Pneumonia in pregnancy William H. Goodnight, MD; David E. Soper, MD

Objective: Historically, pneumonia during pregnancy has been associated with increased morbidity and mortality compared with nonpregnant women. The goal of this article is to review current literature describing pneumonia in pregnancy. This review will identify maternal risk factors, potential complications, and prenatal outcomes associated with pneumonia and describe the contemporary management of the varied causes of pneumonia in pregnancy. Results: Coexisting maternal disease, including asthma and anemia, increase the risk of contracting pneumonia in pregnancy. Neonatal effects of pneumonia in pregnancy include low birth weight and increased risk of preterm birth, and serious maternal complications include respiratory failure. Community-acquired pneumonia is the most common form of pneumonia in pregnancy, with Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae accounting for most identified bacterial organisms. Beta-lactam and macrolide antibiotics are considered safe in pregnancy and are effective for most community-acquired pneumonia in pregnancy. Viral respiratory infections, including

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espite advances in antimicrobial therapy and respiratory care, pneumonia in the antepartum period can be associated with significant maternal and neonatal morbidity (1– 4). The estimated prevalence of antepartum pneumonia ranges from 0.78 to 2.7 per 1000 deliveries (3, 4). This rate is similar to the nonpregnant population, with reported rates of hospitalization for pneumonia of 1.51 per 1,000 deliveries vs. 1.47 per 1,000 nonpregnant controls (5). The onset of pneumonia is not gestational age dependent, with the average diagnosis at 32 wks of estimated gestational age (5). Maternal physiologic adaptations to pregnancy make pneumonia less well tolerated during pregnancy. Pregnancy increases the risk of maternal complica-

From the Division of Maternal–Fetal Medicine (WHG) and the Department of Obstetrics and Gynecology (DES), Medical University of South Carolina, Charleston, SC. The authors have no financial interests to disclose. Copyright © 2005 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000182483.24836.66

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varicella, influenza, and severe acute respiratory syndrome, can be associated with maternal pneumonia. Current antiviral and respiratory therapies can reduce maternal morbidity and mortality from viral pneumonia. Influenza vaccination can reduce the prevalence of respiratory hospitalizations among pregnant women during influenza season. Pneumocystis pneumonia continues to carry significant maternal risk to an immunocompromised population. Prevention and treatment of Pneumocystis pneumonia with trimethoprim/sulfamethoxazole is effective in reducing this risk. Conclusions: Prompt diagnosis and treatment with contemporary antimicrobial therapy and intensive care unit management of respiratory compromise has reduced the maternal morbidity and mortality due to pneumonia in pregnancy. Prevention with vaccination in at-risk populations may reduce the prevalence and severity of pneumonia in pregnant women. (Crit Care Med 2005; 33[Suppl.]:S390 –S397) KEY WORDS: pneumonia; pregnancy; varicella; influenza; severe acute respiratory syndrome; respiratory failure

tions from community-acquired pneumonia, including the need for mechanical ventilation in 10 –20%, bacteremia in 16%, and empyema in 8% of cases (1, 4). Pneumonia is a significant cause of hospitalization for respiratory disorders during pregnancy, accounting for 92 of 294 respiratory admissions in obstetric patients during influenza season (6). Respiratory failure due to pneumonia is the third leading indication for intubation during pregnancy, accounting for 12% of intubated obstetric patients (2). Pneumothorax, atrial fibrillation, and pericardial tamponade complicate another 4% of cases of antepartum pneumonia (1). Maternal mortality from community-acquired pneumonia, though still significant, has been reduced with the use of antibiotics from 23% to ⬍4% (1, 6, 7), with most cases of maternal deaths occurring in patients with coexisting cardiopulmonary disease (1). Pneumonia complicating pregnancy can also have adverse fetal effects. In the series described by Madinger et al. (1), preterm labor occurred in 44% of cases of antepartum pneumonia, with a preterm birth rate of 36%. Munn et al. (4) also

reported a significantly increased risk for the need for tocolysis (22% vs. 4.2% for controls), gestational age at delivery of ⬍34 wks (22% vs. 7.6%, p ⫽ .12), and average gestational age at delivery of 36 wks (38 wks in controls) in pregnancies complicated by pneumonia. Munn et al. (4) demonstrated that pregnancies complicated by pneumonia result in a significantly lower average birth weight at delivery. The relative risk for small gestational age infants from pregnancies complicated by pneumonia is 1.86 (95% confidence interval, 1.01–3.45) (3, 5), with an average birth weight of 400 g less than controls (5). Pneumonia in pregnancy also results in low-birth-weight neonates (weight at delivery, ⬍2500 g) in 33.9% of cases compared with 13.6% of controls (4). The neonatal mortality rate due to antepartum pneumonia ranges from 1.9% to 12%, with most mortality attributable to complications of preterm birth (1, 8). Pregnancy results in significant physiologic changes that can have implications for the maternal response to pneumonia. An understanding of the normal cardiopulmonary adaptations to pregCrit Care Med 2005 Vol. 33, No. 10 (Suppl.)

