CHAPTER 51: Pulmonary Disorders

As indicated by the above, it has long been appreciated that women in advanced pregnancy tolerate lung disease poorly. Nevertheless, pulmonary disorders are frequently encountered during pregnancy. Chronic asthma or an acute exacerbation is the most common and affects up to 8 percent of pregnant women. Moreover, asthma along with community-acquired pneumonia accounted for almost 10 percent of nonobstetrical antepartum hospitalizations in one managed care plan (Gazmararian, 2002). Pneumonia is also a frequent postpartum complication requiring readmission (Belfort, 2010). These and other pulmonary disorders are superimposed on several important pregnancy-induced changes of ventilatory physiology. For example, pregnant women, especially those in the last trimester, are susceptible to complications of severe acute pneumonitis as evidenced by the disparate number of maternal deaths during influenza pandemics.

The important and sometimes marked changes in the respiratory system induced by pregnancy are reviewed in Chapter 4 (Respiratory Tract), and values for associated tests can be found in the Appendix (Serum and Blood Constituents). Lung volumes and capacities that are measured directly to assess pulmonary pathophysiology may be significantly altered. In turn, these change gas concentrations and acid-base values in blood. Some of the physiological alterations induced by pregnancy were summarized by Wise and associates (2006):

1. Vital capacity and inspiratory capacity increase by approximately 20 percent by late pregnancy.

2. Expiratory reserve volume decreases from 1300 mL to approximately 1100 mL.

3. Tidal volume increases approximately 40 percent as a result of respiratory stimulation by progesterone.

4. Minute ventilation increases 30 to 40 percent due to increased tidal volume. As a result, arterial Po₂ increases from 100 to 105 mm Hg.

5. Increasing metabolic demands cause a 30-percent rise in carbon dioxide (CO2) production. But, because of its concomitantly increased diffusion capacity and hyperventilation, the arterial Pco₂ decreases from 40 to 32 mm Hg.

6. Residual volume decreases approximately 20 percent from 1500 mL to approximately 1200 mL.

7. Chest wall compliance is reduced by a third by the expanding uterus and increased intraabdominal pressure. This causes a 10- to 25-percent decrease in functional residual capacity—the sum of expiratory reserve and residual volumes.

In a longitudinal cohort study, Grindheim and colleagues (2012) also showed that forced vital capacity and peak expiratory flow rose progressively across pregnancy after 14 to 16 weeks’ gestation. The end result of these pregnancy-induced changes is substantively increased ventilation due to deeper but not more frequent breathing. These are thought to be stimulated by basal oxygen consumption as it rises incrementally from 20 to 40 mL/min in the second half of pregnancy.

Reactive airway disease is seen frequently in young women and therefore often complicates pregnancy. Asthma prevalence grew steadily in many countries beginning in the mid-1970s but may have plateaued in the United States with a prevalence in adults of approximately 10 percent (Barnes, 2015; Centers for Disease Control and Prevention, 2010c, 2013). The estimated asthma prevalence during pregnancy ranges between 4 and 8 percent, and this appears to be rising (Kelly, 2015; Racusin, 2013). Finally, evidence is accruing that fetal and neonatal environmental exposures may contribute to the origins or mitigation of asthma (Grant, 2016; Litonjua, 2016; Spiegel, 2016).

Pathophysiology

Asthma is a chronic inflammatory airway syndrome with a major hereditary component. Increased airway responsiveness and persistent subacute inflammation are associated with polymorphism genes on chromosomes 5q that include cytokine gene clusters, β-adrenergic and glucocorticoid receptor genes, and the T-cell antigen receptor gene (Barnes, 2015). Asthma is etiologically and clinically heterogeneous, and an environmental allergic stimulant such as influenza or cigarette smoke serves as a promoter for susceptible individuals (Bel, 2013).

The hallmarks of asthma are reversible airway obstruction from bronchial smooth muscle contraction, vascular congestion, tenacious mucus, and mucosal edema. Mucosal inflammation is characterized by infiltration with eosinophils, mast cells, and T lymphocytes. These causes airway inflammation and increased responsiveness to numerous stimuli that include irritants, viral infections, aspirin, cold air, and exercise. Several inflammatory mediators produced by these and other cells include histamine, leukotrienes, prostaglandins, cytokines, IgE, and many others. Importantly, because F-series prostaglandins and ergonovine exacerbate asthma, these commonly used obstetrical drugs should be avoided if possible.

Clinical Course

Pulmonary function changes are more pronounced in asthmatics compared with healthy women (Zairina, 2015). Asthma manifestations range from mild wheezing to severe bronchoconstriction, which obstructs airways and decreases airflow. This lowers the forced expiratory volume in 1 second/forced vital capacity (FEV₁/FVC) ratio and the peak expiratory flow (PEF). The work of breathing progressively increases, and patients note chest tightness, wheezing, or breathlessness. Subsequent alterations in oxygenation primarily reflect ventilation–perfusion mismatching because the distribution of airway narrowing is uneven.

Varied manifestations of asthma have led to a simple classification that considers severity, onset, and duration of symptoms (Table 51-1). With persistent or worsening bronchial obstruction, clinical stages progress as shown in Figure 51-1. Hypoxia initially is mitigated by hyperventilation, which maintains arterial Po₂ within a normal range but lowers Pco₂, creating respiratory alkalosis. As airway narrowing worsens, ventilation–perfusion defects increase, and arterial hypoxemia ensues. With severe obstruction, ventilation becomes impaired as fatigue causes early CO₂ retention. Because of hyperventilation, this may only be seen initially as an arterial Pco₂ returning to the normal range. With continuing obstruction, respiratory failure follows from fatigue.

Although these changes are generally reversible and well tolerated by the healthy nonpregnant individual, even early asthma stages may be dangerous for the pregnant woman and her fetus. This is because smaller functional residual capacity and increased pulmonary shunting render the woman more susceptible to hypoxia and hypoxemia.

Effects of Pregnancy on Asthma

Pregnancy has an unpredictable effect on underlying asthma. In their review of six prospective studies of more than 2000 gravidas, Gluck and Gluck (2006) reported that approximately a third each improved, remained unchanged, or clearly worsened. Exacerbations are more common with severe disease (Ali, 2013). In a study by Schatz and associates (2003), baseline severity correlated with asthma morbidity during pregnancy. With mild disease, 13 percent of women had an exacerbation and 2.3 percent required admission; with moderate disease, these numbers were 26 and 7 percent; and for severe asthma, 52 and 27 percent. Others have reported similar observations (Charlton, 2013; Hendler, 2006). Finally, morbidity rates are disproportionately increased in black compared with white women.

Up to 20 percent of women with mild or moderate asthma have been reported to have an intrapartum exacerbation (Schatz, 2003). Conversely, Wendel and associates (1996) reported exacerbations at the time of delivery in only 1 percent of women. Mabie and coworkers (1992) reported an 18-fold increased exacerbation risk following cesarean versus vaginal delivery.

Pregnancy Outcome

Women with asthma have had improved pregnancy outcomes during the past 20 years. The incidence of spontaneous abortion in women with asthma may be slightly increased (Blais, 2013). Maternal and perinatal outcomes for nearly 30,000 pregnancies in asthmatic women are shown in Table 51-2. Findings are not consistent among these studies. For example, in some, but not all, the incidences of preeclampsia, preterm labor, growth-restricted infants, and perinatal mortality are slightly increased (Murphy, 2011). Other reports cited a small rise in the incidence of placental abruption and previa, preterm rupture of membranes, and gestational diabetes (Getahun, 2006; Wang, 2014). But, in a European report of 37,585 pregnancies of women with asthma, the risks for most obstetrical complications were not increased (Tata, 2007). Finally, Cossette and coworkers (2013) reported a nonsignificant trend between perinatal complications and increasing inhaled-corticosteroid dosage.

