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.
CHAPTER 45 Respiratory Diseases in Pregnancy 939in locations at or near sea level have been published in the Englishliterature.121,124,131-133,137,144,145,147 These studies show that a gravida with Management Approachesmild or moderate asthma can have excellent maternal and perinatal The ultimate goal of asthma therapy during pregnancy is to maintainoutcomes (Table 45-4). These ﬁndings do not contradict the possibility adequate oxygenation of the fetus by prevention of hypoxic episodesthat suboptimal control of asthma during pregnancy is associated with in the mother. Other goals include achievement of minimal or noincreased risk to the mother or infant.145 Lower FEV1 values during maternal symptoms day or night, minimal or no exacerbations, nopregnancy are signiﬁcantly associated with increased risks for low birth limitations of activities, maintenance of normal or near-normal pul-weight and prematurity.148 The two largest studies indicate that classi- monary function, minimal use of short-acting β2-agonists, and minimalﬁcation of asthma severity with therapy tailored according to asthma or no adverse effects from medications. Consultation or comanage-severity can result in excellent perinatal and maternal outcomes.144,145 ment with an asthma specialist is appropriate for evaluation of the roleThis generally conﬁrms the ﬁndings of two earlier and smaller pro- of allergy and irritants, complete pulmonary function studies, or eval-spective cohort studies131,133 in which asthma was managed by asthma uation of the medication plan if there are complications in achievingspecialists. the goals of therapy or the patient has severe asthma. A team approach There are important caveats when interpreting this literature. Pro- is helpful if more than one clinician is managing the asthma and thespective studies have tended to ﬁnd fewer signiﬁcant adverse associa- pregnancy. The effective management of asthma during pregnancytions, possibly because of better asthma surveillance and treatment. relies on four integral components: objective assessment, triggerThe excellent maternal and perinatal outcomes were achieved at centers avoidance, patient education, and pharmacologic therapy.that tended to actively manage asthma during pregnancy. Women whoenroll in research studies tend to be more compliant and better moti- Objective Measures for Assessmentvated than the general public. The lack of ﬁnding more adverse out- and Monitoringcomes among women with severe asthma may also be a function of Subjective measures of lung function by the patient or physicianthe relatively small numbers of this cohort and the resulting lack of provide an insensitive and inaccurate assessment of airway hyperre-power to ﬁnd adverse outcomes that were statistically signiﬁcant. sponsiveness, airway inﬂammation, and asthma severity. The FEV1Nonetheless, these prospective studies are reassuring in their consensus value after a maximal inspiration is the single best measure of pulmo-of good pregnancy outcomes among women with asthma. However, nary function. When adjusted for confounders, a mean FEV1 less thanthey do not suggest that asthma should be considered to be a benign 80% of the predicted value has been signiﬁcantly associated withcondition, because active asthma management was a part of these increased preterm delivery at less than 32 weeks and less than 37 weeksstudies and might have positively inﬂuenced outcomes. and with a birth weight less than 2500 g.148 However, measurement of TABLE 45-4 PROSPECTIVE COHORT STUDIES REPORTING OBSTETRIC AND NEONATAL OUTCOMES Stenius- Stenius- Schatz Aarniala and Dombrowski Bracken et al, Aarniala et al, Mihrshani Jana et al, Teramo, Minerbi-Codish et al, 2004145 2003144 et al, 1996133 1995131 et al, 2003124 1995137 1988121 et al, 1998132 Outcomes (N = 1739) (N = 872) (N = 504) (N = 486) (N = 340) (N = 182) (N = 181) (N = 101) Preterm, < 32 No NR NR NR NR NR NR NR weeks Preterm, < 37 No (yes if No (yes if oral No No No No NR No weeks severe) steroids) Preeclampsia No No (yes if daily No No No NR Yes No symptoms) Cesarean delivery Yes (if NR Yes (if NR No No Yes No moderate elective) or severe) Gestational No (yes if NR No No NR NR No No diabetes severe) Small for No No (yes if daily NR No NR NR NR No gestational age symptoms) Malformation No NR No No NR No NR No Antenatal NR NR No NR NR No No NR hemorrhage Postnatal No NR NR NR NR NR NR NR hemorrhage RDS/HMD No NR NR No NR NR No NR NEC No NR NR No NR NR NR NR Perinatal death No NR No No NR No No NR NICU admission No NR No NR No NR No NR HMD, hyaline membrane disease; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; No, no signiﬁcant association; NR, not reported; RDS, respiratory distress syndrome; Yes, signiﬁcantly increased.
940 CHAPTER 45 Respiratory Diseases in PregnancyFEV1 requires a spirometer. The PEFR correlates well with the FEV1, TABLE 45-5 TYPICAL DOSAGES OF ASTHMAand it can be measured reliably with inexpensive, disposable, portable MEDICATIONSpeak ﬂow meters. PEFR monitoring by the patient provides valuable insight to the Drug Dosagecourse of asthma throughout the day, assesses circadian variation in Albuterol MDI 2-6 puffs as neededpulmonary function, and helps detect early signs of deterioration so Salmeterol DPI 1 puff bidthat timely therapy can be instituted. Patients with persistent asthma Fluticasone and salmeterol 1 inhalation bid, dose depends onshould be evaluated at least monthly, and those with moderate to (Advair) DPI severity of asthmasevere asthma should have daily PEFR monitoring.114 The typical PEFR Montelukast 10-mg tablet at nightin pregnancy should be 380 to 550 L/min. She should establish her Zaﬁrlukast 20 mg twice daily“personal best” PEFR and then calculate her individualized PEFR Prednisone 20-60 mg/day for active symptomszones. The green zone is more than 80% of the personal best PEFR, Theophylline Start at 200 mg PO bid, target serumyellow zone is between 50% and 80% of the personal best value, and levels of 5-12 μg/mL (decreasered zone is less than 50% of the personal best PEFR. dosage by one half if treated with erythromycin or cimetidine) Ipratropium MDI 2-3 puffs q6hAvoiding or Controlling Asthma Triggers Ipratropium nebulizer 1 mL (0.25 mg) q6hLimiting adverse environmental exposures during pregnancy is impor- Cromolyn MDI 2 puffs qidtant for controlling asthma. Irritants and allergens that provoke acutesymptoms also increase airway inﬂammation and hyperresponsive- DPI, dry powder inhaler; MDI, metered-dose inhaler; PO, orally.ness. Avoiding or controlling such triggers can reduce asthma symp-toms, airway hyperresponsiveness, and the need for medical therapy.Association of asthma with allergies is common; 75% to 85% of ment of airway inﬂammation to decrease airway hyperresponsivenesspatients with asthma have positive skin test results for common aller- and prevent asthma symptoms. Typical dosages of commonly usedgens, including animal dander, house dust mites, cockroach antigens, asthma medications are listed in Table 45-5. Low, medium, and highpollens, and molds. Other common nonimmunologic triggers include doses of inhaled corticosteroids are provided in Table 45-6.tobacco smoke, strong odors, air pollutants, food additives such as Although it is assumed that asthma medications are equally effec-sulﬁtes, and certain drugs, including aspirin and β-blockers. Another tive during pregnancy, differences in maternal physiology and phar-trigger can be strenuous physical activity. For some patients, exercise- macokinetics may affect the absorption, distribution, metabolism, andinduced asthma can be avoided with inhalation of albuterol 5 to 60 clearance of medications during pregnancy. Endocrinologic andminutes before exercise. immunologic changes during pregnancy include elevations in free Speciﬁc measures for avoiding asthma triggers include removing plasma cortisol, possible tissue refractoriness to cortisol,149 and changescarpeting, using an allergen-impermeable mattress and pillow covers, in cellular immunity.150weekly washing of bedding in hot water, avoiding tobacco smoke,inhibiting mite and mold growth by reducing humidity, and leaving STEP THERAPYthe house when it is vacuumed. Animal dander control includes weekly The step-care approach to therapy increases the number and fre-bathing of the pet, keeping furry pets out of the bedroom, or removing quency of medications with increasing asthma severity (Table 45-7).the pet from the home. Cockroaches can be controlled by poison or Based on the severity of asthma, medications are considered to bebait traps and eliminating exposed food or garbage. preferred or alternative. Patients not optimally responding to treatment should be stepped up to more intensive medical therapy. After controlPatient Education is achieved and sustained for several months, a step-down approachPatients should be made aware that controlling asthma during preg- can be considered, but it should be undertaken cautiously and gradu-nancy is especially important for the well-being of the fetus. The preg- ally to avoid compromising the stability of the asthma control. Fornant woman should understand that she can reduce symptoms by some patients, it may be prudent to postpone until after birth attemptslimiting asthma triggers. She should have a basic understanding of the to reduce therapy that is effectively controlling the patient’s asthma.114medical management during pregnancy, including self-monitoring of For a patient who had a favorable response to an alternative drugPEFRs and the correct use of inhalers. The patient should be instructed before becoming pregnant, it is preferable to maintain the therapy thaton proper PEFR technique. She should make the measurement while successfully controlled the asthma before pregnancy. However, whenstanding, take a maximum inspiration, and observe the reading on the initiating new treatment for asthma during pregnancy, preferredpeak ﬂow meter. medications should be considered rather than alternative treatment options.114Pharmacologic Therapy A burst of oral corticosteroids is indicated for exacerbations notThe goals of asthma therapy include relieving bronchospasm, protect- responding to initial β2-agonist therapy, regardless of asthma severity.ing the airways from irritant stimuli, mitigating pulmonary and Patients who require increasing inhaled albuterol therapy to controlinﬂammatory responses to an allergen exposure, and resolving the their symptoms may beneﬁt from oral corticosteroids. In such cases, ainﬂammatory process in the airways, leading to improved pulmonary short course of oral prednisone (40 to 60 mg/day) for 1 week followedfunction with reduced airway hyperresponsiveness. The step-care by 7 to 14 days of tapering may be effective.approach uses the least amount of drug intervention necessary tocontrol a patient’s severity of asthma. INHALED CORTICOSTEROIDS It is safer for pregnant women with asthma to be treated with Inhaled corticosteroids are the preferred treatment for the manage-asthma medications than it is for them to have asthma symptoms and ment of all levels of persistent asthma during pregnancy.114 Becauseexacerbations.114 Current pharmacologic therapy emphasizes treat- almost all patients have airway inﬂammation, inhaled corticosteroids
