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Proper functioning of the cardiorespiratory system is imperative to achieve adequate oxygenation of maternal and fetal tissues. The mater-nal cardiorespiratory system undergoes signifi cant changes during gestation to optimize oxygen delivery to the fetus and maternal tissues. Pulmonary disease is one of the most frequent maternal complications during pregnancy, and it may result in signifi cant morbidity or mortal-ity for the mother and her fetus. Depending on the specifi c diagnosis, other maternal complications of pregnancy may have an adverse or positive impact on the pulmonary function of the gravida.

In this chapter, we briefl y review the physiologic adaptations of the respiratory system that occur during gestation. Specifi c respir-atory diseases that occur in pregnancy and the effects of the disease on pregnancy and pregnancy on the disease are discussed. The obstetri-cian should realize that most diagnostic tests useful in evaluating pul-monary function during gestation are not harmful to the fetus and, if indicated, should be performed. Most medications used to treat respi-ratory disease in pregnancy are also well tolerated by the fetus. With few exceptions, the diagnostic and treatment algorithms for respiratory disease closely resemble those used for a nonpregnant woman.

Physiologic Changes of the Respiratory SystemBecause there is no increase in respiratory rate, the increase in maternal minute ventilation results from an increase in tidal volume.1 The almost 50% increase in tidal volume occurs at the expense of an 18% decrease 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 104 mm Hg).2 The PaCO2 decreases early in pregnancy in parallel with the change in ventilation; however, a further progressive decrease in PaCO2 may occur.3 The decrease in PaCO2 is even greater at altitudes where the mother exhibits compensatory hyperventilation in an attempt to maintain the arterial partial pressure of oxygen as high as possible. The decrease in PaCO2 is matched by an equivalent increase in renal excretion of and decrease in plasma bicarbonate concentra-tion; therefore, arterial pH is not altered from the normal nonpregnant level of about 7.4.

It has been suggested that the hyperventilation of pregnancy results primarily from progesterone acting as a respiratory stimulant.4 Because hyperventilation has been observed during the luteal phase of the menstrual cycle and progesterone can produce similar changes in

nonpregnant women, it is likely that this phenomenon results from progestational infl uences.5,6 The PaCO2 is linearly and inversely related to the log of the progesterone concentration.7 Wilbrand and colleagues8 reported that progesterone lowers the carbon dioxide threshold of the respiratory center. During pregnancy, the sensitivity of the respiratory center increases9 so that an increase in PaCO2 of 1 mm Hg increases ventilation by 6 L/min in pregnancy, compared with 1.5 L/min in the nonpregnant state.1,10,11 It is possible that progesterone acts as a primary stimulant to the respiratory center independently of any change in carbon dioxide sensitivity or threshold.4 In addition to stimulating ventilation, progesterone may also increase levels of carbonic anhy-drase B in the red blood cell.12 Schenker and associates13 reported that carbonic anhydrase levels increase in pregnant patients and in women taking oral contraceptives. An increase in the carbonic anhydrase level facilitates carbon dioxide transfer and tends to decrease PaCO2 inde-pendently of any change in ventilation. This respiratory stimulant effect of progesterone has been used in the treatment of respiratory failure and emphysema.6,14,15

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 fi rst trimes-ter and remains at that level throughout pregnancy. The physiologic dead space is increased by about 60 mL in pregnancy. This may result from dilation of the small airways.11 Residual volume is reduced by about 20%,16 from 1200 to 1000 mL.20-22 The vital capacity, which is the maximum volume of gas that can be expired after a maximum inspiration, does not change in pregnancy.16,21-25

Anatomic Changes of the Respiratory SystemObserved changes in the confi guration of the chest during pregnancy are in keeping with the fi ndings of no change in vital capacity and a reduction in residual volume. The effect of pregnancy on pulmonary mechanics has been compared with the effect of a pneumoperitoneum. In both situations, the residual lung volume is decreased, but ventila-tion remains unimpaired. Radiologic studies performed early in preg-nancy have shown that the subcostal angle increases from 68 to 103 degrees before there is any mechanical pressure from the enlarging uterus.26 The level of the diaphragm rises by about 4 cm, and the transverse diameter of the chest increases by 2 cm.27-29 These changes account for the decrease in residual volume because the lungs are

Chapter 45

Respiratory Diseases in PregnancyJanice E. Whitty, MD, and Mitchell P. Dombrowski, MD

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928 CHAPTER 45 Respiratory Diseases in Pregnancy

relatively compressed during forced expiration; however, the excursion of the diaphragm in respiration increases by about 1.5 cm in pregnancy compared with the nonpregnant state.29,30

Oxygen Delivery and ConsumptionOxygen DeliveryAll tissues require oxygen for the combustion of organic compounds to fuel cellular metabolism. The cardiopulmonary system delivers a continuous supply of oxygen and other essential substrates to tissues. Oxygen delivery depends on oxygenation of blood in the lungs, oxygen-carrying capacity of the blood, and cardiac output.31 Under normal conditions, oxygen delivery exceeds oxygen consumption by about 75%.32 The amount of oxygen delivered is determined by the cardiac output (CO, L/min) times the arterial oxygen content (CaO2, mL/O2/min):

Oxygen delivery = CO × CaO2 × 10 (700 to 1400 mL/min)

The arterial oxygen content is determined by the amount of oxygen that is bound to hemoglobin (i.e., arterial blood saturation with oxygen [SaO2]) and by the amount of oxygen that is dissolved in plasma (i.e., arterial partial pressure of oxygen [PaO2 × 0.0031]):

CaO2 = (hemoglobin × 1.34 × SaO2) + (PaO2 × 0.0031)

(16 to 22 mL O2/dL)

As can be seen in this formula, the amount of oxygen dissolved in plasma is negligible, and the arterial oxygen content therefore depends

largely on hemoglobin concentration and arterial oxygen saturation. Oxygen delivery can be impaired by conditions that affect arterial oxygen content or cardiac output (fl ow), 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 patient with hypoxemic respiratory failure does not have suffi cient oxygen available to saturate the hemoglobin molecule. Desaturated hemoglo-bin is altered structurally such that it has a diminished affi nity for oxygen.33

The amount of oxygen available to tissues also is affected by the affi nity of the hemoglobin molecule for oxygen. The oxyhemoglobin dissociation curve (Fig. 45-1) and the conditions that infl uence the binding of oxygen negatively or positively must be considered when attempts are made to maximize oxygen delivery.34 An increase in the plasma pH level or a decrease in temperature or the concentration of 2,3-diphosphoglycerate can increase hemoglobin affi nity for oxygen, shifting the curve to the left and resulting in diminished tissue oxygen-ation. If the plasma pH level, temperature, or 2,3-diphosphoglycerate level increases, hemoglobin affi nity for oxygen decreases, and more oxygen is available to tissues (see Fig. 45-1).34

In certain clinical conditions, such as septic shock and adult respi-ratory distress syndrome, there is maldistribution of fl ow relative to oxygen demand, leading to diminished delivery and consumption of oxygen. The release of vasoactive substances is hypothesized to result in the loss of normal mechanisms of vascular autoregulation, produc-ing regional and microcirculatory imbalances in blood fl ow.35 This mismatching of blood fl ow with metabolic demand causes excessive blood fl ow to some areas and relative hypoperfusion of other areas, limiting optimal systemic use of oxygen.35 The patient with diminished cardiac output resulting from hypovolemia or pump failure is unable to distribute oxygenated blood to tissues. Therapy directed at increas-ing the volume with normal saline or with blood if the hemoglobin

100

pHDPGTemp

pHDPGTemp

90

Per

cent

oxy

hem

oglo

bin

80

70

60

50

40

30

20

10

0 10 20 30 40 50 60 70 80 90 100

O2 tension (mm Hg)P50

FIGURE 45-1 The oxygen-binding curve for human hemoglobin A under physiologic conditions (red curve). The affi nity is shifted by changes in pH, diphosphoglycerate (DPG) concentration, and temperature. P50 is the oxygen tension at one-half saturation.

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929CHAPTER 45 Respiratory Diseases in Pregnancy

level is less than 10 g/dL increases delivery of oxygen in the hypovole-mic patient. The patient with cardiac failure may benefi t from inotro-pic support and afterload reduction in addition to supplementation of intravascular volume.

Relationship of Oxygen Delivery to ConsumptionOxygen consumption is the product of the arteriovenous oxygen content difference (C(a−v)O2) and cardiac output (CO). Under normal conditions, oxygen consumption is a direct function of the metabolic rate36:

Oxygen consumption = C(a−v)O2 × CO × 10

(180 to 280 mL/min)

The oxygen extraction ratio is the fraction of delivered oxygen that actually is consumed:

Oxygen extraction ratio = O2 consumption/O2 delivery (0.25)

The normal oxygen extraction ratio is about 25%. A rise in the oxygen extraction ratio is a compensatory mechanism used when oxygen delivery is inadequate for the level of metabolic activity. A subnormal value suggests fl ow maldistribution, peripheral diffusion defects, or functional shunting.36 As the supply of oxygen is reduced, the fraction extracted from blood increases and oxygen consumption is maintained. If a severe reduction in oxygen delivery occurs, the limits of oxygen extraction are reached, tissues are unable to sustain aerobic energy production, and consumption decreases. The level of oxygen delivery at which oxygen consumption begins to decrease is called critical oxygen delivery (Fig. 45-2).37 At the critical oxygen delivery level, tissues begin to use anaerobic glycolysis, with resultant lactate produc-tion and metabolic acidosis.37 If oxygen deprivation continues, irre-versible tissue damage and death ensue.

Mixed Venous OxygenationThe mixed venous oxygen tension and mixed venous oxygen saturation (SV̄O2) are parameters of tissue oxygenation.37 The normal mixed

venous oxygen tension is 40 mm Hg with a saturation of 73%. Satura-tions less than 60% are abnormally low. These parameters can be measured directly by obtaining a blood sample from the distal port of the pulmonary artery catheter. The SV̄O2 also can be measured con-tinuously with special pulmonary artery catheters equipped with fi ber-optics. Mixed venous oxygenation is a reliable parameter in the patient with hypoxemia or low cardiac output, but fi ndings must be inter-preted with caution. When the SV̄O2 is low, oxygen delivery can be assumed to be low. However, normal or high SV̄O2 values do not guar-antee that tissues are well oxygenated. In conditions such as septic shock and adult respiratory distress syndrome, the maldistribution of systemic fl ow may lead to an abnormally high SV̄O2 value in the face of severe tissue hypoxia.35 The oxygen dissociation curve must be con-sidered when interpreting the SV̄O2 as an indicator of tissue oxygen-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 venous oxygen content is low. SV̄O2 is useful for monitoring trends in a particular patient, because a signifi cant decrease occurs when oxygen delivery has decreased because of hypoxemia or a decrease in cardiac output.

Oxygen Delivery and Consumption in PregnancyThe physiologic anemia of pregnancy results in a reduction in the hemoglobin concentration and arterial oxygen content. Oxygen deliv-ery is maintained at or above normal despite this because of the 50% increase in cardiac output. The pregnant woman therefore depends on cardiac output for maintenance of oxygen delivery more than the nonpregnant patient.38 Oxygen consumption increases steadily throughout pregnancy and is greatest at term, reaching an average of 331 mL/min at rest and 1167 mL/min with exercise.11 During labor, oxygen consumption increases by 40% to 60%, and cardiac output increases by about 22%.39,40 Because oxygen delivery normally far 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, she very quickly can reach the critical oxygen delivery level during labor, compromising herself and her fetus. The obstetrician therefore must make every effort to optimize oxygen delivery before allowing labor to begin in the compromised patient.

Pneumonia in PregnancyPneumonia is fortunately a rare complication of pregnancy, occurring 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 -cant complication of pneumonia complicating pregnancy. Even with antibiotic therapy and modern management, preterm delivery con-tinues to occur for 4% to 43% of gravidas who have pneumonia.42,45,46

The increasing incidence of pneumonia in pregnancy may refl ect the declining general health status of certain segments of the childbear-ing population (e.g., morbid obesity).46 The epidemic of human immunodefi ciency virus (HIV) infection has increased the number of potential mothers who are at risk for opportunistic lung infections.

O2

cons

umpt

ion

DO2crit

O2 delivery

FIGURE 45-2 Relationship of oxygen consumption (VO2) and oxygen delivery (DO2). At the point of critical oxygen delivery, tissues begin to use anaerobic glycolysis, with resultant lactate production and metabolic acidosis. If the oxygen deprivation continues, irreversible tissue damage and death ensue.

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HIV infection is also associated with increased risks of invasive pneu-mococcal disease (odds ratio [OR] = 41.8) and Legionnaire disease (OR = 41.8).47 HIV infection further predisposes the pregnant woman to the infectious complications of acquired immunodefi ciency syn-drome (AIDS).47,48 Reported incidence rates range from 97 to 290 cases per 1000 HIV-infected persons per year. HIV-infected persons are 7.8 times more likely to develop pneumonia than non-HIV-infected indi-viduals with similar risk factors. Women with medical conditions that increase the risk for pulmonary infection, such as cystic fi brosis (CF), are living to childbearing age more frequently than in the past. This disorder contributes to the increased incidence of pneumonia in pregnancy.

