CARBON MONOXIDE POISONING
Acute and chronic pulmonary disorders are frequently encountered during pregnancy. Chronic asthma or an acute exacerbation is the most common and affects up to 4 percent of pregnant women. These disorders along with community-acquired pneumonia accounted for almost 10 percent of nonobstetrical hospitalizations in one managed care plan (Gazmararian, 2002). Pneumonia is also a frequent complication requiring readmission postpartum (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, do not appear to tolerate severe acute pneumonitis as evidenced by the disparate number of maternal deaths during the 1918 and 1957 influenza pandemics.
The important and sometimes marked changes in the respiratory system induced by pregnancy are reviewed in Chapter 4 (p. 62), and values for associated tests can be found in the Appendix (p. 1292). 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 increase in carbon dioxide production, but because of its concomitantly increased diffusion capacity along with 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 abdominal pressure, which causes a 10-to 25-percent decrease in functional residual capacity—the sum of expiratory reserve and residual volumes.
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 increases incrementally from 20 to 40 mL/min in the second half of pregnancy.
Asthma is seen frequently in young women and therefore often complicates pregnancy. Asthma prevalence increased 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, 2012; Centers for Disease Control and Prevention, 2010c). The estimated asthma prevalence during pregnancy ranges between 4 and 8 percent, and this appears to be increasing (Kwon, 2006; Namazy, 2005). Finally, evidence is accruing that fetal as well as neonatal environmental exposures may contribute to the origins of asthma in certain individuals (Harding, 2012; Henderson, 2012).
Asthma is a chronic inflammatory airway syndrome with a major hereditary component. Increased airway responsiveness and persistent subacute inflammation have been associated with genes on chromosomes 5q that include cytokine gene clusters, β-adrenergic and glucocorticoid receptor genes, and the T-cell antigen receptor gene (Barnes, 2012). Asthma is heterogeneous, and there inevitably is an environmental allergic stimulant such as influenza or cigarette smoke in susceptible individuals (Bel, 2013).
The hallmarks of asthma are reversible airway obstruction from bronchial smooth muscle contraction, vascular congestion, tenacious mucus, and mucosal edema. There is mucosal infiltration with eosinophils, mast cells, and T lymphocytes that causes airway inflammation and increased responsiveness to numerous stimuli including irritants, viral infections, aspirin, cold air, and exercise. Several inflammatory mediators produced by these and other cells include histamine, leukotrienes, prostaglandins, cytokines, and many others. IgE also plays a central role in pathophysiology (Strunk, 2006). Because F-series prostaglandins and ergonovine exacerbate asthma, these commonly used obstetrical drugs should be avoided if possible.
Asthma findings range from mild wheezing to severe bronchoconstriction, which obstructs airways and decreases airflow. These reduce the forced expiratory volume in 1 second (FEV1)/forced vital capacity (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 as well as onset and duration of symptoms (Table 51-1). With persistent or worsening bronchial obstruction, stages progress as shown in Figure 51-1. Hypoxia initially is well augmented by hyperventilation, which maintains arterial Po2 within a normal range while causing the Pco2 to decrease with resultant 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.
TABLE 51-1. Classification of Asthma Severity
FIGURE 51-1 Clinical stages of asthma. FEV1 = forced expiratory volume in 1 second.
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 pulmary shunting render the woman more susceptible to hypoxia and hypoxemia.
Effects of Pregnancy on Asthma
There is no evidence that pregnancy has a predictable effect on underlying asthma. In their review of six prospective studies of more than 2000 pregnant women, 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; Murphy, 2005). Carroll and colleagues (2005) reported disparate morbidity in black compared with white women.
Some women have asthma exacerbations during labor and delivery. 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.
Women with asthma have had improved pregnancy outcomes during the past 20 years. From his review, Dombrowski (2006) concluded that, unless disease is severe, pregnancy outcomes are generally excellent. 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, incidences of preeclampsia, preterm labor, growth-restricted infants, and perinatal mortality are slightly increased (Murphy, 2011). Another report cited a small rise in the incidence of placental abruption and in preterm rupture of membranes (Getahun, 2006, 2007). But, in a European report of 37,585 pregnancies of women with asthma, the risks for most obstetrical complications were not increased (Tata, 2007). In the Canadian study in which inhaled-corticosteroid dosage was quantified, Cossette and coworkers (2013) found a nonsignificant trend between perinatal complications and increasing dosage. They concluded that low to moderate doses were not associated with perinatal risks and noted that more data were needed regarding higher doses.