CHAPTER 45 Respiratory Diseases in Pregnancy 941 TABLE 45-6 COMPARATIVE DAILY DOSES FOR INHALED CORTICOSTEROIDS Drug Dose Conversion* Low Dose Medium Dose High Dose Beclomethasone HFA 40 μg/puff 2-6 puffs >6-12 puffs >12 puffs 80 μg/puff 1-3 puffs >3-6 puffs >6 puffs Budesonide 200 μg/inhalation 1-3 puffs >3-6 puffs >6 puffs Flunisolide 250 μg/puff 2-4 puffs 4-8 puffs >8 puffs Fluticasone HFA 44 μg/puff — 2-6 puffs — 110 μg/puff 2 puffs 2-4 puffs >4 puffs 220 μg/puff 1-2 puffs — >2 puffs Fluticasone DPI 50 μg/inhalation 2-6 puffs — — 100 μg/inhalation 1-3 puffs 3-5 puffs >5 puffs 250 μg/inhalation 1 puff 2 puffs >2 puffs Mometasone 200 μg/inhalation 1 puff 2 puffs >2 puffs Triamcinolone 75 μg/puff 4-10 puffs 10-20 puffs >20 puffs *The dose of total daily puffs is usually divided as a twice/day regimen. DPI, dry powder inhaler; HFA, hydroﬂuoroalkane. From National Asthma Education and Prevention Program Full Report of the Expert Panel: Guidelines for the Diagnosis and Management of Asthma, 2007. Available at http://www.nhlbi.nih. gov/guidelines/asthma/asthsumm.pdf (accessed January 2008). TABLE 45-7 STEP-CARE THERAPY FOR ASTHMA DURING PREGNANCY Type of Asthma Preferred Management Alternative Management Mild intermittent No daily medications, albuterol as needed — Mild persistent Low-dose inhaled corticosteroid Cromolyn, leukotriene receptor antagonist, or theophylline (serum level of 5-12 μg/mL) Moderate persistent Low-dose inhaled corticosteroid and salmeterol, Low-dose or (if needed) medium-dose inhaled medium-dose inhaled corticosteroid, or (if needed) corticosteroid and a leukotriene receptor antagonist or medium-dose inhaled corticosteroid and salmeterol theophylline (serum level of 5-12 μg/mL) Severe persistent High-dose inhaled corticosteroid and salmeterol and High-dose inhaled corticosteroid and theophylline (serum (if needed) oral corticosteroid level of 5-12 μg/mL) and (if needed) oral corticosteroidhave been advocated as ﬁrst-line therapy for those with mild asthma.151 steroid before pregnancy, it seems reasonable to continue that medica-The use of inhaled corticosteroids among nonpregnant asthmatics has tion during pregnancy. All inhaled corticosteroids are labeled by thebeen associated with a marked reduction in fatal and near-fatal epi- FDA as pregnancy class C, except budesonide, which is class B.sodes of asthma.152 Inhaled corticosteroids produce clinically impor-tant improvements in bronchial hyperresponsiveness that appear dose INHALED b2-AGONISTSrelated153 and include prevention of increased bronchial hyperrespon- Inhaled β2-agonists are recommended for all degrees of asthmasiveness after seasonal exposure to allergen.154,155 Continued adminis- during pregnancy.114,157 Albuterol has the advantage of a rapid onset oftration is effective in reducing the immediate pulmonary response to effect in the relief of acute bronchospasm by means of smooth musclean allergen challenge. In a prospective, observational study of 504 relaxation, and it is an excellent bronchoprotective agent for pretreat-pregnant women with asthma, 177 patients were not initially treated ment before exercise. Salmeterol and formoterol are long-actingwith inhaled budesonide or inhaled beclomethasone.133 This cohort preparations.had a 17% rate of acute exacerbation rate compared with only a 4% The β2-agonists are associated with tremor, tachycardia, and palpi-rate among those treated with inhaled corticosteroids from the start of tations. They do not block the development of airway hyperrespon-pregnancy. siveness.158 Comparison of an inhaled glucocorticoid, budesonide, with The NAEPP Working Group reviewed 10 studies that included 6113 the inhaled terbutaline raised the question about whether routine usepatients who took inhaled corticosteroids during pregnancy for of terbutaline may result in increased airway hyperresponsiveness.151asthma.114 There is no evidence linking inhaled corticosteroid use with Increased frequency of bronchodilator use may indicate the need forincreases in congenital malformations or adverse perinatal outcomes. additional anti-inﬂammatory therapy; chronic use of short-acting β2-Included among these studies was the Swedish Medical Birth Registry agonists has been associated with an increased risk of death.157,159 Thethat had 2014 infants whose mothers had used inhaled budesonide in β2-agonists appear to be safe based on a NAEPP review of six publishedearly pregnancy.156 Because there are more data on using budesonide studies of a total of 1599 women with asthma who took β2-agonistsduring pregnancy than on using other inhaled corticosteroids, the during pregnancy.114 In a large, prospective study, no signiﬁcant rela-NAEPP considered budesonide to be a preferred medication. However, tionship was found between the use of inhaled β2-agonists (n = 1828)if a woman’s asthma is well controlled by a different inhaled cortico- and adverse pregnancy outcomes.160
942 CHAPTER 45 Respiratory Diseases in Pregnancy CROMOLYN ORAL CORTICOSTEROIDS Cromolyn sodium is virtually devoid of signiﬁcant side effects. It The NAEPP Working Group reviewed eight human studies, includ-blocks the early and late phases of pulmonary response to an allergen ing one report of two meta-analyses.114 Most subjects in these studieschallenge, and it prevents the development of airway hyperresponsive- did not take oral corticosteroids for asthma, and the length, timing,ness.158 Cromolyn does not have any intrinsic bronchodilator or anti- and dose of exposure to the drug were not well described. The panelhistaminic activity. Compared with inhaled corticosteroids, the time concluded that ﬁndings from the evidence are conﬂicting. Oral corti-to maximal clinical beneﬁt is longer for cromolyn. Cromolyn appears costeroid use during the ﬁrst trimester of pregnancy is associated withto be less effective than inhaled corticosteroids in reducing objective a threefold increased risk for isolated cleft lip with or without cleftand subjective manifestations of asthma. Cromolyn appears to be safe palate. Because the background incidence is about 0.1%, the excess riskduring pregnancy160 and is an alternative treatment for mild persistent attributable to oral steroids is 0.2% to 0.3%.172 Oral corticosteroid useasthma.114 during pregnancy by patients who have asthma has been associated with an increased incidence of preeclampsia, preterm delivery, and low THEOPHYLLINE birth weight.126,131,144,160,172 A prospective study found that use of sys- Theophylline is an alternative treatment for mild persistent asthma temic corticosteroids resulted in a deﬁcit of about 200 g in birth weightand an adjunctive treatment for the management of moderate and compared with controls and those exclusively treated with β2-severe persistent asthma during pregnancy.114 Subjective symptoms of agonists.173 However, it is difﬁcult to separate the effects of the oraladverse theophylline effects, including insomnia, heartburn, palpita- corticosteroids on these outcomes from the effects of severe or uncon-tions, and nausea, may be difﬁcult to differentiate from typical preg- trolled asthma.nancy symptoms. High doses have caused jitteriness, tachycardia, Because of the uncertainties in these data and the deﬁnite risks ofand vomiting in mothers and neonates.161,162 Dosing guidelines have severe, uncontrolled asthma to the mother and fetus, the NAEPPrecommended that serum theophylline concentrations be maintained Working Group recommends the use of oral corticosteroids whenat 5 to 12 μg/mL during pregnancy.114 Theophylline can have signiﬁ- indicated for the long-term management of severe asthma or exacerba-cant interactions with other drugs, which can cause decreased clear- tions during pregnancy.114 For the treatment of acute exacerbations,ance with resultant toxicity. For instance, cimetidine can cause a 70% methylprednisolone or other corticosteroids may be given at a dose ofincrease in serum levels, and erythromycin use can increase theophyl- 120 to 180 mg per day in three or four divided doses; after the PEFRline serum levels by 35%.163 reaches 70% of the personal best value, the daily dosage of parenteral The main advantage of theophylline is the long duration of action, or oral corticosteroid, such as prednisone, can be dropped to 60 to10 to 12 hours with the use of sustained-release preparations, which is 80 mg per day.114especially useful in the management of nocturnal asthma.164 Theophyl-line is indicated only for chronic therapy and is not effective for the Management of Allergic Rhinitistreatment of acute exacerbations during pregnancy.165 Theophylline Exacerbating Asthmahas anti-inﬂammatory actions166 that may be mediated by inhibition Rhinitis, sinusitis, and gastroesophageal reﬂux may exacerbate asthmaof leukotriene production and its capacity to stimulate prostaglandin symptoms, and their management should be considered an integralE2 production.167 Theophylline may potentiate the efﬁcacy of inhaled aspect of asthma care. Intranasal corticosteroids are the most effectivecorticosteroids.168 medications for control of allergic rhinitis. Loratadine (Claritin) or The NAEPP reviewed eight human studies that had a total of 660 cetirizine (Zyrtec) are recommended second-generation antihista-women with asthma who took theophylline during pregnancy.114 These mines. Because oral decongestant ingestion during the ﬁrst trimesterstudies and clinical experience conﬁrm the safety of theophylline has been associated with gastroschisis, inhaled decongestants or inhaledat a serum concentration of 5 to 12 μg/mL during pregnancy. In a corticosteroids should be considered before use of oral deconges-randomized, controlled trial, there were no differences in asthma exac- tants.114 Immunotherapy is considered safe during pregnancy, buterbations or perinatal outcomes in a cohort receiving theophylline because of the risk of anaphylaxis, initiation of immunotherapy is notcompared with the cohort receiving inhaled beclomethasone.169 recommended during pregnancy.However, the theophylline cohort had signiﬁcantly more reportedside effects, discontinuation of the study medication, and an increasedproportion of those with an FEV1 less than 80% of the predicted Antenatal Managementvalue. Patients with moderate or severe asthma should be considered to be at risk for pregnancy complications. Adverse outcomes can be increased LEUKOTRIENE MEDIATORS by underestimation of asthma severity and undertreatment of asthma. Leukotrienes are arachidonic acid metabolites that have been impli- The ﬁrst prenatal visit should include a detailed medical history withcated in transducing bronchospasm, mucous secretion, and increased attention to medical conditions that can complicate the managementvascular permeability.170 Bronchoconstriction associated with aspirin of asthma, including active pulmonary disease. The patient should beingestion can be blocked by leukotriene receptor antagonists.171 Treat- questioned about her smoking history and the presence and severityment with the leukotriene receptor antagonist montelukast (Singulair) of symptoms, episodes of nocturnal asthma, the number of days ofhas signiﬁcantly improved pulmonary function as measured by FEV1.170 work missed, and emergency care visits due to asthma. Asthma severityThe leukotriene receptor antagonists zaﬁrlukast (Accolate) and mon- should be determined (see Table 45-3). The type and amount oftelukast are pregnancy category B drugs. There are minimal data asthma medications, including the number of puffs of β2-agonists usedregarding the efﬁcacy or safety of these agents during human preg- each day, should be determined.nancy. Leukotriene receptor antagonists provide an alternative treat- Gravidas with moderate or severe asthma should have schedulingment for mild persistent asthma and an adjunctive treatment for the of prenatal visits based on clinical judgment. In addition to routinemanagement of moderate and severe persistent asthma during care, monthly or more frequent evaluations of asthma history (i.e.,pregnancy.114 emergency visits, hospital admissions, symptom frequency, severity,
