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Respiratory disease

Lauren A plante BASIC RESPIRATORY PHYSIOLOGY IN PREGNANCY See also chapter 2 of Obstetric Evidence Based Guidelines. Increase in minute ventilation (30-40%), predominantly by increase in tidal volume. Lesser increase in oxygen consumption (15-30%) Decrease in expiratory reserve volume and functional residual capacity Reduction in arterial PCO2 and increase in arterial PO2 Quicker to desaturate with hypoventilation

RESPIRATORY CONDITIONS Common: asthma, pneumonia. Less common: tuberculosis. Rare: restrictive lung disease, emphysema, cystic fibrosis, interstitial lung disease, sarcoidosis, acute lung injury/adult respiratory distress syndrome (ALI/ARDS) ASTHMA KEY POINTS Asthma is characterized by airway obstruction, inflammation, and increased responsiveness to stimuli. To be certain of diagnosis, once abnormal forced expiratory volume in one second (FEV1) is found in a patient with historic and physical exams findings consistent with asthma, other differential diagnoses must be excluded.

Asthma is classified as mild intermittent, mild persistent, moderate persistent, and severe persistent by symptoms and peak expiratory flow rate (PEFR) or spirometry. Asthma has historically been associated with small increased risks of preterm birth, low birth weight, perinatal mortality, and preeclampsia, but these risks are probably associated just with undertreatment of asthma; if asthma is adequately treated, it is not associated with a significant increase in adverse perinatal outcomes. Pregnancy has a variable effect on asthma severity, with about two-thirds getting better and one-third worse. The management of asthma in pregnant women should follow the same guidelines as for other nonpregnant patients. Management is based on objective measurements of pulmonary function (PEFR) The management plan should include use of environmental control measures, adequate pharmacotherapy, and patient education regarding symptoms, management, and compliance. Inhalation therapy is preferred to systemic treatments, with inhaled corticosteroids, NOT inhaled -agonist, the mainstay of therapy. Prostaglandin F2 should be avoided.

Classification of asthma severity.

DIAGNOSIS Asthma is characterized by episodic symptoms of airway obstruction, which is at least in part reversible; alternative explanations must be excluded. Airway inflammation with edema and remodeling, rather than simply bronchospasm, is the key. Increased airway responsiveness to stimuli is characteristic. Indicators that suggest a diagnosis of asthma include wheezing, history of recurrent cough, chest tightness or difficulty in breathing; worsening of symptoms with exercise, viral infection, exposure to animal fur or feathers, mold, pollen, house dust mites, tobacco or wood smoke, changes in weather, airborne chemicals or dusts; or worsening of symptoms at night. Physical examination is not always reliable, and may include thoracic hyperexpansion or chest deformity, hunching of shoulders or use of accessory muscles, audible wheezing or a prolonged expiratory phase, increased nasal discharge or nasal polyps, or any manifestation of an allergic skin condition. The more indicators present, the more likely the diagnosis; however, the absence of wheezing does not equal the absence of asthma. If a diagnosis of asthma is being considered, the next step is spirometry to determine whether airflow obstruction is present, and, if so, whether it is reversible. Forced vital capacity (FVC), FEV1, and FEV1/FVC ratio are measured before and after administration of a shortacting bronchodilator. Reduced FEV1 or FEV1/FVC shows airflow limitation, and a 12% or greater improvement in FEV1 after the administration of inhaled albuterol confirms reversibility.

To be certain of an asthma diagnosis, once abnormal FEV1 is found in a patient with history and physical exam findings consistent with asthma, other differential diagnoses

must be excluded, such as chronic obstructive pulmonary disease, congestive heart failure, pulmonary embolus, laryngeal or vocal cord dysfunction, and mechanical airway obstruction. SYMPTOMS Wheezing, shortness of breath, coughing, chest tightness, difficulty in breathing, dyspnea.

INCIDENCE Asthma affects approximately 8% of pregnant women (2). Among U.S. women aged 18 to 44, 5% reported an asthma attack within the preceding 12 months. However, 12% to 14% had received a diagnosis of asthma at some point during their lifetimes (2). Thus, this is a common disease among women of reproductive age. ETIOLOGY/BASIC PATHOPHYSIOLOGY Airway obstruction and inflammation, usually because of excessive response to stimuli, as described above. CLASSIFICATION Asthma severity, that is, the intrinsic intensity of the disease, is classified into four stages.

Mild intermittent asthma

Fewer than two episodes per week AND fewer than two nocturnal episodes per month,plus PEFR better than 80% of personal best (or FEV1 > 80% of predicted), plus less than 20% variation in PEFR in the course of a day.

Mild persistent asthma

Symptoms more than twice a week (but not daily), or nocturnal symptoms more than twice per month, plus Peak expiratory flow (PEF) better than 80% of personal best (or FEV1 > 80% of predicted), plus No more than 20% to 30% variation in PEFR in the course of a day.

Moderate persistent asthma

Daily symptoms, or nocturnal symptoms more than once per week, or PEF between 60% and 80% of personal best (FEV1 6080% of predicted), or PEF variation > 30%.