TABLE 51-2. Maternal and Perinatal Outcomes in Pregnancies Complicated by Asthma
Thus, there appears to be significantly increased morbidity 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 asthmatics 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 forced expiratory volume at 1 second (FEV1) with birthweight and an inverse relationship with rates of gestational hypertension and preterm delivery (Schatz, 2006).
Life-threatening complications from status asthmaticus include muscle fatigue with respiratory arrest, pneumothorax, pneumomediastinum, acute cor pulmonale, and cardiac arrhythmias. Maternal and perinatal mortality rates are substantively increased when mechanical ventilation is required.
With reasonable asthma control, perinatal outcomes are generally good. For example, in the MFMU Network study cited above, there were no significant adverse neonatal sequelae from asthma (Dombrowski, 2004a). The caveat is that severe asthma was uncommon in this closely monitored group. When respiratory alkalosis develops, both 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.
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. The realization that the fetus may be seriously compromised as asthma severity increases underscores the need for aggressive management. 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. Fortunately, considerable data have accrued with no evidence that commonly used antiasthmatic drugs are harmful (Blais, 2007; Källén, 2007; Namazy, 2006). Thus, it is worrisome that Enriquez and coworkers (2006) reported a 13- to 54-percent patient-generated decrease in β-agonist and corticosteroid use between 5 and 13 weeks’ gestation.
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 clinical 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 the peak expiratory flow rate—PEFR—are the best measures 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. Each woman determines her own baseline when asymptomatic—personal best—to compare with values when symptomatic. The PEFR does not change during the course of normal pregnancy (Brancazio, 1997).
Management of Chronic Asthma
The management guidelines of the Working Group on Asthma and Pregnancy include:
1. Patient education—general asthma management and its effect on pregnancy
2. Environmental precipitating factors—avoidance or control. Viral infections—including the common cold—are frequent triggering events (Murphy, 2013).
3. Objective assessment of pulmonary function and fetal well-being—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 should 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, 2012; Rey, 2007).
Treatment depends on disease severity. Although β-agonists help to abate bronchospasm, corticosteroids treat the inflammatory component. 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). And Wendel and colleagues (1996) achieved a 55-percent reduction in readmissions for severe exacerbations in pregnant asthmatics given maintenance inhaled corticosteroids along with β-agonist therapy.
FIGURE 51-2 Stepwise approach to asthma treatment. ICS = inhaled corticosteroids; LABA = long-acting β-agonists; OCS = oral corticosteroids. (Modified from Barnes, 2012.)
Theophylline is a methylxanthine, and its various salts are bronchodilators and possibly antiinflammatory agents. They have been used less frequently since inhaled corticosteroids became available. Some theophylline derivatives are considered useful for oral maintenance therapy if the initial response to inhaled corticosteroids and β-agonists is not optimal. Dombrowski and associates (2004b) conducted a randomized trial with nearly 400 pregnant women with moderate asthma. Oral theophylline was compared with inhaled beclomethasone for maintenance. In both groups, approximately 20 percent had exacerbations. Women taking theophylline had a significantly higher discontinuation rate because of side effects. Pregnancy outcomes were similar in the two groups.
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. For maintenance, they are used in conjunction with inhaled corticosteroids to allow minimal dosing. Approximately half of asthmatics will improve with these drugs (McFadden, 2005). They are not as effective as inhaled corticosteroids (Fanta, 2009). Finally, there is little experience with their use in pregnancy (Bakhireva, 2007).
Cromones include cromolyn and nedocromil, which inhibit mast cell degranulation. They are ineffective for acute asthma and are taken chronically for prevention. They are not as effective as inhaled corticosteroids 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 (Barnes, 2012). However, the threshold for hospitalization is significantly lowered. Intravenous 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 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.
First-line therapy for acute asthma includes a β-adrenergic agonist, such as terbutaline, albuterol, isoetharine, epinephrine, isoproterenol, or metaproterenol, which is given subcutaneously, taken orally, or inhaled. These drugs 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 along with intensive β-agonist therapy. For severe exacerbations, magnesium sulfate may prove efficacious. Corticosteroids should be given early to all patients with severe acute asthma. Unless there is a timely response to bronchodilator and inhaled corticosteroid therapy, oral or parenteral corticosteroids are given (Lazarus, 2010). Intravenous methylprednisolone, 40 to 60 mg, every 6 hours for four doses is commonly used. Equipotent doses of hydrocortisone by infusion or prednisone orally can be given instead. Because their onset of action is several hours, corticosteroids are given initially along with β-agonists for acute asthma.
