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Chapter 45
Respiratory Diseases in Pregnancy
                                                                    Janice E. Whitty, MD, and Mitchell P. Dombrowski, MD




Proper functioning of the cardiorespiratory system is imperative to          nonpregnant women, it is likely that this phenomenon results from
achieve adequate oxygenation of maternal and fetal tissues. The mater-       progestational influences.5,6 The PaCO2 is linearly and inversely related
nal cardiorespiratory system undergoes significant changes during             to the log of the progesterone concentration.7 Wilbrand and colleagues8
gestation to optimize oxygen delivery to the fetus and maternal tissues.     reported that progesterone lowers the carbon dioxide threshold of the
Pulmonary disease is one of the most frequent maternal complications         respiratory center. During pregnancy, the sensitivity of the respiratory
during pregnancy, and it may result in significant morbidity or mortal-       center increases9 so that an increase in PaCO2 of 1 mm Hg increases
ity for the mother and her fetus. Depending on the specific diagnosis,        ventilation by 6 L/min in pregnancy, compared with 1.5 L/min in the
other maternal complications of pregnancy may have an adverse or             nonpregnant state.1,10,11 It is possible that progesterone acts as a primary
positive impact on the pulmonary function of the gravida.                    stimulant to the respiratory center independently of any change in
    In this chapter, we briefly review the physiologic adaptations of         carbon dioxide sensitivity or threshold.4 In addition to stimulating
the respiratory system that occur during gestation. Specific respir-          ventilation, progesterone may also increase levels of carbonic anhy-
atory diseases that occur in pregnancy and the effects of the disease on     drase B in the red blood cell.12 Schenker and associates13 reported that
pregnancy and pregnancy on the disease are discussed. The obstetri-          carbonic anhydrase levels increase in pregnant patients and in women
cian should realize that most diagnostic tests useful in evaluating pul-     taking oral contraceptives. An increase in the carbonic anhydrase level
monary function during gestation are not harmful to the fetus and, if        facilitates carbon dioxide transfer and tends to decrease PaCO2 inde-
indicated, should be performed. Most medications used to treat respi-        pendently of any change in ventilation. This respiratory stimulant
ratory disease in pregnancy are also well tolerated by the fetus. With       effect of progesterone has been used in the treatment of respiratory
few exceptions, the diagnostic and treatment algorithms for respiratory      failure and emphysema.6,14,15
disease closely resemble those used for a nonpregnant woman.                     During gestation, ventilation is increased by the rise in tidal volume
                                                                             from approximately 500 to 700 mL in each breath.1,16-18 Because there
                                                                             is no change in respiratory rate, minute ventilation rises from about
                                                                             7.5 to 10.5 L/min.11,17,19 Minute ventilation increases in the first trimes-
Physiologic Changes of the                                                   ter and remains at that level throughout pregnancy. The physiologic
Respiratory System                                                           dead space is increased by about 60 mL in pregnancy. This may result
                                                                             from dilation of the small airways.11 Residual volume is reduced by
Because there is no increase in respiratory rate, the increase in maternal   about 20%,16 from 1200 to 1000 mL.20-22 The vital capacity, which is
minute ventilation results from an increase in tidal volume.1 The            the maximum volume of gas that can be expired after a maximum
almost 50% increase in tidal volume occurs at the expense of an 18%          inspiration, does not change in pregnancy.16,21-25
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          Anatomic Changes of the
104 mm Hg).2 The PaCO2 decreases early in pregnancy in parallel with
the change in ventilation; however, a further progressive decrease in
                                                                             Respiratory System
PaCO2 may occur.3 The decrease in PaCO2 is even greater at altitudes         Observed changes in the configuration of the chest during pregnancy
where the mother exhibits compensatory hyperventilation in an                are in keeping with the findings of no change in vital capacity and a
attempt to maintain the arterial partial pressure of oxygen as high as       reduction in residual volume. The effect of pregnancy on pulmonary
possible. The decrease in PaCO2 is matched by an equivalent increase         mechanics has been compared with the effect of a pneumoperitoneum.
in renal excretion of and decrease in plasma bicarbonate concentra-          In both situations, the residual lung volume is decreased, but ventila-
tion; therefore, arterial pH is not altered from the normal nonpregnant      tion remains unimpaired. Radiologic studies performed early in preg-
level of about 7.4.                                                          nancy have shown that the subcostal angle increases from 68 to 103
    It has been suggested that the hyperventilation of pregnancy results     degrees before there is any mechanical pressure from the enlarging
primarily from progesterone acting as a respiratory stimulant.4 Because      uterus.26 The level of the diaphragm rises by about 4 cm, and the
hyperventilation has been observed during the luteal phase of the            transverse diameter of the chest increases by 2 cm.27-29 These changes
menstrual cycle and progesterone can produce similar changes in              account for the decrease in residual volume because the lungs are
928      CHAPTER 45             Respiratory Diseases in Pregnancy

relatively compressed during forced expiration; however, the excursion                           largely on hemoglobin concentration and arterial oxygen saturation.
of the diaphragm in respiration increases by about 1.5 cm in pregnancy                           Oxygen delivery can be impaired by conditions that affect arterial
compared with the nonpregnant state.29,30                                                        oxygen content or cardiac output (flow), or both. Anemia leads to low
                                                                                                 arterial oxygen content because of a lack of hemoglobin binding sites
                                                                                                 for oxygen. Carbon monoxide poisoning likewise decreases oxyhemo-
                                                                                                 globin because of blockage of binding sites for oxygen. The patient
Oxygen Delivery                                                                                  with hypoxemic respiratory failure does not have sufficient oxygen
                                                                                                 available to saturate the hemoglobin molecule. Desaturated hemoglo-
and Consumption                                                                                  bin is altered structurally such that it has a diminished affinity for
                                                                                                 oxygen.33
Oxygen Delivery                                                                                      The amount of oxygen available to tissues also is affected by the
All tissues require oxygen for the combustion of organic compounds                               affinity of the hemoglobin molecule for oxygen. The oxyhemoglobin
to fuel cellular metabolism. The cardiopulmonary system delivers                                 dissociation curve (Fig. 45-1) and the conditions that influence the
a continuous supply of oxygen and other essential substrates to                                  binding of oxygen negatively or positively must be considered when
tissues. Oxygen delivery depends on oxygenation of blood in the lungs,                           attempts are made to maximize oxygen delivery.34 An increase in the
oxygen-carrying capacity of the blood, and cardiac output.31 Under                               plasma pH level or a decrease in temperature or the concentration of
normal conditions, oxygen delivery exceeds oxygen consumption by                                 2,3-diphosphoglycerate can increase hemoglobin affinity for oxygen,
about 75%.32 The amount of oxygen delivered is determined by the                                 shifting the curve to the left and resulting in diminished tissue oxygen-
cardiac output (CO, L/min) times the arterial oxygen content (CaO2,                              ation. If the plasma pH level, temperature, or 2,3-diphosphoglycerate
mL/O2/min):                                                                                      level increases, hemoglobin affinity for oxygen decreases, and more
                                                                                                 oxygen is available to tissues (see Fig. 45-1).34
     Oxygen delivery = CO × CaO2 × 10 (700 to 1400 mL/min)                                           In certain clinical conditions, such as septic shock and adult respi-
                                                                                                 ratory distress syndrome, there is maldistribution of flow relative to
    The arterial oxygen content is determined by the amount of oxygen                            oxygen demand, leading to diminished delivery and consumption of
that is bound to hemoglobin (i.e., arterial blood saturation with oxygen                         oxygen. The release of vasoactive substances is hypothesized to result
[SaO2]) and by the amount of oxygen that is dissolved in plasma (i.e.,                           in the loss of normal mechanisms of vascular autoregulation, produc-
arterial partial pressure of oxygen [PaO2 × 0.0031]):                                            ing regional and microcirculatory imbalances in blood flow.35 This
                                                                                                 mismatching of blood flow with metabolic demand causes excessive
       CaO2 = (hemoglobin × 1.34 × SaO2) + (PaO2 × 0.0031)                                       blood flow to some areas and relative hypoperfusion of other areas,
                      (16 to 22 mL O2/dL)                                                        limiting optimal systemic use of oxygen.35 The patient with diminished
                                                                                                 cardiac output resulting from hypovolemia or pump failure is unable
   As can be seen in this formula, the amount of oxygen dissolved in                             to distribute oxygenated blood to tissues. Therapy directed at increas-
plasma is negligible, and the arterial oxygen content therefore depends                          ing the volume with normal saline or with blood if the hemoglobin




                                                                                           100

                                                                                            90              pH
                                                                                                           DPG
                                                                                                          Temp
                                                                                            80

                                                                                            70                                             pH
                                                                   Percent oxyhemoglobin




                                                                                                                                           DPG
                                                                                            60                                             Temp


                                                                                            50

                                                                                            40

                                                                                            30

                                                                                            20

                                                                                            10

FIGURE 45-1 The oxygen-binding curve for human
hemoglobin A under physiologic conditions (red                                               0       10     20     30     40    50     60    70       80     90    100
curve). The affinity is shifted by changes in pH,                                                                          O2 tension (mm Hg)
diphosphoglycerate (DPG) concentration, and temperature.                                                         P50
P50 is the oxygen tension at one-half saturation.
CHAPTER 45           Respiratory Diseases in Pregnancy            929
level is less than 10 g/dL increases delivery of oxygen in the hypovole-         venous oxygen tension is 40 mm Hg with a saturation of 73%. Satura-
mic patient. The patient with cardiac failure may benefit from inotro-            tions less than 60% are abnormally low. These parameters can be
pic support and afterload reduction in addition to supplementation of            measured directly by obtaining a blood sample from the distal port of
intravascular volume.                                                                                                    ¯
                                                                                 the pulmonary artery catheter. The SVO2 also can be measured con-
                                                                                 tinuously with special pulmonary artery catheters equipped with fiber-
                                                                                 optics. Mixed venous oxygenation is a reliable parameter in the patient
Relationship of Oxygen Delivery                                                  with hypoxemia or low cardiac output, but findings must be inter-
to Consumption                                                                                                        ¯
                                                                                 preted with caution. When the SVO2 is low, oxygen delivery can be
Oxygen consumption is the product of the arteriovenous oxygen                                                                    ¯
                                                                                 assumed to be low. However, normal or high SVO2 values do not guar-
content difference (C(a−v)O2) and cardiac output (CO). Under normal              antee that tissues are well oxygenated. In conditions such as septic
conditions, oxygen consumption is a direct function of the metabolic             shock and adult respiratory distress syndrome, the maldistribution of
rate36:                                                                                                                             ¯
                                                                                 systemic flow may lead to an abnormally high SVO2 value in the face
                                                                                 of severe tissue hypoxia.35 The oxygen dissociation curve must be con-
                     Oxygen consumption = C(a−v)O2 × CO × 10                                                        ¯
                                                                                 sidered when interpreting the SVO2 as an indicator of tissue oxygen-
                              (180 to 280 mL/min)                                ation.33 Conditions that result in a left shift of the curve cause the
                                                                                 venous oxygen saturation to be normal or high, even when the mixed
   The oxygen extraction ratio is the fraction of delivered oxygen that                                             ¯
                                                                                 venous oxygen content is low. SVO2 is useful for monitoring trends in
actually is consumed:                                                            a particular patient, because a significant decrease occurs when oxygen
                                                                                 delivery has decreased because of hypoxemia or a decrease in cardiac
             Oxygen extraction ratio = O2 consumption/O2 delivery (0.25)         output.

    The normal oxygen extraction ratio is about 25%. A rise in the
oxygen extraction ratio is a compensatory mechanism used when
                                                                                 Oxygen Delivery and Consumption
oxygen delivery is inadequate for the level of metabolic activity. A             in Pregnancy
subnormal value suggests flow maldistribution, peripheral diffusion               The physiologic anemia of pregnancy results in a reduction in the
defects, or functional shunting.36 As the supply of oxygen is reduced,           hemoglobin concentration and arterial oxygen content. Oxygen deliv-
the fraction extracted from blood increases and oxygen consumption               ery is maintained at or above normal despite this because of the 50%
is maintained. If a severe reduction in oxygen delivery occurs, the limits       increase in cardiac output. The pregnant woman therefore depends
of oxygen extraction are reached, tissues are unable to sustain aerobic          on cardiac output for maintenance of oxygen delivery more than the
energy production, and consumption decreases. The level of oxygen                nonpregnant patient.38 Oxygen consumption increases steadily
delivery at which oxygen consumption begins to decrease is called                throughout pregnancy and is greatest at term, reaching an average of
critical oxygen delivery (Fig. 45-2).37 At the critical oxygen delivery level,   331 mL/min at rest and 1167 mL/min with exercise.11 During labor,
tissues begin to use anaerobic glycolysis, with resultant lactate produc-        oxygen consumption increases by 40% to 60%, and cardiac output
tion and metabolic acidosis.37 If oxygen deprivation continues, irre-            increases by about 22%.39,40 Because oxygen delivery normally far
versible tissue damage and death ensue.                                          exceeds consumption, the normal pregnant patient usually is able to
                                                                                 maintain adequate delivery of oxygen to herself and her fetus, even
                                                                                 during labor. When a pregnant patient has low oxygen delivery, she
Mixed Venous Oxygenation                                                         very quickly can reach the critical oxygen delivery level during labor,
The mixed venous oxygen tension and mixed venous oxygen saturation               compromising herself and her fetus. The obstetrician therefore must
(SVO2) are parameters of tissue oxygenation.37 The normal mixed
  ¯                                                                              make every effort to optimize oxygen delivery before allowing labor to
                                                                                 begin in the compromised patient.