Pneumonia can complicate pregnancy at any time during gestation and may be associated with preterm birth, poor fetal growth, and perinatal loss. In an early report, 17 of 23 patients developed pneumo-nia between 25 and 36 weeks’ gestation.49 In that series, seven gravidas delivered during the course of their acute illness, and there were two maternal deaths. Another report described 39 cases of pneumonia in pregnancy.45 Sixteen gravidas presented before 24 weeks’ gestation, 15 between 25 and 36 weeks’ gestation, and 8 after 36 weeks’ gestation. Twenty-seven patients in this series were followed to completion of pregnancy; only two required delivery during the acute phase of pneu-monia. Of these 27 patients, 3 suffered a fetal loss, and 24 delivered live fetuses, although there was one neonatal death resulting from prematurity.

Madinger and associates42 reported 25 cases of pneumonia occurring among 32,179 deliveries and observed that fetal and obstetric complications were much more common than in earlier studies. Preterm labor complicated 11 of 21 gestations. Eleven patients had pneumonia at the time of delivery. Preterm delivery was more likely for women who had bacteremia, needed mechanical ventilation, and had a serious underlying maternal disease. In addition to the complication of preterm labor, there were three perinatal deaths in this series. Berkowitz and LaSala46 reported 25 patients with pneumonia complicating pregnancy; 14 women had term deliveries, 1 delivered preterm, 3 had a voluntary termination of pregnancy, 3 had term deliveries of growth-restricted infants, and 4 were lost to follow-up. Birth weight was signifi cantly lower in the study group in this series (2770 ± 224 g versus 3173 ± 99 g in the control group; P < .01). In this series, pneumonia complicated 1 of 367 deliveries. The investigators attributed the increase in the incidence of pneumonia in this popula-tion to a decline in general health status, including anemia, a signifi cant incidence of cocaine use (52% versus 10% of the general population), and HIV positivity (24% versus 2% of the general population) in the study group.

BacteriologyMost series describing pneumonia complicating pregnancy have used incomplete methodologies to diagnose the etiologic pathogens for pneumonia, relying primarily on cultures of blood and sputum. In most cases, no pathogen was identifi ed; however, pneumococcus and Haemophilus infl uenzae remain the most common identifi able causes of pneumonia in pregnancy.42,45,46 Because comprehensive serologic testing has rarely been done, the true incidence of viral, Legionella, and Mycoplasma pneumonia in pregnancy is diffi cult to estimate. The data presented by Benedetti, Madinger, Berkowitz, and their respective col-leagues all support pneumococcus as the predominant pathogen causing pneumonia in pregnancy and H. infl uenzae as the second most common organism.42,45,46 In the series of Berkowitz and LaSala,46 one patient was infected with Legionella species.

Pneumonia in pregnancy has several causes, including mumps, infectious mononucleosis, swine infl uenza, infl uenza A, varicella, coc-cidioidomycosis, and other fungi.50 Varicella pneumonia can compli-cate primary varicella infections in 5.2% to 9%51 of infections in pregnancy, compared with 0.3% to 1.8% in the nonpregnant popula-tion.52 Infl uenza A has a higher mortality rate among pregnant women than among nonpregnant patients.53 The increase in virulence of viral infections reported in pregnancy may result from the alterations in maternal immune status that characterize pregnancy, including reduced lymphocyte proliferative response, reduced cell-mediated cytotoxicity by lymphocytes, and a decrease in the number of helper T lymphocytes.53,54 Viral pneumonias can also be complicated by superimposed bacterial infection, particularly pneumococcus.

Aspiration PneumoniaMendelson syndrome describes chemical pneumonitis resulting from the aspiration of gastric contents in pregnancy. Chemical pneumonitis can be superinfected with pathogens present in the oropharynx and gastric juices, primarily anaerobes and gram-negative bacteria.45 Men-delson’s original report of aspiration55 consisted of 44,016 nonfasted obstetric patients between 1932 and 1945, and more than one half had received “operative intervention” with ether by mask without endotra-cheal intubation. He described aspiration in 66 cases (rate of 1 case per 667 patients). Although several of the patients were critically ill from their aspirations, most recovered within 24 to 36 hours, and only two died from this complication (rate of 1 death per 22,008 patients). A review described 37,282 vaginal deliveries; 85% were performed with general anesthesia by mask and without intubation, and 65% to 75% had ingested liquids or solid food within 4 hours of onset of labor.56 The investigators found fi ve mild cases of aspiration (1 per 7456 patients) with no sequelae.56 Another report described one occurrence of “mild aspiration” without adverse outcome among 1870 women undergoing nonintubated peripartum surgery with intravenous ket-amine, benzodiazepines, barbiturates, fentanyl, or some combination of these drugs.57 Soreide and colleagues58 observed four episodes of aspiration each during 36,800 deliveries and 3600 cesarean sections with no mortality. Based on these data, most hospitals permit free intake of clear liquids during labor. The risk of aspiration, pneumonia, and death from general anesthesia appears to be very low. This may refl ect the use of modern techniques and therapy to reduce gastric pH.

Bacterial PneumoniaStreptococcus pneumoniae (pneumococcus) is the most common bacte-rial pathogen that causes pneumonia in pregnancy; H. infl uenzae is the next most common. These pneumonias typically manifest as an acute illness accompanied by fever, chills, and a purulent, productive cough and are seen as a lobar pattern on the chest radiograph (Fig. 45-3). Streptococcal pneumonia produces a “rusty” sputum, with gram-positive diplococci on Gram stain, and it demonstrates asymmetrical consolidation with air bronchograms on the chest radiograph.54 H. infl uenzae is a gram-negative coccobacillus that produces consolida-tion with air bronchograms, often in the upper lobes.54 Less common bacterial pathogens include Klebsiella pneumoniae, which is a gram-negative rod that causes extensive tissue destruction with air broncho-grams, pleural effusion, and cavitation seen on the chest radiograph. Patients with Staphylococcus aureus pneumonia present with pleuritis, chest pain, purulent sputum, and consolidation without air broncho-grams identifi ed on the chest radiograph.54

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Patients infected with atypical pneumonia pathogens, such as Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae (TWAR agent), present with gradual onset of symptoms. They have a lower fever, appear less ill, have mucoid sputum, and have a patchy or interstitial infi ltrate seen on the chest radiograph. The severity of the fi ndings on the chest radiograph usually is out of pro-portion to the mild clinical symptoms. M. pneumoniae is the most common organism responsible for atypical pneumonia and is best detected by the presence of cold agglutinins in about 70% of cases.

The normal physiologic changes in the respiratory system associ-ated with pregnancy result in a loss of ventilatory reserve. Coupled with the immunosuppression that accompanies pregnancy, this puts the mother and fetus at great risk from respiratory infection. Any gravida suspected of having pneumonia should be managed aggres-sively. The pregnant patient should be admitted to the hospital and a thorough investigation undertaken to determine the cause. One study examined 133 women admitted with pneumonia during pregnancy using protocols based on the British Thoracic Society and American Thoracic Society admission guidelines for management of nonpreg-nant individuals. The investigators reported that if the American Tho-racic Society guidelines were used, 25% of the pregnant women with pneumonia could have avoided admission. Using the American crite-ria, none of the gravidas who would have been managed as an outpa-tient had any complications. If the British Thoracic Society guidelines had been used; 66% of the pregnant women in this group would have been assigned to outpatient therapy. However, 14% would have required readmission for complications. Most of the 133 women who were hospitalized with pneumonia in this study did not receive a chest radiograph for confi rmation of the diagnosis. This limits the value of the study for guiding admission criteria for pneumonia in pregnancy. Until additional information is available, admission for all pregnant women with pneumonia is still recommended.

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 identifi cation of the bacterial cause with cultures range from 2.1% to approximately 50%. Review of available clinical data refl ects 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 specifi c. 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 specifi city close to 100%. In one study, the pneumococcal antigen was detected in 26% of patients in whom no pathogens had been identifi ed. This fi nding suggests that cases that are undiagnosed by standard test can be identifi ed 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 specifi city. 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 specifi city 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-acquired pneumonia. The urinary antigen for serogroup 1 should be considered for any patient requiring admission into an intensive care unit for pneumonia.

Percutaneous-transthoracic needle aspiration has been advocated as a valuable and safe method to increase the chance of establishing the causative agent for pneumonia. This test should be reserved for use in compromised individuals, suspected tuberculosis in the absence of a productive cough, selected cases of chronic pneumonia, pneumonia associated with neoplasm or a foreign body, suspected Pneumocystis jiroveci pneumonia, and suspected conditions that necessitate lung biopsy. Cold agglutinins and Legionella titers may also be useful. Empiric antibiotic coverage should be started, usually with a third-generation cephalosporin such as ceftriaxone or cefotaxime. Legionella pneumonia has a high mortality rate and sometimes manifests with consolidation, mimicking pneumococcal pneumonia. It is recom-mended that a macrolide, such as azithromycin, be added to the empiric therapy. Dual coverage has been demonstrated to improve response to therapy even for abbreviated macrolide regimens. This may refl ect the added anti-infl ammatory effect of the macrolides. Azithromycin administration is an independent predictor of a positive outcome and reduced length of hospital stay for patients with mild to moderate community-acquired pneumonia. The use of macrolides to treat community-acquired pneumonia should be limited when possi-ble, because their use has also been associated with increased penicillin resistance by S. pneumoniae.

When admission for pneumonia is required, there is evidence that inpatient and 30-day mortality rates have been reduced when antibiot-ics are administered in less than 8 hours. Current U.S. federal standards require that the fi rst dose of antibiotics be administered within 4 hours of arrival to the hospital. After the results of the sputum culture, blood cultures, Gram stain, and serum studies are obtained and a pathogen has been identifi ed, antibiotic therapy can be directed toward the iden-tifi ed cause. The third-generation cephalosporins are effective agents for most pathogens causing a community-acquired pneumonia. They are also effective against penicillin-resistant S. pneumoniae. The qui-nolones as a class should be avoided in pregnancy because they may

FIGURE 45-3 Right lower lobe pneumonia. Lobar consolidation in the right lower lobe is consistent with pneumococcal pneumonia.

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damage developing fetal cartilage. However, with the emergence of highly resistant bacterial pneumonia, their use may be lifesaving and therefore justifi ed in specifi c circumstances. The respiratory quino-lones are effective against highly penicillin-resistant S. pneumoniae strains, and their use does not increase resistance. The respiratory quinolones include levofl oxacin, gatifl oxacin, and moxifl oxacin. These are ideal agents for community-acquired pneumonia because they are highly active against penicillin-resistant strains of S. pneumoniae. They are also active against Legionella and the other atypical pulmonary pathogens. Another advantage is a favorable pharmacokinetic profi le, such that blood or lung levels are the same whether the drug is admin-istered orally or intravenously. Arguments against more extensive respiratory quinolone use are based on concerns about the potential for developing resistance, the variable incidence of Legionella, and cost. An additional caveat is that the respiratory quinolones are only par-tially effective against Mycobacterium tuberculosis. Evaluation for this infection should be done when considering the use of quinolones for pneumonia.

In addition to antibiotic therapy, oxygen supplementation should be given. Frequent arterial blood gas measurements should be obtained to maintain partial pressure of oxygen at 70 mm Hg, a level necessary to ensure adequate fetal oxygenation. Arterial saturation also can be monitored with pulse oximetry. When the gravida is afebrile for 48 hours and has signs of clinical improvement, an oral cephalosporin can be started and intravenous therapy discontinued. A total of 10 to 14 days of treatment should be completed.

Pneumonia in pregnancy can be complicated by respiratory failure requiring mechanical ventilation. If this occurs, team management should include the obstetrician, maternal-fetal medicine specialist, and intensivist. In addition to meticulous management of the gravida’s respiratory status, the patient should be maintained in the left lateral recumbent position to improve uteroplacental perfusion. The viable fetus should be monitored with continuous fetal monitoring. If posi-tive end-expiratory pressure greater than 10 cm H2O is required to maintain oxygenation, central monitoring with a pulmonary artery catheter should be instituted to adequately monitor volume status and maintain maternal and uteroplacental perfusion. There is no evidence documenting that elective delivery results in overall improvement in respiratory function,59 and elective delivery should be reserved for the usual obstetric indications. However, if there is evidence of fetal com-promise or profound maternal compromise and impending demise, delivery should be accomplished.

Pneumococcal polysaccharide vaccination prevents pneumococcal pneumonia in otherwise healthy populations with an effi cacy of 65% to 84%. The vaccine is safe in pregnancy and should be administered to high-risk gravidas. Those at high risk include individuals with sickle cell disease with autosplenectomy, patients who have a surgical sple-nectomy, and individuals who are immunosuppressed. An additional advantage to maternal immunization with the pneumococcal vaccine is that several studies have demonstrated there is signifi cant transpla-cental transmission of vaccine-specifi c antibodies in infants at birth and at 2 months. Colostrum and breast milk antibodies are also sig-nifi cantly increased in women who have received the pneumococcal vaccine.