Further management depends on the 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 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 likely advisable (Lazarus, 2010). Intensive therapy includes inhaled β-agonists, intravenous corticosteroids, and close observation for worsening respiratory distress or fatigue in breathing (Wendel, 1996). 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. Braman and Kaemmerlen (1990) have shown that management of nonpregnant patients with status asthmaticus in an intensive care setting results in a good outcome in most cases. Consideration should be given to early intubation when maternal respiratory status worsens despite aggressive treatment (see Fig. 51-1). Fatigue, carbon dioxide retention, and hypoxemia are indications for mechanical ventilation. Lo and colleagues (2013) have 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 intravenously every 8 hours during labor and for 24 hours after delivery. The PEFR or FEV1 should be 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 E2. Prostaglandin F2αor 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 justified (Braman, 2006). Influenza bronchitis is managed as discussed below.
According to Anand and Kollef (2009), current classification includes several types of pneumonia. Community-acquired pneumonia (CAP) 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). Other types are nursing home-acquired pneumonia (NHAO) and ventilator-associated pneumonia (VAP).
Community-acquired pneumonia in pregnant women is relatively common and is caused by several bacterial or viral pathogens (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). Mortality from pneumonia is infrequent in young women, but during pregnancy severe pneumonitis with appreciable loss of ventilatory capacity is not as well tolerated (Rogers, 2010). This generalization seems to hold true regardless of the pneumonia etiology. Hypoxemia and acidosis are also poorly tolerated 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 pregnant woman suspected of having pneumonia should undergo chest radiography.
Many bacteria that cause community-acquired pneumonia, such as Streptococcus pneumoniae, are part of the normal resident flora (Bogaert, 2004). 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 (Goodnight, 2005; Sheffield, 2009).
Incidence and Causes
Pregnancy itself does not 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. More than half of adult pneumonias are bacterial, and S pneumoniae is the most common cause. Lim and coworkers (2001) studied 267 nonpregnant inpatients with pneumonia and identified a causative agent in 75 percent—S pneumoniae in 37 percent; influenza A, 14 percent; Chlamydophila pneumoniae, 10 percent; H influenzae, 5 percent; and Mycoplasma pneumoniae and Legionella pneumophila, 2 percent each. More recently, community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as the second most common pathogen in nonpregnant adults (Moran, 2013). These staphylococci may cause necrotizing pneumonia (Mandell, 2012; Rotas, 2007).
Typical symptoms 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 but does not accurately predict the etiology (Fig. 51-3). 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. Thus, sputum cultures, serological testing, cold agglutinin identification, and tests for bacterial antigens are not recommended. At Parkland Hospital, the one exception to this is rapid serological testing for influenza A and B (Sheffield, 2009).
FIGURE 51-3 Chest radiographs in a pregnant woman with right lower lobe pneumonia. A. Complete opacification of the right lower lobe (arrows) is consistent with the clinical suspicion of pneumonia. B.Opacification (arrows) is also seen on the lateral projection.
Although many otherwise healthy young adults can be safely treated as outpatients, at Parkland Hospital we hospitalize all pregnant women with radiographically proven pneumonia. For some, outpatient therapy or 23-hour observation is reasonable with optimal follow-up. Risk factors shown in Table 51-3 should prompt hospitalization.
TABLE 51-3. Criteria for Severe Community-Acquired Pneumoniaa
Respiratory rate ≥ 30/min
Pao2/Fio2 ratio ≤ 250
Leukopenia—WBC < 4000/μL
Thrombocytopenia—platelets < 100,000/μL
Hypothermia—core temperature < 36°C
Hypotension requiring aggressive fluid resuscitation
aCriteria of the Infectious Diseases Society of America/American Thoracic Society.
WBC = white blood cell.
Adapted from Mandell, 2007.
With severe disease, admission to an ICU 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 during pregnancy, and mechanical ventilation may become necessary. Indeed, of the 51 pregnant women who required mechanical ventilation in the review by Jenkins and coworkers (2003), 12 percent had pneumonia.