Increased morbidity appears to be significantly linked to severe disease, poor control, or both. In the study by the Maternal-Fetal Medicine Units (MFMU) Network, delivery before 37 weeks’ gestation was not increased among the 1687 pregnancies of asthmatic women compared with those of 881 controls (Dombrowski, 2004a). But for women with severe asthma, the rate was increased approximately twofold. In a prospective evaluation of 656 asthmatic pregnant women and 1052 pregnant controls, Triche and coworkers (2004) found that women with moderate to severe asthma, regardless of treatment, are at increased risk of preeclampsia. Finally, the MFMU Network study suggests a direct relationship of baseline pregnancy FEV₁ with birthweight and an inverse relationship with rates of gestational hypertension and preterm delivery (Schatz, 2006).

Maternal morbidity includes life-threatening complications from status asthmaticus. This causes muscle fatigue with respiratory arrest, pneumothorax, pneumomediastinum, acute cor pulmonale, and cardiac arrhythmias. Not surprisingly, maternal and perinatal mortality rates rise substantively when mechanical ventilation is required.

Fetal Effects

As discussed, with reasonable asthma control, perinatal outcomes are generally good. In the Network study cited above, rates of adverse neonatal sequelae caused by asthma were not significantly increased (Dombrowski, 2004a). The caveat is that severe asthma was uncommon in this closely monitored group. When respiratory alkalosis develops, earlier animal and human studies suggest that fetal hypoxemia develops well before the alkalosis compromises maternal oxygenation (Rolston, 1974). It is hypothesized that the fetus is jeopardized by decreased uterine blood flow, decreased maternal venous return, and an alkaline-induced leftward shift of the oxyhemoglobin dissociation curve (Chap. 47, Positive End-Expiratory Pressure).

The fetal response to maternal hypoxemia is decreased umbilical blood flow, increased systemic and pulmonary vascular resistance, and decreased cardiac output. Observations by Bracken and colleagues (2003) confirm that the incidence of fetal-growth restriction increases with asthma severity. Because the fetus may be seriously compromised as asthma severity increases, the need for aggressive management is underscored. Monitoring the fetal response is, in effect, an indicator of maternal status.

Possible teratogenic or adverse fetal effects of drugs given to control asthma have been a concern. Several reports show a slightly greater risk for varied abnormalities such as cleft lip and palate and autism spectrum disorders. However, not all studies have verified this (Eltonsy, 2016; Gidaya, 2016; Murphy, 2013b; Wang, 2014). It is worrisome that up to half of these women discontinue essential treatment between 5 and 13 weeks’ gestation (Enriquez, 2006).

Clinical Evaluation

The subjective severity of asthma frequently does not correlate with objective measures of airway function or ventilation. Although clinical examination can also be an inaccurate predictor, useful signs include labored breathing, tachycardia, pulsus paradoxus, prolonged expiration, and use of accessory muscles. Signs of a potentially fatal attack include central cyanosis and altered consciousness.

Arterial blood gas analysis provides objective assessment of maternal oxygenation, ventilation, and acid-base status. With this information, the severity of an acute attack can be assessed (see Fig. 51-1). That said, in a prospective evaluation, Wendel and associates (1996) found that routine arterial blood gas analysis did not help to manage most pregnant women who required admission for asthma control. If used, the results must be interpreted in relation to normal values for pregnancy. For example, a Pco₂>35 mm Hg with a pH <7.35 is consistent with hyperventilation and CO₂ retention in a pregnant woman.

Pulmonary function testing should be routine in the management of chronic and acute asthma. Sequential measurement of the FEV₁ or of the peak expiratory flow rate—PEFR—is the best measure of severity. An FEV₁ less than 1 L, or less than 20 percent of predicted value, correlates with severe disease defined by hypoxia, poor response to therapy, and a high relapse rate. The PEFR correlates well with the FEV₁, and it can be measured reliably with inexpensive portable meters. It is advantageous for each woman to determine her own baseline when asymptomatic to compare with values when symptomatic.

Management of Chronic Asthma

Asthma management by an experienced team produces the most salutary outcomes (Bonham, 2017; Lim, 2014; Wendel, 1996). Management guidelines include:

1. Patient education—general asthma management and its effect on pregnancy.

2. Environmental precipitating factors—avoidance or control. Viral infections that include the common cold are frequent triggering events (Ali, 2013; Murphy, 2013a).

3. Objective assessment of pulmonary function and fetal status—monitor with PEFR or FEV₁.

4. Pharmacological therapy—in appropriate combinations and doses to provide baseline control and treat exacerbations. Compliance may be a problem, and periodic medication reviews are helpful (Sawicki, 2012).

In general, women with moderate to severe asthma ideally measure and record either their FEV₁ or PEFR twice daily. The FEV₁ ideally is >80 percent of predicted. For PEFR, predicted values range from 380 to 550 L/min. Each woman has her own baseline value, and therapeutic adjustments can be made using this (American College of Obstetricians and Gynecologists, 2016a; Rey, 2007).

Treatment depends on disease severity. No therapeutic regimen for management of pregnant asthmatics is universally accepted (Bain, 2014). β-Agonists help abate bronchospasm, and corticosteroids treat inflammation. Regimens recommended for outpatient management are listed in Figure 51-2. For mild asthma, inhaled β-agonists as needed are usually sufficient. For persistent asthma, inhaled corticosteroids are administered every 3 to 4 hours. The goal is to reduce the use of β-agonists for symptomatic relief. A case-control study from Canada with a cohort of more than 15,600 nonpregnant women with asthma showed that inhaled corticosteroids reduced hospitalizations by 80 percent (Blais, 1998). At Parkland Hospital, Wendel and colleagues (1996) achieved a 55-percent reduction in readmissions for severe exacerbations with inhaled steroids.

Theophylline has been used less frequently since inhaled corticosteroids became available. Minimal benefit is gained with use of these compounds and they have a high rate of side effects. However, some theophylline derivatives are considered useful for oral maintenance therapy if the initial response to inhaled corticosteroids and β-agonists is not optimal (Dombrowski, 2004b).

Antileukotrienes inhibit leukotriene synthesis and include zileuton, zafirlukast, and montelukast. These drugs are given orally or by inhalation for prevention, but they are not effective for acute disease (Barnes, 2015). For maintenance, they are used in conjunction with inhaled corticosteroids to allow minimal dosing. Approximately half of asthmatics will improve with these drugs. These agents are not as effective as inhaled corticosteroids, and there is little experience with their use in pregnancy (Fanta, 2009).

Cromones include cromolyn and nedocromil, which inhibit mast cell degranulation. They are ineffective for acute asthma and are used primarily to treat childhood asthma.

Management of Acute Asthma

Treatment of acute asthma during pregnancy is similar to that for the nonpregnant asthmatic. Importantly, the threshold for hospitalization is significantly lower. Intravenous (IV) hydration may help clear pulmonary secretions, and supplemental oxygen is given by mask. The therapeutic aim is to maintain the Po₂ >60 mm Hg, and preferably normal, along with 90- to 95-percent oxygen saturation. Baseline pulmonary function testing includes FEV₁ or PEFR. Continuous pulse oximetry and electronic fetal monitoring, depending on gestational age, may provide useful information. Antibiotics are not given unless there is concomitant pneumonitis, which is caused by the same organisms discussed in Pneumonia (Terraneo, 2014).