Viral Pneumonias

Infl uenzaAn estimated 4 million cases of pneumonia and infl uenza occur annu-ally in the United States, and it is the sixth leading cause of death.60 In

contrast to the general population, pregnant women seem to be at higher risk for infl uenza pneumonia.61,62 Epidemiologic data from the 1918 to 1919 infl uenza A pandemic revealed a maternal mortality rate that approached 50% for pregnant women with infl uenza pneumo-nia.63,64 Three types of infl uenza virus can cause human disease—A, B, and C—but most epidemic infections are caused by infl uenza A.50 Infl uenza A typically has an acute onset after a 1- to 4-day incubation period and fi rst manifests as high fever, coryza, headache, malaise, and cough. In uncomplicated cases, results of the chest examination and chest radiograph are normal.50 If symptoms persist longer than 5 days, especially in a pregnant woman, complications should be suspected. Pneumonia may complicate infl uenza as the result of secondary bacte-rial infection or viral infection of the lung parenchyma.50 In the epi-demic of 1957, autopsies demonstrated that pregnant women died most commonly of fulminant viral pneumonia, whereas nonpregnant patients died most often of secondary bacterial infection.65

A large, nested, case-control study evaluated the rate of infl uenza-related complications over 17 infl uenza seasons among women enrolled in the Tennessee Medicaid system. This study demonstrated a high risk for hospitalization for infl uenza-related reasons in low-risk pregnant women during the last trimester of pregnancy. The study authors esti-mated that 25 of 10,000 women in the third trimester during the infl uenza season are hospitalized with infl uenza-related complications. A later, matched-cohort study using the administrative database of pregnant women enrolled in the Tennessee Medicaid system examined pregnant women between the ages of 25 and 44 years with respiratory hospitalization during the 1985 to 1993 infl uenza seasons. In this population of pregnant women, those with asthma accounted for one half of all respiratory-related hospitalizations during the infl uenza season. Among pregnant women with diagnosis of asthma, 6% required respiratory hospitalization during the infl uenza season (OR = 10.63; 95% confi dence interval [CI], 8.61 to 13.83) compared with women without a medical comorbidity. This study detected no signifi cant increases in adverse perinatal outcome associated with respiratory hos-pitalization during fl u season.

Primary infl uenza pneumonia is characterized by rapid progression from a unilateral infi ltrate to diffuse bilateral disease. The gravida may develop fulminant respiratory failure requiring mechanical ventilation and positive end-expiratory pressure. Aggressive therapy is indicated when pneumonia complicates infl uenza in pregnancy. Antibiotics should be started and directed at the likely pathogens that can cause secondary infection, including S. aureus, pneumococcus, H. infl uenzae, and certain enteric gram-negative bacteria. Antiviral agents, such as oseltamivir and zanamivir, should also be considered.66 It has been recommended that the infl uenza vaccine be given routinely to gravidas in the second and third trimester of pregnancy to prevent the occur-rence of infl uenza and the development of pneumonia. Women at high risk for pulmonary complications, such as those with asthma, chronic obstructive pulmonary disease, cystic fi brosis, and splenectomy, should be vaccinated regardless of the trimester to prevent the occurrence of infl uenza and the development of secondary pneumonia. In addition to maternal protection, prospective studies have demonstrated higher cord blood antibody levels to infl uenza in infants born to mothers immunized during pregnancy. There is a delay in the onset and decrease in severity of infl uenza in infants born with higher antibody levels.

VaricellaVaricella-zoster virus is a DNA virus that usually causes a benign, self-limited illness in children, but it may infect up to 2% of all adults.67 Varicella infection occurs in 0.7 of every 1000 pregnancies.68 Pregnancy may increase the likelihood of varicella pneumonia, complicating the

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primary infection.52 Treatment with acyclovir is safe in pregnancy. In one report,52 there was one intrauterine fetal death. Another report51 documented a 5.2% incidence of varicella pneumonia among gravidas with varicella-zoster infection. The investigators also reported that gravidas who smoke or manifest more than 100 skin lesions are more likely to develop pneumonia.51 Varicella pneumonia occurs most often in the third trimester, and the infection is likely to be severe.52,68,69 The maternal mortality rate for varicella pneumonia may be as high as 35% to 40%, compared with 11% to 17% for nonpregnant individu-als.52,69 Although one review reported a decreased mortality rate, with only three deaths among 28 women with varicella pneumonia,68 another study documented a maternal mortality rate of 35%.52 However, a later report documented 100% survival among 18 gravidas with varicella pneumonia who were treated with acyclovir.51 In this report, there was one intrauterine fetal death at 25 weeks’ gestation in a woman with varicella. In one report of 312 pregnancies, there was no increase in the number of birth defects and no consistent pattern of congenital abnormalities. In another report, 17 other infants were delivered beyond 36 weeks, and there was no evidence of neonatal varicella.51

Varicella pneumonia usually manifests 2 to 5 days after the onset of fever, rash, and malaise and is heralded by the onset of pulmonary symptoms, including cough, dyspnea, pruritic chest pain, and hemop-tysis.52 The severity of the illness may vary from asymptomatic radio-graphic abnormalities to fulminant pneumonitis and respiratory failure (Fig. 45-4).52,70

All gravidas with varicella pneumonia should be aggressively treated with antiviral therapy and admitted to the intensive care unit for close observation or intubation if indicated. Acyclovir, a DNA polymerase inhibitor, should be started. The early use of acyclovir was associated with an improved hospital course after the 5th day and a lower mean temperature, lower respiratory rate, and improved oxygenation.52 Treatment with acyclovir is safe in pregnancy. Among 312 pregnancies, there was no increase in the number of birth defects and no consistent

pattern of congenital abnormalities.71 A dose of 7.5 mg/kg given intra-venously every 8 hours has been recommended.72

Varicella vaccine is an attenuated live virus vaccine that was added to the universal childhood immunization schedule in the United States in 1995. The program of universal childhood vaccination against vari-cella in the United States has resulted in a sharp decline in the rate of death from varicella. However, varicella vaccine is not recommended for use in pregnancy. The overall decline in incidence of adult varicella infection because of childhood vaccination will likely result in a decreased incidence of varicella infection and varicella pneumonia during pregnancy.

A study73 assessed the risk of congenital varicella syndrome and other birth defects in offspring of women who inadvertently received varicella vaccine during pregnancy or within 3 months of conception. Fifty-eight women received their fi rst dose of varicella vaccine during the fi rst or second trimester. No cases (0%) of congenital varicella syndrome were identifi ed among 56 live births (CI, 0 to 15.6). Among the prospective reports of live births, fi ve congenital anomalies were identifi ed in the susceptible cohort or the sample population as a whole. The investigator suggested that although the numbers in the study were small, the results should provide some reassurance to health care providers and women with inadvertent exposure before or during pregnancy.

Pneumocystis jiroveciInfection with the HIV virus signifi cantly increases the risk for pulmo-nary infection. S. pneumoniae and H. infl uenzae are the most com-monly isolated organisms.73 One report74 also identifi ed Pseudomonas aeruginosa as a signifi cant cause of bacterial pneumonia in HIV-infected individuals. Pneumocystis pneumonia, an AIDS-defi ning illness, occurs more frequently when the helper T-cell count (CD4+) is less than 200 cells/mm3. Pneumocystis jiroveci pneumonia (PJP), for-merly designated Pneumocystis carinii pneumonia (PCP), is the most 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 fi ndings, 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 fi elds (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 defi nitive 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-ryngeal candidiasis should receive prophylaxis.83 TMP-SMX is the drug of choice and may provide cross protection against toxoplasmosis and other bacterial infections.84 The usual dose is one double-strength

FIGURE 45-4 Varicella pneumonia. The chest radiograph demonstrates bilateral nodular and interstitial pneumonia of varicella pneumonia.

Ch045-X4224.indd 933 8/26/2008 4:09:43 PM


tablet (150 mg/m2 of TMP and 750 mg/m2 of SMX given three times each week). Adverse reactions such as drug allergy, nausea, fever, neu-tropenia, anemia, thrombocytopenia, and elevated transaminase levels have been reported in 20% to 30% of nonpregnant individuals receiv-ing TMP-SMX therapy.84 Complete blood cell count with a differential cell count and liver function tests should be obtained every 6 to 8 weeks to monitor for toxicity. Other regimens used for prophylaxis for indi-viduals with intolerance to TMP-SMX include aerosolized pentami-dine (300 mg every month by Respirgard II nebulizer) or dapsone (100 mg once daily). Hussain and colleagues85 found that the survival rate for patients treated with SMX alone was 71% (5 of 7 patients) and that the rate with SMX and steroids was 60% (3 of 5 patients); the overall survival rate for both groups was 66.6% (8 of 12 patients). The investigators concluded that PJP has a more aggressive course during pregnancy, with increased morbidity and mortality.85 However, treat-ment with SMX compared with other therapies may result in improved outcome. They also caution that withholding appropriate PJP prophy-laxis may adversely affect maternal and fetal outcomes.85

PJP is a devastating opportunistic infection in pregnant women who are infected with HIV. The maternal mortality rate is extremely high, and prophylaxis with TMP-SMX is indicated during the antepar-tum period for individuals with a CD4+ cell count less than 200/mm3 or a history of oropharyngeal candidiasis and for individuals with a prior history of PJP infection. Initiation of therapy during the ante-partum period can also prevent the rare occurrence of perinatally transmitted PJP.84 When a gravida is demonstrating symptoms consis-tent with a possible infection, a diligent search should be conducted to quickly identify PJP as the cause of pneumonia. When PJP is untreated, the maternal mortality rate can approach 100%. In summary, PJP pneumonia remains a dreaded complication of HIV infection and an AIDS-defi ning illness. There is a very high maternal and fetal mortality rate when PJP complicates pregnancy. Primary prophylaxis against

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 PregnancyTuberculosis 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-notifi cation 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 of active disease, with female cases having a higher progression from 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 these differences.86

The incidence of tuberculosis in the United States began to decline in the early part of the 20th century and fell steadily until 1953, when the introduction of isoniazid led to a dramatic decrease in the number of cases, from 84,000 cases in 1953 to 22,255 cases in 1984.88 However, since 1984, there have been signifi cant changes in tuberculosis morbid-ity trends. From 1985 through 1991, reported cases of tuberculosis increased by 18%, representing approximately 39,000 more cases than expected had the previous downward trend continued. This increase results from many factors, including the HIV epidemic, deterioration in the health care infrastructure, and more cases among immigrants.88,89 Between 1985 and 1992, the number of tuberculosis cases among women of childbearing age increased by 40%.90 One report described tuberculosis-complicated pregnancies in 94.8 cases per 100,000 deliveries between 1991 and 1992.91

The emergence of drug-resistant tuberculosis has become a serious concern. In New York City in 1991, 33% of tuberculosis cases were resistant to at least one drug, and 19% were resistant to isoniazid and rifampin. Multidrug resistance is an additional problem. Many centers advocate directly observed therapy in the treatment of multidrug-resistant disease. Pregnancy complicates treatment of multidrug-resistant tuberculosis for the following reasons:

� Several antimycobacterial drugs are contraindicated during gestation.

� Patients and physicians may fear the effects of chest radiography on the fetus.

� Untreated, infectious, multidrug-resistant tuberculosis may be vertically and laterally transmitted.92

In one report,92 three patients had disease resulting from multidrug-resistant M. tuberculosis, and one had disease resulting from

FIGURE 45-5 Pneumocystis jiroveci pneumonia (PJP). Bilateral alveolar disease is consistent with PJP pneumonia.

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multidrug-resistant Mycobacterium bovis. Only one patient began retreatment during pregnancy because her organism was susceptible to three antituberculosis drugs that were considered nontoxic to the fetus. Despite concern about teratogenicity of the second-line antitu-berculosis medications, careful timing of treatment initiation resulted in clinical cure for the mothers, regardless of some complications because of chronic tuberculosis or therapy. In this series, all infants were born healthy and remained free of tuberculosis.92

DiagnosisMost gravidas with tuberculosis in pregnancy are asymptomatic. All gravidas at high risk for tuberculosis (Table 45-1) should be screened with subcutaneous administration of intermediate-strength purifi ed protein derivative (PPD). If anergy is suspected, control antigens such as candidal, mumps, or tetanus toxoids should be used.93 The sensitiv-ity of the PPD is 90% to 99% for exposure to tuberculosis. The tine test should not be used for screening because of its low sensitivity.

The onset of the recent tuberculosis epidemic stimulated the need for rapid diagnostic tests using molecular biology methods to detect M. tuberculosis in clinical specimens. Two direct amplifi cation tests have been approved by the FDA, the Mycobacterium tuberculosis Direct (MTD) Test (Gen-Probe, San Diego, CA) and the Amplicor Mycobac-terium tuberculosis (MTB) Test (Roche Diagnostic Systems, Branch-burg, NJ). Both tests amplify and detect M. tuberculosis 16S ribosomal DNA.94 When testing acid-fast stained smear–positive respiratory specimens, each test has a sensitivity of greater than 95% and a speci-fi city of essentially 100% for detecting the M. tuberculosis complex.95,96 When testing acid-fast stained smear–negative respiratory specimens, the specifi city remains greater than 95%, but the sensitivity ranges from 40% to 77%.95,96 These tests are FDA approved only for testing acid-fast stained smear–positive respiratory specimens obtained from untreated patients or those who have received no more than 7 days of antituberculosis therapy. The PPD remains the most commonly used screening test for tuberculosis.