CHAPTER 45 Respiratory Diseases in Pregnancy 943nocturnal symptoms, and medication dosages and compliance) and TABLE 45-8 HOME MANAGEMENT OF ACUTEpulmonary function (i.e., FEV1 or PEFR) are recommended. Patients ASTHMA EXACERBATIONSshould be instructed on proper dosing and administration of theirasthma medications. Initial Approach Daily peak ﬂow monitoring should be considered for patients with Use albuterol MDI at a dose of 2-4 puffs (or single nebulizermoderate to severe asthma and especially for patients who have difﬁ- treatment), and measure PEFR.culty perceiving signs of worsening asthma.114 It may be helpful to Poor Responsemaintain an asthma diary containing a daily record of symptoms, peak If PEFR < 50% of predicted, severe wheezing and shortness ofﬂow measurements, activity limitations, medical contacts initiated, breath occur, or fetal movement is decreased, repeat albuteroland regular and as-needed medications taken. Identifying and avoiding at a dose of 2-4 puffs by MDI and obtain emergency care.asthma triggers can lead to improved maternal well-being and lessneed for medications. Speciﬁc recommendations can be made for Incomplete Responseappropriate environmental controls based on the patient’s history of If PEFR is 50-80% of predicted or if wheezing and shortness ofexposure and, when available, skin test reactivity to asthma triggers. breath persist, repeat albuterol treatment at a dose of 2-4 puffs Women who have moderate or severe asthma during pregnancy by MDI at 20-minute intervals up to two more times.may beneﬁt from additional fetal surveillance in the form of ultra- If repeat PEFR is 50-80% of predicted or if fetal movement issound examinations and antenatal fetal testing. Because asthma has decreased, contact caregiver or go for emergency care.been associated with intrauterine growth restriction and preterm birth, Good Responseit is useful to establish pregnancy dating accurately by ﬁrst-trimester If PEFR > 80% of predicted, there is no wheezing or shortness ofultrasound when possible. In the opinion of the NAEPP Working breath, and the fetus is moving normally, patient may continueGroup,114 the evaluation of fetal activity and growth by serial ultra- inhaled albuterol at a dose of 2-4 puffs by MDI every 3-4 hourssound examinations may be considered for women who have subop- as needed.timally controlled asthma, for those with moderate to severe asthma(starting at 32 weeks), and after recovery from a severe asthma exac- MDI, metered-dose inhaler; PEFR, peak expiratory ﬂow rate. Modiﬁed from National Asthma Education and Prevention Programerbation. The intensity of antenatal surveillance of fetal well-being (NAEPP) expert panel report (NAEPP 04): Managing asthma duringshould be considered on the basis of the severity of the asthma and pregnancy: Recommendations for pharmacologic treatment—2004any other high-risk features of the pregnancy. All patients should be update. NHILBI, NIH publication no. 05-3279. Available atinstructed to be attentive to fetal activity. http://www.nhlbi.nih.gov/health/prof/lung/asthma/astpreg/astpreg_ qr.pdf (accessed January 2008).Home Management of Asthma ExacerbationsAn asthma exacerbation that causes minimal problems for the mothermay have severe sequelae for the fetus. An abnormal fetal heart rate administered subcutaneously every 15 minutes for three doses. Thetracing may be the initial manifestation of an asthmatic exacerbation. patient should be assessed for general level of activity, color, pulse rate,A maternal PO2 value of less than 60 mm Hg or hemoglobin saturation use of accessory muscles, and airﬂow obstruction determined by aus-of less than 90% may be associated with profound fetal hypoxia. cultation and FEV1 or PEFR before and after each bronchodilatorAsthma exacerbations in pregnancy should be aggressively managed. treatment. Guidelines for the management of asthma exacerbations arePatients should be given an individualized guide for decision making given in Table 45-9.and rescue management, and they should be educated to recognizesigns and symptoms of early asthma exacerbations, such as coughing, Labor and Delivery Managementchest tightness, dyspnea, or wheezing, or by a 20% decrease in the Asthma medications should not be discontinued during labor andPEFR. Early recognition enables prompt institution of home rescue delivery. Although asthma is usually quiescent during labor, consider-treatment to avoid maternal and fetal hypoxia. ation should be given to assessing PEFRs on admission and at 12-hour Patients should use inhaled albuterol (two to four puffs) every 20 intervals. The patient should be kept hydrated and should receiveminutes for up to 1 hour (Table 45-8). The response is considered to adequate analgesia to decrease the risk of bronchospasm. If systemicbe good if symptoms are resolved or become subjectively mild, normal corticosteroids have been used in the previous 4 weeks, intravenousactivities can be resumed, and the PEFR is more than 70% of the per- corticosteroids (e.g., 100 mg of hydrocortisone every 8 hours) shouldsonal best value. The patient should seek further medical attention if be administered during labor and for the 24-hour period after deliverythe response is incomplete or if fetal activity is decreased. to prevent an adrenal crisis.114 An elective delivery should be postponed if the patient is having an exacerbation.Hospital and Clinic Management It is rarely necessary to perform a cesarean section for an acuteThe principal goal of hospital and clinic management should be the asthma exacerbation. Maternal compromise and fetal compromiseprevention of hypoxia. Measurement of oxygenation by pulse oximetry usually respond to aggressive medical management. Occasionally,is essential, and arterial blood gas determinations should be obtained delivery may improve the respiratory status of a patient with unstableif oxygen saturation remains less than 95%. Chest radiographs usually asthma who has a mature fetus. Prostaglandin E2 or E1 can be used forare not needed. Continuous electronic fetal monitoring should be ini- cervical ripening, the management of spontaneous or induced abor-tiated if gestation has advanced to point of potential fetal viability. tions, or postpartum hemorrhage, although the patient’s respiratoryAlbuterol (2.5 to 5 mg every 20 minutes for three doses and then 2.5 status should be monitored.174 Carboprost (15-methyl PGF2α) andto 10 mg every 1 to 4 hours as needed or 10 to 15 mg/hr administered ergonovine and methylergonovine (Methergine) can cause broncho-continuously) should be delivered by nebulizer driven with oxygen.114 spasm.175 Magnesium sulfate is a bronchodilator, but indomethacinOccasionally, nebulized treatment is not effective because the patient can induce bronchospasm in the aspirin-sensitive patient. There areis moving air poorly; in such cases, terbutaline (0.25 mg) can be no reports of the use of calcium channel blockers for tocolysis among
944 CHAPTER 45 Respiratory Diseases in PregnancyTABLE 45-9 EMERGENCY DEPARTMENT AND HOSPITAL-BASED MANAGEMENT OF ASTHMA EXACERBATIONInitial Assessment and TreatmentObtain a history, perform an examination (e.g., auscultation, use of accessory muscles, heart rate, respiratory rate), assess PEFR or FEV1 and oxygen saturation, and obtain other tests as indicated.Initiate fetal assessment; consider fetal monitoring or BPP, or both, if the fetus is potentially viable.For severe exacerbations (i.e., FEV1 or PEFR < 50% with severe symptoms at rest), administer high-dose albuterol by nebulizer every 20 minutes or continuously for 1 hour and provide inhaled ipratropium bromide and a systemic corticosteroid.Give albuterol by MDI or nebulizer, providing up to three doses in the ﬁrst hour.Administer an oral corticosteroid if there was no immediate response or the patient recently was treated with a systemic corticosteroid.Administer oxygen to maintain a saturation level greater than 95%.Repeat assessment of symptoms, the physical examination, and assessment of PEFR and oxygen saturation.Continue albuterol every 60 minutes for 1 to 3 hours, provided there is improvement.Repeat AssessmentEvaluate the symptoms, perform a physical examination, assess PEFR and oxygen saturation, and obtain other tests as needed.Continue fetal assessment.Good ResponseValues for FEV1 or PEFR are 70% of normal or greater.Response is sustained for 60 minutes after the last treatment.Patient is not in distress.Results of the physical examination are normal.Fetal status is reassuring.Patient is discharged to her home.Incomplete ResponseValues for FEV1 or PEFR are between 50% and 70% of normal.Symptoms are mild or moderate.Continue fetal assessment until the patient is stabilized.Monitor the FEV1 or PEFR, oxygen saturation, and pulse.Continue inhaled albuterol and oxygen.Administer inhaled ipratropium bromide.Administer a systemic (oral or intravenous) corticosteroid.The decision for hospitalization is individualized.Poor ResponseValues for FEV1 or PEFR are less than 50%.Values for PCO2 are greater than 42 mm Hg.Results of the physical examination include severe symptoms, drowsiness, and confusion.Continue fetal assessment.Admit the patient to the intensive care unit.Impending or Actual Respiratory ArrestAdmit the patient to the intensive care unit.Perform intubation and mechanical ventilation with 100% oxygen.Administer nebulized albuterol plus inhaled ipratropium bromide.Administer an intravenous corticosteroid.Intensive Care UnitAdminister inhaled albuterol hourly or continuously plus inhaled ipratropium bromide.Administer an intravenous corticosteroid.Administer oxygen.Intubation and mechanical ventilation may be necessary.Continue fetal assessment until the patient is stabilized.Discharge to HomeContinue treatment with albuterol.Administer an oral systemic corticosteroid if indicated.Initiate or continue inhaled corticosteroid until review at medical follow-up.Provide patient education.Review the patient’s medicine use.Review or initiate an action plan.Recommend close medical follow-up.BPP, biophysical proﬁle; FEV1, forced expiratory volume in 1 second; MDI, metered-dose inhaler; PCO2, carbon dioxide partial pressure; PEFR, peakexpiratory ﬂow rate.Modiﬁed from National Asthma Education and Prevention Program (NAEPP) expert panel report (NAEPP 04): Managing asthma during pregnancy:Recommendations for pharmacologic treatment—2004 update. NHILBI, NIH publication no. 05-3279. Available at http://www.nhlbi.nih.gov/health/prof/lung/asthma/astpreg/astpreg_qr.pdf (accessed January 2008).