First-line therapy for acute asthma includes a short-acting β-adrenergic agonist, such as terbutaline, albuterol, isoetharine, epinephrine, isoproterenol, or metaproterenol, which is given subcutaneously, taken orally, or inhaled. In severely ill women, these drugs can be given IV (Barnes, 2015). They bind to specific cell-surface receptors and activate adenylyl cyclase to increase intracellular cyclic AMP and modulate bronchial smooth muscle relaxation. Long-acting preparations are used for outpatient therapy.

If not previously given for maintenance, inhaled corticosteroids are commenced. A nebulized anticholinergic drug may be added if the response at this point is unsatisfactory (Barnes, 2015). Also, for severe exacerbations, IV magnesium sulfate or theophylline may prove efficacious. Corticosteroids are given early to all patients with severe acute asthma. Unless the response to bronchodilator and inhaled corticosteroid therapy is prompt, oral or parenteral corticosteroids are given (Lazarus, 2010). One regimen is oral prednisone or prednisolone or IV methylprednisolone in a dose of 30 to 45 mg daily for 5 to 10 days without tapering (Barnes, 2015). Because their onset of action is several hours, corticosteroids are given initially along with β-agonists for severe acute asthma.

At this juncture, further management depends on the severity and response to therapy. If initial therapy with β-agonists is associated with improvement of FEV₁ or PEFR to above 70 percent of baseline, then discharge can be considered. Some women may benefit from longer observation. Alternatively, for the woman with obvious respiratory distress, or if the FEV₁ or PEFR is <70 percent of predicted after three doses of β-agonist, admission is usually advisable (Lazarus, 2010). Intensive therapy is continued with inhaled β-agonists, IV corticosteroids, and close observation for worsening respiratory distress or fatigue in breathing (Racusin, 2013). The woman is cared for in the delivery unit or an intermediate or intensive care unit (ICU) (Dombrowski, 2006; Zeeman, 2003).

Status Asthmaticus and Respiratory Failure

Severe asthma of any type not responding after 30 to 60 minutes of intensive therapy is termed status asthmaticus. This has been termed by some as critical asthma symptoms (Kenyon, 2015). Generally, management of nonpregnant patients with status asthmaticus in an intensive care setting results in a good outcome. Consideration should be given to early intubation when maternal respiratory status worsens despite aggressive treatment (see Fig. 51-1). Fatigue, CO₂ retention, and hypoxemia are indications for mechanical ventilation (Chan, 2015). Although Lo and colleagues (2013) described a woman with status asthmaticus in whom cesarean delivery was necessary to effect ventilation, Andrews (2013) cautioned that such clinical situations are uncommon.

Labor and Delivery

For the laboring asthmatic, maintenance medications are continued through delivery. Stress-dose corticosteroids are administered to any woman given systemic corticosteroid therapy within the preceding 4 weeks. The usual dose is 100 mg of hydrocortisone given IV every 8 hours during labor and for 24 hours after delivery. The PEFR or FEV₁ is determined on admission, and serial measurements are taken if symptoms develop.

Oxytocin or prostaglandins E₁ or E₂ are used for cervical ripening and induction. A nonhistamine-releasing narcotic such as fentanyl may be preferable to meperidine for labor, and epidural analgesia is ideal. For surgical delivery, conduction analgesia is preferred because tracheal intubation can trigger severe bronchospasm. Postpartum hemorrhage is treated with oxytocin or prostaglandin E₁ or E₂. Prostaglandin F_2α or ergotamine derivatives are contraindicated because they may cause significant bronchospasm.

Infection of the large airways is manifest by cough without pneumonitis. It is common in adults, especially in winter months. Infections are usually caused by viruses, and of these, influenza A and B, parainfluenza, respiratory syncytial, coronavirus, adenovirus, and rhinovirus are frequent isolates (Wenzel, 2006). Bacterial agents causing community-acquired pneumonia are rarely implicated. The cough of acute bronchitis persists for 10 to 20 days (mean 18 days) and occasionally lasts for a month or longer. According to the 2006 guidelines of the American College of Chest Physicians, routine antibiotic treatment is not indicated (Smith, 2014).

This is a leading cause of death in the United States (Heron, 2016). Current classification includes community-acquired pneumonia (CAP), which is typically encountered in otherwise healthy young women, including during pregnancy. Health-care-associated pneumonia (HCAP) develops in patients in outpatient care facilities and more closely resembles hospital-acquired pneumonia (HAP).

In most cases of community-acquired pneumonia, the offending pathogen is not identified. In a recent study from the Centers for Disease Control and Prevention (CDC), pathogens were identified in only 38 percent of nearly 2500 adults with pneumonia (Jain, 2015). These included viruses in 23 percent, bacteria in 11 percent, both in 3 percent, and fungi or protozoa in 1 percent. Half of bacterial isolates were Streptococcus pneumoniae.

Pneumonia in pregnant women is relatively common (Brito, 2011; Sheffield, 2009). Gazmararian and coworkers (2002) reported that pneumonia accounts for 4.2 percent of antepartum admissions for nonobstetrical complications. Pneumonia is also a frequent indication for postpartum readmission (Belfort, 2010). During influenza season, admission rates for respiratory illnesses double compared with rates in the remaining months (Cox, 2006). Regardless of etiology, mortality from pneumonia is infrequent in young women, but during pregnancy severe pneumonitis with appreciable loss of ventilatory capacity is not as well tolerated (Callaghan, 2015; Rogers, 2010). Hypoxemia and acidosis are also poorly accommodated by the fetus and frequently stimulate preterm labor after midpregnancy. Because many cases of pneumonia follow viral upper respiratory illnesses, worsening or persistence of symptoms may represent developing pneumonia. Any gravida suspected of having pneumonia should undergo chest radiography.

Bacterial Pneumonia

Many bacteria that cause community-acquired pneumonia, such as Streptococcus pneumoniae, are part of the normal resident flora. Some factors that perturb the symbiotic relationship between colonizing bacteria and mucosal phagocytic defenses include acquisition of a virulent strain or bacterial infections following a viral infection. Cigarette smoking and chronic bronchitis favor colonization with S pneumoniae, Haemophilus influenzae, and Legionella species. Other risk factors include asthma, binge drinking, and human immunodeficiency virus (HIV) infection (Sheffield, 2009).

Incidence and Causes

Pregnancy itself does not appear to predispose to pneumonia. Jin and colleagues (2003) reported the antepartum hospitalization rate for pneumonia in Alberta, Canada, to be 1.5 per 1000 deliveries—almost identical to the rate of 1.47 per 1000 for nonpregnant women. Likewise, Yost and associates (2000) reported an incidence of 1.5 per 1000 for pneumonia complicating 75,000 pregnancies cared for at Parkland Hospital. As discussed, at least half are caused by viruses. A fourth are bacterial, and S pneumoniae causes half of the latter. Over the past few years community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a common pathogen that may cause necrotizing pneumonia (Mandell, 2015; Moran, 2013). Occasionally, Legionnaires disease is encountered (Close, 2016).

Diagnosis

Typical symptoms of pneumonia include cough, dyspnea, sputum production, and pleuritic chest pain. Mild upper respiratory symptoms and malaise usually precede these symptoms, and mild leukocytosis is usually present. Chest radiography is essential for diagnosis (Fig. 51-3). Radiographical findings do not accurately predict the etiology, and as discussed, the responsible pathogen is identified in fewer than half of cases. According to the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS), tests to identify a specific agent are optional (Mandell, 2007). Thus, sputum cultures, serological testing, cold agglutinin identification, and tests for bacterial antigens are not routinely recommended. The one exception to this may be rapid serological testing for influenza A and B (Sheffield, 2009).