nancy is important to aid in recognizing the effects of pneumonia and managing respiratory compromise. Hormonal effects of progesterone and beta-human chorionic gonadotropins, alterations in chest shape and dimensions, and elevation of the diaphragm from the pregnant uterus are purported causes of respiratory changes during pregnancy. As a result of these alterations, most patients experience a baseline perception of dyspnea, peaking in the early third trimester (9). Maternal oxygen consumption increases by 15–20% (9). Pulmonary function adaptations to pregnancy result in a 30 – 40% increase in tidal volume (10), with an average tidal volume of 700 mL (9). The respiratory rate and vital capacity are not changed, resulting in a net 20% decrease in expiratory reserve volume, functional residual capacity, and residual volume (10). These changes in pulmonary function may result in a diminished ability to compensate for the effects of respiratory disease during pregnancy. Respiratory and renal adaptations to pregnancy have implications for maternal acid– base status. Pregnancy results in a compensated respiratory alkalosis. As minute ventilation increases by 30 – 40%, PaO2 increases to 104 –108 mm Hg, and PaCO2 decreases to 27–32 mm Hg at baseline (10). The arterial pH remains in the normal range due to increased renal excretion of bicarbonate (10). Alterations from these compensated values due to respiratory illness can affect fetal oxygenation, and minor changes in PaCO2 and PaO2 may indicate a more severe respiratory dysfunction than clinically apparent. Certain immunologic alterations in pregnancy may have effects on maternal susceptibility and response to pneumonia (11). Pregnancy is associated with a decrease in cell-mediated immunity (11, 12), a decrease in helper-T-cell numbers, and a decrease in natural killer cell activity (11). The increased susceptibility to viral and fungal pneumonias in pregnancy has been attributed to the pregnancy-induced decrease in cytotoxic lymphocyte activity (11).

Community-Acquired Pneumonia Pneumonia is the result of an infection of the distal bronchioles and alveoli (9). Most organisms are acquired by inhalation or aspiration of nasopharyngeal secretions (9, 13). Infection causes direct lung injury and interstitial inflammation mediated by the host response. This lung Crit Care Med 2005 Vol. 33, No. 10 (Suppl.)

injury results in intrapulmonary shunting and creation of ventilation–perfusion mismatch, contributing to potential hypoxia (13). In pregnancy, as in the nonpregnant population, the etiological agent is not identified in 40 – 61% of cases of community-acquired pneumonia (1, 7, 14). The most common bacterial agents identified in pregnancy include Streptococcus pneumoniae in 17% of cases and Haemophilus influenzae identified in 6% of cases (15). Viral pneumonia contributes to 5% of identified pathogens in pneumonia during pregnancy, with varicella and influenza the most common viral pathogens (15). Other organisms identified include Mycoplasma, Staphylococcus aureus, Legionella pneumophila, Klebsiella pneumoniae, and Pseudomonas (9, 11, 15–17). Fungal and protozoal organisms can also result in pulmonary infection during pregnancy, usually affecting immunocompromised populations. Identified risk factors for the development of pneumonia during pregnancy include preexisting maternal disease (HIV, asthma, cystic fibrosis), anemia, cocaine use, and alcohol abuse (1, 3, 4, 7, 18). Madinger et al. (1) reported that 24% of patients with antepartum pneumonia had an underlying maternal illness. Maternal asthma (odds ratio, 5.3) and anemia (odds ratio, 9.9) are significantly associated with the development of pneumonia during pregnancy (4). The use of corticosteroids for enhancement of fetal lung maturity and tocolytic agents has also been associated with antepartum pneumonia (15). Among cases of pneumonia during pregnancy, the pneumonia was more likely to be hospital-acquired than community-acquired among patients receiving corticosteroids for fetal lung maturity (4). Tocolytic agents carry an increased risk for pulmonary edema that may worsen the respiratory status of coexisting pneumonia or confuse the diagnosis of pneumonia. As pneumonia increases the risk for preterm labor, judicious use of tocolytic agents during pneumonia is warranted. Clinical symptoms of pneumonia include fever, cough, pleuritic chest pain, rigors, chills, and dyspnea (13). During pregnancy, 59.3% of patients reported a productive cough, 32.2% shortness of breath, and 27.1% reported pleuritic chest pain (4). Physical examination usually reveals tachypnea, dullness to percussion, tactile and vocal fremitus, egophony, and use of accessory muscles of