Severe persistent asthma

Continuous daytime symptoms, or Frequent nocturnal symptoms, or PEF 60% of personal best (FEV1 60% of predicted). PEF variation is typically > 30%. COMPLICATIONS Asthma has historically been associated with small increased risks of preterm birth, low birth weight, perinatal mortality, congenital malformations, and preeclampsia. These risks are probably associated just with undertreatment of asthma: if asthma is adequately controlled, it is not associated with a significant increase in adverse perinatal outcomes . A relationship has been reported between decreased FEV1 during pregnancy and increased risk of low birth weight and prematurity. In addition, women who required hospitalization for asthma during pregnancy, or who reported their asthma control to be poor during pregnancy, were at higher risk for preterm birth, though not for growth restriction . Large studies indicate that therapy tailored according to asthma severity can result in excellent infant and maternal outcomes . There are no randomized prospective trials comparing pregnancy outcomes in treated and untreated asthmatics. Women who decrease their asthma medication during pregnancy deliver infants of lower birth weight and slightly shorter gestational age than those who either increase their medication or make no change. PREGNANCY CONSIDERATIONS

Pregnant women are less likely than others to receive appropriate asthma care. Pregnant women are equally likely to be admitted for an asthma attack, but are less likely to receive corticosteroids in the emergency department (ED), and those who are sent home are less likely to be prescribed outpatient steroids. Pregnant women are far more likely than nonpregnant counterparts to report ongoing symptoms two weeks after an ED visit, perhaps because of the difference in steroid use . Adherence to treatment with inhaled corticosteroids has been reported to be poor in many studies. For example, women reported to decrease their use of inhaled corticosteroids during early pregnancy, as compared with their use of these agents in the 20 weeks before their last menstrual period; this may be due to their reported concern regarding the safety of inhaled corticosteroids during pregnancy. Pregnancy has a variable effect on asthma severity, which may improve, worsen, or remain unchanged. In general, about two-thirds get better, and one-third get worse (2) . Most exacerbations occur between 24 and 36 weeks, while the fewest symptoms occur at term. Of patients with mild disease, 2% were hospitalized during pregnancy, 13% were noted to have an exacerbation, and 13% had symptoms at time of delivery (7). For patients with moderate asthma, 7% were hospitalized and 26% had an exacerbation during pregnancy, with 21% symptomatic at delivery. Among severe asthmatics, 27% were hospitalized and 52% had an exacerbation during pregnancy, and 46% of severe asthmatics were symptomatic at delivery (7). A number of factors have been proposed as predictors of disease worsening during pregnancy (smoking, carrying a female fetus, worsening of rhinitis) but studies are inconsistent (11, 12, 13). MANAGEMENT

The management of asthma in pregnant women should follow the same guidelines as for other patients. The goal is to maintain asthma control during pregnancy. In 2004, the National Asthma Education and Prevention Program (NAEPP) stated, it is safer for pregnant women with asthma to be treated with asthma medications than it is for them to have asthma symptoms and exacerbations. Recent recommendations for asthma management and control

are available from the 2007 NAEPP Guidelines (1), the NAEPP update on managing asthma in pregnancy (14), and from the American College of Obstetricians and Gynecologists (15). However, the latter two publications acknowledge that evidence quality is often limited to consensus or expert opinion.

Eliminate or mitigate asthma triggers. Environmental control measures are shown in Table 24.5.

Preconception care
Multidisciplinary care is recommended for preparation of pregnancy and during pregnancy. Education regarding prognosis, complications, and management of asthma therapy should be reviewed, with emphasis on the fact that asthma therapy should not change in pregnancy compared to the nonpregnant state, but should still aim for maximal relief of symptoms and best pulmonary function, through attentive patient compliance with suggested management

Prenatal care
Achieving and maintaining asthma control requires four components of care: 1. Use of objective measures of lung function such as PEFR, both to ascertain severity, assess asthma control, and to monitor therapy, rather than relying on symptoms. 2. Control of environmental factors and comorbid conditions to eliminate or mitigate asthma triggers. 3. Pharmacotherapy designed to prevent or reverse airway inflammation typical of asthma, as well as drug treatment for exacerbations. 4. Patient education regarding symptoms, management, and compliance.

Work-up of pulmonary function

Asthma control should be assessed on a regular basis (at least at each prenatal visit) by review of symptoms, medications used, and quality of life over the preceding weeks. The PEF can be measured by peak flow meters, which are portable, inexpensive, and disposable. Both FEV1 and PEF remain unchanged in pregnancy in the normal state. Predicted PEF values are based on age, gender, and height. For women, they range from 380 to 550 L/min. Each pregnant woman should establish her personal best during quiescent asthma. PEF > 80% of personal best are normal; values between 50% and 80% are intermediate; values 50% are associated with severe asthma exacerbation. Daily peak flow monitoring using an inexpensive home meter is advisable in cases of moderate or severe asthma, in order to identify presymptomatic airflow obstruction, which may require escalation of therapy. Outcomes have not been proven to be different when symptom-based monitoring is used rather than PEF monitoring (1), but objective measures are particularly valuable for patients with a history of exacerbations, when evaluating a change in therapy, or for those patients whose perception of airflow is poor. PEF results should be recorded in a log and brought to each prenatal visit.