Management

Although many otherwise healthy young adults can be safely treated as outpatients, at Parkland Hospital we hospitalize all pregnant women with radiographically proven pneumonia. Another option is outpatient therapy or 23-hour observation, which is reasonable with optimal follow-up. At least for nonpregnant patients, the pneumonia severity index (PSI) and the CURB-65 scoring system are used as a guide to admission (Mandell, 2015). Neither has been studied in pregnancy. Given that, risk factors shown in Table 51-3 should prompt consideration for hospitalization.

With severe disease, admission to an intensive or intermediate care unit is advisable. Approximately 20 percent of pregnant women admitted to Parkland Hospital for pneumonia require this level of care (Zeeman, 2003). Severe pneumonia is a relatively common cause of acute respiratory distress syndrome (ARDS) during pregnancy, and mechanical ventilation may become necessary (Chap. 47, Clinical Course). Indeed, of the 51 gravidas who required mechanical ventilation in the review by Jenkins and coworkers (2003), 12 percent had pneumonia.

Initial antimicrobial and antiviral treatment is empirical (Mandell, 2015). Because most adult bacterial pneumonias are caused by pneumococci, mycoplasma, or chlamydophila, monotherapy initially is with a macrolide—azithromycin, clarithromycin, or erythromycin (Table 51-4). Yost and colleagues (2000) reported that erythromycin monotherapy, given IV and then orally, was effective in all but one of 99 pregnant women with uncomplicated pneumonia. During influenza season, we routinely administer oseltamivir treatment along with empirical therapy for bacterial pneumonia.

For women with severe disease according to criteria in Table 51-3, Mandell and associates (2007) summarized IDSA/ATS guidelines, which call for either: (1) a respiratory fluoroquinolone—levofloxacin, moxifloxacin, or gemifloxacin; or (2) a macrolide plus a preferred β-lactam—either high-dose amoxicillin or amoxicillin-clavulanate. β-Lactam alternatives include ceftriaxone, cefpodoxime, or cefuroxime (see Table 51-4). In areas in which the resistance of pneumococcal isolates to macrolides is great, these latter regimens are preferred. The teratogenicity risk of fluoroquinolones is low, and these should be given if indicated (Briggs, 2015). If CA-MRSA is suspected, then vancomycin or linezolid is added (Mandell, 2015; Moran, 2013; Wunderink, 2013).

Clinical improvement is usually evident in 48 to 72 hours with resolution of fever in 2 to 4 days. Radiographic abnormalities may take up to 6 weeks to completely resolve (Torres, 2008). Worsening disease is a poor prognostic feature, and subsequent radiography is recommended if fever persists. Even with improvement, however, approximately 20 percent of women develop a pleural effusion. Treatment of uncomplicated pneumonia is recommended for 5 to 7 days (Musher, 2014). Treatment failure may occur in up to 15 percent of cases, and a wider antimicrobial regimen and more extensive diagnostic testing is warranted.

Pregnancy Outcome

During the preantimicrobial era, as many as a third of pregnant women with pneumonia died (Finland, 1939). Although much improved, maternal and perinatal morbidity and mortality remain formidable. In five studies with a total of 632 women published after 1990, almost 7 percent required intubation and mechanical ventilation, and the maternal mortality rate was 0.8 percent.

Prematurely ruptured membranes and preterm delivery are frequent complications and have been reported in up to a third of cases of acute lung infection (Getahun, 2007; Shariatzadeh, 2006). Likely related are older studies reporting a twofold increase in low-birthweight neonates (Sheffield, 2009). In one population-based study from Taiwan of nearly 219,000 births, incidences of preterm and growth-restricted newborns and of preeclampsia and cesarean delivery were significantly increased (Chen, 2012).

Prevention

Two pneumococcal vaccines, a 23-serotype older preparation and a newer 13-serotype vaccine, are used in children (Swamy, 2015). The 23-serotype vaccine is 60- to 70-percent protective, and its use lowers emergence of drug-resistant pneumococci (Kyaw, 2006). The 13-serotype vaccine is not recommended for otherwise healthy pregnant women. It is, however, recommended for women who are immunocompromised, including those with HIV infection; significant smoking history; diabetes; cardiac, pulmonary, or renal disease; and asplenia, such as with sickle-cell disease (Table 9-7). Protection against pneumococcal infection in women with chronic diseases may be less efficacious than in healthy patients (Moberley, 2013).

Influenza Pneumonia

Clinical Presentation

Each year, 10 percent of pregnant women develop influenza (Cantu, 2013). Influenza A and B are RNA viruses that cause respiratory infection, including pneumonitis, that is epidemic in the winter months. The virus is spread by aerosolized droplets and quickly infects ciliated columnar epithelium, alveolar cells, mucus gland cells, and macrophages. Disease onset is 1 to 4 days following exposure. Common symptoms include fever, cough, myalgia, and chills (Sokolow, 2015). In most healthy adults, infection is self-limited.

Pneumonia is the most frequent complication of influenza and mimics bacterial pneumonia. According to the CDC (2010a), infected pregnant women are more likely to be hospitalized and admitted to an ICU. Others have corroborated these observations (Mertz, 2017). At Parkland Hospital during the 2003 to 2004 influenza season, pneumonia developed in 12 percent of gravidas with influenza (Rogers, 2010).

The 2009 to 2010 pandemic with the influenza (A/H1N1)pdm09 strain was particularly severe (Rasmussen, 2014). In an MFMU Network study, 10 percent of pregnant or postpartum women admitted with H1N1 influenza were cared for in an ICU, and 11 percent of these patients died (Varner, 2011). Risk factors included late pregnancy, smoking, and chronic hypertension. Overall, influenza accounted for 12 percent of pregnancy-related deaths during the 2009 to 2010 pandemic (Callaghan, 2015). During the 2013 to 2014 influenza season, a fourth of pregnant women admitted to California ICUs died (Louie, 2015). Of 865 pregnant women with influenza, Oboho and coworkers (2016) noted that 7 percent of their cohort had severe disease, and four women died. If influenza causes ARDS, extracorporeal membrane oxygenation (ECMO) may be lifesaving (Anselmi, 2015; Saad, 2016).

Primary influenza pneumonitis is characterized by sparse sputum production and radiographic interstitial infiltrates (Cohen, 2015). More commonly, either secondary or mixed pneumonia develop from bacterial superinfection by streptococci or staphylococci after 2 to 3 days of initial clinical improvement. The CDC (2007) reported several cases in which CA-MRSA caused influenza-associated pneumonitis with a case-fatality rate of 25 percent. Other possible adverse effects of influenza A and B on pregnancy outcome are discussed in Chapter 64 (Influenza Virus).

Management

Supportive treatment is recommended for uncomplicated influenza, and early antiviral treatment is effective (Jamieson, 2011; Oboho, 2016). Hospitalization is considered for severely ill women, and for those with pneumonia. As discussed, influenza hospitalization rates for those with advanced pregnancy are increased compared with nonpregnant women (Dodds, 2007; Schanzer, 2007). The CDC (2016b) recommends neuraminidase inhibitors given within 2 days of symptom onset for chemoprophylaxis and treatment of influenza A and B (Chap. 64, Mumps Virus). The drugs interfere with release of progeny virus from infected host cells and thus prevent infection of new host cells (Cohen, 2015). Oseltamivir is given orally, 75 mg twice daily, or zanamivir is given by inhalation, 10 mg twice daily. Recommended treatment duration with either is 5 days. The drugs shorten the course of illness by 1 to 2 days, and they probably reduce the risk for pneumonitis (Belgi, 2014; Muthuri, 2014). Our practice is to treat all pregnant women with influenza whether or not pneumonitis is identified (Rasmussen, 2014). Few data guide use of these agents in pregnant women, but the drugs are not teratogenic in animal studies and are considered low risk (Briggs, 2015).