                                                                                 Pneumonia in Pregnancy
                                                                                 Pneumonia is fortunately a rare complication of pregnancy, occurring
  O2 consumption




                                                                                 in 1 of 118 to 2288 deliveries.41,42 However, pneumonia contributes to
                                                                                 considerable maternal mortality and is reportedly the most common
                                                                                 non-obstetric infection to cause maternal mortality in the peripartum
                                                                                 period.43 Maternal mortality was as high as 24% before the introduc-
                                                                                 tion of antibiotic therapy.44 Research reports have documented a dra-
                                                                                 matic decrease in maternal mortality from 0% to 4% with modern
                                                                                 management and antibiotic therapy.42,45,46 Preterm delivery is a signifi-
                                DO2crit
                                                                                 cant complication of pneumonia complicating pregnancy. Even with
                                                                                 antibiotic therapy and modern management, preterm delivery con-
                                          O2 delivery
                                                                                 tinues to occur for 4% to 43% of gravidas who have pneumonia.42,45,46
FIGURE 45-2 Relationship of oxygen consumption (VO2) and
                                                                                     The increasing incidence of pneumonia in pregnancy may reflect
oxygen delivery (DO2). At the point of critical oxygen delivery,                 the declining general health status of certain segments of the childbear-
tissues begin to use anaerobic glycolysis, with resultant lactate                ing population (e.g., morbid obesity).46 The epidemic of human
production and metabolic acidosis. If the oxygen deprivation                     immunodeficiency virus (HIV) infection has increased the number of
continues, irreversible tissue damage and death ensue.                           potential mothers who are at risk for opportunistic lung infections.
930      CHAPTER 45              Respiratory Diseases in Pregnancy

HIV infection is also associated with increased risks of invasive pneu-          Pneumonia in pregnancy has several causes, including mumps,
mococcal disease (odds ratio [OR] = 41.8) and Legionnaire disease            infectious mononucleosis, swine influenza, influenza A, varicella, coc-
(OR = 41.8).47 HIV infection further predisposes the pregnant woman          cidioidomycosis, and other fungi.50 Varicella pneumonia can compli-
to the infectious complications of acquired immunodeficiency syn-             cate primary varicella infections in 5.2% to 9%51 of infections in
drome (AIDS).47,48 Reported incidence rates range from 97 to 290 cases       pregnancy, compared with 0.3% to 1.8% in the nonpregnant popula-
per 1000 HIV-infected persons per year. HIV-infected persons are 7.8         tion.52 Influenza A has a higher mortality rate among pregnant women
times more likely to develop pneumonia than non-HIV-infected indi-           than among nonpregnant patients.53 The increase in virulence of viral
viduals with similar risk factors. Women with medical conditions that        infections reported in pregnancy may result from the alterations in
increase the risk for pulmonary infection, such as cystic fibrosis (CF),      maternal immune status that characterize pregnancy, including
are living to childbearing age more frequently than in the past. This        reduced lymphocyte proliferative response, reduced cell-mediated
disorder contributes to the increased incidence of pneumonia in              cytotoxicity by lymphocytes, and a decrease in the number of helper
pregnancy.                                                                   T lymphocytes.53,54 Viral pneumonias can also be complicated by
    Pneumonia can complicate pregnancy at any time during gestation          superimposed bacterial infection, particularly pneumococcus.
and may be associated with preterm birth, poor fetal growth, 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     Aspiration Pneumonia
delivered during the course of their acute illness, and there were two       Mendelson syndrome describes chemical pneumonitis resulting from
maternal deaths. Another report described 39 cases of pneumonia in           the aspiration of gastric contents in pregnancy. Chemical pneumonitis
pregnancy.45 Sixteen gravidas presented before 24 weeks’ gestation, 15       can be superinfected with pathogens present in the oropharynx and
between 25 and 36 weeks’ gestation, and 8 after 36 weeks’ gestation.         gastric juices, primarily anaerobes and gram-negative bacteria.45 Men-
Twenty-seven patients in this series were followed to completion of          delson’s original report of aspiration55 consisted of 44,016 nonfasted
pregnancy; only two required delivery during the acute phase of pneu-        obstetric patients between 1932 and 1945, and more than one half had
monia. Of these 27 patients, 3 suffered a fetal loss, and 24 delivered       received “operative intervention” with ether by mask without endotra-
live fetuses, although there was one neonatal death resulting from           cheal intubation. He described aspiration in 66 cases (rate of 1 case per
prematurity.                                                                 667 patients). Although several of the patients were critically ill from
    Madinger and associates42 reported 25 cases of pneumonia                 their aspirations, most recovered within 24 to 36 hours, and only two
occurring among 32,179 deliveries and observed that fetal and                died from this complication (rate of 1 death per 22,008 patients). A
obstetric complications were much more common than in earlier                review described 37,282 vaginal deliveries; 85% were performed with
studies. Preterm labor complicated 11 of 21 gestations. Eleven patients      general anesthesia by mask and without intubation, and 65% to 75%
had pneumonia at the time of delivery. Preterm delivery was more             had ingested liquids or solid food within 4 hours of onset of labor.56
likely for women who had bacteremia, needed mechanical ventilation,          The investigators found five mild cases of aspiration (1 per 7456
and had a serious underlying maternal disease. In addition to the            patients) with no sequelae.56 Another report described one occurrence
complication of preterm labor, there were three perinatal deaths in this     of “mild aspiration” without adverse outcome among 1870 women
series. Berkowitz and LaSala46 reported 25 patients with pneumonia           undergoing nonintubated peripartum surgery with intravenous ket-
complicating pregnancy; 14 women had term deliveries, 1 delivered            amine, benzodiazepines, barbiturates, fentanyl, or some combination
preterm, 3 had a voluntary termination of pregnancy, 3 had term              of these drugs.57 Soreide and colleagues58 observed four episodes of
deliveries of growth-restricted infants, and 4 were lost to follow-up.       aspiration each during 36,800 deliveries and 3600 cesarean sections
Birth weight was significantly lower in the study group in this series        with no mortality. Based on these data, most hospitals permit free
(2770 ± 224 g versus 3173 ± 99 g in the control group; P < .01). In this     intake of clear liquids during labor. The risk of aspiration, pneumonia,
series, pneumonia complicated 1 of 367 deliveries. The investigators         and death from general anesthesia appears to be very low. This may
attributed the increase in the incidence of pneumonia in this popula-        reflect the use of modern techniques and therapy to reduce gastric
tion to a decline in general health status, including anemia, a significant   pH.
incidence of cocaine use (52% versus 10% of the general population),
and HIV positivity (24% versus 2% of the general population) in the
study group.                                                                 Bacterial Pneumonia
                                                                             Streptococcus pneumoniae (pneumococcus) is the most common bacte-
                                                                             rial pathogen that causes pneumonia in pregnancy; H. influenzae is the
Bacteriology                                                                 next most common. These pneumonias typically manifest as an acute
Most series describing pneumonia complicating pregnancy have used            illness accompanied by fever, chills, and a purulent, productive cough
incomplete methodologies to diagnose the etiologic pathogens for             and are seen as a lobar pattern on the chest radiograph (Fig. 45-3).
pneumonia, relying primarily on cultures of blood and sputum. In             Streptococcal pneumonia produces a “rusty” sputum, with gram-
most cases, no pathogen was identified; however, pneumococcus and             positive diplococci on Gram stain, and it demonstrates asymmetrical
Haemophilus influenzae remain the most common identifiable causes              consolidation with air bronchograms on the chest radiograph.54 H.
of pneumonia in pregnancy.42,45,46 Because comprehensive serologic           influenzae is a gram-negative coccobacillus that produces consolida-
testing has rarely been done, the true incidence of viral, Legionella, and   tion with air bronchograms, often in the upper lobes.54 Less common
Mycoplasma pneumonia in pregnancy is difficult to estimate. The data          bacterial pathogens include Klebsiella pneumoniae, which is a gram-
presented by Benedetti, Madinger, Berkowitz, and their respective col-       negative rod that causes extensive tissue destruction with air broncho-
leagues all support pneumococcus as the predominant pathogen                 grams, pleural effusion, and cavitation seen on the chest radiograph.
causing pneumonia in pregnancy and H. influenzae as the second most           Patients with Staphylococcus aureus pneumonia present with pleuritis,
common organism.42,45,46 In the series of Berkowitz and LaSala,46 one        chest pain, purulent sputum, and consolidation without air broncho-
patient was infected with Legionella species.                                grams identified on the chest radiograph.54
CHAPTER 45            Respiratory Diseases in Pregnancy            931
                                                                              The workup should include a physical examination, arterial blood
                                                                          gas determinations, a chest radiograph, sputum Gram stain and
                                                                          culture, and blood cultures. Several studies have called into question
                                                                          the use of cultures to identify the microbes of community-acquired
                                                                          pneumonia. Success rates for identification of the bacterial cause with
                                                                          cultures range from 2.1% to approximately 50%. Review of available
                                                                          clinical data reflects an overall reliance on clinical judgment and the
                                                                          patient’s response to treatment to guide therapy. Other tests are avail-
                                                                          able to identify the cause of pneumonia that do not require culture
                                                                          and are more sensitive and specific. An assay approved by the U.S. Food
                                                                          and Drug Administration (FDA) for pneumococcal urinary antigen
                                                                          has been assessed in several studies. The sensitivity for identifying
                                                                          pneumococcal disease in adults is reportedly 60% to 90%, with a
                                                                          specificity close to 100%. In one study, the pneumococcal antigen was
                                                                          detected in 26% of patients in whom no pathogens had been identified.
                                                                          This finding suggests that cases that are undiagnosed by standard test
                                                                          can be identified with the assay. In this study, 10% of samples from
                                                                          patients with pneumonia caused by other agents were positive on the
                                                                          pneumococcal assay, indicating a potential problem with specificity. If
                                                                          the response to therapy directed at pneumococcus is inadequate, cov-
                                                                          erage for other potential pathogens should be added.
                                                                              The test for Legionella urinary antigen has a sensitivity of 70% and
                                                                          specificity of 90% for serogroup 1. This is especially useful in the
                                                                          United States and Europe, because about 85% of Legionella isolates are
                                                                          serogroup 1. Legionella is a common cause of severe community-
FIGURE 45-3 Right lower lobe pneumonia. Lobar consolidation in            acquired pneumonia. The urinary antigen for serogroup 1 should be
the right lower lobe is consistent with pneumococcal pneumonia.           considered for any patient requiring admission into an intensive care
                                                                          unit for pneumonia.
                                                                              Percutaneous-transthoracic needle aspiration has been advocated
    Patients infected with atypical pneumonia pathogens, such as          as a valuable and safe method to increase the chance of establishing
Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia              the causative agent for pneumonia. This test should be reserved for use
pneumoniae (TWAR agent), present with gradual onset of symptoms.          in compromised individuals, suspected tuberculosis in the absence of
They have a lower fever, appear less ill, have mucoid sputum, and have    a productive cough, selected cases of chronic pneumonia, pneumonia
a patchy or interstitial infiltrate seen on the chest radiograph. The      associated with neoplasm or a foreign body, suspected Pneumocystis
severity of the findings on the chest radiograph usually is out of pro-    jiroveci pneumonia, and suspected conditions that necessitate lung
portion to the mild clinical symptoms. M. pneumoniae is the most          biopsy. Cold agglutinins and Legionella titers may also be useful.
common organism responsible for atypical pneumonia and is best            Empiric antibiotic coverage should be started, usually with a third-
detected by the presence of cold agglutinins in about 70% of cases.       generation cephalosporin such as ceftriaxone or cefotaxime. Legionella
    The normal physiologic changes in the respiratory system associ-      pneumonia has a high mortality rate and sometimes manifests with
ated with pregnancy result in a loss of ventilatory reserve. Coupled      consolidation, mimicking pneumococcal pneumonia. It is recom-
with the immunosuppression that accompanies pregnancy, this puts          mended that a macrolide, such as azithromycin, be added to the
the mother and fetus at great risk from respiratory infection. Any        empiric therapy. Dual coverage has been demonstrated to improve
gravida suspected of having pneumonia should be managed aggres-           response to therapy even for abbreviated macrolide regimens. This
sively. The pregnant patient should be admitted to the hospital and a     may reflect the added anti-inflammatory effect of the macrolides.
thorough investigation undertaken to determine the cause. One study       Azithromycin administration is an independent predictor of a positive
examined 133 women admitted with pneumonia during pregnancy               outcome and reduced length of hospital stay for patients with mild to
using protocols based on the British Thoracic Society and American        moderate community-acquired pneumonia. The use of macrolides to
Thoracic Society admission guidelines for management of nonpreg-          treat community-acquired pneumonia should be limited when possi-
nant individuals. The investigators reported that if the American Tho-    ble, because their use has also been associated with increased penicillin
racic Society guidelines were used, 25% of the pregnant women with        resistance by S. pneumoniae.
pneumonia could have avoided admission. Using the American crite-             When admission for pneumonia is required, there is evidence that
ria, none of the gravidas who would have been managed as an outpa-        inpatient and 30-day mortality rates have been reduced when antibiot-
tient had any complications. If the British Thoracic Society guidelines   ics are administered in less than 8 hours. Current U.S. federal standards
had been used; 66% of the pregnant women in this group would have         require that the first dose of antibiotics be administered within 4 hours
been assigned to outpatient therapy. However, 14% would have              of arrival to the hospital. After the results of the sputum culture, blood
required readmission for complications. Most of the 133 women who         cultures, Gram stain, and serum studies are obtained and a pathogen
were hospitalized with pneumonia in this study did not receive a chest    has been identified, antibiotic therapy can be directed toward the iden-
radiograph for confirmation of the diagnosis. This limits the value of     tified cause. The third-generation cephalosporins are effective agents
the study for guiding admission criteria for pneumonia in pregnancy.      for most pathogens causing a community-acquired pneumonia. They
Until additional information is available, admission for all pregnant     are also effective against penicillin-resistant S. pneumoniae. The qui-
women with pneumonia is still recommended.                                nolones as a class should be avoided in pregnancy because they may
932       CHAPTER 45             Respiratory Diseases in Pregnancy