Inhalation Therapy

No limitations at school or work Normal or near-normal pulmonary function assessed by PEF (or FEV1) Prevent hypoxemia Minimal-to-none exacerbations, chronic symptoms, use of short-term -agonists, or medication side effects

Suggested medications
A stepwise approach to manage asthma is recommended to gain and maintain control (Fig. 24.1). Usual drug doses are shown in Table 24.2. Medications for exacerbation are shown in Table 24.3 and 24.4 (all tables are adapted from the NAEPP) (1). Algorithms for home and hospital management of exacerbation can be found in the NAEPP guidelines (Figs. 24.2 and 24.3) (1). Number and frequency of medications increase with increasing asthma severity. On the basis of clinical trials, medications are considered to be preferred'' or alternative'' at each step of therapy. For patients who are not already taking long-term control medications, assess asthma severity and initiate therapy according to level of severity. For patients who are already taking long-term control medications, assess asthma control and step-up therapy if the patient's asthma is not well controlled on current therapy. In general, using short-acting -agonists (SABA) >2 days a week indicates the need for starting or increasing longterm control medications.

Mild intermittent asthma. These patients require no daily medication (step 1). Quick relief can be provided in the form of two to four puffs of a SABA bronchodilator as needed. In the event of exacerbation, PEFR 50 to 80% of predicted should be treated with an inhaled shortacting -mimetic immediately. Values 50% require the same therapy plus immediate visit to emergency room. However, the need to use rescue twice a week or more means a step-up in therapy and a reclassification of severity. These patients can have severe exacerbations interrupting long periods of normal lung function, in which case systemic steroids should be offered. Mild persistent asthma. Treat with a daily inhaled corticosteroid (low dose). Alternative therapies include inhaled cromolyn, leukotriene receptor antagonist (LTRA), or sustainedrelease theophylline adjusted to serum level of 5 to 12 g/mL (step 2). Moderate persistent asthma. Treat with either a medium-dose inhaled corticosteroid or a lowdose inhaled corticosteroid plus a long-acting inhaled -agonist (step 3). If necessary, give the long-acting -agonist (LABA) with a medium-dose corticosteroid (step 4).

Alternative therapies include low-dose or medium-dose inhaled corticosteroid in combination with either theophylline or a LTRA. Severe persistent asthma. These patients require both a high-dose inhaled corticosteroid and a long-acting inhaled -agonist (step 5) and may also require oral corticosteroids (step 6); when feasible, the oral corticosteroids should be discontinued and control maintained with inhaled agents. An alternative therapy would be high-dose inhaled corticosteroid plus sustained-release theophylline titrated to therapeutic serum levels, as above. Inhaled steroids Anti-inflammatory agents decrease edema and secretions in the bronchioles. Indications are shown in Figure 24.1. They are used not for acute relief, but for long-term management (four weeks for maximal benefit). Inhaled corticosteroids are the most consistently effective long-term control medication at all steps of care for persistent asthma. If -agonist (e.g., albuterol) is used two times a week, inhaled steroid therapy should be started. Most of the data on inhaled steroids in human pregnancy come from budesonide (Pulmacort) (12). Inhaled beclomethasone is associated with improved FEV1 and fewer side effects compared to oral theophylline in the only trial comparing them in pregnancy (16). In a large, doubleblind, randomized trial, treatment with low-dose budesonide had no adverse effects on the outcome of pregnancy (17). There is no evidence of increased rates of congenital malformations with the use of inhaled corticosteroids in pregnancy (4,14). Nor is there an effect on fetal growth, preterm birth, rates of gestational hypertension, preeclampsia, and perinatal mortality (6, 7, 1820) A meta-analysis concludes that they are safe in pregnancy (21). Agonists -Agonists relax bronchiolar smooth muscle. There is no consistent evidence of increased rates of congenital malformations with the use of -agonists in pregnancy (14) despite a recent case-control study suggesting an increased risk of gastroschisis when bronchodilators were used during the periconception period (22). Without having adjusted for severity of maternal asthma, it would be premature to conclude that -agonists correlate with gastroschisis. Use of inhaled -agonists does not appear to increase perinatal risks in pregnant

asthmatic patients (including gestational hypertension, preterm birth, low birth weight, fetal growth, and small for gestational age) (6, 7). Short-acting -agonists. These are the treatment of choice for relief of acute symptoms. Regularly scheduled, daily, chronic use of SABA is not recommended. The onset of action is 5 minutes, with a duration of only four to six hours. Long-acting -agonists. Produce bronchodilation for at least 12 hours after a single dose. They are not to be used as monotherapy for long-term control of asthma. Instead, they are used in combination with inhaled corticosteroids for long-term control and prevention of symptoms in moderate or severe persistent asthma. Long-acting -agonists have been shown to be more effective than LTRA or theophylline as add-on therapy to inhaled corticosteroids (1). Combinations of inhaled corticosteroids and long acting beta mimetics Fluticasone and salmeterol (Advair) combination is more effective than either drug alone in nonpregnant trials. Cromolyn Cromolyn sodium is a nonsteroidal anti-inflammatory agent used for chronic management of asthma, not acute exacerbations (four weeks for maximal benefit). There is no evidence of increased rates of congenital malformations with the use of cromolyn in pregnancy (14); this is a safe drug in pregnancy, as is nedocromil. Theophylline Theophylline has a long record of use in pregnancy and no teratogenic effects are known; however, the narrow therapeutic window and potential for maternal and fetal toxicity mandates close monitoring of serum levels. Low-dose theophylline is an alternative to a LABA when inhaled corticosteroids do not suffice to control symptoms, but this is not a preferred therapy (1). Recommendations for target serum theophylline levels have been changed to 5 to 12 g/mL.

