Respiratory Disease in Pregnancy

Pneumonia in Pregnancy

Pneumonia is an infection of the pulmonary parenchyma. The current prevalence of pneumonia during pregnancy is unknown; however, prior retrospective studies have reported a prevalence of approximately 1.5 per 1000 deliveries. This prevalence is comparable to that in the nonpregnant population. The incidence of pneumonia during pregnancy may be increasing primarily as a reflection of the declining health status of certain segments of the childbearing population and the fact that women with certain medical conditions, such as cystic fibrosis (CF) and HIV, are now living to childbearing age more often than in the past.

Pneumonia can be classified as either community-acquired or hospital-acquired , according to the Infectious Disease Society of America's (IDSA) Guidelines. Community-acquired pneumonia (CAP) occurs in patients who have not been hospitalized recently and have not had regular exposure to the healthcare system. CAP is the most common form of pneumonia in pregnancy . CAP is most commonly caused by bacteria (60% to 80% of cases); up to 20% may be associated with atypical bacteria ( Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila ). The remaining 10% to 20% of cases are due to viral infections.

Pneumonia increases maternal morbidity and mortality. It is also a leading nonobstetric cause of hospital admissions and is the most common cause of severe sepsis during pregnancy. Importantly, the physiologic changes in pregnancy increase the risk of maternal complications in patients with pneumonia. These complications include the need for mechanical ventilation (10% to 20%) due to a decreased functional residual capacity and increased oxygen consumption, bacteremia (16%), empyema (8%), pneumothorax, pericardial effusion, and pericardial tamponade. In fact, respiratory failure due to pneumonia accounts for up to 12% of intubations during pregnancy. Despite the latter, maternal outcomes have improved dramatically with the modern use of antibiotic therapy and improved critical care.

Pneumonia may complicate pregnancy at any gestational age and is frequently associated with poor perinatal outcomes. The average gestational age at diagnosis is 32 weeks. A recent study using two nationwide population-based datasets showed that pneumonia was associated with a significantly higher prevalence of low birthweight (9.8% vs. 5.9%), preterm birth (12.3% vs. 7.1%), newborns small for gestational age (20.7% vs. 16.2%), low Apgar scores (0.7% vs. 0.2%), cesarean delivery (55.5% vs. 40.6%), and preeclampsia/eclampsia (2.7% vs. 0.8%) as compared with unaffected pregnant women. Preterm delivery is a significant complication of pneumonia, even with antibiotic therapy and modern management. In one study, preterm labor was more likely in women who experienced bacteremia, required mechanical ventilation, or had a serious underlying maternal disease. Enhanced prostaglandin production and host inflammatory response due to infection may be responsible for preterm labor in these women.

Bacterial Pneumonia

In uncomplicated CAP, current guidelines from the IDSA/American Thoracic Society (ATS) do not recommend obtaining respiratory cultures to isolate a specific causative microorganism because, in most cases, the microbiology of CAP is easily predictable and the current recommended first-line antibiotics will usually provide adequate coverage. Before the antibiotic and vaccination era, Streptococcus pneumoniae was responsible for almost all cases of pneumonia. Although less frequent, likely due to increased vaccination, Streptococcus pneumoniae remains the most common bacterial pathogen to cause pneumonia in pregnancy, followed by H. influenzae. Other common bacteria isolated in CAP include Mycoplasma pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Chlamydophila pneumoniae . Less common bacteria include Pseudomonas aeruginosa, Legionella species, Klebsiella species, Moraxella catarrhalis, Bordetella pertussis, Escherichia coli, Enterobacter , and Serratia. Certain clinical scenarios are very suggestive of the inciting etiology (e.g., alcoholism— Streptococcus pneumoniae , oral anaerobes, Klebsiella pneumoniae ), smoking or chronic obstructive pulmonary disease (COPD— Haemophilus influenzae, Pseudomonas aeruginosa ), aspiration (gram-negative enteric pathogens), lung abscess (multidrug-resistant Staphylococcus aureus [MRSA], oral anaerobes), exposure to birds (Chlamydophila psittaci) , having been in a hotel or on a cruise ship during previous 2 weeks (Legionella), or intravenous drug use (Staphylococcus aureus).

