oxygen saturation remains below 95% on room air, if PEFR remains below 70% of predicted, or if there is evidence of fetal compromise. Intensive care unit admission or intubation is indicated in those with life-threatening asthma that is not responding to bronchodilators and corticosteroids. Indications include a pCO2 higher than 40 mm Hg on ABG, mental status changes, maternal exhaustion, respiratory acidosis, or fetal distress.

B. Physical Examination Tips to Guide Management.

Oxygen saturation measured by pulse oximetry should be followed and maintained above 94% to ensure sufficient oxygenation to both the mother and the fetus. Lung auscultation to assess adequate air movement should be monitored - absence of lung sounds with severe respiratory distress could indicate impending respiratory failure.

Assessment of the fetus during an acute asthma exacerbation includes continuous electronic fetal monitoring and/or a biophysical profile (a non-stress test for a reactive fetal heart rate, ultrasound measurement of amniotic fluid volume, observation of the presence or absence of fetal breathing movements, and observation of body movements and fetal tone), and should be considered if the fetus has reached the stage of viability.

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management.

Monitoring the PEFR until it returns to predicted levels or the patient's previous best will help in assessing if therapy is improving symptoms. In addition, monitoring of the pCO2, pH, and pO2 helps to judge improvement or worsening.

For patients started on systemic corticosteroids, serum glucose levels should be monitored to assess for hyperglycemia.

More frequent ultrasound monitoring may be used for surveillance in women with moderate to severe asthma or sub-optimal control of their asthma after 32 weeks to assess fetal growth.

D. Long-term management.

Self-management, including measurement of PEFR, correct inhaler techniques, adherence to medication, control of environmental triggers, and an action plan with worsening symptoms, enhances asthma control.

Control of existing conditions that can aggravate asthma, such as allergic rhinitis, sinusitis and gastroesophageal reflux, can improve asthma control and reduce the number of exacerbations.

Tobacco use should be discontinued, not only because of the effect on asthma control, but also because of the known adverse effects of smoking on the fetus.

Stepwise therapy based on classification of asthma severity as in the non-pregnant asthmatic should be followed, using the lowest amount of drug intervention necessary to control a patient's severity of asthma. All patients should have an albuterol rescue inhaler to be used for control of acute symptoms.

With increasing severity from mild persistent to severe persistent, ICS (low, medium or high potency), LABAs, leukotriene receptor antagonists, theophylline, and PO corticosteroids can be added in step-wise fashion. Once control is achieved and sustained for several months, a step-down approach can be considered, undertaken cautiously and gradually to avoid compromising the stability of asthma control. For some patients, waiting until after delivery before reducing therapy makes more sense.

E. Common Pitfalls and Side Effects of Management.

Do not begin step-down therapy of medication too early. At times, particularly with moderate to severe asthma, it is best to maintain dosing of medication at the levels that control symptoms, and to attempt step-down therapy after delivery.

ICS can cause oral thrush with long-term use. Patients should be advised to rinse their mouth with water after using.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure.

In patients with the comorbidity of systolic or diastolic heart failure, care must be taken in the use of beta agonists as well as with systemic corticosteroids. As beta-agonists cause an elevation of heart rate, in patients with heart failure this leads to decreased diastolic filling time and a possible worsening of symptoms. Systemic steroids cause fluid retention, which can lead to fluid overload and a heart failure exacerbation.

D. Coronary Artery Disease or Peripheral Vascular Disease.

Because beta agonists increase the heart rate, creating increased demand to the myocardium, this may precipitate ischemia in patients with coronary artery disease.

E. Diabetes or Other Endocrine Issues.

The use of systemic steroids can precipitate hyperglycemia, particularly in patients with a history of diabetes.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

N/A

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

No change in standard management. However, in patients with known hypercoaguable state, a higher pre-test probability for pulmonary embolism is present and should be reviewed more diligently.

K. Dementia or Psychiatric Illness / Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out Considerations While Hospitalized.