Leukotriene modifiers Limited human data are available on the use of LTRA during pregnancy. Several small studies have not shown an increase in the rate of major malformations in offspring of women who took LTRA during pregnancy (23, 24). Mean birth weight was lower and risk of low birth weight and fetal distress was higher in the montelukast-exposed group, a difference that may have been related to asthma severity rather than drug effect. In nonpregnant individuals, these drugs are less effective than inhaled corticosteroids, and do not add much benefit to women already on inhaled steroids. They do not reduce the risk of exacerbation requiring systemic steroids, and are associated with modest improvement in PEF, with very modest decrease in use of rescue short-acting -2 agonists ( 25). These drugs may be considered during pregnancy for women who had a good response to them prior to pregnancy, but they are not a preferred option when initiating therapy. Montelukast and zafirlukast are safe in pregnancy. Zileuton, a 5-lipoxygenase inhibitor, has been advised against in pregnancy based on animal data: human data are lacking (14).

Oral corticosteroids Oral corticosteroids are indicated when combinations of inhaled steroids, -agonists, and cromolyn do not control asthma. Oral steroid use in the first trimester is associated with a possible increased risk of cleft lip (with or without cleft palate) from the background rate of 0.1% to 0.3%, a small excess risk. The use of oral corticosteroids during pregnancy is associated with an increase in incidence of gestational diabetes, preeclampsia, preterm delivery, and low birth weight. These outcomes may be attributed to either the drug or the severity of the disease process. Available data do not allow for the distinction (7). Intravenous corticosteroids may be indicated in severe asthma exacerbation. Antepartum testing Delivery

Asthma medications should be continued in labor. Although asthma is typically quiescent during labor and delivery, PEF should be measured upon admission, and again every 12hours in labor. The idea of giving stress doses of steroids in labor or perioperatively is poorly supported by research (See chapter 25, page 199). Individuals receiving long-term corticosteroids have not, in randomized studies, proven incapable of endogenous steroid production perioperatively. A recent systematic review concludes that there is no need to add stress-dose steroids in the perioperative period, as long as patients continue to get their usual daily dose of steroids; this would not, however, be true for patients with primary adrenal failure or other primary dysfunction of the hypothalamicpituitary axis, who would still require additional glucocorticoid coverage. Thus, extrapolating from work done on surgical patients, one would not expect adrenal crisis, and it would seem satisfactory to continue their regular daily steroid dosing during labor for women who are on prednisone, without adding additional stress doses. Blood pressure should, of course, be carefully monitored (28). Prostaglandin E1 and E2 are safe. Prostaglandin F2 should be avoided, as it can cause bronchospasm.

Anesthesia No specific changes; as a rule, regional anesthetics are preferred to general. Postpartum/breastfeeding The NAEPP found that the use of prednisone, theophylline, antihistamines, inhaled corticosteroids, 2-agonists, and cromolyn is not contraindicated for breast-feeding (14). Breastfeeding does not protect against asthma in offspring (29). PNEUMONIA KEY POINTS The presence of an infiltrate on chest X ray confirms the diagnosis of pneumonia.

Complications of community-acquired pneumonia (CAP) include mechanical ventilation, maternal mortality, low-birth-weight infant, and perinatal mortality. Prompt administration of antibiotics without delay and appropriate antibiotic therapy are the most important principles for effective management. Hospitalization is indicated when a pregnant woman with CAP has coexisting medical conditions such as malignancy, renal failure, immunosuppression, cerebrovascular disease, diabetes, or valvular heart disease, RR 30, diastolic BP 60, systolic BP 90, HR 125, altered mental status, PaCO2 60 on room air, presence of a pleural effusion, hematocrit 30, arterial pH7.35, or multilobe involvement. Most cases of low-risk CAP in pregnancy can be treated with a macrolide, while the more high-risk ones can be treated with a macrolide and a -lactam. Antibiotic therapy should not be changed within the first 72 hours unless clinical deterioration is overt or organism sensitivities become available.

DIAGNOSIS Pneumonia is an infectious process of the lower respiratory tract, which should be suspected if a patient presents with new respiratory symptoms of cough, dyspnea, or sputum production, particularly if fever and abnormal breath sounds are also present. The presence of an infiltrate on chest X ray confirms the diagnosis. ETIOLOGY/BASIC PATHOPHYSIOLOGY Etiology is usually bacterial, viral, or fungal infection of the lungs. Streptococcus pneumoniae (530%) and Mycoplasma pneumoniae (530%) are the most common pathogens, but dozens of different organisms can cause pneumonia (Table 24.6) (30, 31). In CAP, the causative agent is identified in only 40% to 60% of the cases (32). CLASSIFICATION

The distinction between CAP and hospital-acquired pneumonia is made in practice. In the majority of cases, clinical signs and symptoms do not distinguish one pathogen from another. The vast majority of cases of pneumonia in pregnant women in clinical practice and in the literature are cases of CAP. The Infectious Diseases Society of America (IDSA) and The American Thoracic Society (ATS) use the Pneumonia Severity Index (PSI) to stratify CAP by comorbidity and mortality rates (33). Most pregnant patients with CAP will fall into subset I; this is a group that, if nonpregnant, would be appropriately treated as outpatients. There are, however, no reliable data as to inpatient versus outpatient therapy in pregnancy. SYMPTOMS Respiratory symptoms: cough, dyspnea, or sputum production; usually fever.