Immigrants from areas where tuberculosis is endemic may have received the bacillus Calmette-Guérin (BCG) vaccine, and they are likely to have a positive response to the PPD. However, this reactivity should wane over time. The PPD should be used to screen these patients 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 positive with a skin test reaction of 10 mm or more, the individual should be considered infected with tuberculosis and managed accordingly.93

Women with a positive PPD skin test result must be evaluated for active tuberculosis with a thorough physical examination for extrapul-monary disease and a chest radiograph after they are beyond the fi rst trimester.54 Symptoms of active tuberculosis include cough (74%), weight loss (41%), fever (30%), malaise and fatigue (30%), and hemop-tysis (19%).97 Individuals with active pulmonary tuberculosis may have radiographic fi ndings, including adenopathy, multinodular infi ltrates, cavitation, loss of volume in the upper lobes, and upper medial retrac-tion of hilar markings (Fig. 45-6). The fi nding of acid-fast bacilli in early morning sputum specimens confi rms the diagnosis of pulmo-nary tuberculosis. At least three fi rst-morning sputum samples should be examined for the presence of acid-fast bacilli. If sputum cannot be produced, sputum induction, gastric washings, or diagnostic bron-choscopy may be indicated.

Extrapulmonary tuberculosis occurs in up to 16% of cases in the United States; however, the pattern may occur in 60% to 70% of all patients with AIDS.98 Extrapulmonary sites include lymph nodes, bone, kidneys, intestine, meninges, breasts, and endometrium. Extra-pulmonary tuberculosis appears to be rare in pregnancy.99 Extrapul-monary tuberculosis that is confi ned to the lymph nodes has no effect on obstetric outcomes, but tuberculosis at other extrapulmonary sites does adversely affect the outcome of pregnancy.100 Jana and col-leagues100 documented that tuberculosis lymphadenitis did not affect the course of pregnancy, labor, or perinatal outcome. However, com-pared with control women, the 21 women with tubercular involvement of other extrapulmonary sites had higher rates of antenatal hospitaliza-tion (24% versus 2%; P < .0001), infants with low Apgar scores (≤6) soon after birth (19% versus 3%; P = .01), and low-birth-weight (<2500 g) infants (33% versus 11%; P = .01). Rarely, mycobacteria

FIGURE 45-6 Chest radiograph of pulmonary tuberculosis. Radiographic fi ndings may include adenopathy, multinodular infi ltrates, cavitation, loss of volume in the upper lobes, and upper medial retraction of hilar markings.

TABLE 45-1 HIGH-RISK FACTORS FOR TUBERCULOSIS

Human immunodefi ciency virus infectionClose contact with persons known or suspected to have

tuberculosisMedical risk factors known to increase risk for disease if infectedBirth in a country with high tuberculosis prevalenceMedically underserved statusLow incomeAlcohol addictionIntravenous drug useResidency in a long-term care facility (e.g., correctional

institutions, mental institutions, nursing homes and facilities)Health professionals working in high-risk health care facilities

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invade the uteroplacental circulation, and congenital tuberculosis results.49,90,101 The diagnosis of congenital tuberculosis is based on one of the following factors90:

� Demonstration of primary hepatic complex or cavitating hepatic granuloma by percutaneous liver biopsy at birth

� Infection of the maternal genital tract or placenta� Lesions seen in the fi rst week of life� Exclusion of the possibility of postnatal transmission by a

thorough investigation of all contacts, including attendants

PreventionMost gravidas with a positive PPD result in pregnancy are asymptom-atic and have no evidence of active disease; they are classifi ed as infected without active disease. The risk of progression to active disease is highest in the fi rst 2 years of conversion. It is important to prevent the onset of active disease while minimizing maternal and fetal risk. An algorithm for management of the positive PPD is presented in Figure 45-7.102,103 In women with a known recent conversion (2 years) to a positive PPD result and no evidence of active disease, the recom-mended prophylaxis is isoniazid (300 mg/day), starting after the fi rst trimester and continuing for 6 to 9 months.54 Under base-case assump-tions in a Markov decision-analysis model, the fewest cases of tuber-culosis within the cohort occurred with antepartum treatment (1400 per 100,000), compared with no treatment (3300 per 100,000) or postpartum treatment (1800 per 100,000).104 Antepartum treatment

resulted in a marginal increase in life expectancy because of the pre-vented isoniazid-related hepatitis and deaths, compared with no treat-ment or postpartum treatment. Antepartum treatment was the least expensive.104 Isoniazid should be accompanied by pyridoxine (vitamin B6) supplementation (50 mg/day) to prevent the peripheral neuropa-thy that is associated with isoniazid treatment. Women with an unknown or prolonged duration of PPD positivity (>2 years) should receive isoniazid (300 mg/day) for 6 to 9 months after delivery. Isonia-zid prophylaxis is not recommended for women older than 35 years 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 with hepatitis in pregnant and nonpregnant adults. However, monthly monitoring of liver function tests may prevent this adverse outcome. Among individuals receiving isoniazid, 10% to 20% will develop mildly elevated values detected on liver function tests. These changes resolve after the drug is discontinued.105

TreatmentThe gravida with active tuberculosis should be treated initially with isoniazid (300 mg/day) combined with rifampin (600 mg/day) (Table 45-2).106 Resistant disease results from initial infection with resistant strains (33%) or can develop during therapy.107 The development of resistance is more likely in individuals who are noncompliant with therapy. If resistance to isoniazid is identifi ed or anticipated, 2.5 g of ethambutol per day should be added, and the treatment period should

PPD positive(without prior treatment)

CXRnormal

Respiratorysymptoms

Three morningsputum samples forsmear/cx or workup

for extrapulmonary TB

“High risk”or conversionwithin 2 years

Old conversion�2 years or 1st

positive PPD

CXRabnormal

or other evidence of active disease

Three morning sputum samplesfor smear/cx

Workup

If � 35 years,postpartum

INH/B6


INH/B6


INH/B6

Immediateantepartum

3 drugtherapy

Immediateantepartum

3 drugtherapy

AntepartumINH/B6

No respiratory symptoms

Workup

Workup Workup

FIGURE 45-7 Algorithm for the management of a patient with a positive purifi ed 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 fi rst trimester and continuing for 6 to 9 months. B6, pyridoxine; cx, culture; CXR, chest radiograph; INH, isoniazid, TB, tuberculosis.

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be extended to 18 months.108 Ethambutol is teratogenic in animals; however, this effect has not been seen in humans.

The most common side effect of ethambutol therapy is optic neu-ritis. Streptomycin should be avoided during pregnancy because it is associated with cranial nerve VIII damage in neonates.109 Antitubercu-lous agents not recommended for use in pregnancy include ethion-amide, streptomycin, capreomycin, kanamycin, cycloserine, and pyrazinamide.54 However, case reports documenting the use of these antituberculous agents in pregnancy revealed no adverse fetal or neo-natal effects. There were no congenital abnormalities, and pregnancy outcomes for the individuals treated were good. Untreated tuberculosis has been associated with higher morbidity and mortality rates among pregnant women. The management of the gravida with multidrug-resistant tuberculosis should be individualized. The patient should be counseled about the small risk of teratogenicity and understand that the risk of postpartum transmission of tuberculosis to the infant may be higher among those born to patients with drug-resistant tubercu-losis. In patients with active disease at the time of delivery, separation of the mother and newborn should be accomplished to prevent infec-tion of the newborn.

Women who are being treated with antituberculous drugs may breastfeed. Only 0.75% to 2.3% of isoniazid and 0.05% of rifampin are excreted into breast milk. Ethambutol excretion into breast milk is also minimal. However, if the infant is concurrently taking oral antituber-culous therapy, excessive drug levels may be reached in the neonate, and breastfeeding should be avoided. Breastfed infants of women taking isoniazid should receive a multivitamin supplement that includes pyridoxine.54 Neonates of women taking antituberculous therapy should have a PPD skin test at birth and again when 3 months old. Infants born to women with active tuberculosis at the time of delivery should receive isoniazid prophylaxis (10 mg/kg/day) until maternal disease has been inactive for 3 months as evidenced by nega-

tive maternal sputum cultures.54 Infants of women with multidrug-resistant tuberculosis should probably be placed with an alternative caregiver until there is no evidence of active disease in the mother. The newborn should also receive BCG vaccine and isoniazid prophy-laxis.92 Active tuberculosis in the neonate should be treated appropri-ately with isoniazid and rifampin immediately on diagnosis or with multiagent therapy if drug-resistant organisms are identifi ed. Infants and children who are at high risk for intimate and prolonged exposure to untreated or ineffectively treated persons should receive the BCG vaccine.110

In summary, high-risk gravidas should be screened for tuberculosis and treated appropriately with isoniazid prophylaxis for infection without overt disease and with dual antituberculous therapy for active disease. The newborn also should be screened for evidence of tuber-culosis. Proper screening and therapy will lead to a good outcome for the mother and infant in most cases.

Asthma in PregnancyAsthma may be the most common potentially serious medical condi-tion to complicate pregnancy.111 Asthma is characterized by chronic airway infl ammation with increased airway responsiveness to a variety of stimuli and airway obstruction that is partially or completely reversible.111 Approximately 4% to 8% of pregnancies are complicated by asthma.112,113 The prevalence and morbidity rates for asthma are increasing, although the mortality rate has decreased in recent years.

Insight into the pathogenesis of asthma has changed with the rec-ognition that airway infl ammation occurs in almost all cases. The medical management for asthma emphasizes treatment of airway infl ammation to decrease airway responsiveness and prevent asthma symptoms.

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 toxicityKanamycin IM 15-30 mg/kg, up to 1 g Auditory and renal toxicity, rare

vestibular toxicityEthionamide PO 15-20 mg/kg, up to 1 g Gastrointestinal disturbance,

hepatotoxicity, hypersensitivityp-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.

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DiagnosisThe enlarging uterus elevates the diaphragm about 4 cm, reducing the functional residual capacity. However, there are no signifi cant altera-tions in forced vital capacity, peak expiratory fl ow rate (PEFR), or forced expiratory volume in 1 second (FEV1) in normal pregnancies. Shortness of breath at rest or with mild exertion is common and is often referred to as physiologic dyspnea of pregnancy. Asthma is char-acterized by paroxysmal or persistent symptoms, including breathless-ness, chest tightness, cough, and sputum production. The diagnosis of asthma is based on a history of symptoms and results of spirometry. Patients with asthma have improved FEV1 after administration of a short-acting, inhaled β2-agonist and increased sensitivity to inhaled methacholine, although this test is not usually performed during pregnancy.

In 2004, the National Asthma Education and Prevention Program (NAEPP) Working Group on Asthma and Pregnancy114 defi ned mild intermittent, mild persistent, moderate persistent, and severe persistent asthma according to daytime and nighttime symptoms (e.g., wheezing, cough, dyspnea) and objective tests of pulmonary function. The most commonly used pulmonary function parameters are the PEFR and FEV1. The NAEPP guidelines suggest classifying asthma severity in patients not on symptom-controlling drugs and asthma control in patients on symptom-controlling medications (Table 45-3).115 Preg-nant patients with mild asthma according to symptoms and pulmo-nary function who nonetheless required regular medications to control their asthma are similar to those with moderate asthma with respect to asthma exacerbations; those requiring regular systemic corticoste-roids to control asthma symptoms were similar to severe asthmatics with respect to exacerbations.116

Effects of Pregnancy on AsthmaAsthma has been associated with considerable maternal morbidity. In a large, prospective study of pregnant women, those with mild asthma had an exacerbation rate of 12.6% and hospitalization rate of 2.3%; those with moderate asthma had an exacerbation rate of 25.7% and hospitalization rate of 6.8%; and severe asthmatics had an exacerba-tion rate of 51.9% and hospitalization rate of 26.9%.116 The effects of pregnancy on asthma vary. In a large, prospective study, 23% improved and 30% became worse during pregnancy.116 One of the most impor-tant conclusions of this study is that pregnant women with mild or even well-controlled asthma should be monitored by PEFR and FEV1 testing during pregnancy.