Antimicrobial treatment is empirical (Mandell, 2012). Because most adult pneumonias are caused by pneumococci, mycoplasma, or chlamydophila, monotherapy initially is with a macrolide—azithromycin, clarithromycin, or erythromycin. Yost and colleagues (2000) reported that erythromycin monotherapy, given intravenously and then orally, was effective in all but one of 99 pregnant women with uncomplicated 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 β-lactam—high-dose amoxicillin or amoxicillin-clavulanate, which are preferred β-lactams. β-lactam alternatives include ceftriaxone, cefpodoxime, or cefuroxime. In areas in which there is “high-level” resistance of pneumococcal isolates to macrolides, these latter regimens are preferred. The teratogenicity risk of fluoroquinolones is low, and these should be given if indicated (Briggs, 2011). If community-acquired methicillin-resistant S aureus is suspected, then vancomycin or linezolid are added (Mandell, 2012; Sheffield, 2009). At this time, such therapy is empirical, and there are no tested regimens against CA-MRSA (Moran, 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 follow-up radiography is recommended if fever persists. Even with improvement, however, approximately 20 percent of women develop a pleural effusion. Pneumonia treatment is recommended for a minimum of 5 days. Treatment failure may occur in up to 15 percent of cases, and a wider antimicrobial regimen and more extensive diagnostic testing are warranted in these cases.
Pregnancy Outcome with Pneumonia
During the preantimicrobial era, as many as a third of pregnant women with pneumonia died (Finland, 1939). Although much improved, maternal and perinatal mortality rates both remain formidable. In five studies published after 1990, the maternal mortality rate was 0.8 percent of 632 women. Importantly, almost 7 percent of the women required intubation and mechanical ventilation.
Prematurely ruptured membranes and preterm delivery are frequent complications and have been reported in up to a third of cases (Getahun, 2007; Shariatzadeh, 2006). Likely related are older studies reporting a twofold increase in low-birthweight infants (Sheffield, 2009). In a more recent population-based study from Taiwan of nearly 219,000 births, there were significantly increased incidences of preterm and growth-restricted infants as well as preeclampsia and cesarean delivery (Chen, 2012).
Pneumococcal vaccine is 60- to 70-percent protective against its 23 included serotypes. Its use has been shown to decrease emergence of drug-resistant pneumococci (Kyaw, 2006). The vaccine is not recommended for otherwise healthy pregnant women (American College of Obstetricians and Gynecologists, 2013). It is recommended for those 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 9-9, p. 185). Protection against pneumococcal infection in women with chronic diseases may be less efficacious than in healthy patients (Moberley, 2013).
Influenza A and B are RNA viruses that cause respiratory infection, including pneumonitis. Influenza pneumonia can be serious, and it 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 (Longman, 2007). In most healthy adults, infection is self-limited.
Pneumonia is the most frequent complication of influenza, and it is difficult to distinguish from bacterial pneumonia. According to the Centers for Disease Control and Prevention (2010a), infected pregnant women are more likely to be hospitalized as well as admitted to an ICU. At Parkland Hospital during the 2003 to 2004 influenza season, pneumonia developed in 12 percent of pregnant women with influenza (Rogers, 2010). The 2009 influenza pandemic with the H1N1 strain was particularly severe. In a Maternal-Fetal Medicine Units Network study, 10 percent of pregnant or postpartum women admitted with H1N1 influenza were cared for in an ICU, and 11 percent of these ICU patients died (Varner, 2011). Risk factors included late pregnancy, smoking, and chronic hypertension. In California, 22 percent of H1N1-infected women required intensive care, and a third of these died.
Primary influenza pneumonitis is the most severe and is characterized by sparse sputum production and radiographic interstitial infiltrates. More commonly, secondary pneumonia develops from bacterial superinfection by streptococci or staphylococci after 2 to 3 days of initial clinical improvement. The Centers for Disease Control and Prevention (2007b) 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 (p. 1241).
Supportive treatment with antipyretics and bed rest is recommended for uncomplicated influenza. Early antiviral treatment has been shown to be effective (Jamieson, 2011). As discussed, influenza hospitalizations for those with advanced pregnancy are increased compared with nonpregnant women (Dodds, 2007; Schanzer, 2007). Rapid resistance of influenza A (H3N2) strains to amantadine or rimantadine in 2005 prompted the Centers for Disease Control and Prevention (2006) to recommend against their use. Instead, neuraminidase inhibitors were given within 2 days of symptom onset for chemoprophylaxis and treatment of influenza A and B (Chap. 64, p. 1242). The drugs interfere with release of progeny virus from infected host cells and thus prevent infection of new host cells (Moscona, 2005). 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 may reduce the risk for pneumonitis (Jamieson, 2011). Our practice is to treat all pregnant women with influenza whether or not pneumonitis is identified. There are few data regarding use of these agents in pregnant women, but the drugs were not teratogenic in animal studies and are considered low risk (Briggs, 2011).
Other concerns for viral resistance are for avian H5N1 and H7N9 strains isolated in Southeast Asia. These are candidate viruses for an influenza pandemic with a projected mortality rate that exceeds 50 percent (Beigi, 2007; World Health Organization, 2008). Currently, international efforts are being made to produce a vaccine effective against both strains.
