Chapter 45Respiratory Diseases in Pregnancy Janice E. Whitty, MD, and Mitchell P. Dombrowski, MDProper functioning of the cardiorespiratory system is imperative to nonpregnant women, it is likely that this phenomenon results fromachieve adequate oxygenation of maternal and fetal tissues. The mater- progestational inﬂuences.5,6 The PaCO2 is linearly and inversely relatednal cardiorespiratory system undergoes signiﬁcant changes during to the log of the progesterone concentration.7 Wilbrand and colleagues8gestation to optimize oxygen delivery to the fetus and maternal tissues. reported that progesterone lowers the carbon dioxide threshold of thePulmonary disease is one of the most frequent maternal complications respiratory center. During pregnancy, the sensitivity of the respiratoryduring pregnancy, and it may result in signiﬁcant morbidity or mortal- center increases9 so that an increase in PaCO2 of 1 mm Hg increasesity for the mother and her fetus. Depending on the speciﬁc diagnosis, ventilation by 6 L/min in pregnancy, compared with 1.5 L/min in theother maternal complications of pregnancy may have an adverse or nonpregnant state.1,10,11 It is possible that progesterone acts as a primarypositive impact on the pulmonary function of the gravida. stimulant to the respiratory center independently of any change in In this chapter, we brieﬂy review the physiologic adaptations of carbon dioxide sensitivity or threshold.4 In addition to stimulatingthe respiratory system that occur during gestation. Speciﬁc respir- ventilation, progesterone may also increase levels of carbonic anhy-atory diseases that occur in pregnancy and the effects of the disease on drase B in the red blood cell.12 Schenker and associates13 reported thatpregnancy and pregnancy on the disease are discussed. The obstetri- carbonic anhydrase levels increase in pregnant patients and in womencian should realize that most diagnostic tests useful in evaluating pul- taking oral contraceptives. An increase in the carbonic anhydrase levelmonary function during gestation are not harmful to the fetus and, if facilitates carbon dioxide transfer and tends to decrease PaCO2 inde-indicated, should be performed. Most medications used to treat respi- pendently of any change in ventilation. This respiratory stimulantratory disease in pregnancy are also well tolerated by the fetus. With effect of progesterone has been used in the treatment of respiratoryfew exceptions, the diagnostic and treatment algorithms for respiratory failure and emphysema.6,14,15disease closely resemble those used for a nonpregnant woman. During gestation, ventilation is increased by the rise in tidal volume from approximately 500 to 700 mL in each breath.1,16-18 Because there is no change in respiratory rate, minute ventilation rises from about 7.5 to 10.5 L/min.11,17,19 Minute ventilation increases in the ﬁrst trimes-Physiologic Changes of the ter and remains at that level throughout pregnancy. The physiologicRespiratory System dead space is increased by about 60 mL in pregnancy. This may result from dilation of the small airways.11 Residual volume is reduced byBecause there is no increase in respiratory rate, the increase in maternal about 20%,16 from 1200 to 1000 mL.20-22 The vital capacity, which isminute ventilation results from an increase in tidal volume.1 The the maximum volume of gas that can be expired after a maximumalmost 50% increase in tidal volume occurs at the expense of an 18% inspiration, does not change in pregnancy.16,21-25decrease in the functional residual capacity. The resulting hyperventi-lation of pregnancy results in a compensated respiratory alkalosis(i.e., arterial partial pressure of carbon dioxide [PaCO2] ≤ 30 mm Hg)and a modest increase in arterial oxygenation tension (i.e., 101 to Anatomic Changes of the104 mm Hg).2 The PaCO2 decreases early in pregnancy in parallel withthe change in ventilation; however, a further progressive decrease in Respiratory SystemPaCO2 may occur.3 The decrease in PaCO2 is even greater at altitudes Observed changes in the conﬁguration of the chest during pregnancywhere the mother exhibits compensatory hyperventilation in an are in keeping with the ﬁndings of no change in vital capacity and aattempt to maintain the arterial partial pressure of oxygen as high as reduction in residual volume. The effect of pregnancy on pulmonarypossible. The decrease in PaCO2 is matched by an equivalent increase mechanics has been compared with the effect of a pneumoperitoneum.in renal excretion of and decrease in plasma bicarbonate concentra- In both situations, the residual lung volume is decreased, but ventila-tion; therefore, arterial pH is not altered from the normal nonpregnant tion remains unimpaired. Radiologic studies performed early in preg-level of about 7.4. nancy have shown that the subcostal angle increases from 68 to 103 It has been suggested that the hyperventilation of pregnancy results degrees before there is any mechanical pressure from the enlargingprimarily from progesterone acting as a respiratory stimulant.4 Because uterus.26 The level of the diaphragm rises by about 4 cm, and thehyperventilation has been observed during the luteal phase of the transverse diameter of the chest increases by 2 cm.27-29 These changesmenstrual cycle and progesterone can produce similar changes in account for the decrease in residual volume because the lungs are
928 CHAPTER 45 Respiratory Diseases in Pregnancyrelatively compressed during forced expiration; however, the excursion largely on hemoglobin concentration and arterial oxygen saturation.of the diaphragm in respiration increases by about 1.5 cm in pregnancy Oxygen delivery can be impaired by conditions that affect arterialcompared with the nonpregnant state.29,30 oxygen content or cardiac output (ﬂow), or both. Anemia leads to low arterial oxygen content because of a lack of hemoglobin binding sites for oxygen. Carbon monoxide poisoning likewise decreases oxyhemo- globin because of blockage of binding sites for oxygen. The patientOxygen Delivery with hypoxemic respiratory failure does not have sufﬁcient oxygen available to saturate the hemoglobin molecule. Desaturated hemoglo-and Consumption bin is altered structurally such that it has a diminished afﬁnity for oxygen.33Oxygen Delivery The amount of oxygen available to tissues also is affected by theAll tissues require oxygen for the combustion of organic compounds afﬁnity of the hemoglobin molecule for oxygen. The oxyhemoglobinto fuel cellular metabolism. The cardiopulmonary system delivers dissociation curve (Fig. 45-1) and the conditions that inﬂuence thea continuous supply of oxygen and other essential substrates to binding of oxygen negatively or positively must be considered whentissues. Oxygen delivery depends on oxygenation of blood in the lungs, attempts are made to maximize oxygen delivery.34 An increase in theoxygen-carrying capacity of the blood, and cardiac output.31 Under plasma pH level or a decrease in temperature or the concentration ofnormal conditions, oxygen delivery exceeds oxygen consumption by 2,3-diphosphoglycerate can increase hemoglobin afﬁnity for oxygen,about 75%.32 The amount of oxygen delivered is determined by the shifting the curve to the left and resulting in diminished tissue oxygen-cardiac output (CO, L/min) times the arterial oxygen content (CaO2, ation. If the plasma pH level, temperature, or 2,3-diphosphoglyceratemL/O2/min): level increases, hemoglobin afﬁnity for oxygen decreases, and more oxygen is available to tissues (see Fig. 45-1).34 Oxygen delivery = CO × CaO2 × 10 (700 to 1400 mL/min) In certain clinical conditions, such as septic shock and adult respi- ratory distress syndrome, there is maldistribution of ﬂow relative to The arterial oxygen content is determined by the amount of oxygen oxygen demand, leading to diminished delivery and consumption ofthat is bound to hemoglobin (i.e., arterial blood saturation with oxygen oxygen. The release of vasoactive substances is hypothesized to result[SaO2]) and by the amount of oxygen that is dissolved in plasma (i.e., in the loss of normal mechanisms of vascular autoregulation, produc-arterial partial pressure of oxygen [PaO2 × 0.0031]): ing regional and microcirculatory imbalances in blood ﬂow.35 This mismatching of blood ﬂow with metabolic demand causes excessive CaO2 = (hemoglobin × 1.34 × SaO2) + (PaO2 × 0.0031) blood ﬂow to some areas and relative hypoperfusion of other areas, (16 to 22 mL O2/dL) limiting optimal systemic use of oxygen.35 The patient with diminished cardiac output resulting from hypovolemia or pump failure is unable As can be seen in this formula, the amount of oxygen dissolved in to distribute oxygenated blood to tissues. Therapy directed at increas-plasma is negligible, and the arterial oxygen content therefore depends ing the volume with normal saline or with blood if the hemoglobin 100 90 pH DPG Temp 80 70 pH Percent oxyhemoglobin DPG 60 Temp 50 40 30 20 10FIGURE 45-1 The oxygen-binding curve for humanhemoglobin A under physiologic conditions (red 0 10 20 30 40 50 60 70 80 90 100curve). The afﬁnity is shifted by changes in pH, O2 tension (mm Hg)diphosphoglycerate (DPG) concentration, and temperature. P50P50 is the oxygen tension at one-half saturation.