damage developing fetal cartilage. However, with the emergence of             contrast to the general population, pregnant women seem to be at
highly resistant bacterial pneumonia, their use may be lifesaving and         higher risk for influenza pneumonia.61,62 Epidemiologic data from the
therefore justified in specific circumstances. The respiratory quino-           1918 to 1919 influenza A pandemic revealed a maternal mortality rate
lones are effective against highly penicillin-resistant S. pneumoniae         that approached 50% for pregnant women with influenza pneumo-
strains, and their use does not increase resistance. The respiratory          nia.63,64 Three types of influenza virus can cause human disease—A, B,
quinolones include levofloxacin, gatifloxacin, and moxifloxacin. These           and C—but most epidemic infections are caused by influenza A.50
are ideal agents for community-acquired pneumonia because they are            Influenza A typically has an acute onset after a 1- to 4-day incubation
highly active against penicillin-resistant strains of S. pneumoniae. They     period and first manifests as high fever, coryza, headache, malaise, and
are also active against Legionella and the other atypical pulmonary           cough. In uncomplicated cases, results of the chest examination and
pathogens. Another advantage is a favorable pharmacokinetic profile,           chest radiograph are normal.50 If symptoms persist longer than 5 days,
such that blood or lung levels are the same whether the drug is admin-        especially in a pregnant woman, complications should be suspected.
istered orally or intravenously. Arguments against more extensive             Pneumonia may complicate influenza as the result of secondary bacte-
respiratory quinolone use are based on concerns about the potential           rial infection or viral infection of the lung parenchyma.50 In the epi-
for developing resistance, the variable incidence of Legionella, and cost.    demic of 1957, autopsies demonstrated that pregnant women died
An additional caveat is that the respiratory quinolones are only par-         most commonly of fulminant viral pneumonia, whereas nonpregnant
tially effective against Mycobacterium tuberculosis. Evaluation for this      patients died most often of secondary bacterial infection.65
infection should be done when considering the use of quinolones for               A large, nested, case-control study evaluated the rate of influenza-
pneumonia.                                                                    related complications over 17 influenza seasons among women enrolled
    In addition to antibiotic therapy, oxygen supplementation should          in the Tennessee Medicaid system. This study demonstrated a high risk
be given. Frequent arterial blood gas measurements should be obtained         for hospitalization for influenza-related reasons in low-risk pregnant
to maintain partial pressure of oxygen at 70 mm Hg, a level necessary         women during the last trimester of pregnancy. The study authors esti-
to ensure adequate fetal oxygenation. Arterial saturation also can be         mated that 25 of 10,000 women in the third trimester during the
monitored with pulse oximetry. When the gravida is afebrile for 48            influenza season are hospitalized with influenza-related complications.
hours and has signs of clinical improvement, an oral cephalosporin            A later, matched-cohort study using the administrative database of
can be started and intravenous therapy discontinued. A total of 10 to         pregnant women enrolled in the Tennessee Medicaid system examined
14 days of treatment should be completed.                                     pregnant women between the ages of 25 and 44 years with respiratory
    Pneumonia in pregnancy can be complicated by respiratory failure          hospitalization during the 1985 to 1993 influenza seasons. In this
requiring mechanical ventilation. If this occurs, team management             population of pregnant women, those with asthma accounted for one
should include the obstetrician, maternal-fetal medicine specialist, and      half of all respiratory-related hospitalizations during the influenza
intensivist. In addition to meticulous management of the gravida’s            season. Among pregnant women with diagnosis of asthma, 6% required
respiratory status, the patient should be maintained in the left lateral      respiratory hospitalization during the influenza season (OR = 10.63;
recumbent position to improve uteroplacental perfusion. The viable            95% confidence interval [CI], 8.61 to 13.83) compared with women
fetus should be monitored with continuous fetal monitoring. If posi-          without a medical comorbidity. This study detected no significant
tive end-expiratory pressure greater than 10 cm H2O is required to            increases in adverse perinatal outcome associated with respiratory hos-
maintain oxygenation, central monitoring with a pulmonary artery              pitalization during flu season.
catheter should be instituted to adequately monitor volume status and             Primary influenza pneumonia is characterized by rapid progression
maintain maternal and uteroplacental perfusion. There is no evidence          from a unilateral infiltrate to diffuse bilateral disease. The gravida may
documenting that elective delivery results in overall improvement in          develop fulminant respiratory failure requiring mechanical ventilation
respiratory function,59 and elective delivery should be reserved for the      and positive end-expiratory pressure. Aggressive therapy is indicated
usual obstetric indications. However, if there is evidence of fetal com-      when pneumonia complicates influenza in pregnancy. Antibiotics
promise or profound maternal compromise and impending demise,                 should be started and directed at the likely pathogens that can cause
delivery should be accomplished.                                              secondary infection, including S. aureus, pneumococcus, H. influenzae,
    Pneumococcal polysaccharide vaccination prevents pneumococcal             and certain enteric gram-negative bacteria. Antiviral agents, such as
pneumonia in otherwise healthy populations with an efficacy of 65%             oseltamivir and zanamivir, should also be considered.66 It has been
to 84%. The vaccine is safe in pregnancy and should be administered           recommended that the influenza vaccine be given routinely to gravidas
to high-risk gravidas. Those at high risk include individuals with sickle     in the second and third trimester of pregnancy to prevent the occur-
cell disease with autosplenectomy, patients who have a surgical sple-         rence of influenza and the development of pneumonia. Women at high
nectomy, and individuals who are immunosuppressed. An additional              risk for pulmonary complications, such as those with asthma, chronic
advantage to maternal immunization with the pneumococcal vaccine              obstructive pulmonary disease, cystic fibrosis, and splenectomy, should
is that several studies have demonstrated there is significant transpla-       be vaccinated regardless of the trimester to prevent the occurrence of
cental transmission of vaccine-specific antibodies in infants at birth         influenza and the development of secondary pneumonia. In addition
and at 2 months. Colostrum and breast milk antibodies are also sig-           to maternal protection, prospective studies have demonstrated higher
nificantly increased in women who have received the pneumococcal               cord blood antibody levels to influenza in infants born to mothers
vaccine.                                                                      immunized during pregnancy. There is a delay in the onset and decrease
                                                                              in severity of influenza in infants born with higher antibody levels.

Viral Pneumonias                                                              Varicella
                                                                              Varicella-zoster virus is a DNA virus that usually causes a benign, self-
Influenza                                                                      limited illness in children, but it may infect up to 2% of all adults.67
An estimated 4 million cases of pneumonia and influenza occur annu-            Varicella infection occurs in 0.7 of every 1000 pregnancies.68 Pregnancy
ally in the United States, and it is the sixth leading cause of death.60 In   may increase the likelihood of varicella pneumonia, complicating the
CHAPTER 45            Respiratory Diseases in Pregnancy             933
primary infection.52 Treatment with acyclovir is safe in pregnancy. In          pattern of congenital abnormalities.71 A dose of 7.5 mg/kg given intra-
one report,52 there was one intrauterine fetal death. Another report51          venously every 8 hours has been recommended.72
documented a 5.2% incidence of varicella pneumonia among gravidas                   Varicella vaccine is an attenuated live virus vaccine that was added
with varicella-zoster infection. The investigators also reported that           to the universal childhood immunization schedule in the United States
gravidas who smoke or manifest more than 100 skin lesions are more              in 1995. The program of universal childhood vaccination against vari-
likely to develop pneumonia.51 Varicella pneumonia occurs most often            cella in the United States has resulted in a sharp decline in the rate of
in the third trimester, and the infection is likely to be severe.52,68,69 The   death from varicella. However, varicella vaccine is not recommended
maternal mortality rate for varicella pneumonia may be as high as               for use in pregnancy. The overall decline in incidence of adult varicella
35% to 40%, compared with 11% to 17% for nonpregnant individu-                  infection because of childhood vaccination will likely result in a
als.52,69 Although one review reported a decreased mortality rate, with         decreased incidence of varicella infection and varicella pneumonia
only three deaths among 28 women with varicella pneumonia,68                    during pregnancy.
another study documented a maternal mortality rate of 35%.52                        A study73 assessed the risk of congenital varicella syndrome and
However, a later report documented 100% survival among 18 gravidas              other birth defects in offspring of women who inadvertently received
with varicella pneumonia who were treated with acyclovir.51 In this             varicella vaccine during pregnancy or within 3 months of conception.
report, there was one intrauterine fetal death at 25 weeks’ gestation in        Fifty-eight women received their first dose of varicella vaccine during
a woman with varicella. In one report of 312 pregnancies, there was             the first or second trimester. No cases (0%) of congenital varicella
no increase in the number of birth defects and no consistent pattern            syndrome were identified among 56 live births (CI, 0 to 15.6). Among
of congenital abnormalities. In another report, 17 other infants were           the prospective reports of live births, five congenital anomalies were
delivered beyond 36 weeks, and there was no evidence of neonatal                identified in the susceptible cohort or the sample population as a
varicella.51                                                                    whole. The investigator suggested that although the numbers in the
    Varicella pneumonia usually manifests 2 to 5 days after the onset           study were small, the results should provide some reassurance to health
of fever, rash, and malaise and is heralded by the onset of pulmonary           care providers and women with inadvertent exposure before or during
symptoms, including cough, dyspnea, pruritic chest pain, and hemop-             pregnancy.
tysis.52 The severity of the illness may vary from asymptomatic radio-
graphic abnormalities to fulminant pneumonitis and respiratory                  Pneumocystis jiroveci
failure (Fig. 45-4).52,70                                                       Infection with the HIV virus significantly increases the risk for pulmo-
    All gravidas with varicella pneumonia should be aggressively treated        nary infection. S. pneumoniae and H. influenzae are the most com-
with antiviral therapy and admitted to the intensive care unit for close        monly isolated organisms.73 One report74 also identified Pseudomonas
observation or intubation if indicated. Acyclovir, a DNA polymerase             aeruginosa as a significant cause of bacterial pneumonia in HIV-
inhibitor, should be started. The early use of acyclovir was associated         infected individuals. Pneumocystis pneumonia, an AIDS-defining
with an improved hospital course after the 5th day and a lower mean             illness, occurs more frequently when the helper T-cell count (CD4+) is
temperature, lower respiratory rate, and improved oxygenation.52                less than 200 cells/mm3. Pneumocystis jiroveci pneumonia (PJP), for-
Treatment with acyclovir is safe in pregnancy. Among 312 pregnancies,           merly designated Pneumocystis carinii pneumonia (PCP), is the most
there was no increase in the number of birth defects and no consistent          common of the serious opportunistic infections in pregnant women
                                                                                infected with HIV.75,76 P. jiroveci is the number one cause of pregnancy-
                                                                                associated AIDS deaths in the United States.77 Initial reports of PJP in
                                                                                pregnancy described a 100% maternal mortality rate.47,75,78-80 However,
                                                                                in a 2001 review of 22 cases of PJP in pregnancy, the mortality rate was
                                                                                50% (11 of 22 patients).81 However, the mortality rate is still higher
                                                                                than that reported for HIV-infected nonpregnant individuals.81 In that
                                                                                series, respiratory failure developed in 13 patients, and 59% required
                                                                                mechanical ventilation. The survival rate of gravidas requiring mechan-
                                                                                ical ventilation was 31%. In this series, maternal and fetal outcomes
                                                                                were better in cases of PJP that occurred during the third trimester of
                                                                                pregnancy.
                                                                                    A high index of suspicion is necessary when gravidas at risk for HIV
                                                                                infection present with symptoms such as weight loss, fatigue, fever,
                                                                                tachypnea, dyspnea, and nonproductive cough.75 The onset of disease
                                                                                can be insidious, including normal radiographic findings, and it can
                                                                                then proceed to rapid deterioration.75 When the chest radiograph is
                                                                                positive, it typically exhibits bilateral alveolar disease in the perihilar
                                                                                regions and lower lung fields (Fig. 45-5), which can progress to include
                                                                                the entire parenchyma.75 Diagnosis can be accomplished by means of
                                                                                sputum silver stains, bronchial aspiration, or bronchoscope-directed
                                                                                biopsy.82 Lung biopsy is recommended for definitive diagnosis.78
                                                                                    Therapy for PJP in pregnancy includes trimethoprim-sulfamethox-
                                                                                azole (TMP-SMX), which is a category C drug. Gravidas with a history
                                                                                of PJP, a CD4+ lymphocyte count of less than 200/mm3, or oral pha-
FIGURE 45-4 Varicella pneumonia. The chest radiograph                           ryngeal candidiasis should receive prophylaxis.83 TMP-SMX is the drug
demonstrates bilateral nodular and interstitial pneumonia of varicella          of choice and may provide cross protection against toxoplasmosis
pneumonia.                                                                      and other bacterial infections.84 The usual dose is one double-strength
934      CHAPTER 45             Respiratory Diseases in Pregnancy