respiration (9, 13). Auscultation may demonstrate a pleural friction rub, inspiratory rales, or absent breath sounds over the affected lung field (13). Physical examination is only 47– 69% sensitive and 58 –75% specific for pneumonia; therefore, all cases suspicious for pneumonia, even in pregnancy, should be confirmed by chest radiograph (13). Munn et al. (4) demonstrated that 98% of patients with antepartum pneumonia had positive chest radiographs, either at admission or on repeat examinations, with findings including infiltrate, atelectasis, pleural effusion, pneumonitis, or pulmonary edema. Other illnesses in the differential diagnosis that can present with symptoms of pneumonia include pulmonary embolism, cholecystitis, appendicitis, and pyelonephritis. Laboratory evaluation for suspected pneumonia during pregnancy should include a complete blood count and serum chemistries for liver, renal, and glucose evaluation. Evaluation of maternal oxygen status with pulse oximetry or arterial blood gas should be performed (14). As applicable, based on gestational age, fetal status should be evaluated with electronic fetal monitoring. Identification of the etiological agent should be attempted with sputum Gramnegative stain and culture or urinary/ serologic antigen or antibody evaluation (Table 1). Blood cultures may assist in the identification of the etiological agent, especially in admitted patients and patients with severe community-acquired pneumonia (14). However, in most series of pneumonia in pregnancy, blood cultures have been inconsistently performed and are only rarely positive (7, 11, 18). In the nonpregnant population, several severity assessment tools have been developed to predict the course of pneumonia, the need for hospitalization, and to predict mortality. The most commonly used guidelines have been prepared by the American Thoracic Society (ATS) and the British Thoracic Society. The ATS guidelines stratify patients into four groups of severity based on coexisting illness (COPD, asthma, chronic renal failure, alcohol abuse, diabetes, malignancy, chronic liver disease), respiratory rate of ⬎30 breaths/min, diastolic blood pressure of ⬍60 mm Hg or systolic blood pressure of ⬍90 mm Hg, pulse of ⬎125 beats/min, temperature of ⬍35 or ⬎38.3C, sepsis, confusion, white cell count of ⬍4 or ⬎30 ⫻ 109/L, PaO2 of ⬍60 mm Hg or PaCO2 of ⬎50 mm Hg, creatinine of ⬎1.2 mg/dl or blood urea S391

nitrogen of ⬎20 mg/dl, hemoglobin of ⬍9 mg/dl, arterial pH of ⬍7.35, or multilobar involvement or effusion on chest radiograph (14). These criteria indicate optimal location for treatment (e.g., outpatient, inpatient, intensive care unit [ICU]), and they suggest the pathogenesis of the pneumonia directing antibiotic choice (14). Yost et al. (18) retrospectively applied the ATS guidelines to 119 pregnant patients with pneumonia, correctly identifying all patients with a complicated course. Furthermore, they identified that 25% of their patients would have met the criteria for outpatient therapy (18). A simpler version has been proposed by the British Thoracic Society that considers the presence of two of four criteria indicating severe illness. The British Thoracic Society criteria include: respiratory rate of ⬎30 breaths/min, diastolic blood pressure of ⬍60 mm Hg, blood urea nitrogen of ⬎19.1 mg/dl, and confusion (18). Patients with any two of these criteria have a 36-fold increase in mortality compared with more mild illness (18). Although these criteria have been applied only retrospectively to a limited series of pregnant patients, the ATS or British Thoracic Society guidelines may be applicable in predicting the need for admission, ICU admission, and antibiotic choice in pregnant women. Contemporary management of pneumonia in pregnancy includes admission, initiation of antimicrobial therapy, fetal evaluation, and maintenance of normal maternal respiratory function. ATS guidelines recommend treatment with macrolide antibiotic for mild illness, with addition of beta-lactam for severe illness (Table 2) (14). Yost et al. (18) demonstrated monotherapy with erythromycin was inadequate in only 1 of 119 patients with pneumonia in pregnancy, with treatment failures characterized by multilobar involvement, respiratory distress, and valvular heart disease (14). Macrolide and beta-lactam antibiotics have a favorable safety profile in pregnancy and provide adequate coverage for the most common organisms (19, 20). In patients at an increased risk of hospital-acquired pneumonia or aspiration pneumonia, the addition of an aminoglycoside for coverage for Pseudomonas and enteric Gramnegative organisms should be considered (14). Pneumonia in pregnancy results in inflammation and edema of the alveoli, decreasing the number available for oxygen transport (21). Vascular flow remains S392