CHAPTER 45 Respiratory Diseases in Pregnancy 929level is less than 10 g/dL increases delivery of oxygen in the hypovole- venous oxygen tension is 40 mm Hg with a saturation of 73%. Satura-mic patient. The patient with cardiac failure may beneﬁt from inotro- tions less than 60% are abnormally low. These parameters can bepic support and afterload reduction in addition to supplementation of measured directly by obtaining a blood sample from the distal port ofintravascular volume. ¯ the pulmonary artery catheter. The SVO2 also can be measured con- tinuously with special pulmonary artery catheters equipped with ﬁber- optics. Mixed venous oxygenation is a reliable parameter in the patientRelationship of Oxygen Delivery with hypoxemia or low cardiac output, but ﬁndings must be inter-to Consumption ¯ preted with caution. When the SVO2 is low, oxygen delivery can beOxygen consumption is the product of the arteriovenous oxygen ¯ assumed to be low. However, normal or high SVO2 values do not guar-content difference (C(a−v)O2) and cardiac output (CO). Under normal antee that tissues are well oxygenated. In conditions such as septicconditions, oxygen consumption is a direct function of the metabolic shock and adult respiratory distress syndrome, the maldistribution ofrate36: ¯ systemic ﬂow may lead to an abnormally high SVO2 value in the face of severe tissue hypoxia.35 The oxygen dissociation curve must be con- Oxygen consumption = C(a−v)O2 × CO × 10 ¯ sidered when interpreting the SVO2 as an indicator of tissue oxygen- (180 to 280 mL/min) ation.33 Conditions that result in a left shift of the curve cause the venous oxygen saturation to be normal or high, even when the mixed The oxygen extraction ratio is the fraction of delivered oxygen that ¯ venous oxygen content is low. SVO2 is useful for monitoring trends inactually is consumed: a particular patient, because a signiﬁcant decrease occurs when oxygen delivery has decreased because of hypoxemia or a decrease in cardiac Oxygen extraction ratio = O2 consumption/O2 delivery (0.25) output. The normal oxygen extraction ratio is about 25%. A rise in theoxygen extraction ratio is a compensatory mechanism used when Oxygen Delivery and Consumptionoxygen delivery is inadequate for the level of metabolic activity. A in Pregnancysubnormal value suggests ﬂow maldistribution, peripheral diffusion The physiologic anemia of pregnancy results in a reduction in thedefects, or functional shunting.36 As the supply of oxygen is reduced, hemoglobin concentration and arterial oxygen content. Oxygen deliv-the fraction extracted from blood increases and oxygen consumption ery is maintained at or above normal despite this because of the 50%is maintained. If a severe reduction in oxygen delivery occurs, the limits increase in cardiac output. The pregnant woman therefore dependsof oxygen extraction are reached, tissues are unable to sustain aerobic on cardiac output for maintenance of oxygen delivery more than theenergy production, and consumption decreases. The level of oxygen nonpregnant patient.38 Oxygen consumption increases steadilydelivery at which oxygen consumption begins to decrease is called throughout pregnancy and is greatest at term, reaching an average ofcritical oxygen delivery (Fig. 45-2).37 At the critical oxygen delivery level, 331 mL/min at rest and 1167 mL/min with exercise.11 During labor,tissues begin to use anaerobic glycolysis, with resultant lactate produc- oxygen consumption increases by 40% to 60%, and cardiac outputtion and metabolic acidosis.37 If oxygen deprivation continues, irre- increases by about 22%.39,40 Because oxygen delivery normally farversible tissue damage and death ensue. exceeds consumption, the normal pregnant patient usually is able to maintain adequate delivery of oxygen to herself and her fetus, even during labor. When a pregnant patient has low oxygen delivery, sheMixed Venous Oxygenation very quickly can reach the critical oxygen delivery level during labor,The mixed venous oxygen tension and mixed venous oxygen saturation compromising herself and her fetus. The obstetrician therefore must(SVO2) are parameters of tissue oxygenation.37 The normal mixed ¯ make every effort to optimize oxygen delivery before allowing labor to begin in the compromised patient. Pneumonia in Pregnancy Pneumonia is fortunately a rare complication of pregnancy, occurring O2 consumption in 1 of 118 to 2288 deliveries.41,42 However, pneumonia contributes to considerable maternal mortality and is reportedly the most common non-obstetric infection to cause maternal mortality in the peripartum period.43 Maternal mortality was as high as 24% before the introduc- tion of antibiotic therapy.44 Research reports have documented a dra- matic decrease in maternal mortality from 0% to 4% with modern management and antibiotic therapy.42,45,46 Preterm delivery is a signiﬁ- DO2crit cant complication of pneumonia complicating pregnancy. Even with antibiotic therapy and modern management, preterm delivery con- O2 delivery tinues to occur for 4% to 43% of gravidas who have pneumonia.42,45,46FIGURE 45-2 Relationship of oxygen consumption (VO2) and The increasing incidence of pneumonia in pregnancy may reﬂectoxygen delivery (DO2). At the point of critical oxygen delivery, the declining general health status of certain segments of the childbear-tissues begin to use anaerobic glycolysis, with resultant lactate ing population (e.g., morbid obesity).46 The epidemic of humanproduction and metabolic acidosis. If the oxygen deprivation immunodeﬁciency virus (HIV) infection has increased the number ofcontinues, irreversible tissue damage and death ensue. potential mothers who are at risk for opportunistic lung infections.