A major potential concern for viral resistance comes from avian influenza isolates. “Bird flu” with HPAI, H5N8, H5N2, and H5N1 isolates has been reported in the United States by the CDC (Jhung, 2015). In Asia, human infection has been documented with some of these, and mortality rates are high.

Preventively, vaccination for influenza A is recommended by the American College of Obstetricians and Gynecologists (2016b) and the CDC (2016b). Vaccination is discussed in detail in Chapter 64 (Mumps Virus). Prenatal vaccination also affords some temporary protection for infants (Madhi, 2014; Tita, 2016). During the 2014 to 2015 flu season, the CDC reported that only half of pregnant women received influenza vaccine (Ding, 2015).

Varicella Pneumonia

Infection with varicella-zoster virus, the same agent responsible for chicken pox, results in pneumonitis in 5 percent of gravidas (Harger, 2002). Diagnosis and management are considered in Chapter 64 (Varicella-Zoster Virus).

Fungal and Parasitic Pneumonia

Pneumocystis Pneumonia

Fungal and parasitic pulmonary infections are usually of greatest consequence in immunocompromised hosts, especially in women with acquired immunodeficiency syndrome (AIDS). Of these, lung infection with Pneumocystis jiroveci, formerly called Pneumocystis carinii, is a common complication. The opportunistic fungus causes interstitial pneumonia characterized by dry cough, tachypnea, dyspnea, and diffuse radiographic infiltrates. Although this organism can be identified by sputum culture, bronchoscopy with lavage or biopsy may be necessary.

In an earlier report from the AIDS Clinical Trials Centers, Stratton and colleagues (1992) described pneumocystis pneumonia as the most frequent HIV-related disorder in pregnant women. In some cases, tracheal intubation and mechanical ventilation may be required. Ahmad and coworkers (2001) reviewed 22 cases during pregnancy and cited a 50-percent mortality rate. Treatment is with trimethoprim-sulfamethoxazole for 14 to 21 days (Masur, 2015). Alternative agents include the more toxic pentamidine (Walzer, 2005).

For prophylaxis, several international health agencies recommend one double-strength trimethoprim-sulfamethoxazole tablet orally daily for certain groups of HIV-infected pregnant women. These include women with CD4⁺ T-lymphocyte counts <200/μL, those whose CD4⁺ T lymphocytes constitute <14 percent, or if there is an AIDS-defining illness, particularly oropharyngeal candidiasis (Centers for Disease Control and Prevention, 2016a).

Fungal Pneumonia

Any of several fungi can cause pneumonia. In pregnancy, this is usually seen in women with HIV infection or who are otherwise immunocompromised. Infection is usually mild and self-limited. It is characterized initially by cough and fever, and dissemination is infrequent (Mansour, 2015).

Histoplasmosis and blastomycosis do not appear to be more frequent or more severe during pregnancy (Youssef, 2013). Data concerning coccidioidomycosis are conflicting (Bercovitch, 2011; Patel, 2013). In a case-control study from an endemic area, Rosenstein and associates (2001) reported that pregnancy was a significant risk factor for disseminated disease. In another study, however, Caldwell and coworkers (2000) identified 32 serologically confirmed cases during pregnancy and documented dissemination in only three cases. Women with associated erythema nodosum have a better prognosis, whereas mediastinal lymphadenopathy may more likely reflect disseminated disease (Caldwell, 2000; Mayer, 2013). Finally, Crum and Ballon-Landa (2006) reviewed 80 cases of antepartum coccidioidomycosis and found that almost all women diagnosed in the third trimester had disseminated disease. Although the overall maternal mortality rate was 40 percent, it was only 20 percent for 29 cases reported since 1973. Spinello (2007) and Bercovitch (2011) with their colleagues have provided reviews of coccidioidomycosis in pregnancy.

Most cases of cryptococcosis reported during pregnancy manifest as meningitis. Otherwise healthy pregnant women occasionally have cryptococcal pneumonia (Asadi Gharabaghi, 2014; Ely, 1998). Diagnosis is difficult because clinical presentation is similar to that of other community-acquired pneumonias.

Treatment

The 2007 IDSA/ATS guidelines recommend itraconazole as preferred therapy for disseminated fungal infections (Mandell, 2007). Pregnant women have also been given IV amphotericin B or ketoconazole (Paranyuk, 2006; Pilmis, 2015). Amphotericin B has been used extensively in pregnancy with no embryofetal effects. Because of evidence that fluconazole, itraconazole, and ketoconazole may be embryotoxic in large doses in early pregnancy, Briggs and coworkers (2015) recommend that first-trimester use should be avoided if possible.

Three echinocandin derivatives—caspofungin, micafungin, and anidulafungin—are effective for invasive candidiasis (Pilmis, 2015; Reboli, 2007). They are embryotoxic and teratogenic in laboratory animals, and use in human pregnancies has not been reported (Briggs, 2015).

Severe Acute Respiratory Syndrome (SARS)

This coronaviral respiratory infection was first identified in China in 2002, but no new cases have been reported since 2005. It caused atypical pneumonitis with a case-fatality rate of approximately 10 percent (Dolin, 2012). SARS in pregnancy had a case-fatality rate of up to 25 percent (Lam, 2004; Wong, 2004). Ng and coworkers (2006) reported that the placentas from 7 of 19 cases showed abnormal intervillous or subchorionic fibrin deposition in three, and extensive fetal thrombotic vasculopathy in two.

Tuberculosis is still a major worldwide concern. Indeed, it is estimated that a third of the world population is infected (Getahun, 2015). However, it is uncommon in the United States. The incidence of active tuberculosis in this country has plateaued since 2000 (Scott, 2015). More than half of active cases are in immigrants (Centers for Disease Control and Prevention, 2009b). Persons born in the United States have newly acquired infection, whereas foreign-born persons usually have reactivation of latent infection. In this country, tuberculosis is a disease of the elderly, the urban poor, minority groups— especially black Americans, and patients with HIV infection (Khan, 2013; Raviglione, 2015).

Infection is via inhalation of Mycobacterium tuberculosis, which incites a granulomatous pulmonary reaction. In more than 90 percent of patients, infection is contained and is dormant for long periods (Getahun, 2015; Zumla, 2013). In some, especially those who are immunocompromised or who have other diseases, tuberculosis becomes reactivated to cause clinical disease. Manifestations usually include cough with minimal sputum production, low-grade fever, hemoptysis, and weight loss. Various infiltrative patterns are seen on chest radiograph, and cavitation or mediastinal lymphadenopathy may be associated. Acid-fast bacilli are seen on stained smears of sputum in approximately two thirds of culture-positive individuals. Forms of extrapulmonary tuberculosis include lymphadenitis, pleural, genitourinary, skeletal, meningeal, gastrointestinal, and miliary or disseminated (Raviglione, 2015).

Treatment

Resistance to antituberculosis drugs in the United States in the early 1990s was associated with emergence of strains of multidrug-resistant tuberculosis (MDR-TB). Because of this, the CDC (2009a) now recommends a multidrug regimen for initial empirical treatment of patients with symptomatic tuberculosis. Isoniazid, rifampin, pyrazinamide, and ethambutol are given until susceptibility studies are performed (Horsburgh, 2015). Cure rates with 6-month short-course directly observed therapy—DOT—approach 90 percent for new infections (Raviglione, 2015). Other second-line drugs may need to be added. Drug susceptibility is performed on all first isolates.