The suspicion of pneumonia during pregnancy is based on clinical presentation. The symptoms of pneumonia are similar to those in the nonpregnant population. These symptoms include cough in 90% of the cases, productive sputum in 66%, dyspnea in 66%, and pleuritic pain in 50%. Other common symptoms are fever, headaches, sweats, and malaise. A detailed physical examination is always required. Lung examination is commonly consistent with a consolidation pattern, which includes dullness on percussion, egophony, crackles, and increased vocal resonance.

All pregnant patients with high suspicion of pneumonia should undergo a chest radiograph. The estimated fetal radiation after a chest radiography is less than 0.01 mGy and has not been associated with any short- or long-term complications. Therefore chest radiography for the diagnosis of pneumonia should not be withheld from pregnant patients. Radiographic findings consistent with bacterial pneumonia include lobar consolidation, cavitation, air bronchograms, and pleural effusion ( Fig. 43.1 A ). Atypical bacteria—such as Chlamydia pneumoniae or psittaci , M. pneumoniae, and Legionella species—have no pathognomonic signs on chest radiography. However, unilateral or bilateral reticulonodular infiltrates are commonly seen, and they are often accompanied by extrapulmonary symptoms. Of these, L. pneumophila is the most important in terms of severity (see Fig. 43.1B ). Studies have failed to identify a radiographic pathogonomic pattern that might allow reliable differentiation between atypical and typical (e.g., S. pneumoniae ) bacterial pneumonia. In atypical bacterial CAP, the severity of findings on chest radiograph is usually out of proportion to the mild clinical symptoms. Even though the use of chest radiography is crucial for the diagnosis of pneumonia, the findings are not specific to different pathogens.

Recommendations for the routine use of common tests, such as blood and sputum cultures, remain controversial owing to their infrequent positive impact in the management of pneumonia . The IDSA/ATS consensus guidelines on the management of CAP recommend that other testing should be performed only if special circumstances are present ( Table 43.1 ).

Because of the association of pneumonia during pregnancy with adverse obstetric outcomes , any gravida suspected of having pneumonia should be managed aggressively, and hospital admission is usually recommended. Outpatient management of nonsevere pneumonia during pregnancy is acceptable provided that there is optimal follow-up and there are no coexisting conditions (asthma, diabetes, immunocompromised status, cardiac or renal disease). Baseline characteristics associated with severe CAP are described in Box 43.1 . In a study of 133 women admitted with pneumonia during pregnancy and managed using protocols based on the British and ATS admission guidelines for management in nonpregnant individuals, the authors reported that if the ATS guidelines had been used, 25% of the pregnant women with pneumonia could have avoided admission. None of the gravidas who would have been managed as outpatients using the ATS criteria had any complications. Of note, most of the 133 women who were hospitalized with pneumonia in this study did not receive chest radiographs for confirmation of diagnosis, which limits the value of the study for use in guiding admission criteria for pneumonia in pregnancy. Therefore, until additional information is available, admission for all pregnant women with pneumonia is prudent.

Limited retrospective data have suggested that mortality may be decreased in patients receiving the first antibiotic dose within the first 4 to 8 hours of presentation. These studies had weaknesses, and prospective trials have failed to replicate the findings. On the other hand, delayed antibiotic administration is associated with adverse outcomes. Based on these data, the IDSA strongly recommends that when admission for pneumonia is required, the first dose of antibiotic should be given while the patient is in the emergency room .