930 CHAPTER 45 Respiratory Diseases in PregnancyHIV infection is also associated with increased risks of invasive pneu- Pneumonia in pregnancy has several causes, including mumps,mococcal disease (odds ratio [OR] = 41.8) and Legionnaire disease infectious mononucleosis, swine inﬂuenza, inﬂuenza A, varicella, coc-(OR = 41.8).47 HIV infection further predisposes the pregnant woman cidioidomycosis, and other fungi.50 Varicella pneumonia can compli-to the infectious complications of acquired immunodeﬁciency syn- cate primary varicella infections in 5.2% to 9%51 of infections indrome (AIDS).47,48 Reported incidence rates range from 97 to 290 cases pregnancy, compared with 0.3% to 1.8% in the nonpregnant popula-per 1000 HIV-infected persons per year. HIV-infected persons are 7.8 tion.52 Inﬂuenza A has a higher mortality rate among pregnant womentimes more likely to develop pneumonia than non-HIV-infected indi- than among nonpregnant patients.53 The increase in virulence of viralviduals with similar risk factors. Women with medical conditions that infections reported in pregnancy may result from the alterations inincrease the risk for pulmonary infection, such as cystic ﬁbrosis (CF), maternal immune status that characterize pregnancy, includingare living to childbearing age more frequently than in the past. This reduced lymphocyte proliferative response, reduced cell-mediateddisorder contributes to the increased incidence of pneumonia in cytotoxicity by lymphocytes, and a decrease in the number of helperpregnancy. T lymphocytes.53,54 Viral pneumonias can also be complicated by Pneumonia can complicate pregnancy at any time during gestation superimposed bacterial infection, particularly pneumococcus.and may be associated with preterm birth, poor fetal growth, andperinatal loss. In an early report, 17 of 23 patients developed pneumo-nia between 25 and 36 weeks’ gestation.49 In that series, seven gravidas Aspiration Pneumoniadelivered during the course of their acute illness, and there were two Mendelson syndrome describes chemical pneumonitis resulting frommaternal deaths. Another report described 39 cases of pneumonia in the aspiration of gastric contents in pregnancy. Chemical pneumonitispregnancy.45 Sixteen gravidas presented before 24 weeks’ gestation, 15 can be superinfected with pathogens present in the oropharynx andbetween 25 and 36 weeks’ gestation, and 8 after 36 weeks’ gestation. gastric juices, primarily anaerobes and gram-negative bacteria.45 Men-Twenty-seven patients in this series were followed to completion of delson’s original report of aspiration55 consisted of 44,016 nonfastedpregnancy; only two required delivery during the acute phase of pneu- obstetric patients between 1932 and 1945, and more than one half hadmonia. Of these 27 patients, 3 suffered a fetal loss, and 24 delivered received “operative intervention” with ether by mask without endotra-live fetuses, although there was one neonatal death resulting from cheal intubation. He described aspiration in 66 cases (rate of 1 case perprematurity. 667 patients). Although several of the patients were critically ill from Madinger and associates42 reported 25 cases of pneumonia their aspirations, most recovered within 24 to 36 hours, and only twooccurring among 32,179 deliveries and observed that fetal and died from this complication (rate of 1 death per 22,008 patients). Aobstetric complications were much more common than in earlier review described 37,282 vaginal deliveries; 85% were performed withstudies. Preterm labor complicated 11 of 21 gestations. Eleven patients general anesthesia by mask and without intubation, and 65% to 75%had pneumonia at the time of delivery. Preterm delivery was more had ingested liquids or solid food within 4 hours of onset of labor.56likely for women who had bacteremia, needed mechanical ventilation, The investigators found ﬁve mild cases of aspiration (1 per 7456and had a serious underlying maternal disease. In addition to the patients) with no sequelae.56 Another report described one occurrencecomplication of preterm labor, there were three perinatal deaths in this of “mild aspiration” without adverse outcome among 1870 womenseries. Berkowitz and LaSala46 reported 25 patients with pneumonia undergoing nonintubated peripartum surgery with intravenous ket-complicating pregnancy; 14 women had term deliveries, 1 delivered amine, benzodiazepines, barbiturates, fentanyl, or some combinationpreterm, 3 had a voluntary termination of pregnancy, 3 had term of these drugs.57 Soreide and colleagues58 observed four episodes ofdeliveries of growth-restricted infants, and 4 were lost to follow-up. aspiration each during 36,800 deliveries and 3600 cesarean sectionsBirth weight was signiﬁcantly lower in the study group in this series with no mortality. Based on these data, most hospitals permit free(2770 ± 224 g versus 3173 ± 99 g in the control group; P < .01). In this intake of clear liquids during labor. The risk of aspiration, pneumonia,series, pneumonia complicated 1 of 367 deliveries. The investigators and death from general anesthesia appears to be very low. This mayattributed the increase in the incidence of pneumonia in this popula- reﬂect the use of modern techniques and therapy to reduce gastriction to a decline in general health status, including anemia, a signiﬁcant pH.incidence of cocaine use (52% versus 10% of the general population),and HIV positivity (24% versus 2% of the general population) in thestudy group. Bacterial Pneumonia Streptococcus pneumoniae (pneumococcus) is the most common bacte- rial pathogen that causes pneumonia in pregnancy; H. inﬂuenzae is theBacteriology next most common. These pneumonias typically manifest as an acuteMost series describing pneumonia complicating pregnancy have used illness accompanied by fever, chills, and a purulent, productive coughincomplete methodologies to diagnose the etiologic pathogens for and are seen as a lobar pattern on the chest radiograph (Fig. 45-3).pneumonia, relying primarily on cultures of blood and sputum. In Streptococcal pneumonia produces a “rusty” sputum, with gram-most cases, no pathogen was identiﬁed; however, pneumococcus and positive diplococci on Gram stain, and it demonstrates asymmetricalHaemophilus inﬂuenzae remain the most common identiﬁable causes consolidation with air bronchograms on the chest radiograph.54 H.of pneumonia in pregnancy.42,45,46 Because comprehensive serologic inﬂuenzae is a gram-negative coccobacillus that produces consolida-testing has rarely been done, the true incidence of viral, Legionella, and tion with air bronchograms, often in the upper lobes.54 Less commonMycoplasma pneumonia in pregnancy is difﬁcult to estimate. The data bacterial pathogens include Klebsiella pneumoniae, which is a gram-presented by Benedetti, Madinger, Berkowitz, and their respective col- negative rod that causes extensive tissue destruction with air broncho-leagues all support pneumococcus as the predominant pathogen grams, pleural effusion, and cavitation seen on the chest radiograph.causing pneumonia in pregnancy and H. inﬂuenzae as the second most Patients with Staphylococcus aureus pneumonia present with pleuritis,common organism.42,45,46 In the series of Berkowitz and LaSala,46 one chest pain, purulent sputum, and consolidation without air broncho-patient was infected with Legionella species. grams identiﬁed on the chest radiograph.54
CHAPTER 45 Respiratory Diseases in Pregnancy 931 The workup should include a physical examination, arterial blood gas determinations, a chest radiograph, sputum Gram stain and culture, and blood cultures. Several studies have called into question the use of cultures to identify the microbes of community-acquired pneumonia. Success rates for identiﬁcation of the bacterial cause with cultures range from 2.1% to approximately 50%. Review of available clinical data reﬂects an overall reliance on clinical judgment and the patient’s response to treatment to guide therapy. Other tests are avail- able to identify the cause of pneumonia that do not require culture and are more sensitive and speciﬁc. An assay approved by the U.S. Food and Drug Administration (FDA) for pneumococcal urinary antigen has been assessed in several studies. The sensitivity for identifying pneumococcal disease in adults is reportedly 60% to 90%, with a speciﬁcity close to 100%. In one study, the pneumococcal antigen was detected in 26% of patients in whom no pathogens had been identiﬁed. This ﬁnding suggests that cases that are undiagnosed by standard test can be identiﬁed with the assay. In this study, 10% of samples from patients with pneumonia caused by other agents were positive on the pneumococcal assay, indicating a potential problem with speciﬁcity. If the response to therapy directed at pneumococcus is inadequate, cov- erage for other potential pathogens should be added. The test for Legionella urinary antigen has a sensitivity of 70% and speciﬁcity of 90% for serogroup 1. This is especially useful in the United States and Europe, because about 85% of Legionella isolates are serogroup 1. Legionella is a common cause of severe community-FIGURE 45-3 Right lower lobe pneumonia. Lobar consolidation in acquired pneumonia. The urinary antigen for serogroup 1 should bethe right lower lobe is consistent with pneumococcal pneumonia. considered for any patient requiring admission into an intensive care unit for pneumonia. Percutaneous-transthoracic needle aspiration has been advocated Patients infected with atypical pneumonia pathogens, such as as a valuable and safe method to increase the chance of establishingMycoplasma pneumoniae, Legionella pneumophila, and Chlamydia the