Preventively, vaccination for influenza A is recommended and is discussed in detail in Chapter 64 (p. 1242). Prenatal vaccination also affords protection for a third of infants for at least 6 months (Zaman, 2008). During the 2012–2013 flu season, the Centers for Disease Control and Prevention (2013b) reported that only half of pregnant women received the vaccine.
Infection with varicella-zoster virus—chicken pox—results in pneumonitis in 5 percent of pregnant women (Harger, 2002). Diagnosis and management are considered in Chapter 64 (p. 1240).
Fungal and Parasitic 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 in women with AIDS. 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 a report from the AIDS Clinical Trials Centers, Stratton and colleagues (1992) described pneumocystis pneumonia as the most frequent HIV-related disorder in pregnant women. Ahmad and coworkers (2001) reviewed 22 cases during pregnancy and cited a 50-percent mortality rate. Treatment is with trimethoprim-sulfamethoxazole or the more toxic pentamidine (Walzer, 2005). Experience with dapsone or atovaquone is limited. In some cases, tracheal intubation and mechanical ventilation may be required.
As prophylaxis, several international health agencies recommend one double-strength trimethoprim-sulfamethoxazole tablet orally daily for certain HIV-infected pregnant women. These include women with CD4+ T-lymphocyte counts < 200/μL, those whose CD4+ T lymphocytes constitute less than 14 percent, or if there is an AIDS-defining illness, particularly oropharyngeal candidiasis (Centers for Disease Control and Prevention, 2013a; Forna, 2006).
Any of a number of 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.
Histoplasmosis and blastomycosis do not appear to be more common or more severe during pregnancy. Data concerning coccidioidomycosis are conflicting (Bercovitch, 2011; Patel, 2013). In a case-control study from an endemic area, Rosenstein and coworkers (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. Arsura (1998) and Caldwell (2000) and their associates reported that pregnant women with symptomatic infection had a better overall prognosis if there was associated erythema nodosum. Crum and Ballon-Landa (2006) reviewed 80 cases of coccidioidomycosis complicating pregnancy. 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 associates, have provided reviews of coccidioidomycosis in pregnancy.
Most cases of cryptococcosis reported during pregnancy have been reported to manifest as meningitis. Ely and colleagues (1998) described four otherwise healthy pregnant women with cryptococcal pneumonia. Diagnosis is difficult because clinical presentation is similar to that of other community-acquired pneumonias.
The 2007 IDSA/ATS guidelines recommend itraconazole as preferred therapy for disseminated fungal infections (Mandell, 2007). Pregnant women have also been given intravenous amphotericin B or ketoconazole (Hooper, 2007; Paranyuk, 2006). Amphotericin B has been used extensively in pregnancy with no embryo-fetal effects. Because of evidence that fluconazole, itraconazole, and ketoconazole may be embryotoxic in large doses in early pregnancy, Briggs and associates (2011) recommend that first-trimester use should be avoided if possible.
Three echinocandin derivatives—caspofungin, micafungin, and anidulafungin—are effective for invasive candidiasis (Medical Letter, 2006; Reboli, 2007). They are embryotoxic and teratogenic in laboratory animals and use in human pregnancies has not been reported (Briggs, 2011).
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; Longman, 2007; 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.
Although tuberculosis is still a major worldwide concern, it is uncommon in the United States. The incidence of active tuberculosis in this country has plateaued since 2000 (Raviglione, 2012). 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 (Raviglione, 2012).
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 (Zumla, 2013). In some patients, 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 there may be associated cavitation or mediastinal lymphadenopathy. Acid-fast bacilli are seen on stained smears of sputum in approximately two thirds of culture-positive patients. Forms of extrapulmonary tuberculosis include lymphadenitis, pleural, genitourinary, skeletal, meningeal, gastrointestinal, and miliary or disseminated (Raviglione, 2012).
Cure rates with 6-month short-course directly observed therapy—DOT—approach 90 percent for new infections. Resistance to antituberculosis drugs was first manifest in the United States in the early 1990s following the epidemic from 1985 through 1992 (Centers for Disease Control and Prevention, 2007a). Strains of multidrug-resistant tuberculosis (MDR-TB) increased rapidly as tuberculosis incidence fell during the 1990s. Because of this, the Centers for Disease Control and Prevention (2003) 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. Other second-line drugs may need to be added. Drug susceptibility is performed on all first isolates.