Empiric antibiotic coverage usually includes a macrolide for mild illness with the addition of a β-lactam for severe illness. A physician should take into account the possible pathogens involved based on risk factors, rates of local antibiotic resistance, severity, and other comorbidities. Yost and colleagues demonstrated that monotherapy with erythromycin was adequate in 118 of 119 women with pneumonia during pregnancy. First-line agents include azithromycin or erythromycin. In patients with comorbidities—such as alcoholism, diabetes, or immunosuppression—a β-lactam like amoxicillin or amoxicillin-clavulanic acid should be added to the macrolide. In patients with signs of severe pneumonia, a commonly recommended regimen includes the combination of azithromycin and ceftriaxone . In areas with high macrolide- and/or β-lactam–resistant pneumococcus, fluoroquinolones should be the first-line therapy. Quinolones have typically been avoided in pregnancy due to concerns of fetal joint damage, but this concern is theoretical and mostly derived from animal data. Recent studies have failed to show a teratogenic effect of quinolones. With the emergence of highly resistant bacterial pneumonia, their use may be lifesaving and therefore justified in specific circumstances ( Fig. 43.2 ). In severe cases with lack of improvement after appropriate initial empiric treatment, community-acquired methicillin-resistant S. aureus pneumonia (CA-MRSA) should be suspected and either vancomycin or linezolid should be added. Additional therapy with clindamycin has been suggested in difficult-to-treat cases since it has been shown to decrease production of staphylococcal exotoxins; however, this recommendation remains controversial.

Pneumonia may be complicated by respiratory failure requiring mechanical ventilation. In such cases, a multidisciplinary team including obstetricians, maternal-fetal medicine specialists, and intensivists should be involved in the management. The potentially viable fetus should be continuously monitored. There is no evidence to suggest that delivery improves respiratory status; thus elective delivery for the sole purpose of improving maternal oxygenation is not recommended.

Treatment of uncomplicated pneumonia should last 5 days . The patient should show clinical improvement after 48 to 72 hours of therapy. Importantly, radiologic findings may persist for up to 6 weeks but should not be a marker for extended treatment. For patients with more severe presentations, a longer antibiotic course should be considered (7 days). The role of adjuvant steroids in the management of CAP is controversial. Recent guidelines suggest the use of hydrocortisone at doses less than 400 mg/d for 5 to 7 days in severe CAP requiring hospitalization.

Pneumococcal polysaccharide vaccination is recommended to prevent pneumococcal pneumonia among high-risk patients, including those with decreased immunity, alcoholism, asplenia, sickle cell disease, chronic lung or heart disease, and liver disease as well as those who are heavy smokers. The efficacy of this vaccine is in the range of 60% to 80%. The vaccine is safe in pregnancy and should be administered to high-risk pregnant women . Additionally, maternal vaccination during the second and third trimesters results in significant transplacental passage of antibodies with resultant passive neonatal immunization.

Viral Pneumonias

The Centers for Disease Control and Prevention (CDC) estimates that influenza has infected between 9 and 35 million people, caused 140,000 to 710,000 hospitalizations, and resulted in 12,000 to 56,000 deaths annually since 2010 . It is the eighth leading cause of death in the United States. Influenza is caused by an RNA virus. Three subtypes have been identified: A, B, and C. Influenza A can have periodic changes in its antigen characteristics, making this subtype the major pathogen involved in influenza epidemics.

It is well documented that pregnant women have a more severe presentation of influenza than the general population. During the 2009 H1N1 pandemic, in comparison to nonpregnant women, pregnancy was associated with a seven times higher rate of hospitalization, five to seven times higher rate of ICU admissions, four times higher risk of severe disease, and higher mortality rates. With regard to pregnancy outcomes, influenza was associated with higher rates of cesarean delivery and preterm deliveries. A systematic review found an association between first trimester maternal influenza exposure and increased risk of congenital abnormalities.

The virus is transmitted by aerosolized droplets. Patients are typically infectious starting 1 day before the onset of symptoms and continuing for the next 5 days. Symptoms have an acute onset after a 1- to 4-day incubation period; they include high fever, coryza, rhinorrhea, headache, myalgia, malaise, and cough. Pneumonia is a common complication of influenza as the result of either secondary bacterial infection or primary viral infection of the lung parenchyma. Primary influenza pneumonia is characterized by its rapid progression from a unilateral infiltrate to a diffuse bilateral disease. Patients may develop fulminant respiratory failure, which requires mechanical ventilation.