present to these affected alveolar units (21). Supplemental oxygen is required to treat the increased alveolar–arterial oxygenation gradient that results from this ventilation/perfusion mismatch and is necessary in the majority of pregnant patients with pneumonia (3). Treatment of reactive airway disease and chest physical therapy is a useful adjuvant to improve respiratory function. The increased affinity for oxygen by fetal hemoglobin creates an oxygen dissociation curve for fetal hemoglobin that favors transplacental transfer of oxygen from the mother to the fetus. This increased oxygen affinity makes the fetus resistant to mild changes in maternal PaO2. Fetal delivery of oxygen will decrease when the maternal oxygen saturation falls to ⬍90%, corresponding to a PaO2 of 65 mm Hg (21). The goal of therapy therefore should be to maintain the maternal PaO2 of ⬎60 –70 mm Hg with the lowest possible FIO2 to ensure adequate fetal oxygenation (21). Respiratory failure occurs in 10% of patients with pneumonia in pregnancy, despite antibiotic therapy. Indications for ICU admission and intubation with mechanical ventilation include inadequate oxygenation (PaO2 of ⬍60 mm Hg or oxygen saturation of ⬍85% on 0.6 FIO2), inadequate ventilation (PaCO2 of ⬎50 mm Hg), airway protection, sepsis requiring invasive hemodynamic monitoring, or persistent metabolic acidosis (2, 11, 21). As the pathogenesis of respiratory compromise in pneumonia is that of intrapulmonary shunting rather that hypoventilation, the addition of positive end-expiratory pressure will allow a lower FIO2 to prevent collapse of alveoli and reduce the alveolar-arterial oxygen gradient (21). Case reports of the use of high-frequency oscillatory and positive-pressure ventilation and an intravenacaval membrane oxygenator for refractory cases of antepartum pneumonia have been described (11). Elective delivery has also been advocated to improve maternal respiratory status; however, few studies have evaluated maternal respiratory response to delivery. In one case series, nine intubated pregnant patients underwent delivery, resulting in a 28% reduction in oxygen requirement within 24 hrs of delivery (22). No other changes in ventilatory indices or clinical course were identified, leading the authors to conclude that delivery should be performed only for obstetric indications (22).

Fungal Pneumonia Fungal pathogens that have been associated with pneumonia include Cryptococcus neoformans, Histoplasma capsulatum, Sporothrix schenckii, Blastomyces dermatitidis, and Coccidioides immitis (9). These organisms are acquired from environmental sources with regional predilections and usually cause mild, self-limiting disease. Pneumonia in pregnancy with fungal organisms is rare. Isolated fungal pneumonia in pregnancy usually resolves with or without treatment in women without coexisting illness (9, 23). In contrast, disseminated disease carries a more serious prognosis (23, 24). Twenty percent of patients with coccidioidomycosis pneumonia in the third trimester of pregnancy developed disseminated disease, with an increased risk of preterm delivery, perinatal mortality, and a high rate of maternal mortality (24). Disseminated disease was more common with infection in the third trimester (24). Ely et al. (23) reported a 29% maternal mortality rate for disseminated cryptococcal infection in pregnant, immunocompetent women, whereas no maternal deaths were noted in a case series of four patients with isolated antepartum cryptococcal pneumonia. Fungal pneumonia may present with slow onset of cough and dyspnea or an acute onset of pleuritic chest pain with hypoxemia (23). Chest radiographs tend to demonstrate nodular disease and adenopathy, but they may show lobar or multilobar airspace disease (23). The diagnosis may be confirmed by sputum Gram-negative stain and culture for fungal organisms or by the detection of serum fungal antigens. For disseminated disease or severe pneumonia (ATS or British Thoracic Society criteria) treatment with intravenous amphotericin B (pregnancy category B) is recommended, followed by oral fluconazole postpartum (23, 24). Mild, isolated fungal pneumonia may be observed with close monitoring of chest radiographs and respiratory status or treated with amphotericin B or fluconazole (23). Although single-dose oral fluconazole during pregnancy does not seem to increase the risk of congenital malformation (25, 26), case reports suggest long-term, parenteral use is associated with an increased risk of fetal anomalies, including brachycephaly, abnormal facies, abnormal calvarial development, and cleft palate (19, 27). Crit Care Med 2005 Vol. 33, No. 10 (Suppl.)