CHAPTER 45 Respiratory Diseases in Pregnancy 945patients with asthma, although an association with bronchospasm has fusing capacity of no more than 50% of predicted. Five of the patientsnot been observed with wide clinical use. had exercise-induced oxygen desaturation, and four patients required Lumbar anesthesia has the beneﬁt of reducing oxygen consumption supplemental oxygen. In this group, one patient had an adverseand minute ventilation during labor.176 Fentanyl may be a better anal- outcome and was delivered at 31 weeks. She subsequently requiredgesic than meperidine, which causes histamine release, but meperidine mechanical ventilation for 72 hours. All other patients were deliveredis rarely associated with the onset of bronchospasm during labor. A at or beyond 36 weeks with no adverse intrapartum or postpartum2% incidence of bronchospasm has been reported with regional anes- complications. All infants were at or above the 30th percentile forthesia.177 Ketamine is useful for induction of general anesthesia because growth.182 The investigators concluded that restrictive lung disease wasit can prevent bronchospasm.178 Communication between the obstet- well tolerated in pregnancy. However, exercise intolerance is common,ric, anesthetic, and pediatric caregivers is important for optimal care. and these patients may require early oxygen supplementations.182BreastfeedingOnly small amounts of asthma medications enter breast milk. Predni- Sarcoidosissone, theophylline, antihistamines, beclomethasone, β2-agonists, and Sarcoidosis is a systemic granulomatosis disease of undeterminedcromolyn are not considered to be contraindications for breastfeed- origin that often affects young adults. Pregnancy outcome for mosting.114,179 However, among sensitive individuals, theophylline may patients with sarcoidosis is good.183,184 In one study, 35 pregnancies incause toxic effects in the neonate, including vomiting, feeding difﬁcul- 18 patients with sarcoidosis were evaluated retrospectively.183 Thereties, jitteriness, and cardiac arrhythmias. was no effect of the disease process during pregnancy in nine patients, improvement was demonstrated in six patients, and there was a wors- ening of the disease in three patients. During the postpartum period,Overview of Asthma during Pregnancy no relapse occurred in 15 patients; however, progression of the diseaseAsthma is an increasingly common problem during pregnancy. Mild continued in 3 women. Another retrospective study assessed 15 preg-and moderate asthma can be associated with excellent maternal and nancies complicated by maternal sarcoidosis over a 10-year period.184perinatal pregnancy outcomes, especially if patients are managed Eleven of these patients remained stable, two experienced disease pro-according to contemporary NAEPP recommendations. Severe and gression, and two died because of complications of severe sarcoidosis.poorly controlled asthma may be associated with increased prematu- In this group, factors indicating a poor prognosis included parenchy-rity, the need for cesarean delivery, preeclampsia, and growth restric- mal lesions identiﬁed on the chest radiograph, advanced radiographiction. Severe asthma exacerbations can result in maternal morbidity and staging, advanced maternal age, low inﬂammatory activity, require-mortality and can have commensurate adverse pregnancy outcomes. ment for drugs other than steroids, and the presence of extrapulmo-The management of asthma during pregnancy should be based on nary sarcoidosis.184 Both patients who succumbed during gestation hadobjective assessment, trigger avoidance, patient education, and step severe disease at the onset of pregnancy. The overall cesarean sectiontherapy. Asthma medications should be continued during pregnancy rate was 40%, and 4 (27%) of 15 infants weighed less than 2500 g.and while breastfeeding. None of the patients developed preeclampsia. One explanation for the commonly observed improvement in sarcoidosis may be the increased concentration of circulating corticosteroids during pregnancy. However, because sarcoidosis improves spontaneously in manyRestrictive Lung Disease nonpregnant patients, the improvement may be coincident with pregnancy.in Pregnancy Maycock and associates185 reported 16 pregnancies in 10 patients with sarcoidosis. Eight of these patients showed improvement in atClinical Manifestations least some of the manifestations of sarcoidosis during the antepartumRestrictive ventilatory defects occur when lung expansion is limited period. In two patients, no effect was seen. A recurrence of the abnor-because of alterations in the lung parenchyma or because of abnor- mal ﬁndings was observed in the postpartum period within severalmalities in the pleura, chest wall, or the neuromuscular apparatus.180 months after delivery in approximately one half of the patients. SomeThese conditions are characterized by a reduction in lung volumes and had new manifestations of sarcoidosis not previously observed. Anotheran increase in the ratio of FEV1 to forced vital capacity.181 The inter- study examined 17 pregnancies in 10 patients and concluded thatstitial lung diseases include idiopathic pulmonary ﬁbrosis, sarcoidosis, pregnancy had no consistent effect on the course of the disease.186hypersensitivity pneumonitis, pneumomycosis, drug-induced lung Scadding187 separated patients into three categories based on charac-disease, and connective tissue disease. Additional conditions that teristic patterns of their chest radiographs. When the lesions on thecause a restrictive ventilatory defect include pleural and chest wall chest radiograph had resolved before pregnancy, radiographs remaineddiseases and extrathoracic conditions such as obesity, peritonitis, and normal throughout gestation. In women with radiographic changesascites.181 before pregnancy, resolution continued throughout the prenatal Restrictive lung disease in pregnancy has not been well studied. period. Patients with inactive ﬁbrotic residual disease had stable chestConsequently, little is known about the effects of restrictive lung radiographs, and those with active disease tended to have partial ordisease on the outcome of pregnancy or the effects of pregnancy on complete resolution of those changes during pregnancy. However,the disease process. One study presented data on nine pregnant women most patients in the latter group experienced exacerbation of thewith interstitial and restrictive lung disease who were prospectively disease within 3 to 6 months after delivery.managed.182 Diagnoses included idiopathic pulmonary ﬁbrosis, hyper- Patients with pulmonary hypertension complicating restrictivesensitivity pneumonitis, sarcoidosis, kyphoscoliosis, and multiple pul- lung disease may have a mortality rate as high as 50% during gestation.monary emboli. Three of the gravidas had severe disease characterized These patients need close monitoring during the labor, delivery, andby a vital capacity of no more than 1.5 L (50% of predicted) or a dif- postpartum periods. Invasive monitoring with a pulmonary artery
946 CHAPTER 45 Respiratory Diseases in Pregnancycatheter may be indicated to optimize cardiorespiratory function. women with CF are entering reproductive age. Unlike men withGravidas with restrictive lung disease, including pulmonary sarcoid- CF who are infertile for the most part, women with CF are oftenosis, may beneﬁt from early institution of steroid therapy for evidence fertile.of worsening pulmonary status. Individuals with evidence of severe The ﬁrst case of CF complicating pregnancy was reported in 1960,disease need close monitoring and may require supplemental oxygen and a total of 13 pregnancies in 10 patients with CF were reported intherapy during gestation. 1966.193,194 Cohen and colleagues195 conducted a survey of 119 CF During labor, consideration should be given to the early use of centers in the United States and Canada and identiﬁed a total of 129epidural anesthesia if it is not contraindicated. The early institution of pregnancies in 100 women by 1976. Hilman and colleagues188 surveyedpain management in this population can minimize pain, decrease the 127 CF centers in the United States between 1976 and 1982. A total ofsympathetic response, and decrease oxygen consumption during labor 191 pregnancies were reported during this period in women with CFand delivery. The use of general anesthesia should be avoided, if who were between 16 and 36 years old, with a mean age of 22.6 years.188possible, because these patients may develop pulmonary complications The annual number of CF pregnancies reported to the Cystic Fibrosisafter general anesthesia, including pneumonia and difﬁculty weaning Patient Registry doubled between 1986 and 1990, with 52 pregnanciesfrom the ventilator. Close fetal surveillance throughout gestation is reported in 1986, compared with 111 pregnancies reported in 1990. Inindicated because impaired oxygenation may lead to impaired fetal 2006 209 women with CF were pregnant. Because the number ofgrowth and the development of fetal heart rate abnormalities during women with CF achieving pregnancy is steadily increasing, it is imper-labor and delivery. ative that the obstetrician be familiar with the disease. An additional consideration is the need to counsel all women withrestrictive lung disease about the potential for continued impairmentof their respiratory status during pregnancy, particularly if their respi- Effect of Pregnancy on Cystic Fibrosisratory status is deteriorating when they conceive. The individual The physiologic changes associated with pregnancy are well toleratedwith clinical signs consistent with pulmonary hypertension or severe by healthy gravidas, but those with CF may adapt poorly. Duringrestrictive disease should be cautioned about the possibility of pregnancy, there is an increase in resting minute ventilation, which atmaternal mortality resulting from worsening pulmonary function term may approach 150% of control values.196 Enlargement of theduring gestation. abdominal contents and upward displacement of the diaphragm leads In summary, although the literature on restrictive lung disease in to a decrease in functional residual volume and a decrease in residualpregnancy is limited, it supports the conclusion that most patients with volume.196 Pregnancy is also accompanied by subtle alterations in gasrestrictive lung disease complicating pregnancy, including those with exchange with widening of the alveolar-arterial oxygen gradient thatpulmonary sarcoidosis, can have a favorable pregnancy outcome. is most pronounced in the supine position.196 Alterations in pulmo-However, the clinician should keep in mind that patients with restric- nary function are of little consequence in the normal pregnant woman,tive lung disease can have worsening of their clinical condition and but in the gravida with CF, these changes may contribute to respiratorymay succumb during gestation. decompensation that can lead to an increase in morbidity and mortal- ity for the mother and the fetus. Women with CF and advanced lung disease also may have pulmonary hypertension.Cystic Fibrosis in Pregnancy Nutritional requirements are increased during pregnancy, with approximately 300 kcal/day in additional fuel needed to meet theCF involves the exocrine glands and epithelial tissues of the pancreas, requirements of mother and fetus.197 Most patients with CF have pan-sweat glands, and mucous glands in the respiratory, digestive, and creatic exocrine insufﬁciency. Digestive enzymes and bicarbonate ionsreproductive tracts. Chronic obstructive pulmonary disease, pancreatic are diminished, resulting in maldigestion, malabsorption, and malnu-exocrine insufﬁciency, and elevated levels of sweat electrolytes are trition.197 Gastrointestinal manifestations of CF include steatorrhea,present in most patients with CF.188 The disease is genetically transmit- abdominal pain, distal intestinal obstruction syndrome, and rectal pro-ted with an autosomal recessive pattern of inheritance. The CF gene lapse. Gastroesophageal reﬂux, peptic ulcer disease, acute pancreatitis,was identiﬁed and cloned in 1989. The gene is localized to chromo- and intussusception occur to different degrees in patients with CF.some 7, and the molecular defect accounting for most cases has been Partial or complete obstruction of the gastrointestinal tract in olderidentiﬁed.189,190,191 In the United States, approximately 4% of the white children and adults, also known as distal obstruction syndrome, canpopulation are heterozygous carriers of the CF gene. The disease occurs be precipitated by dehydration, a change in eating habits, a change inin 1 of 3200 white live births.192 enzyme brand or dose, or immobility. It is treated with a combination Morbidity and mortality in patients with CF usually result from of laxatives and enemas. Patients with CF are encouraged to eat a dietprogressive chronic bronchial pulmonary disease. Pregnancy and the that provides 120% to 150% of the recommended energy intake ofattendant physiologic changes can stress the pulmonary, cardiovascu- normal age- and sex-matched controls. This is only a guideline, becauselar, and nutritional status of women with CF. The purpose of this in practice, the energy requirement for a patient with CF is that of theirsection is to familiarize the obstetrician and gynecologist with the ideal body weight when malabsorption has been minimized. Researchphysiologic effects of this complex disease, the impact of the disease done by the United Kingdom Dieticians Cystic Fibrosis Interest Groupon pregnancy, and the effect of pregnancy on the disease. found that women with CF who received preconception counseling Survival for patients with CF has increased dramatically since 1940. had a signiﬁcantly greater mean maternal weight gain and signiﬁcantlyAccording to the Cystic Fibrosis Foundation’s Patient Registry (www. heavier infants than women who had not received preconceptioncff.org), survival in 2006 had increased to 37 years. More than 40% advice.198of all people with CF in the United States are 18 years or older.188 Grand and colleagues194 reported 13 pregnancies in 10 women withThis increase in survival of patients with CF likely reﬂects earlier CF. Of these, ﬁve women had a progressive decline in their pulmonarydiagnosis and intervention and the advances in antibiotic therapy function, two of whom died of cor pulmonale in the immediate post-and nutritional support. Because of the improvements in care, more partum period. Pregnancy was well tolerated in 5 of 10 women, 2 of