Tuberculosis and Pregnancy

The considerable influx of women into the United States from Asia, Africa, Mexico, and Central America has been accompanied by an increased frequency of tuberculosis in pregnancy. Sackoff and coworkers (2006) reported positive tuberculin test results in half of 678 foreign-born women attending prenatal clinics in New York City. Almost 60 percent were newly diagnosed. Pillay and colleagues (2004) stress the prevalence of tuberculosis in HIV-positive pregnant women. At Jackson Memorial Hospital in Miami, Schulte and associates (2002) reported that 21 percent of 207 HIV-infected pregnant women had a positive skin test result. Recall also that silent endometrial tuberculosis can cause tubal infertility (Levison, 2010; Raviglione, 2015).

Without therapy, active tuberculosis appears to have adverse effects on pregnancy (Mnyani, 2011). Several studies indicate that outcomes are dependent on the site of infection and gestational age at diagnosis. Jana and colleagues (1994) from India and Figueroa-Damian and Arrendondo-Garcia (1998) from Mexico City noted that active pulmonary tuberculosis was associated with increased incidences of preterm delivery, low-birthweight and growth-restricted newborns, and perinatal mortality. Others have found similar effects (El-Messidi, 2016; Lin, 2010; Sobhy, 2017). From her review, Efferen (2007) cited twofold greater rates of low birthweight, preterm delivery, and preeclampsia. The perinatal mortality rate was increased almost tenfold. Adverse outcomes correlate with late diagnosis, incomplete or irregular treatment, and advanced pulmonary lesions. Conversely, treated tuberculosis is associated with good pregnancy outcomes (Nguyen, 2014; Taylor, 2013).

Extrapulmonary tuberculosis is less common. Jana and coworkers (1999) reported outcomes in 33 pregnant women with renal, intestinal, and skeletal tuberculosis, and a third had low-birthweight newborns. Llewelyn and associates (2000) reported that nine of 13 pregnant women with extrapulmonary disease had delayed diagnoses. Prevost and Fung Kee Fung (1999) reviewed 56 cases of tuberculous meningitis in which a third of mothers died. Spinal tuberculosis may cause paraplegia, but vertebral fusion may prevent it from becoming permanent (Badve, 2011; Nanda, 2002). Psoas abscess develops in 5 percent of those with spinal infections (Nigam, 2013). Other presentations include widespread intraperitoneal tuberculosis simulating ovarian carcinomatosis and degenerating leiomyoma, and hyperemesis gravidarum from tubercular meningitis (Kutlu, 2007; Moore, 2008; Sherer, 2005).

Diagnosis

Two types of tests are used to detect latent or active tuberculosis. One is the time-honored tuberculin skin test (TST), and the others are interferon-gamma release assays (IGRAs), which are becoming preferred (Getahun, 2015; Horsburgh, 2011). IGRAs are blood tests that measure interferon-gamma release in response to antigens present in M tuberculosis, but not bacille Calmette-Guérin (BCG) vaccine (Levison, 2010). The CDC (2005b, 2010b) recommends either skin testing or IGRA testing of gravidas who are in any of the high-risk groups. For those who have received BCG vaccination, IGRA testing is used (Mazurek, 2010).

For skin testing, the preferred antigen is purified protein derivative (PPD) of intermediate strength of 5 tuberculin units. If the intracutaneously applied test result is negative, no further evaluation is needed. A positive skin test result measures ≥5 mm in diameter and requires evaluation for active disease, including a chest radiograph.

Two IGRAs are available: QuantiFERON-TB Gold and T-SPOT.TB tests are recommended by the CDC (2005a,b) for the same indications as skin testing. Although these tests have not been evaluated as extensively as tuberculin skin testing, Kowada (2014) concluded that the tests are cost effective.

Other essential laboratory methods for detection or verification of infection—both active and latent—include microscopy, culture, nucleic acid amplification assay, and drug-susceptibility testing (Horsburgh, 2015; Raviglione, 2015).

Treatment

Latent Infection

In nonpregnant tuberculin-positive patients with latent infection who are younger than 35 years and who have no evidence of active disease, isoniazid, 300 mg orally daily, is given for 9 months. Isoniazid has been used for decades, and it is considered safe in pregnancy (Briggs, 2015; Taylor, 2013). Compliance is a major problem, and Sackoff (2006) and Cruz (2005) and their associates reported a disappointing 10-percent treatment completion. One obvious disconnect is that care for tuberculosis is given in different health systems than prenatal care (Zenner, 2012). These observations are important because most recommend that isoniazid therapy be delayed until after delivery. Because of possibly increased isoniazid-induced hepatitis risk in postpartum women, some even recommend withholding treatment until 3 to 6 months after delivery. That said, neither method is as effective as antepartum treatment to prevent active infection. Boggess and colleagues (2000) reported that only 42 percent of 167 tuberculin-positive asymptomatic women delivered at San Francisco General Hospital completed 6-month therapy that was not begun until the first postpartum visit.

There are exceptions to delayed treatment for latent infection in pregnancy. Known recent skin-test convertors are treated antepartum because the incidence of active infection is 5 percent in the first year (Zumla, 2013). Skin-test-positive women exposed to active infection are also treated because the incidence of infection is 0.5 percent per year. Finally, HIV-positive women are treated because they have an approximate 10-percent annual risk of active disease.

Active Infection

Recommended initial treatment for active tuberculosis in pregnant women is a four-drug regimen with isoniazid, rifampin, ethambutol, and pyrazinamide, along with pyridoxine. For meningitis, levofloxacin may be added (Kalita, 2014). In the first 2-month phase, all four drugs are given—bactericidal phase. This is followed by a 4-month phase of isoniazid and rifampin—continuation phase (Raviglione, 2015; Zumla, 2013). A few reports describe MDR-TB during pregnancy, and treatment options have been reviewed (Horsburgh, 2015; Lessnau, 2003). Breastfeeding is not prohibited during antituberculous therapy.

Treatment of active disease is of special concern if there is antiretroviral naiveté. In these circumstances, beginning concomitant therapy with antituberculosis and antiretroviral therapy can cause the immune reconstitution inflammatory syndrome (IRIS) with toxic drug effects (Lai, 2016; Török, 2011). That said, recent studies support earlier administration of highly active antiretroviral therapy (HAART)—within 2 to 4 weeks—after beginning antituberculosis therapy (Blanc, 2011; Havlir, 2011; Karim, 2011). Also, for HIV-infected women, rifampin or rifabutin use may be contraindicated if certain protease inhibitors or nonnucleoside reverse transcriptase inhibitors are being administered. If there is resistance to rifabutin or rifampin, then pyrazinamide therapy is given. Of the second-line regimens, the aminoglycosides—streptomycin, kanamycin, amikacin, and capreomycin—are ototoxic to the fetus and are contraindicated (Briggs, 2015).

Neonatal Tuberculosis

Tubercular bacillemia can infect the placenta, but the fetus infrequently becomes infected—congenital tuberculosis. The term also applies to newborns who are infected by aspiration of infected secretions at delivery. Each route of infection constitutes approximately half of the cases. Neonatal tuberculosis simulates other congenital infections and manifests with hepatosplenomegaly, respiratory distress, fever, and lymphadenopathy (Dewan, 2014; Osowicki, 2016).

Cantwell and associates (1994) reviewed 29 cases of congenital tuberculosis reported since 1980. Only 12 of the mothers had active infection, and tuberculosis was frequently demonstrated by postpartum endometrial biopsy. Adhikari and colleagues (1997) described 11 South African postpartum women whose endometrial biopsy was culture-positive. Six of their neonates had congenital tuberculosis.

Neonatal infection is unlikely if the mother with active disease has been treated before delivery or if her sputum culture is negative. Because the newborn is susceptible to tuberculosis, most experts recommend isolation from the mother suspected of having active disease. If untreated, the risk of disease in the infant born to a woman with active infection is 50 percent in the first year (Jacobs, 1988).