Repeat assessments of the patient's FEV1 or PEFR measurements should be done for pregnant women admitted for an asthma exacerbation. Using the step-wise approach to therapy outlined above, treatment should be undertaken for PEFR less than 70% predicted, hypoxia or signs of impending respiratory failure.

B. Anticipated Length of Stay.

Once admitted, the goal length of stay should be 24-48 hours, long enough to get symptoms under control and monitor for 24 hours the response to therapy which will be used as an outpatient. Of course, this will vary based on the severity of the exacerbation, the underlying precipitant and the response to therapy.

C. When is the Patient Ready for Discharge?

Patients with FEV1 or PEFR measurements greater than or equal to 70% sustained for 60 minutes after last treatment, no distress, and reassuring fetal status may be discharged. Medication regimen after an acute asthmatic episode should continue treatment with SABAs, 2-4 puffs every 3-4 hours as needed, oral corticosteroids 40 mg total daily for 3-10 days, and an ICS should be initiated or continued.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom?

Outpatient follow-up should be arranged within 5 days after the acute visit. Monthly visits to assess asthma control are recommended for women who require controller therapy during pregnancy. If the obstetrician is comfortable performing this as part of routine obstetrical care, he or she can do it. Otherwise, the patient's primary care physician or asthma specialist should follow the patient regularly. Patients with very poorly controlled asthma should be seen every 1 to 2 weeks until control is achieved.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

A measured PEFR at discharge can be helpful to ensure continued improvement by the first clinic visit.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

The patient should continue to monitor and record their PEFR at home, and bring the results with them to their first post hospitalization clinic visit.

E. Placement Considerations.

N/A

F. Prognosis and Patient Counseling.

Pregnant patients should be counseled on the relationship between asthma control and pregnancy outcomes. Several studies have suggested that better asthma control may improve pregnancy outcomes. All guidelines emphasize that the benefits of treating asthma outweigh the potential risks of any medication side effects. Severe and poorly controlled asthma may be associated with increased prematurity, need for cesarean delivery, pre-eclampsia, spontaneous abortion, small for gestational age, low birth weight, growth restriction, and maternal morbidity and mortality.

Adherence to treatment with ICS has been reported to be poor in many studies, which is associated with an increased frequency of asthma exacerbations. It has been reported that pregnant women with asthma decrease their use of ICS during pregnancy due to concerns regarding their safety. It is important to counsel patients that studies have confirmed the safety of ICS use during all trimesters of pregnancy, as well as the potential adverse effects of uncontrolled asthma on both mother and fetus.

Each individual should establish her personal best with the PEFR in pregnancy, and then with their provider mark on their meter 80% and 50% of what this best is. She should then be taught that 80% or more of PEFR is considered good control; advised that within the 50%-80% range she should urgently arrange an appointment to see her physician or obtain advice regarding change in medication; and at less than 50%, she should be seen immediately, in the emergency department if necessary.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

During flu season, all pregnant women who have not already been vaccinated should receive the influenza vaccine. Both pregnancy and asthma are comorbidities that cause more severe symptoms of flu as compared to non-pregnant women or those without asthma. The flu vaccine is safe in all trimesters of pregnancy.

VII. What's the Evidence?

Bain, E, Pierides, KL, Clifton, VL, Hodyl, NA, Stark, MJ, Crowther, CA, Middleton, P. "Interventions for managing asthma in pregnancy". Cochrane Database of Systematic Reviews. vol. CD010660. 2014.

Chan, A, Juarez, M, Gidwani, N, Albertson, T. "Management of Critical Asthma Syndrome During Pregnancy". Clinical Reviews in Allergy and Immunology. 2015. pp. 45-53.

Rejno, G, Lundholm, C, Gong, T, Larsson, K, Saltvedt, S. "(2014) Asthma during Pregnancy in a Population-Based Study - Pregnancy Complications and Adverse Perinatal Outcomes". PLoS ONE. vol. 9. 2014. pp. e104755.

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