EPIDEMIOLOGY The attack rate for CAP is no different among pregnant women than among women of reproductive age who are not pregnant, approximately 1.5 per 1000 (34). Pregnant women hospitalized with CAP have lower severity scores than their nonpregnant counterparts; this may reflect either a tendency for the disease process to be less severe or a lower threshold for hospitalization during pregnancy. Pneumonia incidence is evenly distributed throughout pregnancy; that is, there is no specific period of vulnerability. RISK FACTORS Smoking and asthma. COMPLICATIONS

Approximately 2% of pregnant women with pneumonia require intubation and mechanical ventilation (35). The risk of maternal mortality with CAP was 2.9% from reports in the 1990s (36). Among women hospitalized for pneumonia during pregnancy, the risk of delivering a small-forgestational-age infant is increased relative to controls, although this may be confounded by different health behaviors in the two groups. Rates of preterm birth and perinatal mortality are increased after pregnancy complicated by pneumonia, though not to statistical significance. Term and preterm premature rupture of membranes have been shown to be increased in women with viral and bacterial pneumonia (37). PREGNANCY CONSIDERATIONS Women hospitalized for CAP during pregnancy appear to be less ill than their nonpregnant counterparts, measured by either severity score or length of stay, but this probably reflects a tendency to hospitalize for less severe disease because of the pregnancy. The rate of preterm delivery is higher among women with a diagnosis of pneumonia than among those with upper-tract respiratory infection or with no respiratory infection (38). In addition, the risk of placental abruption is twice as high among pregnant women hospitalized for pneumonia compared to a control group without respiratory disease (39) although in this large dataset obtained from the National Hospital Discharge Survey, the highest risk of abruption followed not pneumonia but chronic bronchitis. MANAGEMENT Principles Prompt administration of antibiotics without delay and appropriate antibiotic therapy are the most important principles for effective management. Prevention Pneumococcal vaccine prevents 71% of cases of CAP and 32% of related mortality in nonpregnant adults (30). For details on recommended pneumococcal and influenza vaccines, Work-up

Assess severity of illness by physical findings (blood pressure, respiratory rate, mental status, state of hydration) and by radiographic findings (e.g., multilobar involvement and pleural effusion). Laboratory testing for a specific cause is controversial and frequently nonrevealing. The Infectious Disease Society of America and the American Thoracic Society have recommended that diagnostic testing be initiated to determine the cause of CAP if the results would change treatment decisions, for example antimicrobial regimens. This would be most useful in areas of high antibiotic resistance or if unusual pathogens are suspected. A list of clinical indications for more extensive diagnostic testing can be found in the IDSA/ATS Consensus Guidelines (33). Routine diagnostic tests to identify an etiologic diagnosis are optional for the mildly ill, but patients with severe CAP should have the following diagnostic tests: blood cultures, urinary antigen assays for Legionella spp. And S.pneumoniae, and expectorated sputum samples/endotracheal aspirates. Blood culture is positive in 5% to 11% of cases; positive blood cultures are more common in those with severe CAP (40). Blood cultures should be obtained before antibiotic administration.

Treatment Hospitalization The initial management decision after diagnosis is to determine the site of care, that is, outpatient,hospital ward, or ICU. There are no trials addressing benefits of outpatient versus inpatient care for the pregnant woman with pneumonia. Keeping this in mind, physicians may still begin treatment decisions by using a prediction tool for increased mortality, such as the PSI, combined with clinical judgment (33). The PSI was developed to assist physicians in identifying patients at a higher risk of complications and who are more likely to benefit from hospitalization, that is, those with comorbidities, hypoxemia, alteration in vital signs, etc. It has not been validated in pregnancy. Direct admission to ICU is required for patients with septic shock requiring vasopressors, or with acute respiratory failure requiring intubation and

mechanical ventilation. The majority of obstetrical patients will fail to qualify as high risk by these criteria. Retrospectively applying American Thoracic Society guidelines in place at the time of the study (similar to above), only 25% of pregnant patients with a diagnosis of CAP could have been assigned to outpatient care (35). A 23-hour observation period might be useful in deciding whether inpatient treatment is warranted in the pregnant patient. Antibiotics There are no trials to determine which antibiotic regimen is most beneficial for the pregnant woman with pneumonia. No published treatment guidelines alter therapy for pneumonia because of pregnancy. Antibiotic selection should take into account the common causes of CAP, local antibiotic resistance patterns, clinical presentation, comorbid conditions, and recent antibiotic use. The fluoroquinolones are generally avoided in pregnancy because of concerns about interference with cartilage formation in the fetus, and the tetracyclines because of concerns about dentition. However, depending on drug allergies and microbiologic sensitivities, it may be necessary to alter these preferences. Initial choice of antimicrobial treatment is empirical. The ATS and IDSA recommend antibiotic regimens for adults with CAP (40); they are adapted here to exclude, where possible, quinolones and tetracyclines. Previously healthy patient, no recent antibiotic therapy, no risk factors for drugresistant. S.pneumoniae: Erythromycin, azithromycin, or clarithromycin: only 1% of pregnant women with CAPremained febrile with erythromycin 500 mg every six hours (35). Previously healthy, but antibiotics within the past three months for any reason; or comorbidities (chronic heart/lung/liver/kidney disease, or diabetes, or asplenia); or immunocompromise, including immunosuppressant drugs: -lactam plus macrolide; highdose amoxicillin (1 g po tid) or high-dose amoxicillinclavulanate (2 g po bid) are preferred; alternatives include ceftriaxone, cefpodoxime, or cefuroxime (500 mg po bid). Inpatient, not in ICU: -lactam (cefotaxime, ceftriaxone, or ampicillin) plus a macrolide. Inpatient, ICU: -lactam plus azithromycin. For Pseudomonas: Piperacillin-tazobactam, cefepime, imipenem, or meropenem plus ciprofloxacin or