Patients with flu-like symptoms should be promptly evaluated. As per recommendations from the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM), once influenza infection is suspected in pregnant patients or within 2 weeks of delivery, an antiviral medication should be started . Starting antivirals within the first 2 days of symptoms has been associated with lesser disease severity as well as fewer maternal deaths. If the patient is more than 48 hours from onset, treatment should not be withheld. The preferred drug is oseltamivir 75 mg twice a day for 5 days . An alternative therapy is zanamivir 10 mg (two oral inhalations) twice a day for 5 days. Both medications are safe during pregnancy and may be used in any trimester. If a pregnant woman (or up to 2 weeks postdelivery) is exposed to influenza, prophylaxis with oseltamivir 75 mg/d for 10 days should be started without delay. When bacterial pneumonia complicates influenza during pregnancy, antibiotics should be started . Antibiotic therapy should be directed at the likely pathogens that can cause secondary infection: S. aureus, S. pneumoniae (pneumococcus), and H. influenzae.

It is strongly recommended that the inactivated influenza vaccine be given routinely to all pregnant women during flu season (October to mid-May) regardless of trimester . Influenza vaccination during pregnancy reduces the risk of severe respiratory illness by half and provides passive immunization to the neonate.

Varicella zoster virus (VZV) is a DNA virus that usually causes a benign self-limited illness in children (chickenpox) but may cause severe disease in adults. Currently the incidence of varicella during pregnancy is approximately 1.21 cases per 10,000 pregnancies. VZV is transmitted by direct contact to skin lesions or inhalation of infected respiratory tract secretions. VZV has an incubation period of approximately 2 weeks and is highly contagious. Patients are infectious starting 1 to 2 days before the rash onset and until skin lesions have completely crusted.

A VZV infection may have a significant impact during pregnancy. Previous studies suggested a high rate of pneumonia (up to 10%) among pregnant women with the VZV infection. A recent study reported a significantly lower rate of varicella pneumonia (2.5%) among 935 pregnant women with the VZV infection. Varicella pneumonia occurs most often in the third trimester, and it is likely to be severe. With modern management, mortality has decreased dramatically, thanks to the availability of antiviral therapy. Maternal mortality prior to antiviral therapy was reported to be as high as 40%, compared with 15% in the era of antiviral therapy. A more recent study by Zhang et al. reported 23 cases of varicella pneumonia during pregnancy in the United States with no maternal deaths.

Varicella infection during pregnancy may also be associated with poor neonatal outcomes. Congenital varicella syndrome is characterized by skin scars, mental retardation, microcephaly, hydrocephalus, ocular abnormalities, limb defects, low birthweight, and gastrointestinal defects. The syndrome can happen after infection at any time, but its severity is higher with earlier infections, mostly between 8 and 20 weeks of pregnancy.

Primary VZV presents with fever and malaise, followed by a diffuse centrifugal itchy vesicular rash. Varicella pneumonia usually starts 2 to 5 days after these symptoms and is heralded by the onset of pulmonary symptoms such as cough, dyspnea, pruritic chest pain, and hemoptysis. The severity of the illness may vary from asymptomatic radiographic abnormalities to fulminant pneumonitis and respiratory failure.

Acyclovir, a DNA polymerase inhibitor, is the first-line treatment for varicella. All pregnant patients with varicella pneumonia should be aggressively treated with antiviral therapy and admitted to the ICU for close observation . The early use of acyclovir has been associated with improved outcomes. Treatment with acyclovir is safe in pregnancy. A dose of 10 mg/kg intravenously every 8 hours is recommended . Acyclovir should be administered slowly and with adequate hydration to prevent crystal-induced nephropathy. The efficacy of varicella immune globulin (VariZIG) to prevent infection in pregnant patients exposed to varicella has been described. This therapy should be given within the first 10 days of the exposure, but it is not widely available in the United States.

Pneumocystis Jirovecii Pneumonia

Pneumocystis jirovecii pneumonia (PJP) remains the most prevalent opportunistic infection in patients infected with HIV. It is an AIDS-defining illness that occurs more frequently when a patient's helper T-cell (CD4 ⁺ ) count is less than 200/mm ³ . PJP is also prevalent in patients with immunosuppressive therapy for organ transplant, cancer, or autoimmune diseases. The transmission of PJP is not fully understood, although some evidence suggests person-to-person transmission as the most likely mode. Almost half of immunocompetent adults have asymptomatic pulmonary colonization. Up to 60% of pregnant patients diagnosed with PCP will require mechanical ventilation.