Effects of Asthma on PregnancyExisting studies on the effects of asthma on pregnancy have had incon-sistent results in regard to maternal and perinatal outcomes. For example, asthma has been associated with increased perinatal mortal-ity,117 hyperemesis gravidarum,118 hemorrhage,112,118,119 hypertension or preeclampsia,118-125 preterm birth,118,122,123,126-128 hypoxia at birth,118 low birth weight,118,129 increased cesarean section,119,121,122,126,129 small-for-gestational-age status or intrauterine growth restriction,122,123,130 gestational diabetes,119,126 and anomalies.122

In contrast, asthma has not been associated with prematur-ity,112,117,129-132 malformations,112,118,121,123,131 birth injury,118 increased perinatal mortality,118 reduced gestational age,120,121,133-135 reduced mean birth weight,120,121,129,134-136 perinatal death,119,121,131,135,137 low Apgar score,121 neonatal respiratory diffi culty,121 antepartum or postpartum hemorrhage,123,129,133 perinatal complications,124,129 gestational hyper-tension or preeclampsia,126,130,131,138 intrauterine growth restriction,126,131 increased cesarean section,112,132,137 low birth weight,121,132,133,136,137 gestational diabetes,112,124 or respiratory distress syndrome.112

Many of these studies have methodologic inadequacies, including low power, variable inclusion criteria, little or no information regard-ing asthma management or control, and time frames that do not refl ect current management. Some positive fi ndings may result from non-existent or inadequate control for confounders such as oral corticoste-roid treatment, ethnicity, smoking status, obesity, socioeconomic status, and hypertension. Another potential explanation for inconsis-tencies is that most of these studies did not classify asthma severity. Classifi cation of asthma severity has important clinical implications in regard to asthma morbidity and tailoring optimal treatment regi-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-ization for exacerbations or decreased FEV1 values, and low birth weight and low ponderal index.137,141,142 Studies have shown that women with more severe asthma may have the greatest risk for complications during pregnancy,122,126,127,143 whereas better-controlled asthma is associated with decreased risks.131,144,145 Poor control of asthma during pregnancy may be caused by the physician’s reluctance to prescribe medications during pregnancy. Women with asthma signifi cantly reduce their medications, especially inhaled and rescue corticosteroids, during the fi rst trimester.146

There is considerable consistency among prospective studies of the effects of asthma during pregnancy. Eight prospective studies reporting maternal and neonatal outcomes with at least 100 subjects

TABLE 45-3 CLASSIFICATION OF ASTHMA SEVERITY AND CONTROL IN PREGNANT PATIENTS

Signs and Symptoms

Well Controlled* Not Well Controlled* Very Poorly Controlled*

Intermittent† Mild Persistent† Moderate Persistent† Severe Persistent†

Symptom frequency/short-acting β-agonist use

≤2 days per week >2 days per week, but not daily

Daily symptoms Throughout the day

Nighttime awakening ≤2 times per month >2 times per month >1 time per week ≥4 times per weekInterference with normal activity None Minor limitation Some limitation Extremely limitedFEV1 or peak fl ow (percent

predicted/personal best)>80% >80% 60-80% <60%

*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.

Ch045-X4224.indd 938 8/26/2008 4:09:45 PM


in locations at or near sea level have been published in the English literature.121,124,131-133,137,144,145,147 These studies show that a gravida with mild or moderate asthma can have excellent maternal and perinatal outcomes (Table 45-4). These fi ndings do not contradict the possibility that suboptimal control of asthma during pregnancy is associated with increased risk to the mother or infant.145 Lower FEV1 values during pregnancy are signifi cantly associated with increased risks for low birth weight and prematurity.148 The two largest studies indicate that classi-fi cation of asthma severity with therapy tailored according to asthma severity can result in excellent perinatal and maternal outcomes.144,145 This generally confi rms the fi ndings of two earlier and smaller pro-spective cohort studies131,133 in which asthma was managed by asthma specialists.

There are important caveats when interpreting this literature. Pro-spective studies have tended to fi nd fewer signifi cant adverse associa-tions, possibly because of better asthma surveillance and treatment. The excellent maternal and perinatal outcomes were achieved at centers that tended to actively manage asthma during pregnancy. Women who enroll in research studies tend to be more compliant and better moti-vated than the general public. The lack of fi nding more adverse out-comes among women with severe asthma may also be a function of the relatively small numbers of this cohort and the resulting lack of power to fi nd adverse outcomes that were statistically signifi cant. Nonetheless, these prospective studies are reassuring in their consensus of good pregnancy outcomes among women with asthma. However, they do not suggest that asthma should be considered to be a benign condition, because active asthma management was a part of these studies and might have positively infl uenced outcomes.

Management ApproachesThe ultimate goal of asthma therapy during pregnancy is to maintain adequate oxygenation of the fetus by prevention of hypoxic episodes in the mother. Other goals include achievement of minimal or no maternal symptoms day or night, minimal or no exacerbations, no limitations of activities, maintenance of normal or near-normal pul-monary function, minimal use of short-acting β2-agonists, and minimal or no adverse effects from medications. Consultation or comanage-ment with an asthma specialist is appropriate for evaluation of the role of allergy and irritants, complete pulmonary function studies, or eval-uation of the medication plan if there are complications in achieving the goals of therapy or the patient has severe asthma. A team approach is helpful if more than one clinician is managing the asthma and the pregnancy. The effective management of asthma during pregnancy relies on four integral components: objective assessment, trigger avoidance, patient education, and pharmacologic therapy.

Objective Measures for Assessment

and MonitoringSubjective measures of lung function by the patient or physician provide an insensitive and inaccurate assessment of airway hyperre-sponsiveness, airway infl ammation, and asthma severity. The FEV1 value after a maximal inspiration is the single best measure of pulmo-nary function. When adjusted for confounders, a mean FEV1 less than 80% of the predicted value has been signifi cantly associated with increased preterm delivery at less than 32 weeks and less than 37 weeks and with a birth weight less than 2500 g.148 However, measurement of

TABLE 45-4 PROSPECTIVE COHORT STUDIES REPORTING OBSTETRIC AND NEONATAL OUTCOMES

Outcomes

Dombrowski

et al, 2004145

(N = 1739)

Bracken et al,

2003144

(N = 872)

Stenius-

Aarniala

et al, 1996133

(N = 504)

Schatz

et al,

1995131

(N = 486)

Mihrshani

et al, 2003124

(N = 340)

Jana et al,

1995137

(N = 182)

Stenius-

Aarniala and

Teramo,

1988121

(N = 181)

Minerbi-Codish

et al, 1998132

(N = 101)

Preterm, < 32 weeks

No NR NR NR NR NR NR NR

Preterm, < 37 weeks

No (yes if severe)

No (yes if oral steroids)

No No No No NR No

Preeclampsia No No (yes if daily symptoms)

No No No NR Yes No

Cesarean delivery Yes (if moderate or severe)

NR Yes (if elective)

NR No No Yes No

Gestational diabetes

No (yes if severe)

NR No No NR NR No No

Small for gestational age

No No (yes if daily symptoms)

NR No NR NR NR No

Malformation No NR No No NR No NR NoAntenatal

hemorrhageNR NR No NR NR No No NR

Postnatal hemorrhage

No NR NR NR NR NR NR NR

RDS/HMD No NR NR No NR NR No NRNEC No NR NR No NR NR NR NRPerinatal death No NR No No NR No No NRNICU admission No NR No NR No NR No NR

HMD, hyaline membrane disease; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; No, no signifi cant association; NR, not reported;

RDS, respiratory distress syndrome; Yes, signifi cantly increased.

Ch045-X4224.indd 939 8/26/2008 4:09:45 PM


FEV1 requires a spirometer. The PEFR correlates well with the FEV1, and it can be measured reliably with inexpensive, disposable, portable peak fl ow meters.

PEFR monitoring by the patient provides valuable insight to the course of asthma throughout the day, assesses circadian variation in pulmonary function, and helps detect early signs of deterioration so that timely therapy can be instituted. Patients with persistent asthma should be evaluated at least monthly, and those with moderate to severe asthma should have daily PEFR monitoring.114 The typical PEFR in pregnancy should be 380 to 550 L/min. She should establish her “personal best” PEFR and then calculate her individualized PEFR zones. The green zone is more than 80% of the personal best PEFR, yellow zone is between 50% and 80% of the personal best value, and red zone is less than 50% of the personal best PEFR.

Avoiding or Controlling Asthma TriggersLimiting adverse environmental exposures during pregnancy is impor-tant for controlling asthma. Irritants and allergens that provoke acute symptoms also increase airway infl ammation and hyperresponsive-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 patients with asthma have positive skin test results for common aller-gens, including animal dander, house dust mites, cockroach antigens, pollens, and molds. Other common nonimmunologic triggers include tobacco smoke, strong odors, air pollutants, food additives such as sulfi tes, and certain drugs, including aspirin and β-blockers. Another trigger can be strenuous physical activity. For some patients, exercise-induced asthma can be avoided with inhalation of albuterol 5 to 60 minutes before exercise.

Specifi c measures for avoiding asthma triggers include removing carpeting, using an allergen-impermeable mattress and pillow covers, weekly washing of bedding in hot water, avoiding tobacco smoke, inhibiting mite and mold growth by reducing humidity, and leaving the house when it is vacuumed. Animal dander control includes weekly bathing of the pet, keeping furry pets out of the bedroom, or removing the pet from the home. Cockroaches can be controlled by poison or bait traps and eliminating exposed food or garbage.

Patient EducationPatients should be made aware that controlling asthma during preg-nancy is especially important for the well-being of the fetus. The preg-nant woman should understand that she can reduce symptoms by limiting asthma triggers. She should have a basic understanding of the medical management during pregnancy, including self-monitoring of PEFRs and the correct use of inhalers. The patient should be instructed on proper PEFR technique. She should make the measurement while standing, take a maximum inspiration, and observe the reading on the peak fl ow meter.

Pharmacologic TherapyThe goals of asthma therapy include relieving bronchospasm, protect-ing the airways from irritant stimuli, mitigating pulmonary and infl ammatory responses to an allergen exposure, and resolving the infl ammatory process in the airways, leading to improved pulmonary function with reduced airway hyperresponsiveness. The step-care approach uses the least amount of drug intervention necessary to control a patient’s severity of asthma.

It is safer for pregnant women with asthma to be treated with asthma medications than it is for them to have asthma symptoms and exacerbations.114 Current pharmacologic therapy emphasizes treat-

ment of airway infl ammation to decrease airway hyperresponsiveness and prevent asthma symptoms. Typical dosages of commonly used asthma medications are listed in Table 45-5. Low, medium, and high doses of inhaled corticosteroids are provided in Table 45-6.

Although it is assumed that asthma medications are equally effec-tive during pregnancy, differences in maternal physiology and phar-macokinetics may affect the absorption, distribution, metabolism, and clearance of medications during pregnancy. Endocrinologic and immunologic changes during pregnancy include elevations in free plasma cortisol, possible tissue refractoriness to cortisol,149 and changes in cellular immunity.150

STEP THERAPYThe step-care approach to therapy increases the number and fre-

quency of medications with increasing asthma severity (Table 45-7). Based on the severity of asthma, medications are considered to be preferred or alternative. Patients not optimally responding to treatment should be stepped up to more intensive medical therapy. After control is achieved and sustained for several months, a step-down approach can be considered, but it should be undertaken cautiously and gradu-ally to avoid compromising the stability of the asthma control. For some patients, it may be prudent to postpone until after birth attempts to reduce therapy that is effectively controlling the patient’s asthma.114 For a patient who had a favorable response to an alternative drug before becoming pregnant, it is preferable to maintain the therapy that successfully controlled the asthma before pregnancy. However, when initiating new treatment for asthma during pregnancy, preferred medications should be considered rather than alternative treatment options.114

A burst of oral corticosteroids is indicated for exacerbations not responding to initial β2-agonist therapy, regardless of asthma severity. Patients who require increasing inhaled albuterol therapy to control their symptoms may benefi t from oral corticosteroids. In such cases, a short course of oral prednisone (40 to 60 mg/day) for 1 week followed by 7 to 14 days of tapering may be effective.

INHALED CORTICOSTEROIDSInhaled corticosteroids are the preferred treatment for the manage-

ment of all levels of persistent asthma during pregnancy.114 Because almost all patients have airway infl ammation, inhaled corticosteroids

TABLE 45-5 TYPICAL DOSAGES OF ASTHMA MEDICATIONS

Drug Dosage

Albuterol MDI 2-6 puffs as neededSalmeterol DPI 1 puff bidFluticasone and salmeterol

(Advair) DPI1 inhalation bid, dose depends on

severity of asthmaMontelukast 10-mg tablet at nightZafi rlukast 20 mg twice dailyPrednisone 20-60 mg/day for active symptomsTheophylline Start at 200 mg PO bid, target serum

levels of 5-12 μg/mL (decrease dosage by one half if treated with erythromycin or cimetidine)

Ipratropium MDI 2-3 puffs q6hIpratropium nebulizer 1 mL (0.25 mg) q6hCromolyn MDI 2 puffs qid

DPI, dry powder inhaler; MDI, metered-dose inhaler; PO, orally.

Ch045-X4224.indd 940 8/26/2008 4:09:45 PM


have been advocated as fi rst-line therapy for those with mild asthma.151 The use of inhaled corticosteroids among nonpregnant asthmatics has been associated with a marked reduction in fatal and near-fatal epi-sodes of asthma.152 Inhaled corticosteroids produce clinically impor-tant improvements in bronchial hyperresponsiveness that appear dose related153 and include prevention of increased bronchial hyperrespon-siveness after seasonal exposure to allergen.154,155 Continued adminis-tration is effective in reducing the immediate pulmonary response to an allergen challenge. In a prospective, observational study of 504 pregnant women with asthma, 177 patients were not initially treated with inhaled budesonide or inhaled beclomethasone.133 This cohort had a 17% rate of acute exacerbation rate compared with only a 4% rate among those treated with inhaled corticosteroids from the start of pregnancy.