                                                                            Pneumocystis pneumonia with TMP-SMX in HIV-infected adults,
                                                                            including pregnant women and patients receiving highly active anti-
                                                                            retroviral therapy, should begin when the CD4+ cell count is less than
                                                                            200 cells/mm3 or there is a history of oropharyngeal candidiasis. Pro-
                                                                            phylaxis should be discontinued when the CD4+ cell count increases
                                                                            to more than 200 cells/mm3 for a period of 3 months.



                                                                            Tuberculosis in Pregnancy
                                                                            Tuberculosis kills more than 1 million women per year worldwide, and
                                                                            it is estimated that 646 million women and girls are already infected
                                                                            with tuberculosis. In women between 15 and 44 years old in developing
                                                                            countries, tuberculosis is the third most common cause of morbidity
                                                                            and mortality combined, and tuberculosis kills more women than any
                                                                            other infectious disease, including malaria and AIDS.
                                                                                Case-notification rates from countries with a high prevalence of
                                                                            tuberculosis suggest that tuberculosis may be less common among
                                                                            females.86 Epidemiologic information shows differences between men
                                                                            and women in prevalence of infection, rate of progression from infec-
                                                                            tion to disease, incidence of clinical disease, and mortality resulting
                                                                            from tuberculosis. Seventy percent more smear-positive male than
                                                                            female tuberculosis patients are diagnosed every year and reported to
                                                                            the World Health Organization.86 Differences between males and
                                                                            females have also been shown in the development and outcome of
FIGURE 45-5 Pneumocystis jiroveci pneumonia (PJP). Bilateral                active disease, with female cases having a higher progression from
alveolar disease is consistent with PJP pneumonia.                          infection to disease and a higher case-fatality rate.87 The conclusion
                                                                            of a research workshop on gender and tuberculosis was that a com-
                                                                            bination of biologic and social factors is responsible for these
tablet (150 mg/m2 of TMP and 750 mg/m2 of SMX given three times             differences.86
each week). Adverse reactions such as drug allergy, nausea, fever, neu-         The incidence of tuberculosis in the United States began to decline
tropenia, anemia, thrombocytopenia, and elevated transaminase levels        in the early part of the 20th century and fell steadily until 1953, when
have been reported in 20% to 30% of nonpregnant individuals receiv-         the introduction of isoniazid led to a dramatic decrease in the number
ing TMP-SMX therapy.84 Complete blood cell count with a differential        of cases, from 84,000 cases in 1953 to 22,255 cases in 1984.88 However,
cell count and liver function tests should be obtained every 6 to 8 weeks   since 1984, there have been significant changes in tuberculosis morbid-
to monitor for toxicity. Other regimens used for prophylaxis for indi-      ity trends. From 1985 through 1991, reported cases of tuberculosis
viduals with intolerance to TMP-SMX include aerosolized pentami-            increased by 18%, representing approximately 39,000 more cases than
dine (300 mg every month by Respirgard II nebulizer) or dapsone             expected had the previous downward trend continued. This increase
(100 mg once daily). Hussain and colleagues85 found that the survival       results from many factors, including the HIV epidemic, deterioration
rate for patients treated with SMX alone was 71% (5 of 7 patients) and      in the health care infrastructure, and more cases among immigrants.88,89
that the rate with SMX and steroids was 60% (3 of 5 patients); the          Between 1985 and 1992, the number of tuberculosis cases among
overall survival rate for both groups was 66.6% (8 of 12 patients). The     women of childbearing age increased by 40%.90 One report described
investigators concluded that PJP has a more aggressive course during        tuberculosis-complicated pregnancies in 94.8 cases per 100,000
pregnancy, with increased morbidity and mortality.85 However, treat-        deliveries between 1991 and 1992.91
ment with SMX compared with other therapies may result in improved              The emergence of drug-resistant tuberculosis has become a serious
outcome. They also caution that withholding appropriate PJP prophy-         concern. In New York City in 1991, 33% of tuberculosis cases were
laxis may adversely affect maternal and fetal outcomes.85                   resistant to at least one drug, and 19% were resistant to isoniazid and
    PJP is a devastating opportunistic infection in pregnant women          rifampin. Multidrug resistance is an additional problem. Many centers
who are infected with HIV. The maternal mortality rate is extremely         advocate directly observed therapy in the treatment of multidrug-
high, and prophylaxis with TMP-SMX is indicated during the antepar-         resistant disease. Pregnancy complicates treatment of multidrug-
tum period for individuals with a CD4+ cell count less than 200/mm3         resistant tuberculosis for the following reasons:
or a history of oropharyngeal candidiasis and for individuals with a
prior history of PJP infection. Initiation of therapy during the ante-            Several antimycobacterial drugs are contraindicated during
partum period can also prevent the rare occurrence of perinatally                 gestation.
transmitted PJP.84 When a gravida is demonstrating symptoms consis-               Patients and physicians may fear the effects of chest
tent with a possible infection, a diligent search should be conducted to          radiography on the fetus.
quickly identify PJP as the cause of pneumonia. When PJP is untreated,            Untreated, infectious, multidrug-resistant tuberculosis may be
the maternal mortality rate can approach 100%. In summary, PJP                    vertically and laterally transmitted.92
pneumonia remains a dreaded complication of HIV infection and an
AIDS-defining illness. There is a very high maternal and fetal mortality       In one report,92 three patients had disease resulting from
rate when PJP complicates pregnancy. Primary prophylaxis against            multidrug-resistant M. tuberculosis, and one had disease resulting from
CHAPTER 45           Respiratory Diseases in Pregnancy           935
multidrug-resistant Mycobacterium bovis. Only one patient began                 Women with a positive PPD skin test result must be evaluated for
retreatment during pregnancy because her organism was susceptible           active tuberculosis with a thorough physical examination for extrapul-
to three antituberculosis drugs that were considered nontoxic to the        monary disease and a chest radiograph after they are beyond the first
fetus. Despite concern about teratogenicity of the second-line antitu-      trimester.54 Symptoms of active tuberculosis include cough (74%),
berculosis medications, careful timing of treatment initiation resulted     weight loss (41%), fever (30%), malaise and fatigue (30%), and hemop-
in clinical cure for the mothers, regardless of some complications          tysis (19%).97 Individuals with active pulmonary tuberculosis may have
because of chronic tuberculosis or therapy. In this series, all infants     radiographic findings, including adenopathy, multinodular infiltrates,
were born healthy and remained free of tuberculosis.92                      cavitation, loss of volume in the upper lobes, and upper medial retrac-
                                                                            tion of hilar markings (Fig. 45-6). The finding of acid-fast bacilli in
                                                                            early morning sputum specimens confirms the diagnosis of pulmo-
Diagnosis                                                                   nary tuberculosis. At least three first-morning sputum samples should
Most gravidas with tuberculosis in pregnancy are asymptomatic. All          be examined for the presence of acid-fast bacilli. If sputum cannot be
gravidas at high risk for tuberculosis (Table 45-1) should be screened      produced, sputum induction, gastric washings, or diagnostic bron-
with subcutaneous administration of intermediate-strength purified           choscopy may be indicated.
protein derivative (PPD). If anergy is suspected, control antigens such         Extrapulmonary tuberculosis occurs in up to 16% of cases in the
as candidal, mumps, or tetanus toxoids should be used.93 The sensitiv-      United States; however, the pattern may occur in 60% to 70% of all
ity of the PPD is 90% to 99% for exposure to tuberculosis. The tine         patients with AIDS.98 Extrapulmonary sites include lymph nodes,
test should not be used for screening because of its low sensitivity.       bone, kidneys, intestine, meninges, breasts, and endometrium. Extra-
    The onset of the recent tuberculosis epidemic stimulated the need       pulmonary tuberculosis appears to be rare in pregnancy.99 Extrapul-
for rapid diagnostic tests using molecular biology methods to detect        monary tuberculosis that is confined to the lymph nodes has no effect
M. tuberculosis in clinical specimens. Two direct amplification tests        on obstetric outcomes, but tuberculosis at other extrapulmonary
have been approved by the FDA, the Mycobacterium tuberculosis Direct        sites does adversely affect the outcome of pregnancy.100 Jana and col-
(MTD) Test (Gen-Probe, San Diego, CA) and the Amplicor Mycobac-             leagues100 documented that tuberculosis lymphadenitis did not affect
terium tuberculosis (MTB) Test (Roche Diagnostic Systems, Branch-           the course of pregnancy, labor, or perinatal outcome. However, com-
burg, NJ). Both tests amplify and detect M. tuberculosis 16S ribosomal      pared with control women, the 21 women with tubercular involvement
DNA.94 When testing acid-fast stained smear–positive respiratory            of other extrapulmonary sites had higher rates of antenatal hospitaliza-
specimens, each test has a sensitivity of greater than 95% and a speci-     tion (24% versus 2%; P < .0001), infants with low Apgar scores (≤6)
ficity of essentially 100% for detecting the M. tuberculosis complex.95,96   soon after birth (19% versus 3%; P = .01), and low-birth-weight
When testing acid-fast stained smear–negative respiratory specimens,        (<2500 g) infants (33% versus 11%; P = .01). Rarely, mycobacteria
the specificity 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




  TABLE 45-1          HIGH-RISK FACTORS FOR
                      TUBERCULOSIS
 Human immunodeficiency virus infection
 Close contact with persons known or suspected to have
   tuberculosis
 Medical risk factors known to increase risk for disease if infected
 Birth in a country with high tuberculosis prevalence
 Medically underserved status
 Low income
 Alcohol addiction
 Intravenous drug use
 Residency in a long-term care facility (e.g., correctional                 FIGURE 45-6 Chest radiograph of pulmonary tuberculosis.
   institutions, mental institutions, nursing homes and facilities)         Radiographic findings may include adenopathy, multinodular
 Health professionals working in high-risk health care facilities           infiltrates, cavitation, loss of volume in the upper lobes, and upper
                                                                            medial retraction of hilar markings.
936       CHAPTER 45              Respiratory Diseases in Pregnancy

invade the uteroplacental circulation, and congenital tuberculosis              resulted in a marginal increase in life expectancy because of the pre-
results.49,90,101 The diagnosis of congenital tuberculosis is based on one      vented isoniazid-related hepatitis and deaths, compared with no treat-
of the following factors90:                                                     ment or postpartum treatment. Antepartum treatment was the least
                                                                                expensive.104 Isoniazid should be accompanied by pyridoxine (vitamin
      Demonstration of primary hepatic complex or cavitating                    B6) supplementation (50 mg/day) to prevent the peripheral neuropa-
      hepatic granuloma by percutaneous liver biopsy at birth                   thy that is associated with isoniazid treatment. Women with an
      Infection of the maternal genital tract or placenta                       unknown or prolonged duration of PPD positivity (>2 years) should
      Lesions seen in the first week of life                                     receive isoniazid (300 mg/day) for 6 to 9 months after delivery. Isonia-
      Exclusion of the possibility of postnatal transmission by a               zid prophylaxis is not recommended for women older than 35 years
      thorough investigation of all contacts, including attendants              who have an unknown or prolonged PPD positivity in the absence of
                                                                                active disease. The use of isoniazid is discouraged in this group because
                                                                                of an increased risk for hepatotoxicity. Isoniazid is associated with
Prevention                                                                      hepatitis in pregnant and nonpregnant adults. However, monthly
Most gravidas with a positive PPD result in pregnancy are asymptom-             monitoring of liver function tests may prevent this adverse outcome.
atic and have no evidence of active disease; they are classified as infected     Among individuals receiving isoniazid, 10% to 20% will develop mildly
without active disease. The risk of progression to active disease is            elevated values detected on liver function tests. These changes resolve
highest in the first 2 years of conversion. It is important to prevent the       after the drug is discontinued.105
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             Treatment
positive PPD result and no evidence of active disease, the recom-               The gravida with active tuberculosis should be treated initially with
mended prophylaxis is isoniazid (300 mg/day), starting after the first           isoniazid (300 mg/day) combined with rifampin (600 mg/day) (Table
trimester and continuing for 6 to 9 months.54 Under base-case assump-           45-2).106 Resistant disease results from initial infection with resistant
tions in a Markov decision-analysis model, the fewest cases of tuber-           strains (33%) or can develop during therapy.107 The development of
culosis within the cohort occurred with antepartum treatment (1400              resistance is more likely in individuals who are noncompliant with
per 100,000), compared with no treatment (3300 per 100,000) or                  therapy. If resistance to isoniazid is identified or anticipated, 2.5 g of
postpartum treatment (1800 per 100,000).104 Antepartum treatment                ethambutol per day should be added, and the treatment period should