CHAPTER 45 Respiratory Diseases in Pregnancy 947whom went on to have subsequent pregnancies that were similarly well There were no stillbirths, neonatal deaths, or early maternal deaths.tolerated.194 In this study, the pregravid pulmonary status of the patient Three major fetal anomalies were seen, but no infant had CF. Anotherwas the most important predictor of outcome. However, there was no report similarly documented the outcome of 72 pregnancies withquantiﬁcation of pulmonary function. A case report by Novy and col- CF.206leagues199 described pulmonary function and gas exchange in a preg- Pulmonary involvement in CF includes chronic infection of thenant woman with CF. The patient had severe disease as evidenced by airways and bronchiectasis. There is selective infection with certaina vital capacity of only 0.72 L and a PaO2 of 50 mm Hg at presenta- microorganisms, such as S. aureus, H. inﬂuenzae, P. aeruginosa, andtion. The patient suffered a progressive increase in residual volume Burkholderia cepacia. In one report, three of four deaths during preg-and decline in vital capacity that was accompanied by worsening nancy occurred in gravidas colonized with B. cepacia.207 Gilljam andhypoxemia and hypercapnia, resulting in respiratory distress and associates208 reported outcomes for a cohort of pregnancies for womenright-sided heart failure in the early postpartum period.199 Based on with CF from 1963 to 1998. For 92 pregnancies in 54 women, therethe experience with this patient and a review of the literature, the were 11 miscarriages and 7 therapeutic abortions. Forty-nine womeninvestigators recommended therapeutic abortion for any patient dem- gave birth to 74 children. The mean follow-up time was 11 ± 8 years.onstrating progressive pulmonary deterioration and hypoxemia despite One patient was lost to follow-up shortly after delivery, and one wasmaximal medical management.199 lost after 12 years. The overall mortality rate was 19% (9 of 48 patients). In 1980, Cohen and associates195 described 100 patients and a total Absence of B. cepacia (P < .001), pancreatic sufﬁciency (P = .01), andof 129 pregnancies. Ninety-seven pregnancies (75%) were completed, pre-pregnancy FEV1 more than 50% of the predicted value (P = .03)and 89% of these women delivered viable infants. Twenty-seven were associated with better survival rates. When adjusted for the samepercent of these fetuses were delivered preterm. There were 11 perina- parameters, pregnancy did not affect survival compared with the entiretal deaths and no congenital anomalies. In this study, 65% of patients adult female CF population. The decline in FEV1 was comparable withrequired antibiotic therapy before delivery. In 1983, Palmer and col- that in the total CF population. Three women had diabetes mellitus,leagues200 retrospectively reviewed the pre-pregnancy status of eight and seven developed gestational diabetes. There were six pretermwomen with CF who subsequently completed 11 pregnancies. They infants and one neonatal death. CF was diagnosed in two children.found that ﬁve women tolerated pregnancy without difﬁculty but that Gilljam and coworkers208 concluded that the maternal and fetal out-three had irreversible deterioration in their clinical status. The inves- comes were good for most women with CF. Risk factors for mortalitytigators identiﬁed four maternal factors that predicted outcome: clini- are similar to those for the nonpregnant CF population. Pregnanciescal status (i.e., Shwachman score), nutritional status (i.e., percent of should be planned so that there is an opportunity for counseling andpredicted weight for height), the extent of chest radiologic abnormali- optimization of the medical condition. Good communication betweenties (i.e., Brasﬁeld chest radiographic score), and the magnitude of the CF team and the obstetrician is important.208pulmonary function impairment. Women with good clinical study A recent review of 10 pregnancies in 10 cystic ﬁbrosis lung trans-results, good nutritional status (i.e., within 15% of their predicted plant recipients document 9 live births and 1 therapeutic abortion. Fiveideal body weight for height), nearly normal chest radiographs, and were preterm births but all were well at follow-up. Three transplantonly mild obstructive lung disease tolerated pregnancy well without recipients developed rejection during the pregnancy. One woman haddeterioration.200 evidence of rejection prior to conception. All 4 women died within 38 Several reports suggest that patients with mild CF, good nutritional months of delivery. Pregnancy CF in lung transplant patients is feasiblestatus, and less impairment of lung function tolerate pregnancy but carries a high risk of maternal mortality.209well. However, those with poor clinical status, malnutrition, hepaticdysfunction, or advanced lung disease are at increased risk from preg-nancy.201-203 Kent and Farquharson203 reviewed the literature and Counseling Pregnant Women withreported 217 pregnancies. In this series, the frequency of preterm Cystic Fibrosisdelivery was 24.3%, and the perinatal death rate was 7.9%. Poor out- Women with CF should be advised about the potential adverse affectscomes were associated with a maternal weight gain of less than 4.5 kg of pregnancy on maternal health status. Factors that may predict poorand a forced vital capacity of less than 50% of the predicted value. outcome include pre-pregnancy evidence of poor nutritional status,Edenborough and colleagues204 also described pregnancies in women signiﬁcant pulmonary disease with hypoxemia, and pulmonary hyper-with CF. There were 18 live births (81.8%), one third of which were tension. Liver disease and diabetes mellitus are also poor prognosticpreterm deliveries, and 18.2% of patients had abortions. There were factors. Gravidas with poor nutritional status, pulmonary hyperten-four maternal deaths within 3.2 years after delivery. In this series, lung sion (e.g., cor pulmonale), and deteriorating pulmonary function earlyfunction was available before delivery, immediately after delivery, and in gestation should consider therapeutic abortion, because the risk ofafter pregnancy. The investigators demonstrated a decline of 13% in maternal mortality may be unacceptably high.FEV1 and 11% in forced vital capacity during pregnancy. Most patients The woman with CF who is considering pregnancy should considerreturned to baseline pulmonary function after pregnancy. Although the need for strong psychosocial and physical support after delivery.most of the women in this series tolerated pregnancy well, those with The rigors of child rearing may add to the risk of maternal deteriora-moderate to severe lung disease (i.e., FEV1 < 60% of the predicted tion during this period. Her family should be willing to provide physi-value) more often had preterm infants and had increased loss of lung cal and emotional support and should be aware of the potential forfunction compared with those with milder disease.204 deterioration in the mother’s health and the potential for maternal In two other series, pre-pregnancy FEV1 was found to be the most mortality. The need for care of a potentially preterm, growth-restricteduseful predictor of outcomes in pregnant women with CF.204,205 There neonate, with all of its attendant morbidities and potential mortality,was also a positive correlation of pre-pregnancy FEV1 with maternal should be discussed. Long term, the woman and her family shouldsurvival. For the 72 pregnancies identiﬁed, the outcomes were known consider the fact that her life expectancy may be shortened by CF, andfor 69; there were 48 live births (70%), of which 22 were premature plans should be made for rearing of the child in the event of maternal(46%); 14 therapeutic abortions (20%); and 7 miscarriages (10%). death.
948 CHAPTER 45 Respiratory Diseases in Pregnancy failure, refractory hypoxemia, and progressive hypercapnia and respi-Management of the Pregnancy ratory acidosis, may be maternal indications for early delivery. If theComplicated by Cystic Fibrosis fetus is potentially viable, the administration of betamethasone mayCare of the gravida with CF should be a coordinated team effort. Physi- be beneﬁcial. Vaginal delivery should be attempted when possible.cians familiar with the complications and management of CF should Labor, delivery, and the postpartum period can be particularly dan-be included, as well as a maternal-fetal medicine specialist and neona- gerous for the patient with CF. The augmentation in cardiac outputtal team. stresses the cardiovascular system and can lead to cardiopulmonary The gravida should be assessed for potential risk factors, such as failure in the patient with pulmonary hypertension and cor pulmonale.severe lung disease, pulmonary hypertension, poor nutritional status, These patients are also more likely to develop right-sided heart failure.pancreatic failure, and liver disease, preferably before attempting gesta- Heart failure should be treated with aggressive diuresis and supple-tion but certainly during the early months of pregnancy. Gravidas mental oxygen. Management may be optimized by insertion of a pul-should be advised to be 90% of ideal body weight before conception monary artery catheter to monitor right- and left-sided ﬁlling pressures.if possible. A weight gain of 11 to 12 kg is recommended.188 Frequent Pain control can reduce the sympathetic response to labor and tachy-monitoring of weight; levels of blood glucose, hemoglobin, total cardia. This beneﬁts the patient who is demonstrating pulmonary orprotein, serum albumin, and fat-soluble vitamins A and E; and the cardiac compromise. In the patient with a normal partial thrombo-prothrombin time is suggested.188 At each visit, the history of caloric plastin time, insertion of an epidural catheter for continuous epiduralintake and symptoms of maldigestion and malabsorption should be analgesia may be beneﬁcial. This is also useful in the event a cesareantaken, and pancreatic enzymes should be adjusted if needed. Patients delivery is indicated because general anesthesia and its possible effectswho are unable to achieve adequate weight gain through oral nutri- on pulmonary function can be avoided. If general anesthesia is needed,tional supplements may be given nocturnal enteral nasogastric tube preoperative anticholinergic agents should be avoided because theyfeeding. In this situation, the risk of aspiration should be considered, tend to promote drying and inspissation of airway secretions. Closeespecially in patients with a history of gastroesophageal reﬂux, which fetal surveillance is essential because the fetus might have been suffer-is common in CF.188 If malnutrition is severe, parenteral hyper- ing from uteroplacental insufﬁciency during gestation and is morealimentation may be necessary for successful completion of the prone to develop evidence of compromise during labor. Delivery bypregnancy.210 cesarean section should be reserved for the usual obstetric Baseline pulmonary function should be assessed, preferably before indications.conception. Assessment should include forced vital capacity, FEV1, In summary, more women with CF are living to childbearing agelung volumes, pulse oximetry, and arterial blood gas measurements, if and are capable of conceiving. Clinical experience has demonstratedindicated. These values should be serially monitored during gestation, that pregnancy in women with mild CF is well tolerated. Women withand deterioration in pulmonary function should be addressed imme- severe disease have an associated increase in maternal and fetal mor-diately. An echocardiogram can assess the patient for underlying pul- bidity and mortality. The potential risk to any one individual with CFmonary hypertension and cor pulmonale. If pulmonary hypertension desiring pregnancy should be assessed and discussed in detail with theor cor pulmonale is diagnosed, the gravida should be advised about patient and her family.the high risk of maternal mortality. Early recognition and prompt treatment of pulmonary infectionsis important in the management of the pregnant woman with CF.Treatment includes intravenous antibiotics in the appropriate dose, References 1. Prowse CM, Gaensler EAL: Respiratory and acid base changes duringkeeping in mind the increased clearance of these drugs because of pregnancy. Anesthesiology 26:31, 1965.pregnancy and CF. Plasma levels of aminoglycosides should be moni- 2. Templeton A, Kelman GR: Maternal blood-gases, (PAO2−PaO2), physiolog-tored and adjusted as indicated by the results. Chest physical therapy ical shunt and VD/VT in normal pregnancy. Br J Anaesth 48:1001, 1976.and bronchial drainage are also important components of the manage- 3. Boutourline-Young H, Boutourline-Young E: Alveolar carbon dioxidement of pulmonary infections in CF. Because P. aeruginosa is the most levels in pregnant, parturient and lactating subjects. J Obstet Gynaecol Brfrequently isolated bacterium associated with chronic endobronchitis Emp 63:509, 1956.and bronchiectasis, antibiotic regimens should include coverage for 4. Skatrud JB, Dempsey JA, Kaiser DG: Ventilatory response to medroxypro-this organism. gesterone acetate in normal subjects: Time course and mechanism. J Appl Physiol 44:939, 1978. If the patient with CF has pancreatic insufﬁciency and diabetes 5. Goodland RL, Pommerenke WT: Cyclic ﬂuctuations of the alveolar carbonmellitus, careful monitoring of blood glucose levels and insulin therapy dioxide tension during the normal menstrual cycle. Fertil Steril 3:394,are indicated. Pancreatic enzymes may need to be replaced to optimize 1952.the patient’s nutritional status. Because of malabsorption of fats and 6. Lyons HA, Huang CT: Therapeutic use of progesterone in alveolarfrequent use of antibiotics, the CF patient is prone to vitamin K deﬁ- hypoventilation associated with obesity. Am J Med 44:881, 1968.ciency. The prothrombin time should be checked regularly, and paren- 7. Machida GL: Inﬂuence of progesterone on arterial blood and CSFteral vitamin K should be administered if the prothrombin time is acid-base balance in women. J Appl Physiol 51:1433, 1981.elevated. 8. Wilbrand U, Porath CH, Matthaes P, et al: Der einﬂuss der Ovarial- The fetus of a woman with CF is at risk for uteroplacental insufﬁ- steroide auf die Funktion des Atemzentrums. Arch Gynakol 191:507,ciency and intrauterine growth restriction. The maternal nutritional 1959. 9. Lyons HA, Antonio R: The sensitivity of the respiratory center in preg-status and weight gain during pregnancy affect fetal growth. Nonstress nancy and the administration of progesterone. Trans Assoc Am Physicianstesting should be started at 32 weeks’ gestation or sooner if there is 72:173, 1959.evidence of fetal compromise. If there is evidence of severe fetal com- 10. Eng M, Butler J, Bonich JJ: Respiratory function in pregnant obese women.promise, delivery should be accomplished. Likewise, evidence of Am J Obstet Gynecol 123:241, 1975.profound maternal deterioration, such as a marked and sustained 11. Pernoll ML, Metcalfe J, Kovach PA, et al: Ventilation during rest and exer-decline in pulmonary function, development of right-sided heart cise in pregnancy and postpartum. Respir Physiol 25:295, 1975.