Viral Pneumonia Varicella and influenza are the most common pathogens associated with viral pneumonia in pregnancy (7, 9, 11, 28). Other viral pathogeneses have also resulted in pneumonia during pregnancy, including rubella, rubeola, Hantavirus, and severe acute respiratory syndrome (SARS) (9, 29 –31). Viral invasion of lung parenchyma results in an interstitial pneumonitis, exacerbated by the host immune response to the infection (32). The result is significant impairment of pulmonary gas exchange, poorly tolerated by the pregnancy-adapted respiratory system (32). Viral pneumonia is often complicated by acute respiratory failure, secondary bacterial infections, and adult respiratory distress syndrome (9). Although primary varicella infection is a childhood illness, 5–10% of cases occur after age 15 (33, 34). This uncommon adult infection, however, accounts for 25–55% of fatal cases of varicella (33, 34). Approximately 10% of the adult population is susceptible to primary varicella infection (35). The risk of primary varicella infection in at-risk adults after close exposure may be as high as 70% (35). Acute varicella-zoster virus infection affects 0.5– 0.7 of 1,000 pregnancies (33). The varicella virus is a highly contagious human DNA herpes virus transmitted by respiratory droplets and close personal contact (33). Household contact attack rates approach 90% (33). After an incubation period of 10 to 21 days, primary varicella-zoster virus infection presents with fever, headache, and malaise, followed by the characteristic pruritic maculopapular to vesicular rash. Most cases resolve within 7–10 days after the onset of the rash (33). Complications of primary varicella-zoster virus infection, more common in adults, include secondary bacterial cellulitis, encephalitis, or pneumonia (33). Pulmonary involvement in primary varicella-zoster virus infection is noted in 16% of cases (33). Varicella pneumonia complicates 5.5–16.5% of cases of adult primary varicella (36). Approximately 3–5 days after the onset of the rash, signs and symptoms of pneumonia may become present, including a vesicular rash, oral lesions, dyspnea, cough with bloodtinged sputum, malaise, and pleurisy (11, 34, 37). The diagnosis of varicella pneumonia is confirmed by the presence of an interstitial, nodular pattern (“groundglass” appearance) or focal infiltrates on Crit Care Med 2005 Vol. 33, No. 10 (Suppl.)

chest radiograph in a patient with primary varicella symptoms including characteristic rash and fever (36). Presence of maternal immunoglobulin M and seroconversion of immunoglobulin G antibodies from acute to convalescent phase to varicella confirm the diagnosis but requires ⱖ2 wks for seroconversion. Viral culture or polymerase chain reaction identification of varicella DNA from the base of lesion can also confirm the diagnosis of primary varicella. Varicella causes an interstitial pneumonitis mediated by the host immune response (32). Pathologic changes in bronchioles include mononuclear cell infiltrates, capillary endothelial cell injury, intra-alveolar exudates, and hemorrhage (32). These pathologic changes result in significant impairment of pulmonary gas exchange (32). The risk of varicella pneumonia complicating primary varicella-zoster virus infection during pregnancy (0.1–18.3%) is similar to the nonpregnant state. Before the introduction of antiviral therapy, the mortality rate for varicella pneumonia in pregnancy was significantly higher (41%) than in nonpregnant patients (1.5– 12.1%) (36, 38, 39). Contemporary maternal mortality remains high in most reports, ranging from 11% to 35% (11, 32, 37, 39), with one series of 18 patients with no maternal deaths (34). Risk factors for varicella pneumonia include later gestational age (39), history of or current smoking, and skin involvement with ⬎100 vesicles (34). Varicella pneumonia is more likely to occur in the second or third trimester, with average gestational age at onset of 27 wks and average gestational age at delivery of 36 wks (39). Most patients in modern case series are treated with acyclovir, and all demonstrate diffuse nodular densities or diffuse reticular infiltrates on chest radiographs (37, 39). The prominent hypoxemia due to pneumonitis results in a high rate of respiratory failure. Mechanical ventilation may be required in up to 40 –57% of pregnant patients with varicella pneumonia (37, 39). The need for mechanical ventilation increases the mortality rate to 25% (39). The more prevalent use of acyclovir may reduce the risk of respiratory failure, as demonstrated in the case series described by Harger et al (34). Nearly all patients in this series received acyclovir, resulting in an 11% need for mechanical ventilation and no maternal deaths (34). Acyclovir therapy resulted in a reduction in maternal mortality from 36% (historical con-

trol) to 13%, and fetal mortality was reduced from 48% to 6% in a case series described by Broussard et al (40). The management of maternal exposure to varicella during pregnancy is based on the maternal immune status to varicella (Fig. 1). Previous, known varicella infection, previous vaccination, or the presence of serum varicella immunoglobulin G confers immunity and no maternal or fetal risk from exposure. In a susceptible gravid, administration of varicella-zoster immunoglobulin is recommended within 96 hrs of exposure to prevent maternal illness (35, 41, 42). The ability to prevent congenital varicella syndrome with varicella-zoster immunoglobulin is unknown. Administration of oral acyclovir (800 mg five times daily) is recommended for pregnant women with primary varicella infection to prevent serious complications such as pneumonia, but it is most effective if given within the first 24 hrs of the onset of the rash (35, 42). Pregnant women with primary varicella infection who develop respiratory symptoms should be evaluated and managed early for varicella pneumonia. In this situation, admission is likely indicated (35, 36, 42), and fetal and maternal evaluation for hypoxemia and respiratory failure should be undertaken. Intravenous acyclovir is recommended for clinically apparent varicella pneumonia and for a susceptible mother who develops respiratory symptoms within 10 days of a known exposure to varicella (35, 40, 42). The acyclovir dose for varicella pneumonia is 10 mg/kg every 8 hrs intravenously for ⱖ5 days (35, 36, 42). Recognition and treatment of maternal hypoxia is important to reduce maternal and fetal morbidity. Potgieter and Hammond (43) reviewed 15 adult ICU patients with varicella pneumonia. Only three of eight patients achieved adequate oxygenation with face-mask supplementation (43). The majority of varicella patients were managed with face-mask continuous positive airway pressure (43). Indications for continuous positive airway pressure included hypoxemia (PaO2 of ⬍60 mm Hg) with adequate alveolar ventilation (PaCO2 of ⬍42 mm Hg) in cooperative patients able to cough and protect their airway (43). Four of 15 patients failed continuous positive airway pressure by face mask, requiring intubation and positive-pressure ventilation (43). The effective use of face-mask continuous positive airway pressure may reduce potential complications with intuS393