                                                                         PPD positive
                                                                   (without prior treatment)




                                           CXR                                                                     CXR
                                          normal                                                                 abnormal
                                                                                                    or other evidence of active disease


                    Respiratory                        No respiratory symptoms                       Three morning sputum samples
                    symptoms                                                                                 for smear/cx

                                                    “High risk”           Old conversion
                   Three morning                  or conversion            2 years or 1st
                 sputum samples for               within 2 years           positive PPD           Workup                       Workup
                 smear/cx or workup
               for extrapulmonary TB
                                                   Antepartum              If 35 years,
                                                     INH/B6                  postpartum          If 35 years,                 Immediate
                                                                               INH/B6              postpartum                 antepartum
                                                                                                     INH/B6                      3 drug
                Workup             Workup                                                                                       therapy



                Immediate         If 35 years,
                antepartum          postpartum
                   3 drug             INH/B6
                  therapy


           FIGURE 45-7 Algorithm for the management of a patient with a positive purified protein derivative (PPD) result. In
           women with known conversion within the past 2 years to a positive PPD result and no evidence of active disease, the
           recommended prophylaxis is 300 mg of isoniazid per day, starting after the first trimester and continuing for 6 to 9
           months. B6, pyridoxine; cx, culture; CXR, chest radiograph; INH, isoniazid, TB, tuberculosis.
CHAPTER 45            Respiratory Diseases in Pregnancy            937

  TABLE 45-2          ANTITUBERCULOSIS DRUGS

 Drug                       Dosage Route               Daily Dose                 Weekly Dose                   Major Adverse Reactions
 First-Line Drugs (for Initial Treatment)
 Isoniazid                PO, IM                10 mg/kg, up to 300 mg       15 mg/kg, up to 900 mg      Hepatic enzyme elevation, peripheral
                                                                                                           neuropathy hepatitis, hypersensitivity
 Rifampin                   PO                  10 mg/kg, up to 600 mg       10 mg/kg, up to 600 mg      Orange discoloration of secretions and
                                                                                                           urine; nausea, vomiting, hepatitis,
                                                                                                           febrile reaction, purpura (rare)
 Pyrazinamide               PO                  15-30 mg/kg, up to 2 g       50-70 mg/kg, twice          Hepatotoxicity, hyperuricemia, arthralgias,
                                                                                                           rash, gastrointestinal upset
 Ethambutol                 PO                  15 mg/kg, up to 2.5 g        50 mg/kg                    Optic neuritis (decreased red-green color
                                                                                                           discrimination, decreased visual
                                                                                                           acuity), rash
 Streptomycin               IM                  15 mg/kg, up to 1 g          25-30 mg/kg, up to 1 g      Ototoxicity, nephrotoxicity

 Second-Line Drugs (Daily Therapy)
 Capreomycin           IM                       15-30 mg/kg, up to 1 g                                   Auditory, vestibular, and renal toxicity
 Kanamycin             IM                       15-30 mg/kg, up to 1 g                                   Auditory and renal toxicity, rare
                                                                                                           vestibular toxicity
 Ethionamide                PO                  15-20 mg/kg, up to 1 g                                   Gastrointestinal disturbance,
                                                                                                           hepatotoxicity, hypersensitivity
 p-Amino-salicylic acid     PO                  150 mg/kg, up to 1 g                                     Gastrointestinal disturbance,
                                                                                                           hypersensitivity, hepatotoxicity,
                                                                                                           sodium load
 Cycloserine                PO                  15-20 mg/kg, up to 1 g                                   Psychosis, convulsions, rash

 IM, intramuscularly; PO, orally.




be extended to 18 months.108 Ethambutol is teratogenic in animals;            tive maternal sputum cultures.54 Infants of women with multidrug-
however, this effect has not been seen in humans.                             resistant tuberculosis should probably be placed with an alternative
    The most common side effect of ethambutol therapy is optic neu-           caregiver until there is no evidence of active disease in the mother.
ritis. Streptomycin should be avoided during pregnancy because it is          The newborn should also receive BCG vaccine and isoniazid prophy-
associated with cranial nerve VIII damage in neonates.109 Antitubercu-        laxis.92 Active tuberculosis in the neonate should be treated appropri-
lous agents not recommended for use in pregnancy include ethion-              ately with isoniazid and rifampin immediately on diagnosis or with
amide, streptomycin, capreomycin, kanamycin, cycloserine, and                 multiagent therapy if drug-resistant organisms are identified. Infants
pyrazinamide.54 However, case reports documenting the use of these            and children who are at high risk for intimate and prolonged exposure
antituberculous agents in pregnancy revealed no adverse fetal or neo-         to untreated or ineffectively treated persons should receive the BCG
natal effects. There were no congenital abnormalities, and pregnancy          vaccine.110
outcomes for the individuals treated were good. Untreated tuberculosis            In summary, high-risk gravidas should be screened for tuberculosis
has been associated with higher morbidity and mortality rates among           and treated appropriately with isoniazid prophylaxis for infection
pregnant women. The management of the gravida with multidrug-                 without overt disease and with dual antituberculous therapy for active
resistant tuberculosis should be individualized. The patient should be        disease. The newborn also should be screened for evidence of tuber-
counseled about the small risk of teratogenicity and understand that          culosis. Proper screening and therapy will lead to a good outcome for
the risk of postpartum transmission of tuberculosis to the infant may         the mother and infant in most cases.
be higher among those born to patients with drug-resistant tubercu-
losis. In patients with active disease at the time of delivery, separation
of the mother and newborn should be accomplished to prevent infec-
tion of the newborn.
                                                                              Asthma in Pregnancy
    Women who are being treated with antituberculous drugs may                Asthma may be the most common potentially serious medical condi-
breastfeed. Only 0.75% to 2.3% of isoniazid and 0.05% of rifampin are         tion to complicate pregnancy.111 Asthma is characterized by chronic
excreted into breast milk. Ethambutol excretion into breast milk is also      airway inflammation with increased airway responsiveness to a variety
minimal. However, if the infant is concurrently taking oral antituber-        of stimuli and airway obstruction that is partially or completely
culous therapy, excessive drug levels may be reached in the neonate,          reversible.111 Approximately 4% to 8% of pregnancies are complicated
and breastfeeding should be avoided. Breastfed infants of women               by asthma.112,113 The prevalence and morbidity rates for asthma are
taking isoniazid should receive a multivitamin supplement that                increasing, although the mortality rate has decreased in recent years.
includes pyridoxine.54 Neonates of women taking antituberculous                  Insight into the pathogenesis of asthma has changed with the rec-
therapy should have a PPD skin test at birth and again when 3 months          ognition that airway inflammation occurs in almost all cases. The
old. Infants born to women with active tuberculosis at the time of            medical management for asthma emphasizes treatment of airway
delivery should receive isoniazid prophylaxis (10 mg/kg/day) until            inflammation to decrease airway responsiveness and prevent asthma
maternal disease has been inactive for 3 months as evidenced by nega-         symptoms.
938      CHAPTER 45             Respiratory Diseases in Pregnancy

Diagnosis                                                                    Effects of Asthma on Pregnancy
The enlarging uterus elevates the diaphragm about 4 cm, reducing the         Existing studies on the effects of asthma on pregnancy have had incon-
functional residual capacity. However, there are no significant altera-       sistent results in regard to maternal and perinatal outcomes. For
tions in forced vital capacity, peak expiratory flow rate (PEFR), or          example, asthma has been associated with increased perinatal mortal-
forced expiratory volume in 1 second (FEV1) in normal pregnancies.           ity,117 hyperemesis gravidarum,118 hemorrhage,112,118,119 hypertension or
Shortness of breath at rest or with mild exertion is common and is           preeclampsia,118-125 preterm birth,118,122,123,126-128 hypoxia at birth,118 low
often referred to as physiologic dyspnea of pregnancy. Asthma is char-       birth weight,118,129 increased cesarean section,119,121,122,126,129 small-
acterized by paroxysmal or persistent symptoms, including breathless-        for-gestational-age status or intrauterine growth restriction,122,123,130
ness, chest tightness, cough, and sputum production. The diagnosis of        gestational diabetes,119,126 and anomalies.122
asthma is based on a history of symptoms and results of spirometry.              In contrast, asthma has not been associated with prematur-
Patients with asthma have improved FEV1 after administration of a            ity,112,117,129-132 malformations,112,118,121,123,131 birth injury,118 increased
short-acting, inhaled β2-agonist and increased sensitivity to inhaled        perinatal mortality,118 reduced gestational age,120,121,133-135 reduced mean
methacholine, although this test is not usually performed during             birth weight,120,121,129,134-136 perinatal death,119,121,131,135,137 low Apgar
pregnancy.                                                                   score,121 neonatal respiratory difficulty,121 antepartum or postpartum
    In 2004, the National Asthma Education and Prevention Program            hemorrhage,123,129,133 perinatal complications,124,129 gestational hyper-
(NAEPP) Working Group on Asthma and Pregnancy114 defined mild                 tension or preeclampsia,126,130,131,138 intrauterine growth restriction,126,131
intermittent, mild persistent, moderate persistent, and severe persistent    increased cesarean section,112,132,137 low birth weight,121,132,133,136,137 gesta
asthma according to daytime and nighttime symptoms (e.g., wheezing,          tional diabetes,112,124 or respiratory distress syndrome.112
cough, dyspnea) and objective tests of pulmonary function. The most              Many of these studies have methodologic inadequacies, including
commonly used pulmonary function parameters are the PEFR and                 low power, variable inclusion criteria, little or no information regard-
FEV1. The NAEPP guidelines suggest classifying asthma severity in            ing asthma management or control, and time frames that do not reflect
patients not on symptom-controlling drugs and asthma control in              current management. Some positive findings may result from non-
patients on symptom-controlling medications (Table 45-3).115 Preg-           existent or inadequate control for confounders such as oral corticoste-
nant patients with mild asthma according to symptoms and pulmo-              roid treatment, ethnicity, smoking status, obesity, socioeconomic
nary function who nonetheless required regular medications to control        status, and hypertension. Another potential explanation for inconsis-
their asthma are similar to those with moderate asthma with respect          tencies is that most of these studies did not classify asthma severity.
to asthma exacerbations; those requiring regular systemic corticoste-        Classification of asthma severity has important clinical implications in
roids to control asthma symptoms were similar to severe asthmatics           regard to asthma morbidity and tailoring optimal treatment regi-
with respect to exacerbations.116                                            mens.139,140 Asthma medications and poor asthma control leading to
                                                                             hypoxia may explain some of these observations.141 Some data support
                                                                             a relationship between poor asthma control, as indicated by hospital-
Effects of Pregnancy on Asthma                                               ization for exacerbations or decreased FEV1 values, and low birth
Asthma has been associated with considerable maternal morbidity. In          weight and low ponderal index.137,141,142 Studies have shown that women
a large, prospective study of pregnant women, those with mild asthma         with more severe asthma may have the greatest risk for complications
had an exacerbation rate of 12.6% and hospitalization rate of 2.3%;          during pregnancy,122,126,127,143 whereas better-controlled asthma is
those with moderate asthma had an exacerbation rate of 25.7% and             associated with decreased risks.131,144,145 Poor control of asthma during
hospitalization rate of 6.8%; and severe asthmatics had an exacerba-         pregnancy may be caused by the physician’s reluctance to prescribe
tion rate of 51.9% and hospitalization rate of 26.9%.116 The effects of      medications during pregnancy. Women with asthma significantly
pregnancy on asthma vary. In a large, prospective study, 23% improved        reduce their medications, especially inhaled and rescue corticosteroids,
and 30% became worse during pregnancy.116 One of the most impor-             during the first trimester.146
tant conclusions of this study is that pregnant women with mild or               There is considerable consistency among prospective studies of
even well-controlled asthma should be monitored by PEFR and FEV1             the effects of asthma during pregnancy. Eight prospective studies
testing during pregnancy.                                                    reporting maternal and neonatal outcomes with at least 100 subjects