This is a chronic, multisystem inflammatory disease of unknown etiology characterized by an accumulation of T-helper lymphocytes and phagocytes within noncaseating granulomas (Baughman, 2015; Celada, 2015). Predisposition to the disease is genetically determined and characterized by an exaggerated response of helper T lymphocytes to environmental triggers. Pulmonary involvement is most common, followed by skin, eyes, lymph nodes, and then all other organ systems. The prevalence of sarcoid in the United States is 20 to 60 per 100,000, with equal sex distribution. It is more than 10 times more common for blacks than for whites (Baughman, 2015). Most patients are between 20 and 40 years. Clinical presentation varies, but more than half of patients have dyspnea and a dry cough without constitutional symptoms that develop insidiously over months. Disease onset is abrupt in approximately 25 percent of patients, and 10 to 20 percent are asymptomatic at discovery.

Pulmonary symptoms are dominant, and more than 90 percent of patients have an abnormal chest radiograph at some point. Interstitial pneumonitis is the hallmark of pulmonary involvement, and half of affected patients develop permanent radiological changes. Lymphadenopathy, especially of the mediastinum, is present in 75 to 90 percent of cases. A fourth each have uveitis and skin involvement, the latter usually manifest as erythema nodosum. In women, sarcoid causes approximately 10 percent of cases of erythema nodosum (Mert, 2007). Importantly, any other organ system may be involved (Kandolin, 2015; Powe, 2015; Wallmüller, 2012). Confirmation of the diagnosis is with biopsy—preferably a lymph node. However, because the lung may be the only obviously involved organ, tissue acquisition is often difficult.

The overall prognosis for sarcoidosis is good, and it resolves without treatment in 50 percent of patients. Still, quality of life is diminished (de Vries, 2007). In the other 50 percent, permanent organ dysfunction, albeit mild and nonprogressive, persists. Approximately 10 percent die because of their disease.

Glucocorticoids are the most widely used treatment for symptomatic disease. Permanent organ derangement is seldom reversed by their use (Paramothayan, 2002). Thus, the decision to treat is based on symptoms, physical findings, chest radiograph, and pulmonary function tests. Unless respiratory symptoms are prominent, therapy is usually withheld for a several-month observation period. If inflammation does not subside, then prednisone, 1 mg/kg, is given daily and tapered to <10 mg by 6 months (Baughman, 2015). For those with an inadequate response, immunosuppressive or cytotoxic agents and cytokine modulators can be used.

Sarcoidosis and Pregnancy

Because it is uncommon and frequently benign, sarcoidosis is not often seen in pregnancy. Although it seldom affects pregnancy adversely, meningitis, heart failure, and neurosarcoidosis have been described (Cardonick, 2000; Maisel, 1996; Wallmüller, 2012). In a study of the Nationwide Inpatient Sample of 678 cases of sarcoidosis in pregnancy, incidences of preeclampsia, preterm delivery, and thromboembolism were increased (Hadid, 2015). Selroos (1990) studied 252 women with sarcoidosis in Finland, and 15 percent had sarcoidosis during pregnancy. Disease did not progress in the 26 pregnancies in women with active disease. Three aborted spontaneously, and the other 23 women were delivered at term. Agha and coworkers (1982) reported similar experiences with 35 pregnancies at the University of Michigan.

Active sarcoidosis is treated using the same guidelines as for the woman who is not pregnant. Severe disease warrants serial determination of pulmonary function. Symptomatic uveitis, constitutional symptoms, and pulmonary symptoms are treated with prednisone, 1 mg/kg orally per day.

This autosomal recessive exocrinopathy is one of the most common fatal genetic disorders in whites. Cystic fibrosis is caused by one of more than 2000 mutations in a 230-kb gene on the long arm of chromosome 7 that encodes an amino acid polypeptide (Patel, 2015; Sorscher, 2015). This peptide functions as a chloride channel and is termed the cystic fibrosis transmembrane conductance regulator (CFTR). As discussed in Chapter 14 (Cystic Fibrosis), phenotypes vary widely, even among homozygotes for the common ∆F508 mutation (Rowntree, 2003). Approximately 10 to 20 percent of affected newborns are diagnosed shortly after birth because of meconium peritonitis (Boczar, 2015; Sorscher, 2015). Currently, the median predicted survival is 37 years, and nearly 80 percent of females with cystic fibrosis now survive to adulthood (Gillet, 2002; Patel, 2015).

Pathophysiology

Mutations in the chloride channel cause altered epithelial cell membrane transport of electrolytes. This affects all sites in which epithelium expresses CFTR-secretory cells. These include the sinuses, lung, pancreas, liver, and reproductive tract. Disease severity depends on which two alleles are inherited, and approximately 10 percent are disease-causing mutations (Sorscher, 2015). Homozygosity for Phe508del (∆F508) is one of the most severe, and 90 percent of individuals with clinical disease carry at least one F508 allele.

Exocrine gland ductal obstruction develops from thick, viscid secretions (Rowe, 2005). In the lung, submucosal glandular ducts are affected. Eccrine sweat gland abnormalities are the basis for the diagnostic sweat test, characterized by elevated sodium, potassium, and chloride levels in sweat.

Lung involvement is commonplace and is usually the cause of death. Bronchial gland hypertrophy with mucous plugging and small-airway obstruction leads to subsequent infection that ultimately causes chronic bronchitis and bronchiectasis. For complex and not completely explicable reasons, chronic inflammation from Pseudomonas aeruginosa occurs in more than 90 percent of patients. In a minority, S aureus, H influenzae, and Burkholderia cepacia are recovered (Rowe, 2005). Colonization with the last has been reported to signify a worse prognosis, especially in pregnancy (Gillet, 2002). Acute and chronic parenchymal inflammation ultimately causes extensive fibrosis, and along with airway obstruction, ventilation–perfusion mismatch develops. Pulmonary insufficiency is the end result. Lung or heart–lung transplantation has a 5-year survival rate of only 50 to 60 percent (Sorscher, 2015). A few women have successfully undergone pregnancy following lung transplantation (Kruszka, 2002; Shaner, 2012).

Preconceptional Counseling

This CFTR2 resource delineates gene variants with a clear etiological role—http://www.cftr2.org. Women with clinical cystic fibrosis are subfertile because of tenacious cervical mucus. Males have oligospermia or aspermia from vas deferens obstruction, and 98 percent are infertile (Ahmad, 2013). Despite this, the North American Cystic Fibrosis Foundation estimated that 4 percent of affected women become pregnant every year (Edenborough, 1995). The endometrium and tubes express some CFTR but are functionally normal, and the ovaries do not express the CFTR gene (Edenborough, 2001). Both intrauterine insemination and in vitro fertilization can be successful for affected women (Rodgers, 2000). Several ethical considerations regarding plans for pregnancy by these women were reviewed by Wexler and colleagues (2007). One important factor is the long-term prognosis for the mother. For male infertility, Sobczyńska-Tomaszewska and associates (2006) have emphasized the importance of molecular diagnosis.

Screening

The American College of Obstetricians and Gynecologists (2017) recommends that carrier screening be offered to all women currently pregnant or considering conception (Chap. 14, Cystic Fibrosis). The CDC also added cystic fibrosis to newborn screening programs (Southern, 2009) (Chap. 32, Routine Newborn Care).

Prenatal Care

Pregnancy outcome is inversely related to severity of lung dysfunction. Advanced chronic lung disease, hypoxia, and frequent infections may prove deleterious. At least in the past, cor pulmonale was common, but even that does not preclude successful pregnancy (Cameron, 2005). In some women, pancreatic dysfunction may cause poor maternal nutrition. Otherwise normal pregnancy-induced insulin resistance frequently results in gestational diabetes after midpregnancy (Hardin, 2005). In one study of 48 pregnancies, half had pancreatic insufficiency and a third required insulin (Thorpe-Beeston, 2013). Up to 25 percent of patients develop diabetes by age 20, and diabetes is most frequent with the Phe508del homozygous mutation (Giacobbe, 2012; Patel, 2015).