CHAPTER 45 Respiratory Diseases in Pregnancy 94912. Paciorek J, Spencer N: An association between plasma progesterone and 40. Ueland K, Hansen JM: Maternal cardiovascular hemodynamics. II. Posture erythrocyte carbonic anhydrase I concentration in women. Clin Sci and uterine contractions. Am J Obstet Gynecol 103:1, 1969. 58:161, 1980. 41. Oxhorn H: The changing aspects of pneumonia complicating pregnancy.13. Schenker JG, Ben-Yoseph Y, Shapira E: Erythrocyte carbonic anhydrase B Am J Obstet Gynecol 70:1057, 1955. levels during pregnancy and use of oral contraceptives. Obstet Gynecol 42. Madinger NE, Greenspoon JS, Gray-Ellrodt A: Pneumonia during 39:237, 1972. pregnancy: Has modern technology improved maternal and fetal outcome?14. Cullen JH, Brum VC, Reid TWH: The respiratory effects of progesterone Am J Obstet Gynecol 161:657, 1989. in severe pulmonary emphysema. Am J Med 27:551, 1959. 43. Kaunitz AM, Hughes JM, Grimes DA, et al: Causes of maternal mortality15. Sutton FD, Zwillich CW, Creagh CE, et al: Progesterone for outpatient in the United States. Obstet Gynecol 65:605, 1985. treatment of Pickwickian syndrome. Ann Intern Med 83:476, 1975. 44. Finland M, Dublin TD: Pneumococcic pneumonias complicating16. Cugell DW, Frank NR, Gaensler EA, Badger TL: Pulmonary function in pregnancy and the puerperium. JAMA 112:1027, 1939. pregnancy: Serial observations in normal women. Am Rev Tuberc 67:568, 45. Benedetti TJ, Valle R, Ledger W: Antepartum pneumonia in pregnancy. 1953. Am J Obstet Gynecol 144:413, 1982.17. Lehmann V, Fabel H: Lungenfunktionsuntersuchungen an Schwangeren. 46. Berkowitz K, LaSala A: Risk factors associated with the increasing preva- I. Lungenvolumina. Z Geburtshilfe Perinatol 177:387, 1973. lence of pneumonia during pregnancy. Am J Obstet Gynecol 163:981,18. Puranik BM, Kaore SB, Kurhade GA, et al: A longitudinal study of pul- 1990. monary function tests during pregnancy. Indian J Physiol Pharmacol 47. Koonin LM, Ellerbrock TV, Atrash HK, et al: Pregnancy-associated deaths 38:129, 1994. due to AIDS in the United States. JAMA 261:1306, 1989.19. Knuttgen HG, Emerson K: Physiological response to pregnancy at rest and 48. Dinsmoor MJ: HIV infection and pregnancy. Med Clin North Am 73:701, during exercise. J Appl Physiol 36:549, 1974. 1989.20. Gazioglu K, Kaltreider NL, Rosen M, et al: Pulmonary function during 49. Hopwood HG: Pneumonia in pregnancy. Obstet Gynecol 25:875, 1965. pregnancy in normal women and in patients with cardiopulmonary 50. Rodrigues J, Niederman MS: Pneumonia complicating pregnancy. Clin disease. Thorax 25:445, 1970. Chest Med 13:679, 1992.21. Lehmann V, Fabel H: Lungenfunktionsuntersuchungen an Schwangeren. 51. Harger JH, Ernest JM, Thurnau GR, et al: Risk factors and outcome of II. Ventilation, Atemmechanik und Diffusionkapazitt. Z Geburtshilfe Peri- varicella-zoster virus pneumonia in pregnant women. J Infect Dis 185:422, natol 177:397, 1973. 2002.22. Milne JA: The respiratory response to pregnancy. Postgrad Med J 55:318, 52. Haake DA, Zakowski PC, Haake DL, et al: Early treatment with acyclovir 1979. for varicella pneumonia in otherwise healthy adults: Retrospective con-23. Heidenreich J, Kafarnik D, Westenburger U, et al: Statische und Dyna- trolled study and review. Rev Infect Dis 12:788, 1990. mische Ventilationgrossen in der Schwangerschaft und im Wochenbett. 53. McKinney WP, Volkert P, Kaufman J: Fatal swine inﬂuenza pneumonia Arch Gynakol 210:208, 1971. during late pregnancy. Arch Intern Med 150:213, 1990.24. Sims CD, Chamberlain GVP, de Swiet M: Lung function tests in bronchial 54. American College of Obstetricians and Gynecologists (ACOG): Pulmo- asthma during and after pregnancy. BJOG 88:434, 1976. nary disease in pregnancy. ACOG technical bulletin no. 224. Washington,25. Alaily AB, Carrol KB: Pulmonary ventilation in pregnancy. BJOG 85:518, DC, American College of Obstetricians and Gynecologists, 1996. 1978. 55. Mendelson CL: The aspiration of stomach contents into the lungs during26. Thomson KJ, Cohen ME: Studies on the circulation in normal pregnancy. obstetric anesthesia. Am J Obstet Gynecol 52:191, 1946. II. Vital capacity observations in normal pregnant women. Surg Gynecol 56. Krantz ML, Edwards WL: The incidence of nonfatal aspiration in obstetric Obstet 66:591, 1938. patients. Anesthesiology 30:84, 1973.27. Klaften E, Palugyay J: Verleichende Untersuchungen über Lage und 57. Ezri T, Szmuk P, Stein A, et al: Peripartum general anesthesia without Ausdehnung von Herz und Lunge in der Schwangerschaft und im tracheal intubation: Incidence of aspiration pneumonia. Anaesthesia Wochenbett. Arch Gynakol 131:347, 1927. 55:421, 2000.28. Klaften E, Palugyay J: Zur Physiologie der Atmung in der Schwangerschaft. 58. Soreide E, Bjornestad E, Steen PA: An audit of perioperative aspiration Arch Gynakol 129:414, 1926. pneumonitis in gynaecological and obstetric patients. Acta Anaesth Scand29. Mobius WV: Abrung und Schwangerschaft. Munch Med Wochenschr 40:14, 1996. 103:1389, 1961. 59. Tomlinson MW, Caruthers TJ, Whitty JE, et al: Does delivery improve30. McGinty AP: The comparative effect of pregnancy and phrenic nerve maternal condition in the respiratory-compromised gravida? Obstet interruption on the diaphragm and their relation to pulmonary tubercu- Gynecol 91:108, 1998. losis. Am J Obstet Gynecol 35:237, 1938. 60. National Center for Health Statistics: National hospital discharge survey:31. Barcroft J: On anoxemia. Lancet 11:485, 1920. Annual summary 1990. Vital Health Stat 13:1, 1992.32. Cain SM: Peripheral uptake and delivery in health and disease. Clin Chest 61. Kort BA, Cefalo RC, Baker VV: Fatal inﬂuenza A pneumonia in pregnancy. Med 4:139, 1983. Am J Perinatol 3:179, 1986.33. Bryan-Brown CW, Baek SM, Makabali G, et al: Consumable oxygen: 62. Mullooly JP, Barker WH, Nolan TF Jr: Risk of acute respiratory disease Oxygen availability in relation to oxyhemoglobin dissociation. Crit Care among pregnant women during inﬂuenza A epidemics. Public Health Rep Med 1:17, 1973. 101:205, 1986.34. Perutz MF: Hemoglobin structure and respiratory transport. Sci Am 63. Harris JW: Inﬂuenza occurring in pregnant women. JAMA 72:978, 1919. 239:92, 1978. 64. Freeman DW, Barno A: Deaths from Asian inﬂuenza associated with preg-35. Rackow EC, Astiz M: Pathophysiology and treatment of septic shock. nancy. Am J Obstet Gynecol 78:1172, 1959. JAMA 266:548, 1991. 65. Hollingsworth HM, Pratter MR, Irwin RS: Acute respiratory failure in36. Shoemaker WC, Ayres S, Grenvik A, et al: Textbook of Critical Care, 2nd pregnancy. J Intensive Care Med 4:11, 1989. ed. Philadelphia, WB Saunders, 1989. 66. Prevention and Control of Inﬂuenza: Recommendations of the Advisory37. Shibutani K, Komatsu T, Kubal K, et al: Critical level of oxygen delivery Committee on Immunization Practices (ACIP). MMWR 56:1-54, 2007. in anesthetized man. Crit Care Med 11:640, 1983. 67. Cox SM, Cunningham FG, Luby J: Management of varicella pneumonia38. Barron W, Lindheimer M: Medical Disorders During Pregnancy. St. Louis, complicating pregnancy. Am J Perinatol 7:300, 1990. CV Mosby, 1991, p 234. 68. Esmonde TG, Herdman G, Anderson G: Chickenpox pneumonia: An39. Gemzell CA, Robbe H, Strom G, et al: Observations on circulatory changes association with pregnancy. Thorax 44:812, 1989. and muscular work in normal labor. Acta Obstet Gynaecol Scand 36:75, 69. Smego RA, Asperilla MO: Use of acyclovir for varicella pneumonia during 1957. pregnancy. Obstet Gynecol 78:1112, 1991.