  TABLE 45-3          CLASSIFICATION OF ASTHMA SEVERITY AND CONTROL IN PREGNANT PATIENTS
                                        Well Controlled*                     Not Well Controlled*                         Very Poorly Controlled*

 Signs and Symptoms                         Intermittent†          Mild Persistent†        Moderate Persistent†                 Severe Persistent†
 Symptom frequency/short-acting         ≤2 days per week          >2 days per week,        Daily symptoms                       Throughout the day
   β-agonist use                                                    but not daily
 Nighttime awakening                    ≤2 times per month        >2 times per month       >1 time per week                     ≥4 times per week
 Interference with normal activity      None                      Minor limitation         Some limitation                      Extremely limited
 FEV1 or peak flow (percent              >80%                      >80%                     60-80%                               <60%
   predicted/personal best)

 *Asthma control: assess in patients on long-term-control medications to determine whether step-up, step-down, or no change in therapy is indicated.
 †
  Asthma severity: assess severity for patients who are not on long-term-control medications, see Table 45-7 to determine starting controller therapy
 based on severity.
 FEV1, forced expiratory volume in 1 second.
CHAPTER 45                 Respiratory Diseases in Pregnancy        939
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       Management Approaches
mild or moderate asthma can have excellent maternal and perinatal                       The ultimate goal of asthma therapy during pregnancy is to maintain
outcomes (Table 45-4). These findings do not contradict the possibility                  adequate oxygenation of the fetus by prevention of hypoxic episodes
that suboptimal control of asthma during pregnancy is associated with                   in the mother. Other goals include achievement of minimal or no
increased risk to the mother or infant.145 Lower FEV1 values during                     maternal symptoms day or night, minimal or no exacerbations, no
pregnancy are significantly associated with increased risks for low birth                limitations of activities, maintenance of normal or near-normal pul-
weight and prematurity.148 The two largest studies indicate that classi-                monary function, minimal use of short-acting β2-agonists, and minimal
fication of asthma severity with therapy tailored according to asthma                    or no adverse effects from medications. Consultation or comanage-
severity can result in excellent perinatal and maternal outcomes.144,145                ment with an asthma specialist is appropriate for evaluation of the role
This generally confirms the findings of two earlier and smaller pro-                      of allergy and irritants, complete pulmonary function studies, or eval-
spective cohort studies131,133 in which asthma was managed by asthma                    uation of the medication plan if there are complications in achieving
specialists.                                                                            the goals of therapy or the patient has severe asthma. A team approach
    There are important caveats when interpreting this literature. Pro-                 is helpful if more than one clinician is managing the asthma and the
spective studies have tended to find fewer significant adverse associa-                   pregnancy. The effective management of asthma during pregnancy
tions, possibly because of better asthma surveillance and treatment.                    relies on four integral components: objective assessment, trigger
The excellent maternal and perinatal outcomes were achieved at centers                  avoidance, patient education, and pharmacologic therapy.
that tended to actively manage asthma during pregnancy. Women who
enroll in research studies tend to be more compliant and better moti-                   Objective Measures for Assessment
vated than the general public. The lack of finding more adverse out-                     and Monitoring
comes among women with severe asthma may also be a function of                          Subjective measures of lung function by the patient or physician
the relatively small numbers of this cohort and the resulting lack of                   provide an insensitive and inaccurate assessment of airway hyperre-
power to find adverse outcomes that were statistically significant.                       sponsiveness, airway inflammation, and asthma severity. The FEV1
Nonetheless, these prospective studies are reassuring in their consensus                value after a maximal inspiration is the single best measure of pulmo-
of good pregnancy outcomes among women with asthma. However,                            nary function. When adjusted for confounders, a mean FEV1 less than
they do not suggest that asthma should be considered to be a benign                     80% of the predicted value has been significantly associated with
condition, because active asthma management was a part of these                         increased preterm delivery at less than 32 weeks and less than 37 weeks
studies and might have positively influenced outcomes.                                   and with a birth weight less than 2500 g.148 However, measurement of




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

                                                                                                                                  Stenius-
                                                                  Stenius-           Schatz                                     Aarniala and
                         Dombrowski        Bracken et al,         Aarniala            et al,     Mihrshani        Jana et al,     Teramo,      Minerbi-Codish
                         et al, 2004145       2003144          et al, 1996133        1995131    et al, 2003124      1995137        1988121      et al, 1998132
  Outcomes                (N = 1739)         (N = 872)           (N = 504)          (N = 486)     (N = 340)        (N = 182)     (N = 181)        (N = 101)
  Preterm, < 32          No                NR                  NR                      NR            NR               NR            NR               NR
    weeks
  Preterm, < 37          No (yes if        No (yes if oral     No                      No            No               No            NR               No
    weeks                 severe)           steroids)
  Preeclampsia           No                No (yes if daily    No                      No            No               NR            Yes              No
                                            symptoms)
  Cesarean delivery      Yes (if           NR                  Yes (if                 NR            No               No            Yes              No
                           moderate                              elective)
                           or severe)
  Gestational            No (yes if        NR                  No                      No            NR               NR            No               No
    diabetes               severe)
  Small for              No                No (yes if daily    NR                      No            NR               NR            NR               No
    gestational age                         symptoms)
  Malformation           No                NR                  No                      No            NR               No            NR               No
  Antenatal              NR                NR                  No                      NR            NR               No            No               NR
    hemorrhage
  Postnatal              No                NR                  NR                      NR            NR               NR            NR               NR
    hemorrhage
  RDS/HMD                No                NR                  NR                      No            NR               NR            No               NR
  NEC                    No                NR                  NR                      No            NR               NR            NR               NR
  Perinatal death        No                NR                  No                      No            NR               No            No               NR
  NICU admission         No                NR                  No                      NR            No               NR            No               NR