causative agent for pneumonia. This test should be reserved for usepneumoniae (TWAR agent), present with gradual onset of symptoms. in compromised individuals, suspected tuberculosis in the absence ofThey have a lower fever, appear less ill, have mucoid sputum, and have a productive cough, selected cases of chronic pneumonia, pneumoniaa patchy or interstitial inﬁltrate seen on the chest radiograph. The associated with neoplasm or a foreign body, suspected Pneumocystisseverity of the ﬁndings on the chest radiograph usually is out of pro- jiroveci pneumonia, and suspected conditions that necessitate lungportion to the mild clinical symptoms. M. pneumoniae is the most biopsy. Cold agglutinins and Legionella titers may also be useful.common organism responsible for atypical pneumonia and is best Empiric antibiotic coverage should be started, usually with a third-detected by the presence of cold agglutinins in about 70% of cases. generation cephalosporin such as ceftriaxone or cefotaxime. Legionella The normal physiologic changes in the respiratory system associ- pneumonia has a high mortality rate and sometimes manifests withated with pregnancy result in a loss of ventilatory reserve. Coupled consolidation, mimicking pneumococcal pneumonia. It is recom-with the immunosuppression that accompanies pregnancy, this puts mended that a macrolide, such as azithromycin, be added to thethe mother and fetus at great risk from respiratory infection. Any empiric therapy. Dual coverage has been demonstrated to improvegravida suspected of having pneumonia should be managed aggres- response to therapy even for abbreviated macrolide regimens. Thissively. The pregnant patient should be admitted to the hospital and a may reﬂect the added anti-inﬂammatory effect of the macrolides.thorough investigation undertaken to determine the cause. One study Azithromycin administration is an independent predictor of a positiveexamined 133 women admitted with pneumonia during pregnancy outcome and reduced length of hospital stay for patients with mild tousing protocols based on the British Thoracic Society and American moderate community-acquired pneumonia. The use of macrolides toThoracic Society admission guidelines for management of nonpreg- treat community-acquired pneumonia should be limited when possi-nant individuals. The investigators reported that if the American Tho- ble, because their use has also been associated with increased penicillinracic Society guidelines were used, 25% of the pregnant women with resistance by S. pneumoniae.pneumonia could have avoided admission. Using the American crite- When admission for pneumonia is required, there is evidence thatria, none of the gravidas who would have been managed as an outpa- inpatient and 30-day mortality rates have been reduced when antibiot-tient had any complications. If the British Thoracic Society guidelines ics are administered in less than 8 hours. Current U.S. federal standardshad been used; 66% of the pregnant women in this group would have require that the ﬁrst dose of antibiotics be administered within 4 hoursbeen assigned to outpatient therapy. However, 14% would have of arrival to the hospital. After the results of the sputum culture, bloodrequired readmission for complications. Most of the 133 women who cultures, Gram stain, and serum studies are obtained and a pathogenwere hospitalized with pneumonia in this study did not receive a chest has been identiﬁed, antibiotic therapy can be directed toward the iden-radiograph for conﬁrmation of the diagnosis. This limits the value of tiﬁed cause. The third-generation cephalosporins are effective agentsthe study for guiding admission criteria for pneumonia in pregnancy. for most pathogens causing a community-acquired pneumonia. TheyUntil additional information is available, admission for all pregnant are also effective against penicillin-resistant S. pneumoniae. The qui-women with pneumonia is still recommended. nolones as a class should be avoided in pregnancy because they may
932 CHAPTER 45 Respiratory Diseases in Pregnancydamage developing fetal cartilage. However, with the emergence of contrast to the general population, pregnant women seem to be athighly resistant bacterial pneumonia, their use may be lifesaving and higher risk for inﬂuenza pneumonia.61,62 Epidemiologic data from thetherefore justiﬁed in speciﬁc circumstances. The respiratory quino- 1918 to 1919 inﬂuenza A pandemic revealed a maternal mortality ratelones are effective against highly penicillin-resistant S. pneumoniae that approached 50% for pregnant women with inﬂuenza pneumo-strains, and their use does not increase resistance. The respiratory nia.63,64 Three types of inﬂuenza virus can cause human disease—A, B,quinolones include levoﬂoxacin, gatiﬂoxacin, and moxiﬂoxacin. These and C—but most epidemic infections are caused by inﬂuenza A.50are ideal agents for community-acquired pneumonia because they are Inﬂuenza A typically has an acute onset after a 1- to 4-day incubationhighly active against penicillin-resistant strains of S. pneumoniae. They period and ﬁrst manifests as high fever, coryza, headache, malaise, andare also active against Legionella and the other atypical pulmonary cough. In uncomplicated cases, results of the chest examination andpathogens. Another advantage is a favorable pharmacokinetic proﬁle, chest radiograph are normal.50 If symptoms persist longer than 5 days,such that blood or lung levels are the same whether the drug is admin- especially in a pregnant woman, complications should be suspected.istered orally or intravenously. Arguments against more extensive Pneumonia may complicate inﬂuenza as the result of secondary bacte-respiratory quinolone use are based on concerns about the potential rial infection or viral infection of the lung parenchyma.50 In the epi-for developing resistance, the variable incidence of Legionella, and cost. demic of 1957, autopsies demonstrated that pregnant women diedAn additional caveat is that the respiratory quinolones are only par- most commonly of fulminant viral pneumonia, whereas nonpregnanttially effective against Mycobacterium tuberculosis. Evaluation for this patients died most often of secondary bacterial infection.65infection should be done when considering the use of quinolones for A large, nested, case-control study evaluated the rate of inﬂuenza-pneumonia. related complications over 17 inﬂuenza seasons among women enrolled In addition to antibiotic therapy, oxygen supplementation should in the Tennessee Medicaid system. This study demonstrated a high riskbe given. Frequent arterial blood gas measurements should be obtained for hospitalization for inﬂuenza-related reasons in low-risk pregnantto maintain partial pressure of oxygen at 70 mm Hg, a level necessary women during the last trimester of pregnancy. The study authors esti-to ensure adequate fetal oxygenation. Arterial saturation also can be mated that 25 of 10,000 women in the third trimester during themonitored with pulse oximetry. When the gravida is afebrile for 48 inﬂuenza season are hospitalized with inﬂuenza-related complications.hours and has signs of clinical improvement, an oral cephalosporin A later, matched-cohort study using the administrative database ofcan be started and intravenous therapy discontinued. A total of 10 to pregnant women enrolled in the Tennessee Medicaid system examined14 days of treatment should be completed. pregnant women between the ages of 25 and 44 years with respiratory Pneumonia in pregnancy can be complicated by respiratory failure hospitalization during the 1985 to 1993 inﬂuenza seasons. In thisrequiring mechanical ventilation. If this occurs, team management population of pregnant women, those with asthma accounted for oneshould include the obstetrician, maternal-fetal medicine specialist, and half of all respiratory-related hospitalizations during the inﬂuenzaintensivist. In addition to meticulous management of the gravida’s season. Among pregnant women with diagnosis of asthma, 6% requiredrespiratory status, the patient should be maintained in the left lateral respiratory hospitalization during the inﬂuenza season (OR = 10.63;recumbent position to improve uteroplacental perfusion. The viable 95% conﬁdence interval [CI], 8.61 to 13.83) compared with womenfetus should be monitored with continuous fetal monitoring. If posi- without a medical comorbidity. This study detected no signiﬁcanttive end-expiratory pressure greater than 10 cm H2O is required to increases in adverse perinatal outcome associated with respiratory hos-maintain oxygenation, central monitoring with a pulmonary artery pitalization during ﬂu season.catheter should be instituted to adequately monitor volume status and Primary inﬂuenza pneumonia is characterized by rapid progressionmaintain maternal and uteroplacental perfusion. There is no evidence from a unilateral inﬁltrate to diffuse bilateral disease. The gravida maydocumenting that elective delivery results in overall improvement in develop fulminant respiratory failure requiring mechanical ventilationrespiratory function,59 and elective delivery should be reserved for the and positive end-expiratory pressure. Aggressive therapy is indicatedusual obstetric indications. However, if there is evidence of fetal com- when pneumonia complicates inﬂuenza in pregnancy. Antibioticspromise or profound maternal compromise and impending demise, should be started and directed at the likely pathogens that can causedelivery should be accomplished. secondary infection, including S. aureus, pneumococcus, H. inﬂuenzae, Pneumococcal polysaccharide vaccination prevents pneumococcal and certain enteric gram-negative bacteria. Antiviral