950 CHAPTER 45 Respiratory Diseases in Pregnancy70. Harris RE, Rhades ER: Varicella pneumonia complicating pregnancy: 99. Hamadeh MA, Glassroth J: Tuberculosis and pregnancy. Chest 101:1114, Report of a case and review of literature. Obstet Gynecol 25:734, 1965. 1992.71. Andrews EB, Yankaskas BC, Cordero JF, et al: Acyclovir in pregnancy reg- 100. Jana N, Vasishta K, Saha SC, et al: Obstetrical outcomes among women istry: Six years’ experience. Obstet Gynecol 79:7, 1992. with extrapulmonary tuberculosis. N Engl J Med 341:645, 1999.72. Brown ZA, Baker DA: Acyclovir therapy during pregnancy. Obstet Gynecol 101. Vallejo JC, Starke JR: Tuberculosis and pregnancy. Clin Chest Med 13:693, 73:526, 1989. 1992.73. Pickard RE: Varicella pneumonia in pregnancy. Am J Obstet Gynecol 102. Sackoff JE, Pfeiffer MR, Driver CR, et al: Tuberculosis prevention for 101:504, 1968. non-US-born pregnant women. Am J Obstet Gynecol 194:451, 2006.74. Afessa B, Green B: Bacterial pneumonia in hospitalized patients with HIV 103. Riley L: Pneumonia and tuberculosis in pregnancy. Infect Dis Clin North infection. The pulmonary complications, ICU support, and prognostic Am 11:119, 1997. factors of hospitalized patients with HIV (PIP) study. Chest 117:1017, 104. Boggess KA, Myers ER, Hamilton CD: Antepartum or postpartum isonia- 2000. zid treatment of latent tuberculosis infection. Obstet Gynecol 96:757,75. Minkoff H, deRegt R, Landesman S, Schwarz R: Pneumocystis carinii asso- 2000. ciated with acquired immunodeﬁciency syndrome in pregnancy: A report 105. Robinson CA, Rose NC: Tuberculosis: Current implications and manage- of three maternal deaths. Obstet Gynecol 67:284, 1986. ment in obstetrics. Obstet Gynecol Surv 51:115, 1999.76. Armstrong D: Aerosol pentamidine. Ann Intern Med 109:852, 1988. 106. Myers JP: New recommendations for the treatment of tuberculosis. Curr77. Stratton P, Mofenson LM, Willoughby AD: Human immunodeﬁciency Opin Infect Dis 18:133, 2005. virus infection in pregnant women under care at AIDS clinical trials in 107. Van Rie A, Warren R, Richardson M, et al: Classiﬁcation of drug-resistant the United States. Obstet Gynecol 79:364, 1992. tuberculosis in an epidemic era. Lancet 356:22, 2000.78. Jensen LP, O’Sullivan MJ, Gomez-del-Rio M, et al: Acquired immunode- 108. Fox CW, George RB: Current concepts in the management and prevention ﬁciency (AIDS) in pregnancy. Am J Obstet Gynecol 148:1145, 1984. of tuberculosis in adults. J La State Med Soc 144:363, 1992.79. Antoine C, Morris M, Douglas G: Maternal and fetal mortality in acquired 109. Robinson GC, Cambion K: Hearing loss in infants of tuberculosis mothers immunodeﬁciency syndrome. N Y State J Med 86:443, 1986. treated with streptomycin during pregnancy. N Engl J Med 271:949,80. Kell PD, Barton SE, Smith DE, et al: A maternal death caused by AIDS. 1964. Case report. BJOG 98:725, 1991. 110. Rendig EK Jr: The place of BCG vaccine in the management of infants81. Ahmad H, Mehta NJ, Manikal VM, et al: Pneumocystis carinii pneumonia born to tuberculosis mothers. N Engl J Med 281:520, 1969. in pregnancy. Chest 120:666, 2001. 111. Schatz M, Zeiger RS, Hoffman CP: Intrauterine growth is related to ges-82. Clinton M, Niederman M, Matthay R: Maternal pulmonary disorders tational pulmonary function in pregnant asthmatic women. Kaiser-Per- complicating pregnancy. In Reece EA, Hobbins JC, Mahoney MJ, et al manente Asthma and Pregnancy Study Group. Chest 98:389, 1990. (eds): Medicine of the Fetus and Mother. Philadelphia, Lippincott, 1992, 112. Alexander S, Dodds L, Armson BA: Perinatal outcomes in women with p 317. asthma during pregnancy. Obstet Gynecol 92:435, 1998.83. Hicks ML, Nolan GH, Maxwell SL, et al: Acquired immuno-deﬁciency 113. Kwon HL, Belanger K, Bracken M. Asthma prevalence among pregnant syndrome and Pneumocystis carinii infection in a pregnant woman. Obstet and childbearing-aged women in the United States: Estimates from Gynecol 76:480, 1990. national health surveys. Ann Epidemiol 13:317, 2003.84. Bardeguez AD: Management of HIV infection for the childbearing age 114. National Asthma Education and Prevention Program: Expert Panel woman. Clin Obstet Gynecol 39:344, 1996. Report: Managing asthma during pregnancy: Recommendations for phar-85. Hussain A, Mehta NJ, Manikal VM, et al: Pneumocystis carinii pneumonia macologic treatment—2004 update. NHLBI, NIH publication no. 05- in pregnancy. Chest 120:666, 2001. 3279. Available at http://www.nhlbi.nih.gov/health/prof/lung/asthma/86. Diwan VK, Thorson A: Sex, gender and tuberculosis. Lancet 353:1000, astpreg/astpreg_qr.pdf (accessed January 2008). 1999. 115. National Asthma Education and Prevention Program: Full Report of the87. Holmes CB, Hausler H, Numm P: A review of sex differences in the Expert Panel: Guidelines for the Diagnosis and Management of Asthma, epidemiology of tuberculosis. Int J Tuberc Lung Dis 2:96, 1998. 2007. Available at http://www.nhlbi.nih.gov/health/prof/lung/asthma/88. Initial therapy for tuberculosis in the era of multidrug resistance— astpreg/astpreg_full.pdf (accessed January 2008). recommendations of the advisory council for the elimination of tuber- 116. Schatz M., Dombrowski MP, Wise R, et al, for the NICHD Maternal-Fetal culosis. MMWR Morb Mortal Wkly Rep 42:536, 1993. Medicine Units Network, and NHLBI. Asthma morbidity during preg-89. Frieden TR, Sterling T, Pablos-Mendez A, et al: The emergence of drug- nancy can be predicted by severity classiﬁcation. J Allergy Clin Immunol resistant tuberculosis in New York City. N Engl J Med 328:521, 1993. 112:28, 2003.90. Cantwell MF, Shehab AM, Costello AM: Brief report: Congenital tubercu- 117. Gordon M, Niswander KR, Brerendes H, Kantor AG: Fetal morbidity fol- losis. N Engl J Med 330:1051, 1994. lowing potentially anoxigenic obstetric conditions. VII. Bronchial asthma.91. Margono F, Mroveh J, Garely A, et al: Resurgence of active tuberculosis Am J Obstet Gynecol 106:421, 1970. among pregnant women. Obstet Gynecol 83:911, 1994. 118. Bahna SL, Bjerkedal T: The course and outcome of pregnancy in women92. Nitta AT, Milligan D: Management of four pregnant women with with bronchial asthma. Acta Allergol 27:397, 1972. multidrug-resistant tuberculosis. Clin Infect Dis 28:1298, 1999. 119. Wen SW, Demissie K, Liu S: Adverse outcomes in pregnancies of asthmatic93. Centers for Disease Control: The use of preventive therapy for tuberculo- women: Results from a Canadian population. Ann Epidemiol 11:7, sis infection in the United States. MMWR Morb Mortal Wkly Rep 39:9, 2001. 1990. 120. Dombrowski MP, Bottoms SF, Boike GM, Wald J: Incidence of preeclamp-94. Grifﬁth DE: Mycobacteria as pathogens of respiratory infection. Infect Dis sia among asthmatic patients lower with theophylline. Am J Obstet Clin North Am 12:593, 1998. Gynecol 155:265, 1986.95. American Thoracic Society Workshop: Rapid diagnostic tests for tuber- 121. Stenius-Aarniala BS, Teramo PK: Asthma and pregnancy: A prospective culosis—what is the appropriate use? Am J Respir Crit Care Med 155:1804, study of 198 pregnancies. Thorax 43:12, 1988. 1997. 122. Demisse K, Breckenridge MB, Rhoads GG: Infant and maternal outcomes96. Barnes PF: Rapid diagnostic tests for tuberculosis, progress but no gold in the pregnancies of asthmatic women. Am J Respir Crit Care Med standard. Am J Respir Crit Care Med 155:1497, 1997. 158:1091, 1998.97. Good JT, Iseman MD, Davidson PT, et al: Tuberculosis in association with 123. Liu S, Wen SW, Demissie K, et al: Maternal asthma and pregnancy out- pregnancy. Am J Obstet Gynecol 140:492, 1981. comes: A retrospective cohort study. Am J Obstet Gynecol 184:90, 2001.98. American Thoracic Society: Mycobacteriosis and the acquired immuno- 124. Mihrshani S, Belousov E, Marks GB, Peat J: Pregnancy and birth outcomes deﬁciency syndrome. Am Rev Respir Dis 136:492, 1987. in families with asthma. J Asthma 40:181, 2003.
CHAPTER 45 Respiratory Diseases in Pregnancy 951125. Rudra CB, Williams MA, Frederick IO, Luthy DA: Maternal asthma and 149. Nolten W, Rueckert P: Elevated free cortisol index in pregnancy: Possible risk of preeclampsia, a case-control study. J Reprod Med 51:94, 2006. regulatory mechanisms. Am J Obstet Gynecol 139:492, 1981.126. Perlow JH, Montgomery D, Morgan MA, et al: Severity of asthma and 150. Bailey K, Herrod H, Younger R, Shaver D: Functional aspects of T- perinatal outcome. Am J Obstet Gynecol 167:963, 1992. lymphocyte subsets in pregnancy. Obstet Gynecol 66:211, 1985.127. Kallen B, Rydhstroem H, Aberg A: Asthma during pregnancy–a popula- 151. Haahtela T, Jarvinen M, Kava T, et al: Comparison of β2-agonist, terbuta- tion based study. Eur J Epidemiol 16:167, 2000. line, with an inhaled corticosteroid, budesonide, in newly detected asthma.128. Sorensen TK, Dempsey JC, Xiao R, et al: Maternal asthma and risk of N Engl J Med 325:338, 1991. preterm delivery. Ann Epidemiol 13:267, 2003. 152. Ernst P, Spitzer WO, Suissa S, et al: Risk of fatal and near-fatal asthma in129. Lao TT, Huengsburg M: Labour and delivery in mothers with asthma. Eur relation to inhaled corticosteroid use. JAMA 268:3462, 1992. J Obstet Gynecol Reprod Biol 35:183, 1990. 153. Kraan J, Koeter GH, van der Mark TW, et al: Dosage and time effects of130. Mabie WC, Barton JR, Wasserstrum N, Sibai BM: Clinical observations an inhaled budesonide on bronchial hyperactivity. Am Rev Respir Dis 137:44, asthma in pregnancy. J Matern Fetal Med 1:45, 1992. 1988.131. Schatz M, Zeiger RS, Hoffman CP, et al: Perinatal outcomes in the preg- 154. Lowhagen O, Rak S: Modiﬁcation of bronchial hyperreactivity after nancies of asthmatic women: A prospective controlled analysis. Am J treatment with sodium cromoglycate during pollen season. J Allergy Clin Respir Crit Care Med 151:1170, 1995. Immunol 75:460, 1985.132. Minerbi-Codish I, Fraser D, Avnun L, et al: Inﬂuence of asthma in preg- 155. Woolcock AJ, Jenkins C: Corticosteroids in the modulation of bronchial nancy on labor and the newborn. Respiration 65:130, 1998. hyperresponsiveness. Immunol Allergy Clin North Am 10:543, 1990.133. Stenius-Aarniala BSM, Hedman J, Teramo KA: Acute asthma during preg- 156. Kallen B, Rydhstroem H, Aberg A: Congenital malformations after use of nancy. Thorax 51:411, 1996. inhaled budesonide in early pregnancy. Obstet Gynecol 93:392, 1999.134. Olesen C, Thrane N, Nielsen GL, et al: A population-based prescription 157. Sears MR, Taylor DR, Print CG, et al: Regular inhaled β-agonist treatment study of asthma drugs during pregnancy: Changing the intensity of in bronchial asthma. Lancet 336:1391, 1990. asthma therapy and perinatal outcomes. Respiration 68:256, 2001. 