The NAEPP Working Group reviewed 10 studies that included 6113 patients who took inhaled corticosteroids during pregnancy for asthma.114 There is no evidence linking inhaled corticosteroid use with increases in congenital malformations or adverse perinatal outcomes. Included among these studies was the Swedish Medical Birth Registry that had 2014 infants whose mothers had used inhaled budesonide in early pregnancy.156 Because there are more data on using budesonide during pregnancy than on using other inhaled corticosteroids, the NAEPP considered budesonide to be a preferred medication. However, if a woman’s asthma is well controlled by a different inhaled cortico-

steroid before pregnancy, it seems reasonable to continue that medica-tion during pregnancy. All inhaled corticosteroids are labeled by the FDA as pregnancy class C, except budesonide, which is class B.

INHALED b2-AGONISTSInhaled β2-agonists are recommended for all degrees of asthma

during pregnancy.114,157 Albuterol has the advantage of a rapid onset of effect in the relief of acute bronchospasm by means of smooth muscle relaxation, and it is an excellent bronchoprotective agent for pretreat-ment before exercise. Salmeterol and formoterol are long-acting preparations.

The β2-agonists are associated with tremor, tachycardia, and palpi-tations. They do not block the development of airway hyperrespon-siveness.158 Comparison of an inhaled glucocorticoid, budesonide, with the inhaled terbutaline raised the question about whether routine use of terbutaline may result in increased airway hyperresponsiveness.151 Increased frequency of bronchodilator use may indicate the need for additional anti-infl ammatory therapy; chronic use of short-acting β2-agonists has been associated with an increased risk of death.157,159 The β2-agonists appear to be safe based on a NAEPP review of six published studies of a total of 1599 women with asthma who took β2-agonists during pregnancy.114 In a large, prospective study, no signifi cant rela-tionship was found between the use of inhaled β2-agonists (n = 1828) and adverse pregnancy outcomes.160

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 puffs80 μg/puff 1-3 puffs >3-6 puffs >6 puffs

Budesonide 200 μg/inhalation 1-3 puffs >3-6 puffs >6 puffsFlunisolide 250 μg/puff 2-4 puffs 4-8 puffs >8 puffsFluticasone HFA 44 μg/puff — 2-6 puffs —

110 μg/puff 2 puffs 2-4 puffs >4 puffs220 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 puffs250 μg/inhalation 1 puff 2 puffs >2 puffs

Mometasone 200 μg/inhalation 1 puff 2 puffs >2 puffsTriamcinolone 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, hydrofl uoroalkane.

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,

medium-dose inhaled corticosteroid, or (if needed) medium-dose inhaled corticosteroid and salmeterol

Low-dose or (if needed) medium-dose inhaled corticosteroid and a leukotriene receptor antagonist or theophylline (serum level of 5-12 μg/mL)

Severe persistent High-dose inhaled corticosteroid and salmeterol and (if needed) oral corticosteroid

High-dose inhaled corticosteroid and theophylline (serum level of 5-12 μg/mL) and (if needed) oral corticosteroid

Ch045-X4224.indd 941 8/26/2008 4:09:45 PM


CROMOLYNCromolyn sodium is virtually devoid of signifi cant side effects. It

blocks the early and late phases of pulmonary response to an allergen challenge, and it prevents the development of airway hyperresponsive-ness.158 Cromolyn does not have any intrinsic bronchodilator or anti-histaminic activity. Compared with inhaled corticosteroids, the time to maximal clinical benefi t is longer for cromolyn. Cromolyn appears to be less effective than inhaled corticosteroids in reducing objective and subjective manifestations of asthma. Cromolyn appears to be safe during pregnancy160 and is an alternative treatment for mild persistent asthma.114

THEOPHYLLINETheophylline is an alternative treatment for mild persistent asthma

and an adjunctive treatment for the management of moderate and severe persistent asthma during pregnancy.114 Subjective symptoms of adverse theophylline effects, including insomnia, heartburn, palpita-tions, and nausea, may be diffi cult to differentiate from typical preg-nancy symptoms. High doses have caused jitteriness, tachycardia, and vomiting in mothers and neonates.161,162 Dosing guidelines have recommended that serum theophylline concentrations be maintained at 5 to 12 μg/mL during pregnancy.114 Theophylline can have signifi -cant interactions with other drugs, which can cause decreased clear-ance with resultant toxicity. For instance, cimetidine can cause a 70% increase in serum levels, and erythromycin use can increase theophyl-line serum levels by 35%.163

The main advantage of theophylline is the long duration of action, 10 to 12 hours with the use of sustained-release preparations, which is especially useful in the management of nocturnal asthma.164 Theophyl-line is indicated only for chronic therapy and is not effective for the treatment of acute exacerbations during pregnancy.165 Theophylline has anti-infl ammatory actions166 that may be mediated by inhibition of leukotriene production and its capacity to stimulate prostaglandin E2 production.167 Theophylline may potentiate the effi cacy of inhaled corticosteroids.168

The NAEPP reviewed eight human studies that had a total of 660 women with asthma who took theophylline during pregnancy.114 These studies and clinical experience confi rm the safety of theophylline at a serum concentration of 5 to 12 μg/mL during pregnancy. In a randomized, controlled trial, there were no differences in asthma exac-erbations or perinatal outcomes in a cohort receiving theophylline compared with the cohort receiving inhaled beclomethasone.169 However, the theophylline cohort had signifi cantly more reported side effects, discontinuation of the study medication, and an increased proportion of those with an FEV1 less than 80% of the predicted value.

LEUKOTRIENE MEDIATORSLeukotrienes are arachidonic acid metabolites that have been impli-

cated in transducing bronchospasm, mucous secretion, and increased vascular permeability.170 Bronchoconstriction associated with aspirin ingestion can be blocked by leukotriene receptor antagonists.171 Treat-ment with the leukotriene receptor antagonist montelukast (Singulair) has signifi cantly improved pulmonary function as measured by FEV1.

170 The leukotriene receptor antagonists zafi rlukast (Accolate) and mon-telukast are pregnancy category B drugs. There are minimal data regarding the effi cacy or safety of these agents during human preg-nancy. Leukotriene receptor antagonists provide an alternative treat-ment for mild persistent asthma and an adjunctive treatment for the management of moderate and severe persistent asthma during pregnancy.114

ORAL CORTICOSTEROIDSThe NAEPP Working Group reviewed eight human studies, includ-

ing one report of two meta-analyses.114 Most subjects in these studies did not take oral corticosteroids for asthma, and the length, timing, and dose of exposure to the drug were not well described. The panel concluded that fi ndings from the evidence are confl icting. Oral corti-costeroid use during the fi rst trimester of pregnancy is associated with a threefold increased risk for isolated cleft lip with or without cleft palate. Because the background incidence is about 0.1%, the excess risk attributable to oral steroids is 0.2% to 0.3%.172 Oral corticosteroid use during pregnancy by patients who have asthma has been associated with an increased incidence of preeclampsia, preterm delivery, and low birth weight.126,131,144,160,172 A prospective study found that use of sys-temic corticosteroids resulted in a defi cit of about 200 g in birth weight compared with controls and those exclusively treated with β2-agonists.173 However, it is diffi cult to separate the effects of the oral corticosteroids on these outcomes from the effects of severe or uncon-trolled asthma.

Because of the uncertainties in these data and the defi nite risks of severe, uncontrolled asthma to the mother and fetus, the NAEPP Working Group recommends the use of oral corticosteroids when indicated for the long-term management of severe asthma or exacerba-tions during pregnancy.114 For the treatment of acute exacerbations, methylprednisolone or other corticosteroids may be given at a dose of 120 to 180 mg per day in three or four divided doses; after the PEFR reaches 70% of the personal best value, the daily dosage of parenteral or oral corticosteroid, such as prednisone, can be dropped to 60 to 80 mg per day.114

Management of Allergic Rhinitis

Exacerbating AsthmaRhinitis, sinusitis, and gastroesophageal refl ux may exacerbate asthma symptoms, and their management should be considered an integral aspect of asthma care. Intranasal corticosteroids are the most effective medications for control of allergic rhinitis. Loratadine (Claritin) or cetirizine (Zyrtec) are recommended second-generation antihista-mines. Because oral decongestant ingestion during the fi rst trimester has been associated with gastroschisis, inhaled decongestants or inhaled corticosteroids should be considered before use of oral deconges-tants.114 Immunotherapy is considered safe during pregnancy, but because of the risk of anaphylaxis, initiation of immunotherapy is not recommended during pregnancy.

Antenatal ManagementPatients with moderate or severe asthma should be considered to be at risk for pregnancy complications. Adverse outcomes can be increased by underestimation of asthma severity and undertreatment of asthma. The fi rst prenatal visit should include a detailed medical history with attention to medical conditions that can complicate the management of asthma, including active pulmonary disease. The patient should be questioned about her smoking history and the presence and severity of symptoms, episodes of nocturnal asthma, the number of days of work missed, and emergency care visits due to asthma. Asthma severity should be determined (see Table 45-3). The type and amount of asthma medications, including the number of puffs of β2-agonists used each day, should be determined.

Gravidas with moderate or severe asthma should have scheduling of prenatal visits based on clinical judgment. In addition to routine care, monthly or more frequent evaluations of asthma history (i.e., emergency visits, hospital admissions, symptom frequency, severity,

Ch045-X4224.indd 942 8/26/2008 4:09:45 PM


nocturnal symptoms, and medication dosages and compliance) and pulmonary function (i.e., FEV1 or PEFR) are recommended. Patients should be instructed on proper dosing and administration of their asthma medications.

Daily peak fl ow monitoring should be considered for patients with moderate to severe asthma and especially for patients who have diffi -culty perceiving signs of worsening asthma.114 It may be helpful to maintain an asthma diary containing a daily record of symptoms, peak fl ow measurements, activity limitations, medical contacts initiated, and regular and as-needed medications taken. Identifying and avoiding asthma triggers can lead to improved maternal well-being and less need for medications. Specifi c recommendations can be made for appropriate environmental controls based on the patient’s history of exposure and, when available, skin test reactivity to asthma triggers.

Women who have moderate or severe asthma during pregnancy may benefi t from additional fetal surveillance in the form of ultra-sound examinations and antenatal fetal testing. Because asthma has been associated with intrauterine growth restriction and preterm birth, it is useful to establish pregnancy dating accurately by fi rst-trimester ultrasound when possible. In the opinion of the NAEPP Working Group,114 the evaluation of fetal activity and growth by serial ultra-sound examinations may be considered for women who have subop-timally controlled asthma, for those with moderate to severe asthma (starting at 32 weeks), and after recovery from a severe asthma exac-erbation. The intensity of antenatal surveillance of fetal well-being should be considered on the basis of the severity of the asthma and any other high-risk features of the pregnancy. All patients should be instructed to be attentive to fetal activity.

Home Management of Asthma ExacerbationsAn asthma exacerbation that causes minimal problems for the mother may have severe sequelae for the fetus. An abnormal fetal heart rate tracing may be the initial manifestation of an asthmatic exacerbation. A maternal PO2 value of less than 60 mm Hg or hemoglobin saturation of less than 90% may be associated with profound fetal hypoxia. Asthma exacerbations in pregnancy should be aggressively managed. Patients should be given an individualized guide for decision making and rescue management, and they should be educated to recognize signs and symptoms of early asthma exacerbations, such as coughing, chest tightness, dyspnea, or wheezing, or by a 20% decrease in the PEFR. Early recognition enables prompt institution of home rescue treatment to avoid maternal and fetal hypoxia.

Patients should use inhaled albuterol (two to four puffs) every 20 minutes for up to 1 hour (Table 45-8). The response is considered to be good if symptoms are resolved or become subjectively mild, normal activities can be resumed, and the PEFR is more than 70% of the per-sonal best value. The patient should seek further medical attention if the response is incomplete or if fetal activity is decreased.

Hospital and Clinic ManagementThe principal goal of hospital and clinic management should be the prevention of hypoxia. Measurement of oxygenation by pulse oximetry is essential, and arterial blood gas determinations should be obtained if oxygen saturation remains less than 95%. Chest radiographs usually are not needed. Continuous electronic fetal monitoring should be ini-tiated if gestation has advanced to point of potential fetal viability. Albuterol (2.5 to 5 mg every 20 minutes for three doses and then 2.5 to 10 mg every 1 to 4 hours as needed or 10 to 15 mg/hr administered continuously) should be delivered by nebulizer driven with oxygen.114 Occasionally, nebulized treatment is not effective because the patient is moving air poorly; in such cases, terbutaline (0.25 mg) can be

administered subcutaneously every 15 minutes for three doses. The patient should be assessed for general level of activity, color, pulse rate, use of accessory muscles, and airfl ow obstruction determined by aus-cultation and FEV1 or PEFR before and after each bronchodilator treatment. Guidelines for the management of asthma exacerbations are given in Table 45-9.