The symptoms of PJP are nonspecific and include dyspnea, fever, tachypnea, and nonproductive cough. Typical radiographic features of PJP are bilateral perihilar interstitial infiltrates that become increasingly homogeneous and diffuse as the disease progresses (see Fig. 43.1C ). The diagnosis of PJP requires microscopic examination to identify P. jirvecii from a clinical source, such as sputum, bronchoalveolar fluid, or lung tissue. P. jirvecii cannot be propagated in culture. The fungus has trophic forms as well as a cyst state, which can be detected with a modified Papanicolaou, Wright-Giemsa, or Gram-Weigert stain. Polymerase chain reaction (PCR) has higher detection rates than conventional staining.

Trimethoprim/sulfamethoxazole (TMP/SMX) 15 to 20 mg/kg per day orally or intravenously divided into 3 doses for 21 days is the preferred regimen for PJP . In patients with moderate to severe presentations, corticosteroids have been shown to decrease mortality significantly. If indicated, corticosteroids should be started as soon as the antibiotic therapy is initiated. Primary prophylaxis against PJP with TMP/SMX in HIV-infected adults, including pregnant women and patients receiving highly active antiretroviral therapy (HAART), should begin when the CD4 ⁺ count is less than 200/mm ³ or when the patient has a history of oropharyngeal candidiasis. The use of HAART as well as prophylaxis with TMP/SMX has decreased the incidence of PJP pneumonia in developed countries.

Tuberculosis in Pregnancy

The actual incidence of tuberculosis (TB) in the United States is fewer than 10 cases per 100,000, comparable to that of other developed nations. Most cases diagnosed in the United States are from patients emigrating from endemic countries. The last significant peak of TB incidence was between 1985 and 1991, when reported cases of TB increased by 18% due to the HIV epidemic. Since then, the incidence has decreased by 50%. In the United States, the incidence of TB infection during pregnancies between 2003 and 2011 was reported to be 26.2 per 100 000 births. In 2016, the number of new cases diagnosed in the United States was 9287; of these, 67.9% were diagnosed in foreign-born patients.

Mycobacterium tuberculosis is carried in airborne particles. Once the bacilli are transmitted, they can remain in an inactive (latent TB) or active state (active TB). Most pregnant women diagnosed with TB in pregnancy have latent TB and are asymptomatic (patients are not contagious with latent TB). There is no evidence that pregnancy accelerates progression to the active disease. A large cohort in the United Kingdom reported higher rates of active TB during the postpartum period.

Unlike latent TB, active TB has a significant impact on pregnancy outcomes, including increased risk of preterm birth, low birthweight, intrauterine growth restriction (IUGR), cesarean delivery, and perinatal mortality.

Prevention

In patients with latent TB, the risk of progression to active disease is highest in the first 2 years of conversion. During the first 18 months after conversion, the incidence of active disease reaches 5% and then remains at 5% thereafter. In women with a known recent conversion to a positive TST (within 2 years) or who are immunosuppressed, the recommended prophylaxis is INH 300 mg/d, starting after the first trimester and continuing for 6 to 9 months. INH should be accompanied by pyridoxine (vitamin B ₆ ) supplementation, 50 mg/d, to prevent the peripheral neuropathy associated with INH treatment ( Fig. 43.3 ). Women with an unknown or prolonged duration of TST positivity (>2 years) should receive INH 300 mg/d for 6 to 9 months after delivery. INH is associated with an increased risk of hepatitis when taken during pregnancy and postpartum. The absolute risk for liver inflammation in pregnancy from INH use is rare; therefore this therapy should be instituted when the risk for conversion to active disease is high. Monthly monitoring of liver function tests may prevent this adverse outcome. Among individuals receiving INH, 10% to 20% develop mildly elevated liver function tests. These changes resolve once the drug has been discontinued. Breastfeeding should be encouraged in patients with latent TB. The small levels of INH in breast milk do not produce hepatotoxicity. Pyridoxine supplementation should be given to exclusively breastfed infants.

BCG vaccines are commonly given at birth in countries with a high prevalence of TB. It has been given to prevent childhood tuberculous meningitis and miliary disease. It is not generally recommended in the United States. It is contraindicated during pregnancy as well as in immunosuppressed patients.