Figure 1. Prophylaxis for maternal varicella during pregnancy. IgG, immunoglobulin G; VZIG, varicella-zoster immunoglobulin.

bation and mechanical ventilation while correcting the profound hypoxemia associated with varicella pneumonia. The addition of corticosteroids to antibiotics and oxygen therapy has shown improvement in respiratory function in serious respiratory conditions such as acute respiratory distress syndrome and viral pneumonia. Corticosteroids may reduce the host intrapulmonary inflammatory response, thereby decreasing the degree of hypoxemia (32). The addition of corticosteroids to antiviral therapy among ICU patients with varicella pneumonia resulted in a reduction in length of ICU and hospital stays and improvement in survival (32). No patient in the steroid group died, whereas mortality in the conventional therapy group was 33% (32). Cheng et al. (38) reviewed 120 cases of varicella pneumonia. The mortality rate S394

among patients treated with antiviral agents alone was 10.3%, whereas the addition of corticosteroids resulted in 100% survival in 19 patients with varicella pneumonia (38). Hydrocortisone was used in a dose of 200 mg intravenously every 6 hrs for 48 hrs (32, 38). Lee et al. (44) described the use of extracorporeal life support in seven patients with varicella pneumonia with respiratory failure unresponsive to medical therapy, two of whom developed pneumonia during pregnancy. Indications for extracorporeal life support in this series included shunt fraction of ⬎30%, alveolar–arterial gradient of ⬎600 torr, or PaO2/FIO2 ratio of ⬍80, despite maximal conventional therapy (44). Overall survival was five of seven patients; one patient who developed pneumonia at 17 wks of gestational age

died, and the other peripartum patient survived (44). Maternal varicella infection can have fetal effects as well. Preterm birth occurred in 14.3% of pregnancies with primary varicella infection (45). Intrauterine infection by varicella can be documented in 24% of infants (46). Maternal primary varicella infection between 8 and 20 wks of gestational age can result in development of the fetal congenital varicella syndrome in approximately 1.2–2% of cases (45, 46). This syndrome is characterized by scarring in a dermatomal distribution, cataracts, chorioretinitis, limb hypoplasia, and microcephaly (45). The onset of maternal primary varicella infection 5 days before to 2 days after delivery can result in neonatal infection in 17–30% of newborns, with a neonatal mortality rate of 31% (47). Use of varicella-zoster immunoglobulin reduces the neonatal mortality rate to 7% (47). Whereas preconceptional evaluation of maternal risk to varicella and vaccination before conception can prevent primary varicella infection in pregnancy, early evaluation and treatment with varicella-zoster immunoglobulin and acyclovir may prevent serious complications of maternal disease. Treatment of varicella pneumonia with acyclovir and correction of respiratory failure can reduce maternal mortality. Influenza A and B are common worldwide causes of respiratory illness; influenza A is the most virulent strain in humans. The influenza virus is classified by four hemagglutinin and two neuraminidase antigen subtypes. Major antigen changes, known as shifts, occur slowly and give rise to epidemics (48). Minor antigen changes or drifts occur more frequently and are classified by year and location of identification (48). Influenza vaccine preparation is based on predicted drifts for the upcoming season determined by worldwide influenza activity (48, 49). Influenza infection is usually a self-limited infection, characterized by malaise, fever, myalgia, cough, rhinorrhea, and nausea/vomiting (9, 11, 50, 51). Pregnancy increases the risk of complications from influenza (50). During influenza epidemics of 1918 and 1957, mortality from influenza during pregnancy reached 30 –50% (11, 50). Pregnant women during influenza season are affected more frequently than nonpregnant women, with influenza-related morbidity occurring in 10.5 of 10,000 (95% confidence interval, 6.7–14.3) pregnant Crit Care Med 2005 Vol. 33, No. 10 (Suppl.)