 HMD, hyaline membrane disease; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; No, no significant association; NR, not reported;
 RDS, respiratory distress syndrome; Yes, significantly increased.
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  • 1. Chapter 45 Respiratory Diseases in Pregnancy Janice E. Whitty, MD, and Mitchell P. Dombrowski, MD Proper functioning of the cardiorespiratory system is imperative to nonpregnant women, it is likely that this phenomenon results from achieve adequate oxygenation of maternal and fetal tissues. The mater- progestational influences.5,6 The PaCO2 is linearly and inversely related nal cardiorespiratory system undergoes significant changes during to the log of the progesterone concentration.7 Wilbrand and colleagues8 gestation to optimize oxygen delivery to the fetus and maternal tissues. reported that progesterone lowers the carbon dioxide threshold of the Pulmonary disease is one of the most frequent maternal complications respiratory center. During pregnancy, the sensitivity of the respiratory during pregnancy, and it may result in significant morbidity or mortal- center increases9 so that an increase in PaCO2 of 1 mm Hg increases ity for the mother and her fetus. Depending on the specific diagnosis, ventilation by 6 L/min in pregnancy, compared with 1.5 L/min in the other maternal complications of pregnancy may have an adverse or nonpregnant state.1,10,11 It is possible that progesterone acts as a primary positive impact on the pulmonary function of the gravida. stimulant to the respiratory center independently of any change in In this chapter, we briefly review the physiologic adaptations of carbon dioxide sensitivity or threshold.4 In addition to stimulating the respiratory system that occur during gestation. Specific respir- ventilation, progesterone may also increase levels of carbonic anhy- atory diseases that occur in pregnancy and the effects of the disease on drase B in the red blood cell.12 Schenker and associates13 reported that pregnancy and pregnancy on the disease are discussed. The obstetri- carbonic anhydrase levels increase in pregnant patients and in women cian should realize that most diagnostic tests useful in evaluating pul- taking oral contraceptives. An increase in the carbonic anhydrase level monary function during gestation are not harmful to the fetus and, if facilitates carbon dioxide transfer and tends to decrease PaCO2 inde- indicated, should be performed. Most medications used to treat respi- pendently of any change in ventilation. This respiratory stimulant ratory disease in pregnancy are also well tolerated by the fetus. With effect of progesterone has been used in the treatment of respiratory few exceptions, the diagnostic and treatment algorithms for respiratory failure and emphysema.6,14,15 disease closely resemble those used for a nonpregnant woman. During gestation, ventilation is increased by the rise in tidal volume from approximately 500 to 700 mL in each breath.1,16-18 Because there is no change in respiratory rate, minute ventilation rises from about 7.5 to 10.5 L/min.11,17,19 Minute ventilation increases in the first trimes- Physiologic Changes of the ter and remains at that level throughout pregnancy. The physiologic Respiratory System dead space is increased by about 60 mL in pregnancy. This may result from dilation of the small airways.11 Residual volume is reduced by Because there is no increase in respiratory rate, the increase in maternal about 20%,16 from 1200 to 1000 mL.20-22 The vital capacity, which is minute ventilation results from an increase in tidal volume.1 The the maximum volume of gas that can be expired after a maximum almost 50% increase in tidal volume occurs at the expense of an 18% inspiration, does not change in pregnancy.16,21-25 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 Anatomic Changes of the 104 mm Hg).2 The PaCO2 decreases early in pregnancy in parallel with the change in ventilation; however, a further progressive decrease in Respiratory System PaCO2 may occur.3 The decrease in PaCO2 is even greater at altitudes Observed changes in the configuration of the chest during pregnancy where the mother exhibits compensatory hyperventilation in an are in keeping with the findings of no change in vital capacity and a attempt to maintain the arterial partial pressure of oxygen as high as reduction in residual volume. The effect of pregnancy on pulmonary possible. The decrease in PaCO2 is matched by an equivalent increase mechanics has been compared with the effect of a pneumoperitoneum. in renal excretion of and decrease in plasma bicarbonate concentra- In both situations, the residual lung volume is decreased, but ventila- tion; therefore, arterial pH is not altered from the normal nonpregnant tion remains unimpaired. Radiologic studies performed early in preg- level of about 7.4. nancy have shown that the subcostal angle increases from 68 to 103 It has been suggested that the hyperventilation of pregnancy results degrees before there is any mechanical pressure from the enlarging primarily from progesterone acting as a respiratory stimulant.4 Because uterus.26 The level of the diaphragm rises by about 4 cm, and the hyperventilation has been observed during the luteal phase of the transverse diameter of the chest increases by 2 cm.27-29 These changes menstrual cycle and progesterone can produce similar changes in account for the decrease in residual volume because the lungs are
  • 2. 928 CHAPTER 45 Respiratory Diseases in Pregnancy relatively compressed during forced expiration; however, the excursion largely on hemoglobin concentration and arterial oxygen saturation. of the diaphragm in respiration increases by about 1.5 cm in pregnancy Oxygen delivery can be impaired by conditions that affect arterial compared with the nonpregnant state.29,30 oxygen content or cardiac output (flow), or both. Anemia leads to low arterial oxygen content because of a lack of hemoglobin binding sites for oxygen. Carbon monoxide poisoning likewise decreases oxyhemo- globin because of blockage of binding sites for oxygen. The patient Oxygen Delivery with hypoxemic respiratory failure does not have sufficient oxygen available to saturate the hemoglobin molecule. Desaturated hemoglo- and Consumption bin is altered structurally such that it has a diminished affinity for oxygen.33 Oxygen Delivery The amount of oxygen available to tissues also is affected by the All tissues require oxygen for the combustion of organic compounds affinity of the hemoglobin molecule for oxygen. The oxyhemoglobin to fuel cellular metabolism. The cardiopulmonary system delivers dissociation curve (Fig. 45-1) and the conditions that influence the a continuous supply of oxygen and other essential substrates to binding of oxygen negatively or positively must be considered when tissues. Oxygen delivery depends on oxygenation of blood in the lungs, attempts are made to maximize oxygen delivery.34 An increase in the oxygen-carrying capacity of the blood, and cardiac output.31 Under plasma pH level or a decrease in temperature or the concentration of normal conditions, oxygen delivery exceeds oxygen consumption by 2,3-diphosphoglycerate can increase hemoglobin affinity for oxygen, about 75%.32 The amount of oxygen delivered is determined by the shifting the curve to the left and resulting in diminished tissue oxygen- cardiac output (CO, L/min) times the arterial oxygen content (CaO2, ation. If the plasma pH level, temperature, or 2,3-diphosphoglycerate mL/O2/min): level increases, hemoglobin affinity for oxygen decreases, and more oxygen is available to tissues (see Fig. 45-1).34 Oxygen delivery = CO × CaO2 × 10 (700 to 1400 mL/min) In certain clinical conditions, such as septic shock and adult respi- ratory distress syndrome, there is maldistribution of flow relative to The arterial oxygen content is determined by the amount of oxygen oxygen demand, leading to diminished delivery and consumption of that is bound to hemoglobin (i.e., arterial blood saturation with oxygen oxygen. The release of vasoactive substances is hypothesized to result [SaO2]) and by the amount of oxygen that is dissolved in plasma (i.e., in the loss of normal mechanisms of vascular autoregulation, produc- arterial partial pressure of oxygen [PaO2 × 0.0031]): ing regional and microcirculatory imbalances in blood flow.35 This mismatching of blood flow with metabolic demand causes excessive CaO2 = (hemoglobin × 1.34 × SaO2) + (PaO2 × 0.0031) blood flow to some areas and relative hypoperfusion of other areas, (16 to 22 mL O2/dL) limiting optimal systemic use of oxygen.35 The patient with diminished cardiac output resulting from hypovolemia or pump failure is unable As can be seen in this formula, the amount of oxygen dissolved in to distribute oxygenated blood to tissues. Therapy directed at increas- plasma is negligible, and the arterial oxygen content therefore depends ing the volume with normal saline or with blood if the hemoglobin 100 90 pH DPG Temp 80 70 pH Percent oxyhemoglobin DPG 60 Temp 50 40 30 20 10 FIGURE 45-1 The oxygen-binding curve for human hemoglobin A under physiologic conditions (red 0 10 20 30 40 50 60 70 80 90 100 curve). The affinity is shifted by changes in pH, O2 tension (mm Hg) diphosphoglycerate (DPG) concentration, and temperature. P50 P50 is the oxygen tension at one-half saturation.
  • 3. CHAPTER 45 Respiratory Diseases in Pregnancy 929 level is less than 10 g/dL increases delivery of oxygen in the hypovole- venous oxygen tension is 40 mm Hg with a saturation of 73%. Satura- mic patient. The patient with cardiac failure may benefit from inotro- tions less than 60% are abnormally low. These parameters can be pic support and afterload reduction in addition to supplementation of measured directly by obtaining a blood sample from the distal port of intravascular volume. ¯ the pulmonary artery catheter. The SVO2 also can be measured con- tinuously with special pulmonary artery catheters equipped with fiber- optics. Mixed venous oxygenation is a reliable parameter in the patient Relationship of Oxygen Delivery with hypoxemia or low cardiac output, but findings must be inter- to Consumption ¯ preted with caution. When the SVO2 is low, oxygen delivery can be Oxygen consumption is the product of the arteriovenous oxygen ¯ assumed to be low. However, normal or high SVO2 values do not guar- content difference (C(a−v)O2) and cardiac output (CO). Under normal antee that tissues are well oxygenated. In conditions such as septic conditions, oxygen consumption is a direct function of the metabolic shock and adult respiratory distress syndrome, the maldistribution of rate36: ¯ systemic flow may lead to an abnormally high SVO2 value in the face of severe tissue hypoxia.35 The oxygen dissociation curve must be con- Oxygen consumption = C(a−v)O2 × CO × 10 ¯ sidered when interpreting the SVO2 as an indicator of tissue oxygen- (180 to 280 mL/min) ation.33 Conditions that result in a left shift of the curve cause the venous oxygen saturation to be normal or high, even when the mixed The oxygen extraction ratio is the fraction of delivered oxygen that ¯ venous oxygen content is low. SVO2 is useful for monitoring trends in actually is consumed: a particular patient, because a significant decrease occurs when oxygen delivery has decreased because of hypoxemia or a decrease in cardiac Oxygen extraction ratio = O2 consumption/O2 delivery (0.25) output. The normal oxygen extraction ratio is about 25%. A rise in the oxygen extraction ratio is a compensatory mechanism used when Oxygen Delivery and Consumption oxygen delivery is inadequate for the level of metabolic activity. A in Pregnancy subnormal value suggests flow maldistribution, peripheral diffusion The physiologic anemia of pregnancy results in a reduction in the defects, or functional shunting.36 As the supply of oxygen is reduced, hemoglobin concentration and arterial oxygen content. Oxygen deliv- the fraction extracted from blood increases and oxygen consumption ery is maintained at or above normal despite this because of the 50% is maintained. If a severe reduction in oxygen delivery occurs, the limits increase in cardiac output. The pregnant woman therefore depends of oxygen extraction are reached, tissues are unable to sustain aerobic on cardiac output for maintenance of oxygen delivery more than the energy production, and consumption decreases. The level of oxygen nonpregnant patient.38 Oxygen consumption increases steadily delivery at which oxygen consumption begins to decrease is called throughout pregnancy and is greatest at term, reaching an average of critical oxygen delivery (Fig. 45-2).37 At the critical oxygen delivery level, 331 mL/min at rest and 1167 mL/min with exercise.11 During labor, tissues begin to use anaerobic glycolysis, with resultant lactate produc- oxygen consumption increases by 40% to 60%, and cardiac output tion and metabolic acidosis.37 If oxygen deprivation continues, irre- increases by about 22%.39,40 Because oxygen delivery normally far versible tissue damage and death ensue. exceeds consumption, the normal pregnant patient usually is able to maintain adequate delivery of oxygen to herself and her fetus, even during labor. When a pregnant patient has low oxygen delivery, she Mixed Venous Oxygenation very quickly can reach the critical oxygen delivery level during labor, The mixed venous oxygen tension and mixed venous oxygen saturation compromising herself and her fetus. The obstetrician therefore must (SVO2) are parameters of tissue oxygenation.37 The normal mixed ¯ make every effort to optimize oxygen delivery before allowing labor to begin in the compromised patient. Pneumonia in Pregnancy Pneumonia is fortunately a rare complication of pregnancy, occurring O2 consumption in 1 of 118 to 2288 deliveries.41,42 However, pneumonia contributes to considerable maternal mortality and is reportedly the most common non-obstetric infection to cause maternal mortality in the peripartum period.43 Maternal mortality was as high as 24% before the introduc- tion of antibiotic therapy.44 Research reports have documented a dra- matic decrease in maternal mortality from 0% to 4% with modern management and antibiotic therapy.42,45,46 Preterm delivery is a signifi- DO2crit cant complication of pneumonia complicating pregnancy. Even with antibiotic therapy and modern management, preterm delivery con- O2 delivery tinues to occur for 4% to 43% of gravidas who have pneumonia.42,45,46 FIGURE 45-2 Relationship of oxygen consumption (VO2) and The increasing incidence of pneumonia in pregnancy may reflect oxygen delivery (DO2). At the point of critical oxygen delivery, the declining general health status of certain segments of the childbear- tissues begin to use anaerobic glycolysis, with resultant lactate ing population (e.g., morbid obesity).46 The epidemic of human production and metabolic acidosis. If the oxygen deprivation immunodeficiency virus (HIV) infection has increased the number of continues, irreversible tissue damage and death ensue. potential mothers who are at risk for opportunistic lung infections.
  • 4. 930 CHAPTER 45 Respiratory Diseases in Pregnancy HIV infection is also associated with increased risks of invasive pneu- Pneumonia in pregnancy has several causes, including mumps, mococcal disease (odds ratio [OR] = 41.8) and Legionnaire disease infectious mononucleosis, swine influenza, influenza A, varicella, coc- (OR = 41.8).47 HIV infection further predisposes the pregnant woman cidioidomycosis, and other fungi.50 Varicella pneumonia can compli- to the infectious complications of acquired immunodeficiency syn- cate primary varicella infections in 5.2% to 9%51 of infections in drome (AIDS).47,48 Reported incidence rates range from 97 to 290 cases pregnancy, compared with 0.3% to 1.8% in the nonpregnant popula- per 1000 HIV-infected persons per year. HIV-infected persons are 7.8 tion.52 Influenza A has a higher mortality rate among pregnant women times more likely to develop pneumonia than non-HIV-infected indi- than among nonpregnant patients.53 The increase in virulence of viral viduals with similar risk factors. Women with medical conditions that infections reported in pregnancy may result from the alterations in increase the risk for pulmonary infection, such as cystic fibrosis (CF), maternal immune status that characterize pregnancy, including are living to childbearing age more frequently than in the past. This reduced lymphocyte proliferative response, reduced cell-mediated disorder contributes to the increased incidence of pneumonia in cytotoxicity by lymphocytes, and a decrease in the number of helper pregnancy. T lymphocytes.53,54 Viral pneumonias can also be complicated by Pneumonia can complicate pregnancy at any time during gestation superimposed bacterial infection, particularly pneumococcus. and may be associated with preterm birth, poor fetal growth, 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 Aspiration Pneumonia delivered during the course of their acute illness, and there were two Mendelson syndrome describes chemical pneumonitis resulting from maternal deaths. Another report described 39 cases of pneumonia in the aspiration of gastric contents in pregnancy. Chemical pneumonitis pregnancy.45 Sixteen gravidas presented before 24 weeks’ gestation, 15 can be superinfected with pathogens present in the oropharynx and between 25 and 36 weeks’ gestation, and 8 after 36 weeks’ gestation. gastric juices, primarily anaerobes and gram-negative bacteria.45 Men- Twenty-seven patients in this series were followed to completion of delson’s original report of aspiration55 consisted of 44,016 nonfasted pregnancy; only two required delivery during the acute phase of pneu- obstetric patients between 1932 and 1945, and more than one half had monia. Of these 27 patients, 3 suffered a fetal loss, and 24 delivered received “operative intervention” with ether by mask without endotra- live fetuses, although there was one neonatal death resulting from cheal intubation. He described aspiration in 66 cases (rate of 1 case per prematurity. 