Labor and Delivery ManagementAsthma medications should not be discontinued during labor and delivery. Although asthma is usually quiescent during labor, consider-ation should be given to assessing PEFRs on admission and at 12-hour intervals. The patient should be kept hydrated and should receive adequate analgesia to decrease the risk of bronchospasm. If systemic corticosteroids have been used in the previous 4 weeks, intravenous corticosteroids (e.g., 100 mg of hydrocortisone every 8 hours) should be administered during labor and for the 24-hour period after delivery to prevent an adrenal crisis.114 An elective delivery should be postponed if the patient is having an exacerbation.

It is rarely necessary to perform a cesarean section for an acute asthma exacerbation. Maternal compromise and fetal compromise usually respond to aggressive medical management. Occasionally, delivery may improve the respiratory status of a patient with unstable asthma who has a mature fetus. Prostaglandin E2 or E1 can be used for cervical ripening, the management of spontaneous or induced abor-tions, or postpartum hemorrhage, although the patient’s respiratory status should be monitored.174 Carboprost (15-methyl PGF2α) and ergonovine and methylergonovine (Methergine) can cause broncho-spasm.175 Magnesium sulfate is a bronchodilator, but indomethacin can induce bronchospasm in the aspirin-sensitive patient. There are no reports of the use of calcium channel blockers for tocolysis among

TABLE 45-8 HOME MANAGEMENT OF ACUTE ASTHMA EXACERBATIONS

Initial Approach

Use albuterol MDI at a dose of 2-4 puffs (or single nebulizer treatment), and measure PEFR.

Poor Response

If PEFR < 50% of predicted, severe wheezing and shortness of breath occur, or fetal movement is decreased, repeat albuterol at a dose of 2-4 puffs by MDI and obtain emergency care.

Incomplete Response

If PEFR is 50-80% of predicted or if wheezing and shortness of breath persist, repeat albuterol treatment at a dose of 2-4 puffs by MDI at 20-minute intervals up to two more times.

If repeat PEFR is 50-80% of predicted or if fetal movement is decreased, contact caregiver or go for emergency care.

Good Response

If PEFR > 80% of predicted, there is no wheezing or shortness of breath, and the fetus is moving normally, patient may continue inhaled albuterol at a dose of 2-4 puffs by MDI every 3-4 hours as needed.

MDI, metered-dose inhaler; PEFR, peak expiratory fl ow rate.

Modifi ed 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).

Ch045-X4224.indd 943 8/26/2008 4:09:46 PM


TABLE 45-9 EMERGENCY DEPARTMENT AND HOSPITAL-BASED MANAGEMENT OF ASTHMA EXACERBATION

Initial Assessment and Treatment

Obtain 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 fi rst 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 Assessment

Evaluate the symptoms, perform a physical examination, assess PEFR and oxygen saturation, and obtain other tests as needed.Continue fetal assessment.

Good Response

Values 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 Response

Values 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 Response

Values 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 Arrest

Admit 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 Unit

Administer 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 Home

Continue 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 profi le; FEV1, forced expiratory volume in 1 second; MDI, metered-dose inhaler; PCO2, carbon dioxide partial pressure; PEFR, peak

expiratory fl ow rate.

Modifi ed 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).

Ch045-X4224.indd 944 8/26/2008 4:09:46 PM


patients with asthma, although an association with bronchospasm has not been observed with wide clinical use.

Lumbar anesthesia has the benefi t of reducing oxygen consumption and minute ventilation during labor.176 Fentanyl may be a better anal-gesic than meperidine, which causes histamine release, but meperidine is rarely associated with the onset of bronchospasm during labor. A 2% incidence of bronchospasm has been reported with regional anes-thesia.177 Ketamine is useful for induction of general anesthesia because it can prevent bronchospasm.178 Communication between the obstet-ric, anesthetic, and pediatric caregivers is important for optimal care.

BreastfeedingOnly small amounts of asthma medications enter breast milk. Predni-sone, theophylline, antihistamines, beclomethasone, β2-agonists, and cromolyn are not considered to be contraindications for breastfeed-ing.114,179 However, among sensitive individuals, theophylline may cause toxic effects in the neonate, including vomiting, feeding diffi cul-ties, jitteriness, and cardiac arrhythmias.

Overview of Asthma during PregnancyAsthma is an increasingly common problem during pregnancy. Mild and moderate asthma can be associated with excellent maternal and perinatal pregnancy outcomes, especially if patients are managed according to contemporary NAEPP recommendations. Severe and poorly controlled asthma may be associated with increased prematu-rity, the need for cesarean delivery, preeclampsia, and growth restric-tion. Severe asthma exacerbations can result in maternal morbidity and mortality and can have commensurate adverse pregnancy outcomes. The management of asthma during pregnancy should be based on objective assessment, trigger avoidance, patient education, and step therapy. Asthma medications should be continued during pregnancy and while breastfeeding.

Restrictive Lung Disease in PregnancyClinical ManifestationsRestrictive ventilatory defects occur when lung expansion is limited because of alterations in the lung parenchyma or because of abnor-malities in the pleura, chest wall, or the neuromuscular apparatus.180 These conditions are characterized by a reduction in lung volumes and an increase in the ratio of FEV1 to forced vital capacity.181 The inter-stitial lung diseases include idiopathic pulmonary fi brosis, sarcoidosis, hypersensitivity pneumonitis, pneumomycosis, drug-induced lung disease, and connective tissue disease. Additional conditions that cause a restrictive ventilatory defect include pleural and chest wall diseases and extrathoracic conditions such as obesity, peritonitis, and ascites.181

Restrictive lung disease in pregnancy has not been well studied. Consequently, little is known about the effects of restrictive lung disease on the outcome of pregnancy or the effects of pregnancy on the disease process. One study presented data on nine pregnant women with interstitial and restrictive lung disease who were prospectively managed.182 Diagnoses included idiopathic pulmonary fi brosis, hyper-sensitivity pneumonitis, sarcoidosis, kyphoscoliosis, and multiple pul-monary emboli. Three of the gravidas had severe disease characterized by a vital capacity of no more than 1.5 L (50% of predicted) or a dif-

fusing capacity of no more than 50% of predicted. Five of the patients had exercise-induced oxygen desaturation, and four patients required supplemental oxygen. In this group, one patient had an adverse outcome and was delivered at 31 weeks. She subsequently required mechanical ventilation for 72 hours. All other patients were delivered at or beyond 36 weeks with no adverse intrapartum or postpartum complications. All infants were at or above the 30th percentile for growth.182 The investigators concluded that restrictive lung disease was well tolerated in pregnancy. However, exercise intolerance is common, and these patients may require early oxygen supplementations.182

SarcoidosisSarcoidosis is a systemic granulomatosis disease of undetermined origin that often affects young adults. Pregnancy outcome for most patients with sarcoidosis is good.183,184 In one study, 35 pregnancies in 18 patients with sarcoidosis were evaluated retrospectively.183 There 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, no relapse occurred in 15 patients; however, progression of the disease continued in 3 women. Another retrospective study assessed 15 preg-nancies complicated by maternal sarcoidosis over a 10-year period.184 Eleven of these patients remained stable, two experienced disease pro-gression, and two died because of complications of severe sarcoidosis. In this group, factors indicating a poor prognosis included parenchy-mal lesions identifi ed on the chest radiograph, advanced radiographic staging, advanced maternal age, low infl ammatory activity, require-ment for drugs other than steroids, and the presence of extrapulmo-nary sarcoidosis.184 Both patients who succumbed during gestation had severe disease at the onset of pregnancy. The overall cesarean section rate was 40%, and 4 (27%) of 15 infants weighed less than 2500 g. 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 many nonpregnant patients, the improvement may be coincident with pregnancy.

Maycock and associates185 reported 16 pregnancies in 10 patients with sarcoidosis. Eight of these patients showed improvement in at least some of the manifestations of sarcoidosis during the antepartum period. In two patients, no effect was seen. A recurrence of the abnor-mal fi ndings was observed in the postpartum period within several months after delivery in approximately one half of the patients. Some had new manifestations of sarcoidosis not previously observed. Another study examined 17 pregnancies in 10 patients and concluded that pregnancy had no consistent effect on the course of the disease.186 Scadding187 separated patients into three categories based on charac-teristic patterns of their chest radiographs. When the lesions on the chest radiograph had resolved before pregnancy, radiographs remained normal throughout gestation. In women with radiographic changes before pregnancy, resolution continued throughout the prenatal period. Patients with inactive fi brotic residual disease had stable chest radiographs, and those with active disease tended to have partial or complete resolution of those changes during pregnancy. However, most patients in the latter group experienced exacerbation of the disease within 3 to 6 months after delivery.

Patients with pulmonary hypertension complicating restrictive lung disease may have a mortality rate as high as 50% during gestation. These patients need close monitoring during the labor, delivery, and postpartum periods. Invasive monitoring with a pulmonary artery

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catheter may be indicated to optimize cardiorespiratory function. Gravidas with restrictive lung disease, including pulmonary sarcoid-osis, may benefi t from early institution of steroid therapy for evidence of worsening pulmonary status. Individuals with evidence of severe disease need close monitoring and may require supplemental oxygen therapy during gestation.

During labor, consideration should be given to the early use of epidural anesthesia if it is not contraindicated. The early institution of pain management in this population can minimize pain, decrease the sympathetic response, and decrease oxygen consumption during labor and delivery. The use of general anesthesia should be avoided, if possible, because these patients may develop pulmonary complications after general anesthesia, including pneumonia and diffi culty weaning from the ventilator. Close fetal surveillance throughout gestation is indicated because impaired oxygenation may lead to impaired fetal growth and the development of fetal heart rate abnormalities during labor and delivery.

An additional consideration is the need to counsel all women with restrictive lung disease about the potential for continued impairment of their respiratory status during pregnancy, particularly if their respi-ratory status is deteriorating when they conceive. The individual with clinical signs consistent with pulmonary hypertension or severe restrictive disease should be cautioned about the possibility of maternal mortality resulting from worsening pulmonary function during gestation.

In summary, although the literature on restrictive lung disease in pregnancy is limited, it supports the conclusion that most patients with restrictive lung disease complicating pregnancy, including those with pulmonary sarcoidosis, can have a favorable pregnancy outcome. However, the clinician should keep in mind that patients with restric-tive lung disease can have worsening of their clinical condition and may succumb during gestation.

Cystic Fibrosis in PregnancyCF involves the exocrine glands and epithelial tissues of the pancreas, sweat glands, and mucous glands in the respiratory, digestive, and reproductive tracts. Chronic obstructive pulmonary disease, pancreatic exocrine insuffi ciency, and elevated levels of sweat electrolytes are present in most patients with CF.188 The disease is genetically transmit-ted with an autosomal recessive pattern of inheritance. The CF gene was identifi ed and cloned in 1989. The gene is localized to chromo-some 7, and the molecular defect accounting for most cases has been identifi ed.189,190,191 In the United States, approximately 4% of the white population are heterozygous carriers of the CF gene. The disease occurs in 1 of 3200 white live births.192

Morbidity and mortality in patients with CF usually result from progressive chronic bronchial pulmonary disease. Pregnancy and the attendant physiologic changes can stress the pulmonary, cardiovascu-lar, and nutritional status of women with CF. The purpose of this section is to familiarize the obstetrician and gynecologist with the physiologic effects of this complex disease, the impact of the disease on pregnancy, and the effect of pregnancy on the disease.

Survival for patients with CF has increased dramatically since 1940. According to the Cystic Fibrosis Foundation’s Patient Registry (www.cff.org), survival in 2006 had increased to 37 years. More than 40% of all people with CF in the United States are 18 years or older.188 This increase in survival of patients with CF likely refl ects earlier diagnosis and intervention and the advances in antibiotic therapy and nutritional support. Because of the improvements in care, more

women with CF are entering reproductive age. Unlike men with CF who are infertile for the most part, women with CF are often fertile.

The fi rst case of CF complicating pregnancy was reported in 1960, and a total of 13 pregnancies in 10 patients with CF were reported in 1966.193,194 Cohen and colleagues195 conducted a survey of 119 CF centers in the United States and Canada and identifi ed a total of 129 pregnancies in 100 women by 1976. Hilman and colleagues188 surveyed 127 CF centers in the United States between 1976 and 1982. A total of 191 pregnancies were reported during this period in women with CF who were between 16 and 36 years old, with a mean age of 22.6 years.188 The annual number of CF pregnancies reported to the Cystic Fibrosis Patient Registry doubled between 1986 and 1990, with 52 pregnancies reported in 1986, compared with 111 pregnancies reported in 1990. In 2006 209 women with CF were pregnant. Because the number of women with CF achieving pregnancy is steadily increasing, it is imper-ative that the obstetrician be familiar with the disease.

Effect of Pregnancy on Cystic FibrosisThe physiologic changes associated with pregnancy are well tolerated by healthy gravidas, but those with CF may adapt poorly. During pregnancy, there is an increase in resting minute ventilation, which at term may approach 150% of control values.196 Enlargement of the abdominal contents and upward displacement of the diaphragm leads to a decrease in functional residual volume and a decrease in residual volume.196 Pregnancy is also accompanied by subtle alterations in gas exchange with widening of the alveolar-arterial oxygen gradient that is most pronounced in the supine position.196 Alterations in pulmo-nary function are of little consequence in the normal pregnant woman, but in the gravida with CF, these changes may contribute to respiratory 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.