agents, such aspneumonia in otherwise healthy populations with an efﬁcacy of 65% oseltamivir and zanamivir, should also be considered.66 It has beento 84%. The vaccine is safe in pregnancy and should be administered recommended that the inﬂuenza vaccine be given routinely to gravidasto high-risk gravidas. Those at high risk include individuals with sickle in the second and third trimester of pregnancy to prevent the occur-cell disease with autosplenectomy, patients who have a surgical sple- rence of inﬂuenza and the development of pneumonia. Women at highnectomy, and individuals who are immunosuppressed. An additional risk for pulmonary complications, such as those with asthma, chronicadvantage to maternal immunization with the pneumococcal vaccine obstructive pulmonary disease, cystic ﬁbrosis, and splenectomy, shouldis that several studies have demonstrated there is signiﬁcant transpla- be vaccinated regardless of the trimester to prevent the occurrence ofcental transmission of vaccine-speciﬁc antibodies in infants at birth inﬂuenza and the development of secondary pneumonia. In additionand at 2 months. Colostrum and breast milk antibodies are also sig- to maternal protection, prospective studies have demonstrated higherniﬁcantly increased in women who have received the pneumococcal cord blood antibody levels to inﬂuenza in infants born to mothersvaccine. immunized during pregnancy. There is a delay in the onset and decrease in severity of inﬂuenza in infants born with higher antibody levels.Viral Pneumonias Varicella Varicella-zoster virus is a DNA virus that usually causes a benign, self-Inﬂuenza limited illness in children, but it may infect up to 2% of all adults.67An estimated 4 million cases of pneumonia and inﬂuenza occur annu- Varicella infection occurs in 0.7 of every 1000 pregnancies.68 Pregnancyally in the United States, and it is the sixth leading cause of death.60 In may increase the likelihood of varicella pneumonia, complicating the
CHAPTER 45 Respiratory Diseases in Pregnancy 933primary infection.52 Treatment with acyclovir is safe in pregnancy. In pattern of congenital abnormalities.71 A dose of 7.5 mg/kg given intra-one report,52 there was one intrauterine fetal death. Another report51 venously every 8 hours has been recommended.72documented a 5.2% incidence of varicella pneumonia among gravidas Varicella vaccine is an attenuated live virus vaccine that was addedwith varicella-zoster infection. The investigators also reported that to the universal childhood immunization schedule in the United Statesgravidas who smoke or manifest more than 100 skin lesions are more in 1995. The program of universal childhood vaccination against vari-likely to develop pneumonia.51 Varicella pneumonia occurs most often cella in the United States has resulted in a sharp decline in the rate ofin the third trimester, and the infection is likely to be severe.52,68,69 The death from varicella. However, varicella vaccine is not recommendedmaternal mortality rate for varicella pneumonia may be as high as for use in pregnancy. The overall decline in incidence of adult varicella35% to 40%, compared with 11% to 17% for nonpregnant individu- infection because of childhood vaccination will likely result in aals.52,69 Although one review reported a decreased mortality rate, with decreased incidence of varicella infection and varicella pneumoniaonly three deaths among 28 women with varicella pneumonia,68 during pregnancy.another study documented a maternal mortality rate of 35%.52 A study73 assessed the risk of congenital varicella syndrome andHowever, a later report documented 100% survival among 18 gravidas other birth defects in offspring of women who inadvertently receivedwith varicella pneumonia who were treated with acyclovir.51 In this varicella vaccine during pregnancy or within 3 months of conception.report, there was one intrauterine fetal death at 25 weeks’ gestation in Fifty-eight women received their ﬁrst dose of varicella vaccine duringa woman with varicella. In one report of 312 pregnancies, there was the ﬁrst or second trimester. No cases (0%) of congenital varicellano increase in the number of birth defects and no consistent pattern syndrome were identiﬁed among 56 live births (CI, 0 to 15.6). Amongof congenital abnormalities. In another report, 17 other infants were the prospective reports of live births, ﬁve congenital anomalies weredelivered beyond 36 weeks, and there was no evidence of neonatal identiﬁed in the susceptible cohort or the sample population as avaricella.51 whole. The investigator suggested that although the numbers in the Varicella pneumonia usually manifests 2 to 5 days after the onset study were small, the results should provide some reassurance to healthof fever, rash, and malaise and is heralded by the onset of pulmonary care providers and women with inadvertent exposure before or duringsymptoms, including cough, dyspnea, pruritic chest pain, and hemop- pregnancy.tysis.52 The severity of the illness may vary from asymptomatic radio-graphic abnormalities to fulminant pneumonitis and respiratory Pneumocystis jirovecifailure (Fig. 45-4).52,70 Infection with the HIV virus signiﬁcantly increases the risk for pulmo- All gravidas with varicella pneumonia should be aggressively treated nary infection. S. pneumoniae and H. inﬂuenzae are the most com-with antiviral therapy and admitted to the intensive care unit for close monly isolated organisms.73 One report74 also identiﬁed Pseudomonasobservation or intubation if indicated. Acyclovir, a DNA polymerase aeruginosa as a signiﬁcant cause of bacterial pneumonia in HIV-inhibitor, should be started. The early use of acyclovir was associated infected individuals. Pneumocystis pneumonia, an AIDS-deﬁningwith an improved hospital course after the 5th day and a lower mean illness, occurs more frequently when the helper T-cell count (CD4+) istemperature, lower respiratory rate, and improved oxygenation.52 less than 200 cells/mm3. Pneumocystis jiroveci pneumonia (PJP), for-Treatment with acyclovir is safe in pregnancy. Among 312 pregnancies, merly designated Pneumocystis carinii pneumonia (PCP), is the mostthere was no increase in the number of birth defects and no consistent common of the serious opportunistic infections in pregnant women infected with HIV.75,76 P. jiroveci is the number one cause of pregnancy- associated AIDS deaths in the United States.77 Initial reports of PJP in pregnancy described a 100% maternal mortality rate.47,75,78-80 However, in a 2001 review of 22 cases of PJP in pregnancy, the mortality rate was 50% (11 of 22 patients).81 However, the mortality rate is still higher than that reported for HIV-infected nonpregnant individuals.81 In that series, respiratory failure developed in 13 patients, and 59% required mechanical ventilation. The survival rate of gravidas requiring mechan- ical ventilation was 31%. In this series, maternal and fetal outcomes were better in cases of PJP that occurred during the third trimester of pregnancy. A high index of suspicion is necessary when gravidas at risk for HIV infection present with symptoms such as weight loss, fatigue, fever, tachypnea, dyspnea, and nonproductive cough.75 The onset of disease can be insidious, including normal radiographic ﬁndings, and it can then proceed to rapid deterioration.75 When the chest radiograph is positive, it typically exhibits bilateral alveolar disease in the perihilar regions and lower lung ﬁelds (Fig. 45-5), which can progress to include the entire parenchyma.75 Diagnosis can be accomplished by means of sputum silver stains, bronchial aspiration, or bronchoscope-directed biopsy.82 Lung biopsy is recommended for deﬁnitive diagnosis.78 Therapy for PJP in pregnancy includes trimethoprim-sulfamethox- azole (TMP-SMX), which is a category C drug. Gravidas with a history of PJP, a CD4+ lymphocyte count of less than 200/mm3, or oral pha-FIGURE 45-4 Varicella pneumonia. The chest radiograph ryngeal candidiasis should receive prophylaxis.83 TMP-SMX is the drugdemonstrates bilateral nodular and interstitial pneumonia of varicella of choice and may provide cross protection against toxoplasmosispneumonia. and other bacterial infections.84 The usual dose is one double-strength