In 2005, there was a worldwide emergence of extensively drug-resistant tuberculosis—XDR-TB. This is defined as resistance in vitro to at least the first-line drugs isoniazid and rifampin as well as to three or more of the six main classes of second-line drugs—aminoglycosides, polypeptides, fluoroquinolones, thioamides, cycloserine, and para-aminosalicylic acid (Centers for Disease Control and Prevention, 2009a). Like their predecessor MDR-TB, these extensively resistant strains predominate in foreign-born persons (Tino, 2007).
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 pregnant women. Sackoff and coworkers (2006) reported positive-tuberculin tests in half of 678 foreign-born women attending perinatal 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. Margono and coworkers (1994) reported that for two New York City hospitals, more than half of pregnant women with active tuberculosis were HIV positive. 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).
Without antituberculosis therapy, active tuberculosis appears to have adverse effects on pregnancy (Anderson, 1997; Mnyani, 2011). Contemporaneous experiences are few, however, because antitubercular therapy has diminished the frequency of severe disease. Outcomes are dependent on the site of infection and timing of diagnosis in relation to delivery. Jana and colleagues (1994) from India and Figueroa-Damian and Arrendondo-Garcia (1998) from Mexico City reported that active pulmonary tuberculosis was associated with increased incidences of preterm delivery, low-birthweight and growth-restricted infants, and perinatal mortality. From her review, Efferen (2007) cited twofold increased rates of low-birthweight and preterm infants as well as preeclampsia. The perinatal mortality rate was increased almost tenfold. Adverse outcomes correlate with late diagnosis, incomplete or irregular treatment, and advanced pulmonary lesions. From Taiwan, 761 pregnant women diagnosed with tuberculosis had a higher incidence of low-birthweight and growth-restricted infants (Lin, 2010).
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). Other presentations include widespread intraperitoneal tuberculosis simulating ovarian carcinomatosis and degenerating leiomyoma, and hyperemesis gravidarum from tubercular meningitis (Kutlu, 2007; Moore, 2008; Sherer, 2005).
There are two types of tests 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 (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 (Ernst, 2007; Levison, 2010). The Centers for Disease Control and Prevention (2005b, 2010b) recommend either skin testing or IGRA testing of pregnant women who are in any of the high-risk groups shown in Table 51-4. For those who received BCG vaccination, IGRA testing is used (Mazurek, 2010).
TABLE 51-4. Groups at High Risk for Having Latent Tuberculosis Infection
Contact with infectious person(s)
Working or living in homeless shelters
Illicit drug use
Detainees and prisoners
HIV = human immunodeficiency virus.
From the Centers for Disease Control and Prevention, 2005a.
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 (Centers for Disease Control and Prevention, 2005a, 2010b). It also may be interpreted according to risk factors proposed by the American Thoracic Society/Centers for Disease Control and Prevention (1990). For very high-risk patients—that is, those who are HIV-positive, those with abnormal chest radiography, or those who have a recent contact with an active case—5 mm or greater is considered a reason to treat. For those at high risk—foreign-born individuals, intravenous drug users who are HIV-negative, low-income populations, or those with medical conditions that increase the risk for tuberculosis—10 mm or greater is considered treatable. For persons with none of these risk factors, 15 mm or greater is defined as requiring treatment.
There are two IGRAs available: QuantiFERON-TB Gold and T-SPOT.TB tests are recommended by the Centers for Disease Control and Prevention (2005a,b) for the same indications as skin testing. These tests have not been evaluated as extensively as tuberculin skin testing. Lalvani (2007) reviewed them and found them to be useful in identifying patients with latent tuberculosis and at risk for progression to active disease. Kowada (2014) concluded that these tests are cost effective.
Essential laboratory methods for detection or verification of infection—both active and latent—include microscopy, culture, nucleic acid amplification assay, and drug-susceptibility testing (Centers for Disease Control and Prevention, 2009a, 2010b).
Latent Infection. Different schemes are recommended for latent and active tuberculosis. In nonpregnant tuberculin-positive patients 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, 2011; 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 health systems different from 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 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 given until the first postpartum visit.
There are exceptions to delayed treatment 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 treated because the incidence of infection is 0.5 percent per year.
HIV-positive women are treated because they have an approximate 10-percent annual risk of active disease. Treatment of these women 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 (Török, 2011). Recent studies, however, support earlier administration of highly active antiretroviral therapy (HAART)—within 2 to 4 weeks—after beginning antituberculosis therapy (Blanc, 2011; Havlir, 2011; Karim, 2011).