women, compared with a rate of 1.91 of 10,000 (95% confidence interval, 1.51– 2.31) nonpregnant controls (52). This rate is similar to nonpregnant patients with coexisting illness (52). Excess rates of influenza, pneumonia, upper respiratory infection, and respiratory symptoms are experienced by pregnant women compared with a nonpregnant population, especially in relation to new antigenic shifts in viral activity (53). Influenza pneumonia occurred in 12% of patients in a series of 102 pregnant patients with influenza during the 2003– 2004 season (51). One patient required intubation and mechanical ventilation (8%), and there were no maternal deaths (51). Other complications included meningitis (1%) and myocarditis (1%). Influenza pneumonia carries significant mortality in pregnant and nonpregnant patients from respiratory failure, with mortality ranging from 12.5% to 42.1% (28, 50). Antiviral medications are effective in preventing and treating influenza illness. Amantadine and rimantadine are effective against influenza A, with prophylactic use preventing 70 –90% of illnesses among exposed patients (49). Administered within the first 48 hrs of the onset of illness, amantadine and rimantadine are effective in shortening the course of symptoms and decreasing viral load present in secretions (49). Case reports of amantadine use in pregnancy have been reassuring in its safety profile, with rare reports of cardiac defects after first-trimester exposure slightly above the expected population rate (18, 54, 55). Newer antiviral medications include the neuraminidase inhibitors zanamivir and oseltamivir. These agents are indicated for prophylaxis and treatment for both influenza A and B if administered within the first 48 hrs of the onset of illness (49). Complications such as sinusitis, bronchitis, and otitis media are reduced with the use of neuraminidase inhibitors (49). There are no studies of the use of neuraminidase inhibitors in pregnancy (19). The use of antiviral medications can reduce the mortality from influenza pneumonia from 42.1% in conservatively managed patients to 27.3% (38). As in varicella pneumonia, the addition of corticosteroids to conservative treatment also demonstrates reduced mortality from influenza pneumonia to a rate of 12.5% in a limited case series (38). SARS is a new viral illness first described in 2002. SARS results in an atypical pneumonia caused by a previously Crit Care Med 2005 Vol. 33, No. 10 (Suppl.)

undescribed coronavirus that can rapidly progress to respiratory failure (31). Symptoms usually develop 2–7 days after exposure and include fever, chills, rigors, headache, malaise, and myalgia (56). A nonproductive cough or dyspnea develops over 3–7 days. This respiratory phase can progress to hypoxemia and respiratory failure in 10 –20% or cases (56). Chest radiographs demonstrate generalized, patchy, interstitial infiltrates, and laboratory evaluation can demonstrate leukopenia, thrombocytopenia, elevated creatine kinase, and elevated hepatic transaminases (56). Confirmation of the diagnosis is made by polymerase chain reaction for SARS virus on two different specimens, seroconversion by enzymelinked immunosorbent assay, or viral isolation by culture (56, 57). The overall mortality rate for SARS is 3%, whereas serious illness resulting in ICU admission carries a 20% mortality rate (56). Wong et al. (31) reviewed 12 cases of SARS occurring during pregnancy, seven during the first trimester and five occurring in the second or third trimesters. Fifty percent of the patients were admitted to the ICU, 33% requiring mechanical ventilation for a range of 16 –37 days (31). The maternal mortality rate was 25% in this small sample, compared with an overall case fatality rate of 3% (31, 56). Neonatal morbidity was high, with four of the seven patients presenting in the first trimester complicated by spontaneous abortion (31). Of the five pregnancies presenting after 26 wks, three were delivered preterm for maternal or fetal indications. Of the two remaining pregnancies, one delivered at 33 wks and one at 37 wks, both complicated by a small for gestational age fetus and placenta weight less than the fifth percentile (31). Placental pathology demonstrated avascular villi and placental infarcts, presumed secondary to the maternal hypoxemia and circulatory insufficiency of SARS (31). No SARS virus was detected in any fetus or placenta (31). All patients were treated with antibiotics, ribavirin, and corticosteroids. A review of SARS cases by Cheng et al. (38) demonstrated a reduction in mortality in nonpregnant SARS patients with treatment with ribavirin, oseltamivir, steroids, or combination steroids and antiviral medications. Mortality with conservative therapy was 15.4%, whereas the use of antiviral medications, with or without corticosteroids, resulted in a mortality rate of 2–7% (38). As with other viral respiratory infections, SARS carries

an increased risk of maternal and fetal morbidity and mortality during pregnancy.