934 CHAPTER 45 Respiratory Diseases in Pregnancy Pneumocystis pneumonia with TMP-SMX in HIV-infected adults, including pregnant women and patients receiving highly active anti- retroviral therapy, should begin when the CD4+ cell count is less than 200 cells/mm3 or there is a history of oropharyngeal candidiasis. Pro- phylaxis should be discontinued when the CD4+ cell count increases to more than 200 cells/mm3 for a period of 3 months. Tuberculosis in Pregnancy Tuberculosis kills more than 1 million women per year worldwide, and it is estimated that 646 million women and girls are already infected with tuberculosis. In women between 15 and 44 years old in developing countries, tuberculosis is the third most common cause of morbidity and mortality combined, and tuberculosis kills more women than any other infectious disease, including malaria and AIDS. Case-notiﬁcation rates from countries with a high prevalence of tuberculosis suggest that tuberculosis may be less common among females.86 Epidemiologic information shows differences between men and women in prevalence of infection, rate of progression from infec- tion to disease, incidence of clinical disease, and mortality resulting from tuberculosis. Seventy percent more smear-positive male than female tuberculosis patients are diagnosed every year and reported to the World Health Organization.86 Differences between males and females have also been shown in the development and outcome ofFIGURE 45-5 Pneumocystis jiroveci pneumonia (PJP). Bilateral active disease, with female cases having a higher progression fromalveolar disease is consistent with PJP pneumonia. infection to disease and a higher case-fatality rate.87 The conclusion of a research workshop on gender and tuberculosis was that a com- bination of biologic and social factors is responsible for thesetablet (150 mg/m2 of TMP and 750 mg/m2 of SMX given three times differences.86each week). Adverse reactions such as drug allergy, nausea, fever, neu- The incidence of tuberculosis in the United States began to declinetropenia, anemia, thrombocytopenia, and elevated transaminase levels in the early part of the 20th century and fell steadily until 1953, whenhave been reported in 20% to 30% of nonpregnant individuals receiv- the introduction of isoniazid led to a dramatic decrease in the numbering TMP-SMX therapy.84 Complete blood cell count with a differential of cases, from 84,000 cases in 1953 to 22,255 cases in 1984.88 However,cell count and liver function tests should be obtained every 6 to 8 weeks since 1984, there have been signiﬁcant changes in tuberculosis morbid-to monitor for toxicity. Other regimens used for prophylaxis for indi- ity trends. From 1985 through 1991, reported cases of tuberculosisviduals with intolerance to TMP-SMX include aerosolized pentami- increased by 18%, representing approximately 39,000 more cases thandine (300 mg every month by Respirgard II nebulizer) or dapsone expected had the previous downward trend continued. This increase(100 mg once daily). Hussain and colleagues85 found that the survival results from many factors, including the HIV epidemic, deteriorationrate for patients treated with SMX alone was 71% (5 of 7 patients) and in the health care infrastructure, and more cases among immigrants.88,89that the rate with SMX and steroids was 60% (3 of 5 patients); the Between 1985 and 1992, the number of tuberculosis cases amongoverall survival rate for both groups was 66.6% (8 of 12 patients). The women of childbearing age increased by 40%.90 One report describedinvestigators concluded that PJP has a more aggressive course during tuberculosis-complicated pregnancies in 94.8 cases per 100,000pregnancy, with increased morbidity and mortality.85 However, treat- deliveries between 1991 and 1992.91ment with SMX compared with other therapies may result in improved The emergence of drug-resistant tuberculosis has become a seriousoutcome. They also caution that withholding appropriate PJP prophy- concern. In New York City in 1991, 33% of tuberculosis cases werelaxis may adversely affect maternal and fetal outcomes.85 resistant to at least one drug, and 19% were resistant to isoniazid and PJP is a devastating opportunistic infection in pregnant women rifampin. Multidrug resistance is an additional problem. Many centerswho are infected with HIV. The maternal mortality rate is extremely advocate directly observed therapy in the treatment of multidrug-high, and prophylaxis with TMP-SMX is indicated during the antepar- resistant disease. Pregnancy complicates treatment of multidrug-tum period for individuals with a CD4+ cell count less than 200/mm3 resistant tuberculosis for the following reasons:or a history of oropharyngeal candidiasis and for individuals with aprior history of PJP infection. Initiation of therapy during the ante- Several antimycobacterial drugs are contraindicated duringpartum period can also prevent the rare occurrence of perinatally gestation.transmitted PJP.84 When a gravida is demonstrating symptoms consis- Patients and physicians may fear the effects of chesttent with a possible infection, a diligent search should be conducted to radiography on the fetus.quickly identify PJP as the cause of pneumonia. When PJP is untreated, Untreated, infectious, multidrug-resistant tuberculosis may bethe maternal mortality rate can approach 100%. In summary, PJP vertically and laterally transmitted.92pneumonia remains a dreaded complication of HIV infection and anAIDS-deﬁning illness. There is a very high maternal and fetal mortality In one report,92 three patients had disease resulting fromrate when PJP complicates pregnancy. Primary prophylaxis against multidrug-resistant M. tuberculosis, and one had disease resulting from
CHAPTER 45 Respiratory Diseases in Pregnancy 935multidrug-resistant Mycobacterium bovis. Only one patient began Women with a positive PPD skin test result must be evaluated forretreatment during pregnancy because her organism was susceptible active tuberculosis with a thorough physical examination for extrapul-to three antituberculosis drugs that were considered nontoxic to the monary disease and a chest radiograph after they are beyond the ﬁrstfetus. Despite concern about teratogenicity of the second-line antitu- trimester.54 Symptoms of active tuberculosis include cough (74%),berculosis medications, careful timing of treatment initiation resulted weight loss (41%), fever (30%), malaise and fatigue (30%), and hemop-in clinical cure for the mothers, regardless of some complications tysis (19%).97 Individuals with active pulmonary tuberculosis may havebecause of chronic tuberculosis or therapy. In this series, all infants radiographic ﬁndings, including adenopathy, multinodular inﬁltrates,were born healthy and remained free of tuberculosis.92 cavitation, loss of volume in the upper lobes, and upper medial retrac- tion of hilar markings (Fig. 45-6). The ﬁnding of acid-fast bacilli in early morning sputum specimens conﬁrms the diagnosis of pulmo-Diagnosis nary tuberculosis. At least three ﬁrst-morning sputum samples shouldMost gravidas with tuberculosis in pregnancy are asymptomatic. All be examined for the presence of acid-fast bacilli. If sputum cannot begravidas at high risk for tuberculosis (Table 45-1) should be screened produced, sputum induction, gastric washings, or diagnostic bron-with subcutaneous administration of intermediate-strength puriﬁed choscopy may be indicated.protein derivative (PPD). If anergy is suspected, control antigens such Extrapulmonary tuberculosis occurs in up to 16% of cases in theas candidal, mumps, or tetanus toxoids should be used.93 The sensitiv- United States; however, the pattern may occur in 60% to 70% of allity of the PPD is 90% to 99% for exposure to tuberculosis. The tine patients with AIDS.98 Extrapulmonary sites include lymph nodes,test should not be used for screening because of its low sensitivity. bone, kidneys, intestine, meninges, breasts, and endometrium. Extra- The onset of the recent tuberculosis epidemic stimulated the need pulmonary tuberculosis appears to be rare in pregnancy.99 Extrapul-for rapid diagnostic tests using molecular biology methods to detect monary tuberculosis that is conﬁned to the lymph nodes has no effectM. tuberculosis in clinical specimens. Two direct ampliﬁcation tests on obstetric outcomes, but tuberculosis at other extrapulmonaryhave been approved by the FDA, the Mycobacterium tuberculosis Direct sites does adversely affect the outcome of pregnancy.100 Jana and col-(MTD) Test (Gen-Probe, San Diego, CA) and the Amplicor Mycobac- leagues100 documented that tuberculosis lymphadenitis did not affectterium tuberculosis (MTB) Test (Roche Diagnostic Systems, Branch- the course of pregnancy, labor, or perinatal outcome. However, com-burg, NJ). Both tests amplify and detect M. tuberculosis 16S ribosomal pared with control women, the 21 women with tubercular involvementDNA.94 When testing acid-fast stained smear–positive respiratory of other extrapulmonary sites had higher rates of antenatal hospitaliza-specimens, each test has a sensitivity of greater than 95% and a speci- tion (24% versus 2%; P < .0001), infants with low Apgar scores (≤6)ﬁcity of essentially 100% for detecting the M. tuberculosis complex.95,96 soon after birth (19% versus 3%; P = .01), and low-birth-weightWhen testing acid-fast stained smear–negative respiratory specimens, (<2500 g) infants (33% versus 11%; P = .01). Rarely, mycobacteriathe speciﬁcity remains greater than 95%, but the sensitivity rangesfrom 40% to 77%.95,96 These tests are FDA approved only for testingacid-fast stained smear–positive respiratory specimens obtained fromuntreated patients or those who have received no more than 7 days ofantituberculosis therapy. The PPD remains the most commonly usedscreening test for tuberculosis. Immigrants from areas where tuberculosis is endemic may havereceived the bacillus Calmette-Guérin (BCG) vaccine, and they arelikely to have a positive response to the PPD. However, this reactivityshould wane over time. The PPD should be used to screen thesepatients for tuberculosis unless their skin tests are known to be posi-tive.93 If BCG vaccine was given 10 years earlier and the PPD is positivewith a skin test reaction of 10 mm or more, the individual should beconsidered infected with tuberculosis and managed accordingly.93 TABLE 45-1 HIGH-RISK FACTORS FOR TUBERCULOSIS Human immunodeﬁciency virus infection Close contact with persons known or suspected to have tuberculosis Medical risk factors known to increase risk for disease if infected Birth in a country with high tuberculosis prevalence Medically underserved status Low income Alcohol addiction Intravenous drug use Residency in a long-term care facility (e.g., correctional FIGURE 45-6 Chest radiograph of pulmonary tuberculosis. institutions, mental institutions, nursing homes and facilities) Radiographic ﬁndings may include adenopathy, multinodular Health professionals working in high-risk health care facilities inﬁltrates, cavitation, loss of volume in the upper lobes, and upper medial retraction of hilar markings.