Active Infection. Recommended initial treatment for active tuberculosis in pregnant patients is a four-drug regimen with isoniazid, rifampin, ethambutol, and pyrazinamide, along with pyridoxine. 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, 2012; Zumla, 2013). Reports of MDR-TB during pregnancy are few, and Lessnau and Qarah (2003) and Shin and coworkers (2003) have reviewed treatment options. Breast feeding is not prohibited during antituberculous therapy.
As discussed above, beginning concomitant antituberculosis and antiretroviral therapy may cause the immune reconstitution inflammatory syndrome, and risks versus benefits are assessed. 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, 2011).
Neonatal Tuberculosis. Tubercular bacillemia can infect the placenta, but it is uncommon that the fetus 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. A rare case of congenital tuberculosis caused by in vitro fertilization (IVF) was reported (Doudier, 2008). Neonatal tuberculosis simulates other congenital infections and manifests with hepatosplenomegaly, respiratory distress, fever, and lymphadenopathy (Smith, 2002).
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 authors 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).
Sarcoidosis is a chronic, multisystem disease of unknown etiology characterized by an accumulation of T lymphocytes and phagocytes within noncaseating granulomas (Baughman, 2012). Predisposition to the disease is genetically determined and characterized by an exaggerated response of helper T lymphocytes to environmental triggers (Moller, 2007; Spagnolo, 2007). Pulmonary involvement is most common, followed by skin, eyes, and lymph nodes. The prevalence of sarcoid in the United States is 20 to 60 per 100,000, with equal sex distribution, but it is 3 to 17 times more common for black compared with white persons (Baughman, 2012). 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 about 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 (Lynch, 2007). Interstitial pneumonitis is the hallmark of pulmonary involvement. Approximately 50 percent of affected patients develop permanent radiological changes. Lymphadenopathy, especially of the mediastinum, is present in 75 to 90 percent of cases, and 25 percent have uveitis. A fourth have skin involvement, usually manifest as erythema nodosum. In women, sarcoid causes about 10 percent of cases of erythema nodosum (Acosta, 2013; Mert, 2007). Finally, any other organ system may be involved. Confirmation of the diagnosis is with biopsy, and 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, there is diminished quality of life (de Vries, 2007). In the other 50 percent, permanent organ dysfunction, albeit mild and nonprogressive, persists. About 10 percent die because of their disease.
Glucocorticoids are the most widely used treatment, and methotrexate is second-line medication. 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 for 4 to 6 weeks (Baughman, 2012). For those with an inadequate response, cytotoxic agents or cytokine modulators may be indicated.
Sarcoidosis and Pregnancy
Because sarcoidosis is uncommon and is frequently benign, it is not often seen in pregnancy. De Regt (1987) described 14 cases in 20,000 pregnancies during a 12-year period—almost 1 in 1500. Although sarcoidosis seldom affects pregnancy adversely, serious complications such as meningitis, heart failure, and neurosarcoidosis have been described (Cardonick, 2000; Maisel, 1996; Seballos, 1994).
In general, perinatal outcomes are unaffected by sarcoidosis. Selroos (1990) reviewed 655 patients with sarcoidosis referred to the Mjölbolsta Hospital District in Finland. Of 252 women between 18 and 50 years, 15 percent had sarcoidosis during pregnancy or within 1 year postpartum. There was no evidence for disease progression in the 26 pregnancies in women with active disease. Three aborted spontaneously, and the other 23 women were delivered at term. In 18 pregnancies in 12 women with inactive disease, pregnancy outcomes were good. 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.
One of the most common fatal genetic disorders in whites, cystic fibrosis is caused by one of more than 1500 mutations in a 230-kb gene on the long arm of chromosome 7 that encodes an amino acid polypeptide (Boucher, 2012). This peptide functions as a chloride channel and is termed the cystic fibrosis transmembrane conductance regulator (CFTR). There is a wide phenotypic variation, even among homozygotes for the common ΔF508 mutation (Rowntree, 2003). This is discussed in greater detail in Chapter 14 (p. 295). Approximately 20 percent of affected individuals are diagnosed shortly after birth because of meconium peritonitis (Boucher, 2012). Currently, nearly 80 percent of females with cystic fibrosis now survive to adulthood, and their median survival is about 30 years (Gillet, 2002).
Mutations in the chloride channel cause altered epithelial cell membrane transport of electrolytes. This affects all organs that express CFTR—secretory cells, sinuses, lung, pancreas, liver, and reproductive tract. Disease severity depends on which two alleles are inherited, and homozygosity for ΔF508 is one of the most severe (McKone, 2003).