158. Cockcroft DW, Murdock KY: Comparative effects of inhaled salbutamol,135. Norjavaara E, de Verdier MG: Normal pregnancy outcomes in a popula- sodium cromoglycate, and beclomethasone dipropionate on allergen- tion-based study including 2968 pregnant women exposed to budesonide. induced early asthmatic responses, last asthmatic responses, and increased J Allergy Clin Immunol 111:736, 2003. bronchial responsiveness to histamine. J Allergy Clin Immunol 79:734,136. Doucette JT, Bracken MB: Possible role of asthma in the risk of preterm 1987. labor and delivery. Epidemiology 4:143, 1993. 159. Spitzer WO, Suissa S, Ernst P, et al: The use of beta-agonists and the137. Jana N, Vasishta K, Saha SC, Khunnu B: Effect of bronchial asthma on the risk of death and near death from asthma. N Engl J Med 326:501, course of pregnancy, labour and perinatal outcome. J Obstet Gynaecol 1992. 21:227, 1995. 160. Schatz M, Dombrowski MP, Wise R, et al, for the NICHD Maternal-Fetal138. Lehrer S, Stone J, Lapinski R, et al: Association between pregnancy- Medicine Units Network and the NHLBI: The relationship of asthma induced hypertension and asthma during pregnancy. Am J Obstet Gynecol medication use to perinatal outcomes. J Allergy Clin Immunol 113:104, 168:1463, 1993. 2004.139. National Asthma Education Program Report of the Working Group on 161. Arwood LL, Dasta JF, Friedman C: Placental transfer of theophylline: Two Asthma and Pregnancy: Management of asthma during pregnancy. NIH case reports. Pediatrics 63:844, 1979. publication no. 93-3279A. Bethesda, National Institutes of Health, 162. Yeh TF, Pildes RS: Transplacental aminophylline toxicity in a neonate September 1993. [letter]. Lancet 1:910, 1977.140. National Asthma Education and Prevention Program Expert Panel Report 163. Hendeles L, Jenkins J, Temple R: Revised FDA labeling guideline for 2: Guidelines for the Diagnosis and Management of Asthma. NHLBI, NIH theophylline oral dosage forms. Pharmacotherapy 15:409, 1995. Publication no. 97-4051. Bethesda, National Institutes of Health and 164. Joad JP, Ahrens RC, Lindgren SD, Weinberger MM: Relative efﬁcacy of National Heart, Lung, and Blood Institute, April 1997. maintenance therapy with theophylline, inhaled albuterol, and the com-141. Schatz M, Dombrowski M: Asthma and allergy during pregnancy: Out- bination for chronic asthma. J Allergy Clin Immunol 79:78, 1987. comes of pregnancy in asthmatic women. Immunol Asthma Clin North 165. Wendel PJ, Ramin SM, Barnett-Hamm C, et al: Asthma treatment in Am 20:1, 2000. pregnancy: A randomized controlled study. Am J Obstet Gynecol 175:150,142. Fitzsimons R, Greenberger PA, Patterson R: Outcome of pregnancy in 1996. women requiring corticosteroids for severe asthma. J Allergy Clin Immunol 166. Pauwels R, Van Renterghem D, Van der Straeten M, et al: The effect of 78:349, 1986. theophylline and enprofylline on allergen-induced bronchoconstriction.143. Greenberger PA, Patterson R: The outcome of pregnancy complicated by J Allergy Clin Immunol 76:583, 1985. severe asthma. Allergy Proc 9:539, 1988. 167. Juergens UR, Degenhardt V, Stober M, Vetter H: New insights in the144. Bracken MB, Triche EW, Belanger K, et al: Asthma symptoms, severity, bronchodilatory and anti-inﬂammatory mechanisms of action of theoph- and drug therapy: A prospective study of effects on 2205 pregnancies. ylline. Arzneimittelforschung 49:694, 1999. Obstet Gynecol 1024:739, 2003. 168. Evans DJ, Taylor DA, Zetterstrom O, et al: A comparison of low-dose145. Dombrowski MP, Schatz M, Wise R, et al, for the National Institute inhaled budesonide plus theophylline and high-dose inhaled budesonide of Child Health and Human Development (NICHD) Maternal-Fetal for moderate asthma. N Engl J Med 337:1412, 1997. Medicine Units Network and the National Heart, Lung, and Blood 169. Dombrowski MP, Schatz M, Wise R, et al, for the National Institute of Institute (NHLBI): Asthma during pregnancy. Obstet Gynecol 103:5, Child Health and Human Development (NICHD) Maternal-Fetal Medi- 2004. cine Units Network and the National Heart, Lung, and Blood Institute146. Enriquez R, Pingsheng W, Griffen MR, et al: Cessation of asthma medica- (NHLBI): Randomized trial of inhaled beclomethasone dipropionate tion in early pregnancy. Am J Obstet Gynecol 195:149, 2006. versus theophylline for moderate asthma during pregnancy. Am J Obstet147. Triche EW, Saftlas AF, Belanger D, et al: Association of asthma diagnosis, Gynecol 190:737, 2004. severity, symptoms, and treatment with risk of preeclampsia. Obstet 170. Knorr B, Matz J, Bernstein JA, et al: Montelukast for chronic asthma in 6 Gynecol 104:585, 2004. to 14 year old children. JAMA 279:1181, 1998.148. Schatz MS, Dombrowski MP, Wise R, et al, for the National Institute of 171. Wenzel SE: New approaches to anti-inﬂammatory therapy for asthma. Am Child Health and Human Development (NICHD) Maternal-Fetal Medi- J Med 104:287, 1998. cine Units Network and the National Heart, Lung, and Blood Institute 172. Park-Wyllie L, Mazzotta P, Pastuszak A, et al: Birth defects after maternal (NHLBI): Spirometry is related to perinatal outcomes in pregnant women exposure to corticosteroids: Prospective cohort study and meta-analysis with asthma. Am J Obstet Gynecol 194:120, 2006. of epidemiological studies. Teratology 62:385, 2000.
952 CHAPTER 45 Respiratory Diseases in Pregnancy173. Bakhireva LN, Jones KL, Schatz M, et al: Asthma medication use 192. Kotloff RM, FitzSimmons SC, Fiel SB: Fertility and pregnancy in patients in pregnancy and fetal growth. J Allergy Clin Immunol 116:503, with cystic ﬁbrosis. Clin Chest Med 13:623, 1992. 2005. 193. Siegel B, Siegel S: Pregnancy and delivery in a patient with CF of the174. Towers CV, Briggs GG, Rojas JA: The use of prostaglandin E2 in pregnant pancreas: Report of a case. Obstet Gynecol 16:439, 1960. patients with asthma. Am J Obstet Gynecol 190:1777, 2004. 194. Grand RJ, Talamo RC, di Sant’Agnese PA, et al: Pregnancy in cystic ﬁbrosis175. Crawford JS: Bronchospasm following ergonovine. Anesthesiology 35:397, of the pancreas. JAMA 195:993, 1966. 1980. 195. Cohen LF, di Sant’Agnese PA, Friedlander J: Cystic ﬁbrosis and pregnancy:176. Hägerdal M, Morgan CW, Sumner AE, Gutsche BB: Minute ventilation A national survey. Lancet 2:842, 1980. and oxygen consumption during labor with epidural analgesia. Anesthe- 196. Weinberger SE, Weiss ST, Cohen WR, et al: Pregnancy and the lung. Am siology 59:425, 1983. Rev Respir Dis 121:559, 1980.177. Fung DL: Emergency anesthesia for asthma patients. Clin Rev Allergy 197. Rush D, Johnstone FD, King JC: Nutrition and pregnancy. In Burrows 3:127, 1985. GN, Ferris TF (eds): Medical Complications During Pregnancy, 3rd ed.178. Hirshman CA, Downes H, Farbood A, Bergman NA: Ketamine block of Philadelphia, WB Saunders, 1988. bronchospasm in experimental canine asthma. Br J Anaesth 51:713, 198. Dowsett J: An overview of nutritional issues for the adult with cystic 1979. ﬁbrosis. Nutrition 16:566, 2000.179. American Academy of Pediatrics Committee on Drugs: Transfer of drugs 199. Novy MJ, Tyler JM, Shwachman H, et al: Cystic ﬁbrosis and pregnancy. and other chemicals into human milk. Pediatrics 84:924, 1989. Report of a case with a study of pulmonary function and arterial blood180. West JB: Pulmonary Pathophysiology. Baltimore, Williams & Wilkins, gases. Obstet Gynecol 30:530, 1967. 1978, p 92. 200. Palmer J, Dillon-Baker C, Tecklin JS, et al: Pregnancy in patients with181. King TE Jr: Restrictive lung disease in pregnancy. Clin Chest Med 13:607, cystic ﬁbrosis. Ann Intern Med 99:596, 1983. 1992. 201. Corkey CW, Newth CJ, Corey M, Levison H: Pregnancy in cystic ﬁbrosis:182. Boggess KA, Easterling TR, Raghu G: Management and outcome of preg- A better prognosis in patients with pancreatic function? Am J Obstet nant women with interstitial and restrictive lung disease. Am J Obstet Gynecol 140:737, 1981. Gynecol 173:1007, 1995. 202. Canny GJ, Corey M, Livingstone RA, et al: Pregnancy and cystic ﬁbrosis.183. Agha FP, Vade A, Amendola MA, et al: Effects of pregnancy on sarcoidosis. Obstet Gynecol 77:850, 1991. Surg Gynecol Obstet 155:817, 1982. 203. Kent NE, Farquharson DF: Cystic ﬁbrosis in pregnancy. Can Med Assoc J184. Haynes de Regt R: Sarcoidosis and pregnancy. Obstet Gynecol 70:369, 149:809, 1993. 1987. 204. Edenborough FP, Stableforth DE, Webb AK, et al: Outcome of pregnancy185. Maycock RL, Sullivan RD, Greening RR, et al: Sarcoidosis and pregnancy. in women with cystic ﬁbrosis. Thorax 50:170, 1995. JAMA 164:158, 1957. 205. Olson GL: Cystic ﬁbrosis in pregnancy. Semin Perinatol 21:307, 1997.186. Reisﬁeld DR: Boeck’s sarcoid and pregnancy. Am J Obstet Gynecol 75:795, 206. Edenborough FP, Mackenzie WE, Stableforth DE: The outcome of 72 1958. pregnancies in 55 women with cystic ﬁbrosis in the United Kingdom187. Scadding JG: Sarcoidosis. London, Eyre & Spottiswoode, 1967. 1977-1996. BJOG 107:254, 2000.188. Hilman BC, Aitken ML, Constantinescu M: Pregnancy in patients with 207. Tanser SJ, Hodson ME, Geddes DM: Case reports of death during preg- cystic ﬁbrosis. Clin Obstet Gynecol 39:70, 1996. nancy in patients with cystic ﬁbrosis—three out of four patients were189. Kerem B, Rommens JM, Buchanan JA, et al: Identiﬁcation of the cystic colonized with Burkholderia cepacia. Respir Med 94:1004, 2000. ﬁbrosis gene: Genetic analysis. Science 245:1073, 1989. 208. Gilljam M, Antoniou M, Shin J, et al: Pregnancy in cystic ﬁbrosis. Chest190. Riordan JR, Rommens JM, Kerem B, et al: Identiﬁcation of the cystic 118:85, 2000. ﬁbrosis gene: Cloning and characterization of complementary DNA. 209. Gyi KM, Hodson ME, Yacoub MY: Pregnancy in cystic ﬁbrosis lung trans- Science 245:1066, 1989. plant recipients: Case series and review. J Cystic Fibrosis 5:171-175,191. Rommens JM, Iannuzzi MC, Kerem B, et al: Identiﬁcation of the cystic 2006. ﬁbrosis gene: Chromosome walking and jumping. Science 245:1059, 210. Cole BN, Seltzer MH, Kassabian J, et al: Parenteral nutrition in a pregnant 1989. cystic ﬁbrosis patient. JPEN J Parenter Enteral Nutr 11:205, 1987.