936 CHAPTER 45 Respiratory Diseases in Pregnancyinvade the uteroplacental circulation, and congenital tuberculosis resulted in a marginal increase in life expectancy because of the pre-results.49,90,101 The diagnosis of congenital tuberculosis is based on one vented isoniazid-related hepatitis and deaths, compared with no treat-of the following factors90: ment or postpartum treatment. Antepartum treatment was the least expensive.104 Isoniazid should be accompanied by pyridoxine (vitamin Demonstration of primary hepatic complex or cavitating B6) supplementation (50 mg/day) to prevent the peripheral neuropa- hepatic granuloma by percutaneous liver biopsy at birth thy that is associated with isoniazid treatment. Women with an Infection of the maternal genital tract or placenta unknown or prolonged duration of PPD positivity (>2 years) should Lesions seen in the ﬁrst week of life receive isoniazid (300 mg/day) for 6 to 9 months after delivery. Isonia- Exclusion of the possibility of postnatal transmission by a zid prophylaxis is not recommended for women older than 35 years thorough investigation of all contacts, including attendants who have an unknown or prolonged PPD positivity in the absence of active disease. The use of isoniazid is discouraged in this group because of an increased risk for hepatotoxicity. Isoniazid is associated withPrevention hepatitis in pregnant and nonpregnant adults. However, monthlyMost gravidas with a positive PPD result in pregnancy are asymptom- monitoring of liver function tests may prevent this adverse outcome.atic and have no evidence of active disease; they are classiﬁed as infected Among individuals receiving isoniazid, 10% to 20% will develop mildlywithout active disease. The risk of progression to active disease is elevated values detected on liver function tests. These changes resolvehighest in the ﬁrst 2 years of conversion. It is important to prevent the after the drug is discontinued.105onset of active disease while minimizing maternal and fetal risk. Analgorithm for management of the positive PPD is presented in Figure45-7.102,103 In women with a known recent conversion (2 years) to a Treatmentpositive PPD result and no evidence of active disease, the recom- The gravida with active tuberculosis should be treated initially withmended prophylaxis is isoniazid (300 mg/day), starting after the ﬁrst isoniazid (300 mg/day) combined with rifampin (600 mg/day) (Tabletrimester and continuing for 6 to 9 months.54 Under base-case assump- 45-2).106 Resistant disease results from initial infection with resistanttions in a Markov decision-analysis model, the fewest cases of tuber- strains (33%) or can develop during therapy.107 The development ofculosis within the cohort occurred with antepartum treatment (1400 resistance is more likely in individuals who are noncompliant withper 100,000), compared with no treatment (3300 per 100,000) or therapy. If resistance to isoniazid is identiﬁed or anticipated, 2.5 g ofpostpartum treatment (1800 per 100,000).104 Antepartum treatment ethambutol per day should be added, and the treatment period should PPD positive (without prior treatment) CXR CXR normal abnormal or other evidence of active disease Respiratory No respiratory symptoms Three morning sputum samples symptoms for smear/cx “High risk” Old conversion Three morning or conversion 2 years or 1st sputum samples for within 2 years positive PPD Workup Workup smear/cx or workup for extrapulmonary TB Antepartum If 35 years, INH/B6 postpartum If 35 years, Immediate INH/B6 postpartum antepartum INH/B6 3 drug Workup Workup therapy Immediate If 35 years, antepartum postpartum 3 drug INH/B6 therapy FIGURE 45-7 Algorithm for the management of a patient with a positive puriﬁed protein derivative (PPD) result. In women with known conversion within the past 2 years to a positive PPD result and no evidence of active disease, the recommended prophylaxis is 300 mg of isoniazid per day, starting after the ﬁrst trimester and continuing for 6 to 9 months. B6, pyridoxine; cx, culture; CXR, chest radiograph; INH, isoniazid, TB, tuberculosis.
CHAPTER 45 Respiratory Diseases in Pregnancy 937 TABLE 45-2 ANTITUBERCULOSIS DRUGS Drug Dosage Route Daily Dose Weekly Dose Major Adverse Reactions First-Line Drugs (for Initial Treatment) Isoniazid PO, IM 10 mg/kg, up to 300 mg 15 mg/kg, up to 900 mg Hepatic enzyme elevation, peripheral neuropathy hepatitis, hypersensitivity Rifampin PO 10 mg/kg, up to 600 mg 10 mg/kg, up to 600 mg Orange discoloration of secretions and urine; nausea, vomiting, hepatitis, febrile reaction, purpura (rare) Pyrazinamide PO 15-30 mg/kg, up to 2 g 50-70 mg/kg, twice Hepatotoxicity, hyperuricemia, arthralgias, rash, gastrointestinal upset Ethambutol PO 15 mg/kg, up to 2.5 g 50 mg/kg Optic neuritis (decreased red-green color discrimination, decreased visual acuity), rash Streptomycin IM 15 mg/kg, up to 1 g 25-30 mg/kg, up to 1 g Ototoxicity, nephrotoxicity Second-Line Drugs (Daily Therapy) Capreomycin IM 15-30 mg/kg, up to 1 g Auditory, vestibular, and renal toxicity Kanamycin IM 15-30 mg/kg, up to 1 g Auditory and renal toxicity, rare vestibular toxicity Ethionamide PO 15-20 mg/kg, up to 1 g Gastrointestinal disturbance, hepatotoxicity, hypersensitivity p-Amino-salicylic acid PO 150 mg/kg, up to 1 g Gastrointestinal disturbance, hypersensitivity, hepatotoxicity, sodium load Cycloserine PO 15-20 mg/kg, up to 1 g Psychosis, convulsions, rash IM, intramuscularly; PO, orally.be extended to 18 months.108 Ethambutol is teratogenic in animals; tive maternal sputum cultures.54 Infants of women with multidrug-however, this effect has not been seen in humans. resistant tuberculosis should probably be placed with an alternative The most common side effect of ethambutol therapy is optic neu- caregiver until there is no evidence of active disease in the mother.ritis. Streptomycin should be avoided during pregnancy because it is The newborn should also receive BCG vaccine and isoniazid prophy-associated with cranial nerve VIII damage in neonates.109 Antitubercu- laxis.92 Active tuberculosis in the neonate should be treated appropri-lous agents not recommended for use in pregnancy include ethion- ately with isoniazid and rifampin immediately on diagnosis or withamide, streptomycin, capreomycin, kanamycin, cycloserine, and multiagent therapy if drug-resistant organisms are identiﬁed. Infantspyrazinamide.54 However, case reports documenting the use of these and children who are at high risk for intimate and prolonged exposureantituberculous agents in pregnancy revealed no adverse fetal or neo- to untreated or ineffectively treated persons should receive the BCGnatal effects. There were no congenital abnormalities, and pregnancy vaccine.110outcomes for the individuals treated were good. Untreated tuberculosis In summary, high-risk gravidas should be screened for tuberculosishas been associated with higher morbidity and mortality rates among and treated appropriately with isoniazid prophylaxis for infectionpregnant women. The management of the gravida with multidrug- without overt disease and with dual antituberculous therapy for activeresistant tuberculosis should be individualized. The patient should be disease. The newborn also should be screened for evidence of tuber-counseled about the small risk of teratogenicity and understand that culosis. Proper screening and therapy will lead to a good outcome forthe risk of postpartum transmission of tuberculosis to the infant may the mother and infant in most cases.be higher among those born to patients with drug-resistant tubercu-losis. In patients with active disease at the time of delivery, separationof the mother and newborn should be accomplished to prevent infec-tion of the newborn. Asthma in Pregnancy Women who are being treated with antituberculous drugs may Asthma may be the most common potentially serious medical condi-breastfeed. Only 0.75% to 2.3% of isoniazid and 0.05% of rifampin are tion to complicate pregnancy.111 Asthma is characterized by chronicexcreted into breast milk. Ethambutol excretion into breast milk is also airway inﬂammation with increased airway responsiveness to a varietyminimal. However, if the infant is concurrently taking oral antituber- of stimuli and airway obstruction that is partially or completelyculous therapy, excessive drug levels may be reached in the neonate, reversible.111 Approximately 4% to 8% of pregnancies are complicatedand breastfeeding should be avoided. Breastfed infants of women by asthma.112,113 The prevalence and morbidity rates for asthma aretaking isoniazid should receive a multivitamin supplement that increasing, although the mortality rate has decreased in recent years.includes pyridoxine.54 Neonates of women taking antituberculous Insight into the pathogenesis of asthma has changed with the rec-therapy should have a PPD skin test at birth and again when 3 months ognition that airway inﬂammation occurs in almost all cases. Theold. Infants born to women with active tuberculosis at the time of medical management for asthma emphasizes treatment of airwaydelivery should receive isoniazid prophylaxis (10 mg/kg/day) until inﬂammation to decrease airway responsiveness and prevent asthmamaternal disease has been inactive for 3 months as evidenced by nega- symptoms.