levofloxacin, Or Piperacillin-tazobactam, cefepime, imipenem, or meropenem plus aminoglycoside plus azithromycin. For community-acquired methicillin-resistant. Staphylococcus aureus: Add vancomycin or linezolid In summary, most cases of low-risk CAP in pregnancy can be treated with a macrolide, while the more high-risk ones can be treated with a macrolide and a -lactam. Uncommon pathogens do exist, and should be considered if response to therapy is inadequate or incomplete. Typical responses to therapy include defervescence in two to four days, with resolution of leukocytosis in the same time period. The chest X ray may take longer to clear, as may the auscultatory findings. Antibiotic therapy should not be changed within the first 72 hours unless clinical deterioration is overt or organism sensitivities become available. There is no evidence in nonpregnant adults that intravenous and oral therapy differ in efficacy. Patients should be switched from intravenous to oral therapy when hemodynamically stable and improving clinically, able to ingest medications and have a normally functioning GI tract. If the pathogen and sensitivities are known, the narrowest spectrum agent should be chosen for oral therapy, but in most cases this will not be possible, and oral agents should duplicate the spectrum of the parenteral agents used. The American Thoracic Society and the Infectious Diseases Society of America recommend discharge to home the same day that clinical stability is achieved (afebrile, no tachypnea nor tachycardia, normotensive, normoxemic, normal mental status, and able to tolerate oral intake) and the switch to oral agents is made. Inpatient observation while receiving oral therapy is not necessary. A follow-up inpatient chest X ray is not indicated. There are inadequate data to determine the best duration of antimicrobial treatment for CAP. With older agents, a duration of 10 to 14 days is commonly prescribed, but newer agents have longer half-lives and therefore may be curative over shorter courses of therapy, for example, five to seven days; trials are under way. Regardless of the total duration, it is recommended that patients with CAP be treated for a minimum of five days, should be afebrile for 48 to 72 hours, and should be clinically stable before discontinuation of therapy (40). Oxygen support should be provided as needed. Antepartum testing

No specific indication. Delivery No specific changes. Anesthesia No specific changes. Postpartum/breastfeeding No specific changes.

TUBERCULOSIS KEY POINTS Definite diagnosis of active infection is based on culture (of suspected site: sputum for pulmonary TB) for Mycobacterium tuberculosis . Sputum culture is also important for drug sensitivity testing. Diagnosis of latent tuberculosis infection is based on a positive tuberculin test (or interferon gamma-release assay, IGRA) and the absence of signs, symptoms, or proof of active disease. Pregnancy does not influence the progression from latent to active disease. The treatment for latent tuberculosis infection in pregnancy is isoniazid 300 mg daily for six to nine months. Treatment of active tuberculosis consists of an initial two-month phase of therapy, including isoniazid, rifampin, pyrazinamide, and ethambutol. Directly observed therapy is usually recommended. For the following four

months, continue isoniazid and rifampin. Treatment for active tuberculosis is not altered by pregnancy.

EPIDEMIOLOGY/INCIDENCE Although still rare in the developed world, there were nine million new TB cases in 2009 worldwide, and 1.5 million deaths; TB is one of the top three causes of death for women of reproductive age (72). HIV coinfection (about 12% worldwide) accounts for a significant portion of the tuberculosis burden. Even resource-rich countries have seen a resurgence of TB over the past few years, as a result of an increase in immigrant populations. The national incidence of TB in pregnancy in the UK in 2008 was estimated at 4 per 100,000 maternities (73). All but one of the TB patients in this study were non-Western immigrants, and half had extrapulmonary disease. Few had undergone tuberculin skin testing, despite recommendations to the contrary.

ETIOLOGY/BASIC PATHOPHYSIOLOGY The pathogenesis of tuberculosis infection and disease in pregnant women is similar to that in nonpregnant women. Spread (by airborne droplets) is facilitated by the ability of these small particles to remain airborne for hours after being emitted from an infected respiratory tract. Once the Mycobacterium is taken up by alveolar macrophages, the infection may either be contained by granuloma formation or may progress to active disease (74). Most patients develop cell-mediated immunity, which is demonstrated by conversion of the tuberculin skin test, and which constitutes latent tuberculosis infection. In some patients, the replication of M. tuberculosis cannot be contained, and active disease occurs. Latent tuberculosis infection can develop into active tuberculosis, especially in individuals with risk factors. Pulmonary disease is the most common but not the only form of active tuberculosis, which can manifest