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 frequently 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. S aureus, H influenzae, and Burkholderia cepacia are recovered in a minority (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, there is a ventilation–perfusion mismatch. Pulmonary insufficiency is the end result. Lung or heart–lung transplantation has a 5-year survival rate of 33 percent (Aurora, 1999). A few women have successfully undergone pregnancy following lung transplantation (Kruszka, 2002; Shaner, 2012).
Women with 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 estimates 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 IVF have been used successfully in affected women (Rodgers, 2000). Several ethical considerations of undertaking pregnancy by these women were reviewed by Wexler and colleagues (2007). For male infertility, Sobczyńska-Tomaszewska and associates (2006) have emphasized the importance of molecular diagnosis.
The American College of Obstetricians and Gynecologists (2011) recommends that carrier screening be offered to at-risk couples. This is discussed in detail in Chapter 14 (p. 295). The Centers for Disease Control and Prevention also added cystic fibrosis to newborn screening programs (Comeau, 2007). This is discussed also in Chapter 32 (p. 632) and was the subject of a Cochrane Database review (Southern, 2009).
Pregnancy with Cystic Fibrosis
Pregnancy outcome is inversely related to severity of lung dysfunction. Severe 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. Normal pregnancy-induced insulin resistance frequently results in gestational diabetes after midpregnancy (Hardin, 2005; McMullen, 2006). In one study of 48 pregnancies, half had pancreatic insufficiency and a third required insulin (Thorpe-Beeson, 2013). Diabetes is most frequent with the ΔF508 homozygous mutation (Giacobbe, 2012).
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). An important factor to be considered in childbearing is the long-term prognosis for the mother. When matched with nonpregnant women by disease severity, recent reports indicate no deleterious effects on long-term survival (McMullen, 2006; Schechter, 2013).
Prepregnancy counseling is imperative. Women who choose to become pregnant should have close surveillance for development of superimposed infection, diabetes, and heart failure. They are followed closely with serial pulmonary function testing, for management as well as for 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 (Boucher, 2012). Inhaled 7-percent saline has been shown to produce short-and long-term benefits (Donaldson, 2006; Elkins, 2006). Nutritional status is assessed and appropriate dietary counseling given. Pancreatic insufficiency is treated with replacement of oral pancreatic enzyme.
Infection is heralded by increasing cough and mucus production. Oral semisynthetic penicillins or cephalosporins usually suffice to treat staphylococcal infections. Pseudomonas infection is most problematic in adults. Inhaled tobramycin and colistin have been used successfully to control this organism (Boucher, 2012; Ratjen, 2003).
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.
When Cohen and coworkers (1980) conducted the first major survey of cystic fibrosis centers, severity was assessed by the Schwachman-Kulezycki or Taussig scores based on radiological and clinical criteria. Although pregnancy outcomes were not disastrous, 18 percent of 129 women died within 2 years of giving birth. In a later review through 1991, Kent and Farquharson (1993) described similar outcomes in 215 pregnancies in 160 women.
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 from 11 cystic fibrosis centers in the United Kingdom. If prepregnancy FEV1 was < 60 percent of predicted, there was substantive risk for preterm delivery, respiratory complications, and death of the mother within a few years of childbirth. Thorpe-Beeson and associates (2013) reported similar findings.
Fitzsimmons and coworkers (1996) performed a case-control study of 258 women with cystic fibrosis who had a live birth. The 889 matched controls were women with cystic fibrosis who had not been pregnant. Pregnancy had no effect on worsening of any serious complications, and 8 percent in both groups had died by 2 years. Gillet and colleagues (2002) reported 75 pregnancies from the French Cystic Fibrosis Registry. Almost 20 percent of infants were delivered preterm, and 30 percent had growth restriction. The one maternal death was due to Pseudomonas sepsis in a woman whose prepregnancy FEV1was 60 percent. Long-term, however, 17 percent of women died and four infants had confirmed cystic fibrosis. Likewise, in the study by Thorpe-Beeson (2013) cited above, four of eight women whose FEV1was < 40 to 50 percent died from 2 to 8 years after delivery.
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 infants. Maternal outcomes were less favorable—three developed rejection during pregnancy, and all three had progressively declining pulmonary function and died of chronic rejection by 38 months after delivery.
CARBON MONOXIDE POISONING
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).
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. 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).
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 there has been “significant” carbon monoxide exposure (Aubard, 2000; Ernst, 1998). The problem is how to define significant exposure. 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 fetal heart rate variable decelerations. 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 (2013)—at Duke University, there are 700 chambers in North and Central America and the Caribbean. Consultation from DAN is available at 919-684-9111.
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