938 CHAPTER 45 Respiratory Diseases in PregnancyDiagnosis Effects of Asthma on PregnancyThe enlarging uterus elevates the diaphragm about 4 cm, reducing the Existing studies on the effects of asthma on pregnancy have had incon-functional residual capacity. However, there are no signiﬁcant altera- sistent results in regard to maternal and perinatal outcomes. Fortions in forced vital capacity, peak expiratory ﬂow rate (PEFR), or example, asthma has been associated with increased perinatal mortal-forced expiratory volume in 1 second (FEV1) in normal pregnancies. ity,117 hyperemesis gravidarum,118 hemorrhage,112,118,119 hypertension orShortness of breath at rest or with mild exertion is common and is preeclampsia,118-125 preterm birth,118,122,123,126-128 hypoxia at birth,118 lowoften referred to as physiologic dyspnea of pregnancy. Asthma is char- birth weight,118,129 increased cesarean section,119,121,122,126,129 small-acterized by paroxysmal or persistent symptoms, including breathless- for-gestational-age status or intrauterine growth restriction,122,123,130ness, chest tightness, cough, and sputum production. The diagnosis of gestational diabetes,119,126 and anomalies.122asthma is based on a history of symptoms and results of spirometry. In contrast, asthma has not been associated with prematur-Patients with asthma have improved FEV1 after administration of a ity,112,117,129-132 malformations,112,118,121,123,131 birth injury,118 increasedshort-acting, inhaled β2-agonist and increased sensitivity to inhaled perinatal mortality,118 reduced gestational age,120,121,133-135 reduced meanmethacholine, although this test is not usually performed during birth weight,120,121,129,134-136 perinatal death,119,121,131,135,137 low Apgarpregnancy. score,121 neonatal respiratory difﬁculty,121 antepartum or postpartum In 2004, the National Asthma Education and Prevention Program hemorrhage,123,129,133 perinatal complications,124,129 gestational hyper-(NAEPP) Working Group on Asthma and Pregnancy114 deﬁned mild tension or preeclampsia,126,130,131,138 intrauterine growth restriction,126,131intermittent, mild persistent, moderate persistent, and severe persistent increased cesarean section,112,132,137 low birth weight,121,132,133,136,137 gestaasthma according to daytime and nighttime symptoms (e.g., wheezing, tional diabetes,112,124 or respiratory distress syndrome.112cough, dyspnea) and objective tests of pulmonary function. The most Many of these studies have methodologic inadequacies, includingcommonly used pulmonary function parameters are the PEFR and low power, variable inclusion criteria, little or no information regard-FEV1. The NAEPP guidelines suggest classifying asthma severity in ing asthma management or control, and time frames that do not reﬂectpatients not on symptom-controlling drugs and asthma control in current management. Some positive ﬁndings may result from non-patients on symptom-controlling medications (Table 45-3).115 Preg- existent or inadequate control for confounders such as oral corticoste-nant patients with mild asthma according to symptoms and pulmo- roid treatment, ethnicity, smoking status, obesity, socioeconomicnary function who nonetheless required regular medications to control status, and hypertension. Another potential explanation for inconsis-their asthma are similar to those with moderate asthma with respect tencies is that most of these studies did not classify asthma severity.to asthma exacerbations; those requiring regular systemic corticoste- Classiﬁcation of asthma severity has important clinical implications inroids to control asthma symptoms were similar to severe asthmatics regard to asthma morbidity and tailoring optimal treatment regi-with respect to exacerbations.116 mens.139,140 Asthma medications and poor asthma control leading to hypoxia may explain some of these observations.141 Some data support a relationship between poor asthma control, as indicated by hospital-Effects of Pregnancy on Asthma ization for exacerbations or decreased FEV1 values, and low birthAsthma has been associated with considerable maternal morbidity. In weight and low ponderal index.137,141,142 Studies have shown that womena large, prospective study of pregnant women, those with mild asthma with more severe asthma may have the greatest risk for complicationshad an exacerbation rate of 12.6% and hospitalization rate of 2.3%; during pregnancy,122,126,127,143 whereas better-controlled asthma isthose with moderate asthma had an exacerbation rate of 25.7% and associated with decreased risks.131,144,145 Poor control of asthma duringhospitalization rate of 6.8%; and severe asthmatics had an exacerba- pregnancy may be caused by the physician’s reluctance to prescribetion rate of 51.9% and hospitalization rate of 26.9%.116 The effects of medications during pregnancy. Women with asthma signiﬁcantlypregnancy on asthma vary. In a large, prospective study, 23% improved reduce their medications, especially inhaled and rescue corticosteroids,and 30% became worse during pregnancy.116 One of the most impor- during the ﬁrst trimester.146tant conclusions of this study is that pregnant women with mild or There is considerable consistency among prospective studies ofeven well-controlled asthma should be monitored by PEFR and FEV1 the effects of asthma during pregnancy. Eight prospective studiestesting during pregnancy. reporting maternal and neonatal outcomes with at least 100 subjects TABLE 45-3 CLASSIFICATION OF ASTHMA SEVERITY AND CONTROL IN PREGNANT PATIENTS Well Controlled* Not Well Controlled* Very Poorly Controlled* Signs and Symptoms Intermittent† Mild Persistent† Moderate Persistent† Severe Persistent† Symptom frequency/short-acting ≤2 days per week >2 days per week, Daily symptoms Throughout the day β-agonist use but not daily Nighttime awakening ≤2 times per month >2 times per month >1 time per week ≥4 times per week Interference with normal activity None Minor limitation Some limitation Extremely limited FEV1 or peak ﬂow (percent >80% >80% 60-80% <60% predicted/personal best) *Asthma control: assess in patients on long-term-control medications to determine whether step-up, step-down, or no change in therapy is indicated. † Asthma severity: assess severity for patients who are not on long-term-control medications, see Table 45-7 to determine starting controller therapy based on severity. FEV1, forced expiratory volume in 1 second.