in 20% of cases (extrapulmonary tuberculosis) as meningitis, osteitis, genitourinary involvement, or disseminated disease. RISK FACTORS/ASSOCIATIONS HIV is the most important risk factor. Poorly controlled diabetes, renal failure, malignancy, steroids, malnutrition, and vitamin A or D deficiency are other risk factors for acquiring active M. tuberculosis infection (74). DIAGNOSIS Definitive diagnosis of active infection is still made by culture (of suspected site, e.g., sputum) or M. tuberculosis. Smear demonstrating acid-fast bacilli is a technique for rapid diagnosis (74). Diagnosis of latent tuberculosis requires a newly positive tuberculin test in the absence of disease (thus no symptoms, X-ray findings, bacilli on smear, or positive culture). The most widely used method to detect respiratory TB in most disease-endemic countries is the sputum smear microscopy test developed in the 19th century, drawbacks of which include low sensitivity (especially in children and in HIV-positive individuals), inability to determine drug susceptibility, and variable performance depending on operator training and skill. In December 2010, the WHO endorsed a novel rapid test for tuberculosis, a fully automated molecular test for TB case detection plus rifampicin resistance testing. Other than adding sputum and reagent to the cartridge, there is little for the technician to do (75). In a multinational study of about 1500 nonpregnant adults, this assay identified 98% of patients with smear-positive and culture-positive tuberculosis (including more than 70% of patients with smear-negative and culture-positive disease) and correctly identified 98% of bacteria that were resistant to rifampin (75). The effect of pregnancy on this test has not been studied, but it is counterintuitive to assume pregnancy would affect it. PREGNANCY CONSIDERATIONS Tuberculosis attack rates appear to be comparable in the pregnant and nonpregnant states. Presentation is similar among both pregnant and nonpregnant patients, but diagnosis may be delayed in pregnancy because of the ubiquity of constitutional complaints during early

pregnancy. Pregnancy is not known to influence the progression from latent to active disease, nor has it been shown to affect the response to treatment. Pregnancy is not associated with higher (or lower) prevalence of anergy compared to other HIV-negative adults. There are conflicting data on the effect of TB on maternal and neonatal outcomes. In a recent population-based study in Taiwan, women known to have TB during pregnancyall of whom were treateddemonstrated an absolute increase of 23% in the rate of low-birthweight babies, with no difference in preterm births, compared to controls (76). An earlier case-control study from India suggested higher rates of both preterm birth and small for gestational age newborns among women undergoing treatment for pulmonary TB, compared to matched controls (77), but a later Indian casecontrol study found no difference in perinatal outcome (78). Congenital TB, which is very rare, is associated with maternal HIV infection, tuberculous endometritis, and miliary tuberculosis (79). It can occur hematogenously via the placenta and umbilical vein or by fetal aspiration or ingestion of infected amniotic fluid. Neonatal TB develops following exposure of an infant to the mother's aerosolized respiratory sections. This is more common than congenital TB, and diagnosis of neonatal TB can lead to diagnosis of previously unrecognized TB in the mother (80).

MANAGEMENT Principles Management of M. tuberculosis infection in pregnancy should be multidisciplinary, with involvement of obstetrician, maternal-fetal medicine, and infectious diseases specialists. Screening Tuberculin skin testing Tuberculin skin testing (TST) is the method historically used to detect both latent and active

disease. TST can be performed safely in pregnant women, and pregnancy does not alter the response to the TST (81). Using standardized purified protein derivative (PPD), 0.1 mL (5 tuberculin units) is administered intradermally in the volar surface of the forearm. The reaction is read 48 to 72 hours after the injection, although reading is accurate up to a week after challenge. Targeted (not universal) tuberculin testing is recommended so as to identify individuals who are at increased risk for developing M. tuberculosis infection and who would benefit by treatment of latent tuberculosis infection. Testing is discouraged among persons without these risk factors. Persons at increased risk for development of active disease are those who were recently infected (i.e., converted from a positive to a negative skin test within the preceding two years), as well as those who have latent infection plus an increased risk of progression to overt disease. Table 24.8 shows some of indications for testing in pregnancy: it is not an exhaustive list but is limited to those conditions that may be found in pregnancy. Interpretation of PPD results is shown in Table 24.9 (82).

Work-up Women with a cough lasting for > 2 weeks or with symptoms as described above, especially with risk factors or from high-prevalence areas, should be worked up for tuberculosis. Radiographic findings suggesting tuberculosis include upper lobe infiltrate, cavitary lesions, and hilar adenopathy. Sputum smear can be negative even in active disease (1520% of cases). Sputum culture is required both for definite diagnosis and for drug sensitivity testing (74), although both false-positive and falsenegative results have been reported. Growth generally occurs in 7 to 21 days, but may take 6 weeks or longer. Prevention BCG (bacille CalmetteGuerin) vaccine has >70% efficacy in preventing M. tuberculosis infection in children, but not great efficacy in adults. TST cannot distinguish between induration induced by BCG or M. tuberculosis infection. A history of BCG vaccination is ignored when administering and interpreting a tuberculin skin test. BCG should not be administered during pregnancy for the prevention of tuberculosis, since it is a live vaccine. IGRA testing is useful in evaluating for TB in women with prior BCG vaccine. Therapy Latent tuberculosis infection The treatment for latent tuberculosis infection in pregnancy is isoniazid 300 mg daily for six to nine months (81). Alternative rifampin-based regimens have not been evaluated in pregnancy. Because isoniazid can interfere with pyridoxine metabolism and thereby precipitate peripheral neuropathy, coadministration of pyridoxine 25 mg/day is advisable. Isoniazid is 60% to 90% effective in reducing the risk of progression from tuberculosis latent infection to active disease. The most important but rare (1/1000) side effect of isoniazid is