Cystic fibrosis per se is not affected by pregnancy (Schechter, 2013). Early reports of a deleterious effect on the course of cystic fibrosis were related to severe disease (Olson, 1997). When matched with nonpregnant women by disease severity, recent reports indicate no deleterious effects on long-term survival (Schechter, 2013).

Management

Prepregnancy counseling is imperative. Women who choose to become pregnant require close surveillance for development of superimposed infection, diabetes, and heart failure. Serial pulmonary function testing assists management and estimating prognosis. When the FEV₁ is at least 70 percent, women usually tolerate pregnancy well. Emphasis is placed on postural drainage, bronchodilator therapy, and infection control.

β-Adrenergic bronchodilators help control airway constriction. Inhaled recombinant human deoxyribonuclease I improves lung function by reducing sputum viscosity (Sorscher, 2015). Inhaled 7-percent saline produces short- and long-term benefits (Elkins, 2006). Nutritional status is assessed and appropriate dietary counseling given. Pancreatic insufficiency requires replacement of oral pancreatic enzymes. Promising new therapy to correct CFTR protein dysfunction was recently described by Wainwright and colleagues (2015). Using a combination of lumacaftor and ivacaftor, these investigators showed that patients homozygous for the Phe508del mutation were significantly benefitted. No reports of either drug are available regarding pregnant women.

Infection is heralded by increasing cough and mucus production. Oral semisynthetic penicillins or cephalosporins usually suffice to treat staphylococcal infections. Pseudomonas infection is problematic, and inhaled tobramycin and colistin have been used successfully to control this organism. Immediate hospitalization and aggressive therapy are warranted for serious pulmonary infections. The threshold for hospitalization with other complications is low. For labor and delivery, epidural analgesia is recommended (Deighan, 2014).

Pregnancy Outcome

Earlier reports chronicled the poor maternal and perinatal outcomes of women with cystic fibrosis (Cohen, 1980; Kent, 1993). More recent reports describe better outcomes, but there still are serious complications. Disease severity is now quantified by pulmonary function studies, which are the best predictor of pregnancy and long-term maternal outcome. Edenborough and colleagues (2000) reported 69 pregnancies and found that if prepregnancy FEV₁ was <60 percent of predicted, the risk for preterm delivery, respiratory complications, and death of the mother within a few years of childbirth was substantive. Thorpe-Beeston (2013) and Fitzsimmons (1996) and their associates reported similar findings. Gillet and colleagues (2002) reported 75 pregnancies from the French Cystic Fibrosis Registry. Almost 20 percent of newborns were delivered preterm, and 30 percent had growth restriction. The one maternal death was due to Pseudomonas sepsis in a woman whose prepregnancy FEV₁ was 60 percent. Long-term, however, 17 percent of women died, and four infants had confirmed cystic fibrosis.

Maternal complications are daunting. Patel and coworkers (2015) recently queried the National Inpatient Sample database and reported that the prevalence of cystic fibrosis in pregnancy had a significant linear increase from 2000 to 2010. They analyzed 1119 affected women in more than 12 million births and reported a litany of risks (Table 51-5). In contrast, perinatal outcomes were surprisingly good.

Lung Transplantation

Cystic fibrosis is a common antecedent disease leading to lung transplantation. Gyi and coworkers (2006) reviewed 10 pregnancies in such women and reported nine liveborn neonates. Maternal outcomes were less favorable. Of the three gravidas who developed rejection during pregnancy, all had progressively declining pulmonary function and died of chronic rejection by 38 months after delivery.

Carbon monoxide is a ubiquitous gas, and most nonsmoking adults have a carbon monoxyhemoglobin saturation of 1 to 3 percent. In cigarette smokers, levels may be as high as 5 to 10 percent. Carbon monoxide is the most frequent cause of poisoning worldwide (Stoller, 2007). Toxic levels are often encountered in inadequately ventilated areas warmed by space heaters.

Carbon monoxide is particularly toxic because it is odorless and tasteless and has a high affinity for hemoglobin binding. Thus, it displaces oxygen and impedes its transfer with resultant hypoxia. Besides acute sequelae including death and anoxic encephalopathy, cognitive defects develop in as many as half of patients following loss of consciousness or in those with carbon monoxide levels >25 percent (Weaver, 2002). Hypoxic brain damage has a predilection for the cerebral cortex and white matter and for the basal ganglia (Lo, 2007; Prockop, 2007). A Parkinson syndrome sometimes follows after recovery (Hemphill, 2015).

Pregnancy and Carbon Monoxide Poisoning

Through several physiological alterations, the rate of endogenous carbon monoxide production almost doubles in normal pregnancy (Longo, 1977). Although the pregnant woman is not more susceptible to carbon monoxide poisoning, the fetus does not tolerate excessive exposure (Friedman, 2015). With chronic exposure, maternal symptoms usually appear when the carboxyhemoglobin concentration is 5 to 20 percent. Symptoms include headache, weakness, dizziness, physical and visual impairment, palpitations, and nausea and vomiting. With acute exposure, concentrations of 30 to 50 percent produce symptoms of impending cardiovascular collapse. Levels >50 percent may be fatal for the mother.

Because hemoglobin F has an even higher affinity for carbon monoxide, fetal carboxyhemoglobin levels are 10 to 15 percent higher than those in the mother. This may be due to facilitated diffusion (Longo, 1977). Importantly, the half-life of carboxyhemoglobin is 2 hours in the mother but 7 hours in the fetus. Because carbon monoxide is bound so tightly to hemoglobin F, the fetus may be hypoxic even before maternal carbon monoxide levels are appreciably elevated. Several anomalies are associated with embryonic exposure, and anoxic encephalopathy is the primary sequela of later fetal exposure (Alehan, 2007; Aubard, 2000).

Treatment

For all victims, treatment of carbon monoxide poisoning is supportive along with immediate administration of 100-percent inspired oxygen. Indications for hyperbaric oxygen treatment in nonpregnant individuals are unclear (Kao, 2005). Weaver and associates (2002) reported that hyperbaric oxygen treatment minimized the incidence of cognitive defects in adults at both 6 weeks and 1 year compared with that with normobaric oxygen. Hyperbaric oxygen is generally recommended in pregnancy if carbon monoxide exposure has been “significant” (Aubard, 2000; Ernst, 1998). The problem is how to define significant exposure (Friedman, 2015). Although maternal carbon monoxide levels are not accurately predictive of those in the fetus, some clinicians recommend hyperbaric therapy if maternal levels exceed 15 to 20 percent. With fetal heart rate pattern evaluation, Towers and Corcoran (2009) described affected fetuses to have an elevated baseline, diminished variability, and absent accelerations and decelerations. Treatment of the affected newborn with hyperbaric oxygen is also controversial (Bar, 2007).

Elkharrat and colleagues (1991) reported successful hyperbaric treatments in 44 pregnant women. Silverman and Montano (1997) reported successful management of a woman whose abnormal neurological and cardiopulmonary findings abated in a parallel fashion with resolution of associated variable decelerations in fetal heart rate. Greingor and coworkers (2001) used 2.5-atm hyperbaric 100-percent oxygen for 90 minutes in a 21-week pregnant woman who was delivered of a healthy infant at term. According to the Divers Alert Network—DAN (2016)—at Duke University, 700 chambers are located in North and Central America. Emergency consultation from the Network is available at 919–684–9111.