Nutritional requirements are increased during pregnancy, with approximately 300 kcal/day in additional fuel needed to meet the requirements of mother and fetus.197 Most patients with CF have pan-creatic exocrine insuffi ciency. Digestive enzymes and bicarbonate ions are diminished, resulting in maldigestion, malabsorption, and malnu-trition.197 Gastrointestinal manifestations of CF include steatorrhea, abdominal pain, distal intestinal obstruction syndrome, and rectal pro-lapse. Gastroesophageal refl ux, peptic ulcer disease, acute pancreatitis, and intussusception occur to different degrees in patients with CF. Partial or complete obstruction of the gastrointestinal tract in older children and adults, also known as distal obstruction syndrome, can be precipitated by dehydration, a change in eating habits, a change in enzyme brand or dose, or immobility. It is treated with a combination of laxatives and enemas. Patients with CF are encouraged to eat a diet that provides 120% to 150% of the recommended energy intake of normal age- and sex-matched controls. This is only a guideline, because in practice, the energy requirement for a patient with CF is that of their ideal body weight when malabsorption has been minimized. Research done by the United Kingdom Dieticians Cystic Fibrosis Interest Group found that women with CF who received preconception counseling had a signifi cantly greater mean maternal weight gain and signifi cantly heavier infants than women who had not received preconception advice.198

Grand and colleagues194 reported 13 pregnancies in 10 women with CF. Of these, fi ve women had a progressive decline in their pulmonary function, two of whom died of cor pulmonale in the immediate post-partum period. Pregnancy was well tolerated in 5 of 10 women, 2 of

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whom went on to have subsequent pregnancies that were similarly well tolerated.194 In this study, the pregravid pulmonary status of the patient was the most important predictor of outcome. However, there was no quantifi cation of pulmonary function. A case report by Novy and col-leagues199 described pulmonary function and gas exchange in a preg-nant woman with CF. The patient had severe disease as evidenced by a vital capacity of only 0.72 L and a PaO2 of 50 mm Hg at presenta-tion. The patient suffered a progressive increase in residual volume and decline in vital capacity that was accompanied by worsening hypoxemia and hypercapnia, resulting in respiratory distress and right-sided heart failure in the early postpartum period.199 Based on the experience with this patient and a review of the literature, the investigators recommended therapeutic abortion for any patient dem-onstrating progressive pulmonary deterioration and hypoxemia despite maximal medical management.199

In 1980, Cohen and associates195 described 100 patients and a total of 129 pregnancies. Ninety-seven pregnancies (75%) were completed, and 89% of these women delivered viable infants. Twenty-seven percent of these fetuses were delivered preterm. There were 11 perina-tal deaths and no congenital anomalies. In this study, 65% of patients required antibiotic therapy before delivery. In 1983, Palmer and col-leagues200 retrospectively reviewed the pre-pregnancy status of eight women with CF who subsequently completed 11 pregnancies. They found that fi ve women tolerated pregnancy without diffi culty but that three had irreversible deterioration in their clinical status. The inves-tigators identifi ed four maternal factors that predicted outcome: clini-cal status (i.e., Shwachman score), nutritional status (i.e., percent of predicted weight for height), the extent of chest radiologic abnormali-ties (i.e., Brasfi eld chest radiographic score), and the magnitude of pulmonary function impairment. Women with good clinical study results, good nutritional status (i.e., within 15% of their predicted ideal body weight for height), nearly normal chest radiographs, and only mild obstructive lung disease tolerated pregnancy well without deterioration.200

Several reports suggest that patients with mild CF, good nutritional status, and less impairment of lung function tolerate pregnancy well. However, those with poor clinical status, malnutrition, hepatic dysfunction, or advanced lung disease are at increased risk from preg-nancy.201-203 Kent and Farquharson203 reviewed the literature and reported 217 pregnancies. In this series, the frequency of preterm delivery was 24.3%, and the perinatal death rate was 7.9%. Poor out-comes were associated with a maternal weight gain of less than 4.5 kg and a forced vital capacity of less than 50% of the predicted value. Edenborough and colleagues204 also described pregnancies in women with CF. There were 18 live births (81.8%), one third of which were preterm deliveries, and 18.2% of patients had abortions. There were four maternal deaths within 3.2 years after delivery. In this series, lung function was available before delivery, immediately after delivery, and after pregnancy. The investigators demonstrated a decline of 13% in FEV1 and 11% in forced vital capacity during pregnancy. Most patients returned to baseline pulmonary function after pregnancy. Although most of the women in this series tolerated pregnancy well, those with moderate to severe lung disease (i.e., FEV1 < 60% of the predicted value) more often had preterm infants and had increased loss of lung function compared with those with milder disease.204

In two other series, pre-pregnancy FEV1 was found to be the most useful predictor of outcomes in pregnant women with CF.204,205 There was also a positive correlation of pre-pregnancy FEV1 with maternal survival. For the 72 pregnancies identifi ed, the outcomes were known for 69; there were 48 live births (70%), of which 22 were premature (46%); 14 therapeutic abortions (20%); and 7 miscarriages (10%).

There were no stillbirths, neonatal deaths, or early maternal deaths. Three major fetal anomalies were seen, but no infant had CF. Another report similarly documented the outcome of 72 pregnancies with CF.206

Pulmonary involvement in CF includes chronic infection of the airways and bronchiectasis. There is selective infection with certain microorganisms, such as S. aureus, H. infl uenzae, P. aeruginosa, and Burkholderia cepacia. In one report, three of four deaths during preg-nancy occurred in gravidas colonized with B. cepacia.207 Gilljam and associates208 reported outcomes for a cohort of pregnancies for women with CF from 1963 to 1998. For 92 pregnancies in 54 women, there were 11 miscarriages and 7 therapeutic abortions. Forty-nine women gave birth to 74 children. The mean follow-up time was 11 ± 8 years. One patient was lost to follow-up shortly after delivery, and one was lost after 12 years. The overall mortality rate was 19% (9 of 48 patients). Absence of B. cepacia (P < .001), pancreatic suffi ciency (P = .01), and pre-pregnancy FEV1 more than 50% of the predicted value (P = .03) were associated with better survival rates. When adjusted for the same parameters, pregnancy did not affect survival compared with the entire adult female CF population. The decline in FEV1 was comparable with that in the total CF population. Three women had diabetes mellitus, and seven developed gestational diabetes. There were six preterm infants and one neonatal death. CF was diagnosed in two children. Gilljam and coworkers208 concluded that the maternal and fetal out-comes were good for most women with CF. Risk factors for mortality are similar to those for the nonpregnant CF population. Pregnancies should be planned so that there is an opportunity for counseling and optimization of the medical condition. Good communication between the CF team and the obstetrician is important.208

A recent review of 10 pregnancies in 10 cystic fi brosis lung trans-plant recipients document 9 live births and 1 therapeutic abortion. Five were preterm births but all were well at follow-up. Three transplant recipients developed rejection during the pregnancy. One woman had evidence of rejection prior to conception. All 4 women died within 38 months of delivery. Pregnancy CF in lung transplant patients is feasible but carries a high risk of maternal mortality.209

Counseling Pregnant Women with Cystic FibrosisWomen with CF should be advised about the potential adverse affects of pregnancy on maternal health status. Factors that may predict poor outcome include pre-pregnancy evidence of poor nutritional status, signifi cant pulmonary disease with hypoxemia, and pulmonary hyper-tension. Liver disease and diabetes mellitus are also poor prognostic factors. Gravidas with poor nutritional status, pulmonary hyperten-sion (e.g., cor pulmonale), and deteriorating pulmonary function early in gestation should consider therapeutic abortion, because the risk of maternal mortality may be unacceptably high.

The woman with CF who is considering pregnancy should consider the need for strong psychosocial and physical support after delivery. The rigors of child rearing may add to the risk of maternal deteriora-tion during this period. Her family should be willing to provide physi-cal and emotional support and should be aware of the potential for deterioration in the mother’s health and the potential for maternal mortality. The need for care of a potentially preterm, growth-restricted neonate, with all of its attendant morbidities and potential mortality, should be discussed. Long term, the woman and her family should consider the fact that her life expectancy may be shortened by CF, and plans should be made for rearing of the child in the event of maternal death.

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Management of the Pregnancy Complicated by Cystic FibrosisCare of the gravida with CF should be a coordinated team effort. Physi-cians familiar with the complications and management of CF should be included, as well as a maternal-fetal medicine specialist and neona-tal team.

The gravida should be assessed for potential risk factors, such as severe lung disease, pulmonary hypertension, poor nutritional status, pancreatic failure, and liver disease, preferably before attempting gesta-tion but certainly during the early months of pregnancy. Gravidas should be advised to be 90% of ideal body weight before conception if possible. A weight gain of 11 to 12 kg is recommended.188 Frequent monitoring of weight; levels of blood glucose, hemoglobin, total protein, serum albumin, and fat-soluble vitamins A and E; and the prothrombin time is suggested.188 At each visit, the history of caloric intake and symptoms of maldigestion and malabsorption should be taken, and pancreatic enzymes should be adjusted if needed. Patients who are unable to achieve adequate weight gain through oral nutri-tional supplements may be given nocturnal enteral nasogastric tube feeding. In this situation, the risk of aspiration should be considered, especially in patients with a history of gastroesophageal refl ux, which is common in CF.188 If malnutrition is severe, parenteral hyper-alimentation may be necessary for successful completion of the pregnancy.210

Baseline pulmonary function should be assessed, preferably before conception. Assessment should include forced vital capacity, FEV1, lung volumes, pulse oximetry, and arterial blood gas measurements, if indicated. These values should be serially monitored during gestation, and deterioration in pulmonary function should be addressed imme-diately. An echocardiogram can assess the patient for underlying pul-monary hypertension and cor pulmonale. If pulmonary hypertension or cor pulmonale is diagnosed, the gravida should be advised about the high risk of maternal mortality.

Early recognition and prompt treatment of pulmonary infections is important in the management of the pregnant woman with CF. Treatment includes intravenous antibiotics in the appropriate dose, keeping in mind the increased clearance of these drugs because of pregnancy and CF. Plasma levels of aminoglycosides should be moni-tored and adjusted as indicated by the results. Chest physical therapy and bronchial drainage are also important components of the manage-ment of pulmonary infections in CF. Because P. aeruginosa is the most frequently isolated bacterium associated with chronic endobronchitis and bronchiectasis, antibiotic regimens should include coverage for this organism.

If the patient with CF has pancreatic insuffi ciency and diabetes mellitus, careful monitoring of blood glucose levels and insulin therapy are indicated. Pancreatic enzymes may need to be replaced to optimize the patient’s nutritional status. Because of malabsorption of fats and frequent use of antibiotics, the CF patient is prone to vitamin K defi -ciency. The prothrombin time should be checked regularly, and paren-teral vitamin K should be administered if the prothrombin time is elevated.

The fetus of a woman with CF is at risk for uteroplacental insuffi -ciency and intrauterine growth restriction. The maternal nutritional status and weight gain during pregnancy affect fetal growth. Nonstress testing should be started at 32 weeks’ gestation or sooner if there is evidence of fetal compromise. If there is evidence of severe fetal com-promise, delivery should be accomplished. Likewise, evidence of profound maternal deterioration, such as a marked and sustained decline in pulmonary function, development of right-sided heart

failure, refractory hypoxemia, and progressive hypercapnia and respi-ratory acidosis, may be maternal indications for early delivery. If the fetus is potentially viable, the administration of betamethasone may be benefi cial. Vaginal delivery should be attempted when possible.

Labor, delivery, and the postpartum period can be particularly dan-gerous for the patient with CF. The augmentation in cardiac output stresses the cardiovascular system and can lead to cardiopulmonary failure in the patient with pulmonary hypertension and cor pulmonale. These patients are also more likely to develop right-sided heart failure. Heart failure should be treated with aggressive diuresis and supple-mental oxygen. Management may be optimized by insertion of a pul-monary artery catheter to monitor right- and left-sided fi lling pressures. Pain control can reduce the sympathetic response to labor and tachy-cardia. This benefi ts the patient who is demonstrating pulmonary or cardiac compromise. In the patient with a normal partial thrombo-plastin time, insertion of an epidural catheter for continuous epidural analgesia may be benefi cial. This is also useful in the event a cesarean delivery is indicated because general anesthesia and its possible effects on pulmonary function can be avoided. If general anesthesia is needed, preoperative anticholinergic agents should be avoided because they tend to promote drying and inspissation of airway secretions. Close fetal surveillance is essential because the fetus might have been suffer-ing from uteroplacental insuffi ciency during gestation and is more prone to develop evidence of compromise during labor. Delivery by cesarean section should be reserved for the usual obstetric indications.

In summary, more women with CF are living to childbearing age and are capable of conceiving. Clinical experience has demonstrated that pregnancy in women with mild CF is well tolerated. Women with severe disease have an associated increase in maternal and fetal mor-bidity and mortality. The potential risk to any one individual with CF desiring pregnancy should be assessed and discussed in detail with the patient and her family.

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