hepatitis; the concern that this may be more common among pregnant women (which prompted a consideration of routinely deferring treatment to the puerperium) is based on a single investigation in which five cases of isoniazid hepatitis were identified among nearly 4000 pregnant women (86): statistical significance was absent. Age > 35 years is no longer considered a contraindication to isoniazid use (82) . Pregnant and postpartum women should have pretreatment liver transaminases and bilirubin function tests, and if these are normal, isoniazid can be started. Liver function tests should be obtained monthly. Isoniazid should be discontinued in a symptomatic or jaundiced patient if alanine aminotransferase (ALT) is more than three times the upper limit of normal, and in an asymptomatic patient if ALT is more than five times the upper limit of normal (87). Advantages of beginning treatment during pregnancy include better compliance and less loss to follow-up. A decision analysis suggests that antepartum treatment of latent tuberculosis infection is more efficient at preventing additional cases of TB within the population (88). Recent infection with tuberculosis (i.e., a recent conversion of TST) or HIV coinfection increases the risk for transplacental spread of tubercle bacilli, and thus for congenital tuberculosis, which implies that treatment for latent infection in these cases should be especially expeditious and compliant. Active tuberculosis infection Single-drug therapy is not acceptable for active TB. Multiple drugs for six months or more can cure > 95% of patients (Tables 24.10 and 24.11) (88). The treatment regimen is two-part, with an initial period of intensive therapy to kill actively growing bacilli, shortening the time the individual is infectious to others, followed by a second phase in which microbiologic cure is the goal. The usual treatment for new patients with TB is an initial two-month phase of isoniazid, rifampin, pyrazinamide, and ethambutol. Drugs may be given as fixed-dose combinations. Strict adherence to the regimen is important in minimizing drug resistance; for this reason directly observed therapy is usually recommended. For the following four months, isoniazid and rifampin are continued. In settings where isoniazid resistance is high and the patient's strain of TB has not been tested for isoniazid resistance, the four-month continuation phase should also include ethambutol. Treatment in pregnancy

Treatment regimens and alternatives are available from the Centers for Disease Control and Prevention, the American Thoracic Society, the National Institute for Clinical Excellence, and the WHO. Those interested in these topics may bookmark the CDC's Find TB Resources Web site at, which contains links to these sites. In the case of multidrug-resistant (MDR) or extensively drug-resistant (XDR) tuberculosis, treatment becomes considerably more complex. Retreatment is beyond the scope of this chapter.

Tuberculosis treatment is not altered by pregnancy. Isoniazid, rifampin, pyrazinamide, and ethambutol are not teratogenic, and the WHO recommends their use in pregnant women (89). Streptomycin exposure in utero has been associated with infant hearing loss, and so it is contraindicated in pregnancy. There are no adequate well-controlled reliable studies in human pregnancy. Although there has been some discussion in the literature about deferring treatment of latent tuberculosis infection to the postpartum period (see above), there is no defensible argument for deferring treatment of active disease during pregnancy. Pregnant women who are untreated pose an infection risk to the population at large as well as to their own infants. Drug resistance MDR-TBresistant to isoniazid and rifampinaccounts for about 1% of isolates in the United States. (90) Worldwide, MDR-TB accounts for about 4% of cases ( 91), although in some areas of the Russian Federation this rate is as high as 25%. Approximately 5% to 10% of MDR-TB strains are believed to be XDR, that is, also resistant to second-line anti-TB drugs. Pregnant women with MDR tuberculosis should be treated despite the limited safety data, because of the grave public health implications. Tuberculosis strains that are known to be resistant to one or more of the first-line drugs are treated with alternative agents, for example, capreomycin, cycloserine, fluoroquinolones, paraaminosalicylate, thiacetazone,

amoxacillin-clavulanic acid, clofazimine, or clarithromycin. Kanamycin, streptomycin, and amikacin, which are ototoxic, have been associated with hearing loss in newborns whose mothers were treated during pregnancy. Ethionamide not only worsens nausea associated with pregnancy but has also been associated with congenital anomalies in animal studies: the WHO recommends against its use in pregnancy, if possible (92). For all the second-line drugs, well-designed controlled studies in pregnant women are unavailable. The literature on treatment of drug-resistant TB during pregnancy is limited to case reports or case series (93 96). Therapy of MDR tuberculosis during pregnancy should be driven by microbiologic susceptibility patterns (obtained by direct culture or known to be prevalent in the area), modified where possible by fetal concerns. For example, the WHO suggests that therapy of drug-resistant TB may be delayed until the second trimester after a discussion with the patient of the risks and benefits (90). The individual practitioner is unlikely to make solo decisions about the treatment of MDR-TB, as this is a role commonly filled by the health Infection control issues Women with active pulmonary tuberculosis are infectious, but if the organism is sensitive, two weeks of multidrug therapy renders them noninfectious, so special precautions are not necessary thereafter. If the duration of therapy is shorter, or if MDR tuberculosis is present or suspected, the mother must be isolated in a negative pressure room for labor, and personal protective equipment should be worn by staff. Measures for the infant may include prophylactic isoniazid, BCG vaccination, orin cases of MDR or XDR tuberculosis separation from the mother. Antepartum testing No specific indications. Delivery Cord blood and placenta should be tested for acid-fast bacilli. Postpartum/breastfeeding Maternal tuberculosis treatment is not altered by breast-feeding. Pyridoxine should be

administered to the breast-feeding infant even if the infant is not receiving isoniazid therapy (79, 81). Neonate should undergo TST, chest X ray, lumbar puncture, and M. tuberculosis smear and culture if mother had TB during pregnancy. If tuberculosis is suspected in the child, the child should be adequately treated.