Pneumonia in Immunocompromised Patients Certain pathogens can cause pneumonia in immunocompromised patients. These include bacteria (Staphylococcus, Mycoplasma, and Mycobacterium), fungal, viral, and parasitic organisms (including Pneumocystis carinii) (9). Pneumocystis pneumonia is the most common cause of AIDS-related death among pregnant patients (58). Most patients present with dry cough, tachypnea, and dyspnea, and chest radiographs demonstrate diffuse interstitial infiltrates. In most cases, the diagnosis can be made by histiologic staining of sputum, although bronchoscopy may be necessary in some cases. Pneumocystis pneumonia in pregnancy carries significant risk to the mother and fetus. In a review of 22 cases of Pneumocystis pneumonia in pregnancy, Ahmad et al. (58) demonstrated a 59% rate of respiratory failure with need for mechanical ventilation. The overall mortality in this series was 50%, compared with 1–16% in a nonpregnant population (58). Fetal mortality was high, with five intrauterine deaths and four neonatal deaths (58). Although the patients in this series were treated with trimethoprim/sulfamethoxazole (TMP/ SMX), with or without corticosteroids, the episode of Pneumocystis pneumonia was the presenting illness of HIV/AIDS for these patients (58). The current recommendation for treatment of Pneumocystis pneumonia is TMP/SMX (20, 59). For patients with PaO2 of ⬎70 mm Hg, oral TMP/SMX at a dose of two doublestrength tablets every 8 hrs or 15 mg·kg⫺1·day⫺1 (TMP component) every 8 hrs intravenously for 21 days is recommended (20, 59). For severe cases, with PaO2 of ⬍70 mm Hg or alveolar–arterial oxygen gradient of ⬎35 mm Hg, oral prednisone or intravenous methylprednisolone are initiated before addition of TMP/SMX (20, 59). Early diagnosis of HIV infection and the use of antiretroviral therapy can reduce the risk of severe Pneumocystis pneumonia in pregnancy. Current recommendations for prophylaxis against pulmonary opportunistic infections in HIV include TMP/SMX daily for patients with previous Pneumocystis infection or CD4 lymphocyte count of ⬍200/␮L (60). Alternative medications S395

include dapsone or aerosolized pentamidine (60). Prophylaxis for Mycobacterium avium-intracellulare is recommended for patients with CD4 counts of ⬍50/␮L, with 1200 mg azithromycin weekly, and yearly influenza and pneumococcal vaccinations are recommended (60).

Prevention of Pneumonia Several strategies are effective in preventing pneumonia in high-risk populations and can be applied to women of childbearing age or during pregnancy. Vaccinations are available for influenza, pneumococcus, and varicella. The influenza vaccine is an inactivated virus, created annually to account for yearly antigenic drift (48). The vaccine is effective in reducing influenza complications, including pneumonia and death, and in decreasing physician office visits and days missed from work among vaccinated populations (48, 49). Vaccination against influenza is able to prevent influenza illness in 70 –90% of healthy adults ⬍65 yrs of age during influenza season (48, 49). A live, attenuated intranasal vaccine is also available. No adverse fetal outcomes have been identified in women who received the inactivated vaccine during pregnancy (19). The risk for influenza-related respiratory illness in pregnancy is similar to high-risk nonpregnant populations, and potential morbidity from influenza is increased in pregnancy (8, 48). Therefore, the influenza vaccine is recommended for all women who will be pregnant during influenza season, regardless of gestational age (48). Evaluation of maternal risk for varicella, including documentation of known varicella infection or detection of serum varicella immunoglobulin G, should be ascertained during preconceptional evaluation or in early pregnancy. A live attenuated vaccine (Varivax) became available in 1995 (47). Varicella vaccination is recommended for susceptible women considering pregnancy at 1–3 months before pregnancy or postpartum (47). Vaccination may reduce the risk of congenital varicella syndrome and decrease morbidity from adult complications of varicella (47). The varicella vaccine is not recommended for use during pregnancy. The pneumococcal vaccine (Pneumovax, Pnu-Imune) is composed of purified capsular polysaccharide antigens from the 23 clinically relevant pneumococcal types and is effective in decreasing the prevalence of pneumococcal pneumonia S396

in high-risk populations (61). The pneumococcal vaccine is recommended to women with underlying medical illnesses, including immunocompromised states, asplenia, sickle cell disease, diabetes, or chronic cardiopulmonary disease (61). The pneumococcal vaccine carries little biological suspicion for fetal effect; therefore, it may be given during pregnancy in women with the listed risk factors (19). Several strategies may be employed to reduce the risk of aspiration pneumonia during pregnancy. Pregnancy results in smooth-muscle relaxation of the gastrointestinal tract, delaying gastric emptying and decreasing the tone of the gastroesophageal sphincter. The use of cricoid pressure during intubation attempts, premedication with oral antacids (Bicitra) before anesthesia, and careful use of sedation in pregnant women has been suggested to decrease the risk of aspiration (9).

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