667 patients). Although several of the patients were critically ill from Madinger and associates42 reported 25 cases of pneumonia their aspirations, most recovered within 24 to 36 hours, and only two occurring among 32,179 deliveries and observed that fetal and died from this complication (rate of 1 death per 22,008 patients). A obstetric complications were much more common than in earlier review described 37,282 vaginal deliveries; 85% were performed with studies. Preterm labor complicated 11 of 21 gestations. Eleven patients general anesthesia by mask and without intubation, and 65% to 75% had pneumonia at the time of delivery. Preterm delivery was more had ingested liquids or solid food within 4 hours of onset of labor.56 likely for women who had bacteremia, needed mechanical ventilation, The investigators found five mild cases of aspiration (1 per 7456 and had a serious underlying maternal disease. In addition to the patients) with no sequelae.56 Another report described one occurrence complication of preterm labor, there were three perinatal deaths in this of “mild aspiration” without adverse outcome among 1870 women series. Berkowitz and LaSala46 reported 25 patients with pneumonia undergoing nonintubated peripartum surgery with intravenous ket- complicating pregnancy; 14 women had term deliveries, 1 delivered amine, benzodiazepines, barbiturates, fentanyl, or some combination preterm, 3 had a voluntary termination of pregnancy, 3 had term of these drugs.57 Soreide and colleagues58 observed four episodes of deliveries of growth-restricted infants, and 4 were lost to follow-up. aspiration each during 36,800 deliveries and 3600 cesarean sections Birth weight was significantly lower in the study group in this series with no mortality. Based on these data, most hospitals permit free (2770 ± 224 g versus 3173 ± 99 g in the control group; P < .01). In this intake of clear liquids during labor. The risk of aspiration, pneumonia, series, pneumonia complicated 1 of 367 deliveries. The investigators and death from general anesthesia appears to be very low. This may attributed the increase in the incidence of pneumonia in this popula- reflect the use of modern techniques and therapy to reduce gastric tion to a decline in general health status, including anemia, a significant pH. incidence of cocaine use (52% versus 10% of the general population), and HIV positivity (24% versus 2% of the general population) in the study group. Bacterial Pneumonia Streptococcus pneumoniae (pneumococcus) is the most common bacte- rial pathogen that causes pneumonia in pregnancy; H. influenzae is the Bacteriology next most common. These pneumonias typically manifest as an acute Most series describing pneumonia complicating pregnancy have used illness accompanied by fever, chills, and a purulent, productive cough incomplete methodologies to diagnose the etiologic pathogens for and are seen as a lobar pattern on the chest radiograph (Fig. 45-3). pneumonia, relying primarily on cultures of blood and sputum. In Streptococcal pneumonia produces a “rusty” sputum, with gram- most cases, no pathogen was identified; however, pneumococcus and positive diplococci on Gram stain, and it demonstrates asymmetrical Haemophilus influenzae remain the most common identifiable causes consolidation with air bronchograms on the chest radiograph.54 H. of pneumonia in pregnancy.42,45,46 Because comprehensive serologic influenzae is a gram-negative coccobacillus that produces consolida- testing has rarely been done, the true incidence of viral, Legionella, and tion with air bronchograms, often in the upper lobes.54 Less common Mycoplasma pneumonia in pregnancy is difficult to estimate. The data bacterial pathogens include Klebsiella pneumoniae, which is a gram- presented by Benedetti, Madinger, Berkowitz, and their respective col- negative rod that causes extensive tissue destruction with air broncho- leagues all support pneumococcus as the predominant pathogen grams, pleural effusion, and cavitation seen on the chest radiograph. causing pneumonia in pregnancy and H. influenzae as the second most Patients with Staphylococcus aureus pneumonia present with pleuritis, common organism.42,45,46 In the series of Berkowitz and LaSala,46 one chest pain, purulent sputum, and consolidation without air broncho- patient was infected with Legionella species. grams identified on the chest radiograph.54
  • 5. CHAPTER 45 Respiratory Diseases in Pregnancy 931 The workup should include a physical examination, arterial blood gas determinations, a chest radiograph, sputum Gram stain and culture, and blood cultures. Several studies have called into question the use of cultures to identify the microbes of community-acquired pneumonia. Success rates for identification of the bacterial cause with cultures range from 2.1% to approximately 50%. Review of available clinical data reflects an overall reliance on clinical judgment and the patient’s response to treatment to guide therapy. Other tests are avail- able to identify the cause of pneumonia that do not require culture and are more sensitive and specific. An assay approved by the U.S. Food and Drug Administration (FDA) for pneumococcal urinary antigen has been assessed in several studies. The sensitivity for identifying pneumococcal disease in adults is reportedly 60% to 90%, with a specificity close to 100%. In one study, the pneumococcal antigen was detected in 26% of patients in whom no pathogens had been identified. This finding suggests that cases that are undiagnosed by standard test can be identified with the assay. In this study, 10% of samples from patients with pneumonia caused by other agents were positive on the pneumococcal assay, indicating a potential problem with specificity. If the response to therapy directed at pneumococcus is inadequate, cov- erage for other potential pathogens should be added. The test for Legionella urinary antigen has a sensitivity of 70% and specificity of 90% for serogroup 1. This is especially useful in the United States and Europe, because about 85% of Legionella isolates are serogroup 1. Legionella is a common cause of severe community- FIGURE 45-3 Right lower lobe pneumonia. Lobar consolidation in acquired pneumonia. The urinary antigen for serogroup 1 should be the right lower lobe is consistent with pneumococcal pneumonia. considered for any patient requiring admission into an intensive care unit for pneumonia. Percutaneous-transthoracic needle aspiration has been advocated Patients infected with atypical pneumonia pathogens, such as as a valuable and safe method to increase the chance of establishing Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia the causative agent for pneumonia. This test should be reserved for use pneumoniae (TWAR agent), present with gradual onset of symptoms. in compromised individuals, suspected tuberculosis in the absence of They have a lower fever, appear less ill, have mucoid sputum, and have a productive cough, selected cases of chronic pneumonia, pneumonia a patchy or interstitial infiltrate seen on the chest radiograph. The associated with neoplasm or a foreign body, suspected Pneumocystis severity of the findings on the chest radiograph usually is out of pro- jiroveci pneumonia, and suspected conditions that necessitate lung portion to the mild clinical symptoms. M. pneumoniae is the most biopsy. Cold agglutinins and Legionella titers may also be useful. common organism responsible for atypical pneumonia and is best Empiric antibiotic coverage should be started, usually with a third- detected by the presence of cold agglutinins in about 70% of cases. generation cephalosporin such as ceftriaxone or cefotaxime. Legionella The normal physiologic changes in the respiratory system associ- pneumonia has a high mortality rate and sometimes manifests with ated with pregnancy result in a loss of ventilatory reserve. Coupled consolidation, mimicking pneumococcal pneumonia. It is recom- with the immunosuppression that accompanies pregnancy, this puts mended that a macrolide, such as azithromycin, be added to the the mother and fetus at great risk from respiratory infection. Any empiric therapy. Dual coverage has been demonstrated to improve gravida suspected of having pneumonia should be managed aggres- response to therapy even for abbreviated macrolide regimens. This sively. The pregnant patient should be admitted to the hospital and a may reflect the added anti-inflammatory effect of the macrolides. thorough investigation undertaken to determine the cause. One study Azithromycin administration is an independent predictor of a positive examined 133 women admitted with pneumonia during pregnancy outcome and reduced length of hospital stay for patients with mild to using protocols based on the British Thoracic Society and American moderate community-acquired pneumonia. The use of macrolides to Thoracic Society admission guidelines for management of nonpreg- treat community-acquired pneumonia should be limited when possi- nant individuals. The investigators reported that if the American Tho- ble, because their use has also been associated with increased penicillin racic Society guidelines were used, 25% of the pregnant women with resistance by S. pneumoniae. pneumonia could have avoided admission. Using the American crite- When admission for pneumonia is required, there is evidence that ria, none of the gravidas who would have been managed as an outpa- inpatient and 30-day mortality rates have been reduced when antibiot- tient had any complications. If the British Thoracic Society guidelines ics are administered in less than 8 hours. Current U.S. federal standards had been used; 66% of the pregnant women in this group would have require that the first dose of antibiotics be administered within 4 hours been assigned to outpatient therapy. However, 14% would have of arrival to the hospital. After the results of the sputum culture, blood required readmission for complications. Most of the 133 women who cultures, Gram stain, and serum studies are obtained and a pathogen were hospitalized with pneumonia in this study did not receive a chest has been identified, antibiotic therapy can be directed toward the iden- radiograph for confirmation of the diagnosis. This limits the value of tified cause. The third-generation cephalosporins are effective agents the study for guiding admission criteria for pneumonia in pregnancy. for most pathogens causing a community-acquired pneumonia. They Until additional information is available, admission for all pregnant are also effective against penicillin-resistant S. pneumoniae. The qui- women with pneumonia is still recommended. nolones as a class should be avoided in pregnancy because they may
  • 6. 932 CHAPTER 45 Respiratory Diseases in Pregnancy damage developing fetal cartilage. However, with the emergence of contrast to the general population, pregnant women seem to be at highly resistant bacterial pneumonia, their use may be lifesaving and higher risk for influenza pneumonia.61,62 Epidemiologic data from the therefore justified in specific circumstances. The respiratory quino- 1918 to 1919 influenza A pandemic revealed a maternal mortality rate lones are effective against highly penicillin-resistant S. pneumoniae that approached 50% for pregnant women with influenza pneumo- strains, and their use does not increase resistance. The respiratory nia.63,64 Three types of influenza virus can cause human disease—A, B, quinolones include levofloxacin, gatifloxacin, and moxifloxacin. These and C—but most epidemic infections are caused by influenza A.50 are ideal agents for community-acquired pneumonia because they are Influenza A typically has an acute onset after a 1- to 4-day incubation highly active against penicillin-resistant strains of S. pneumoniae. They period and first manifests as high fever, coryza, headache, malaise, and are also active against Legionella and the other atypical pulmonary cough. In uncomplicated cases, results of the chest examination and pathogens. Another advantage is a favorable pharmacokinetic profile, chest radiograph are normal.50 If symptoms persist longer than 5 days, such that blood or lung levels are the same whether the drug is admin- especially in a pregnant woman, complications should be suspected. istered orally or intravenously. Arguments against more extensive Pneumonia may complicate influenza as the result of secondary bacte- respiratory quinolone use are based on concerns about the potential rial infection or viral infection of the lung parenchyma.50 In the epi- for developing resistance, the variable incidence of Legionella, and cost. demic of 1957, autopsies demonstrated that pregnant women died An additional caveat is that the respiratory quinolones are only par- most commonly of fulminant viral pneumonia, whereas nonpregnant tially effective against Mycobacterium tuberculosis. Evaluation for this patients died most often of secondary bacterial infection.65 infection should be done when considering the use of quinolones for A large, nested, case-control study evaluated the rate of influenza- pneumonia. related complications over 17 influenza seasons among women enrolled In addition to antibiotic therapy, oxygen supplementation should in the Tennessee Medicaid system. This study demonstrated a high risk be given. Frequent arterial blood gas measurements should be obtained for hospitalization for influenza-related reasons in low-risk pregnant to maintain partial pressure of oxygen at 70 mm Hg, a level necessary women during the last trimester of pregnancy. The study authors esti- to ensure adequate fetal oxygenation. Arterial saturation also can be mated that 25 of 10,000 women in the third trimester during the monitored with pulse oximetry. When the gravida is afebrile for 48 influenza season are hospitalized with influenza-related complications. hours and has signs of clinical improvement, an oral cephalosporin A later, matched-cohort study using the administrative database of can be started and intravenous therapy discontinued. A total of 10 to pregnant women enrolled in the Tennessee Medicaid system examined 14 days of treatment should be completed. pregnant women between the ages of 25 and 44 years with respiratory Pneumonia in pregnancy can be complicated by respiratory failure hospitalization during the 1985 to 1993 influenza seasons. In this requiring mechanical ventilation. If this occurs, team management population of pregnant women, those with asthma accounted for one should include the obstetrician, maternal-fetal medicine specialist, and half of all respiratory-related hospitalizations during the influenza intensivist. In addition to meticulous management of the gravida’s season. Among pregnant women with diagnosis of asthma, 6% required respiratory status, the patient should be maintained in the left lateral respiratory hospitalization during the influenza season (OR = 10.63; recumbent position to improve uteroplacental perfusion. The viable 95% confidence interval [CI], 8.61 to 13.83) compared with women fetus should be monitored with continuous fetal monitoring. If posi- without a medical comorbidity. This study detected no significant tive end-expiratory pressure greater than 10 cm H2O is required to increases in adverse perinatal outcome associated with respiratory hos- maintain oxygenation, central monitoring with a pulmonary artery pitalization during flu season. catheter should be instituted to adequately monitor volume status and Primary influenza pneumonia is characterized by rapid progression maintain maternal and uteroplacental perfusion. There is no evidence from a unilateral infiltrate to diffuse bilateral disease. The gravida may documenting that elective delivery results in overall improvement in develop fulminant respiratory failure requiring mechanical ventilation respiratory function,59 and elective delivery should be reserved for the and positive end-expiratory pressure. Aggressive therapy is indicated usual obstetric indications. However, if there is evidence of fetal com- when pneumonia complicates influenza in pregnancy. Antibiotics promise or profound maternal compromise and impending demise, should be started and directed at the likely pathogens that can cause delivery should be accomplished. secondary infection, including S. aureus, pneumococcus, H. influenzae, Pneumococcal polysaccharide vaccination prevents pneumococcal and certain enteric gram-negative bacteria. Antiviral agents, such as pneumonia in otherwise healthy populations with an efficacy of 65% oseltamivir and zanamivir, should also be considered.66 It has been to 84%. The vaccine is safe in pregnancy and should be administered recommended that the influenza vaccine be given routinely to gravidas to high-risk gravidas. Those at high risk include individuals with sickle in the second and third trimester of pregnancy to prevent the occur- cell disease with autosplenectomy, patients who have a surgical sple- rence of influenza and the development of pneumonia. Women at high nectomy, and individuals who are immunosuppressed. An additional risk for pulmonary complications, such as those with asthma, chronic advantage to maternal immunization with the pneumococcal vaccine obstructive pulmonary disease, cystic fibrosis, and splenectomy, should is that several studies have demonstrated there is significant transpla- be vaccinated regardless of the trimester to prevent the occurrence of cental transmission of vaccine-specific antibodies in infants at birth influenza and the development of secondary pneumonia. In addition and at 2 months. Colostrum and breast milk antibodies are also sig- to maternal protection, prospective studies have demonstrated higher nificantly increased in women who have received the pneumococcal cord blood antibody levels to influenza in infants born to mothers vaccine. immunized during pregnancy. There is a delay in the onset and decrease in severity of influenza in infants born with higher antibody levels. Viral Pneumonias Varicella Varicella-zoster virus is a DNA virus that usually causes a benign, self- Influenza limited illness in children, but it may infect up to 2% of all adults.67 An estimated 4 million cases of pneumonia and influenza occur annu- Varicella infection occurs in 0.7 of every 1000 pregnancies.68 Pregnancy ally in the United States, and it is the sixth leading cause of death.60 In may increase the likelihood of varicella pneumonia, complicating the
  • 7. CHAPTER 45 Respiratory Diseases in Pregnancy 933 primary infection.52 Treatment with acyclovir is safe in pregnancy. In pattern of congenital abnormalities.71 A dose of 7.5 mg/kg given intra- one report,52 there was one intrauterine fetal death. Another report51 venously every 8 hours has been recommended.72 documented a 5.2% incidence of varicella pneumonia among gravidas Varicella vaccine is an attenuated live virus vaccine that was added with varicella-zoster infection. The investigators also reported that to the universal childhood immunization schedule in the United States gravidas who smoke or manifest more than 100 skin lesions are more in 1995. The program of universal childhood vaccination against vari- likely to develop pneumonia.51 Varicella pneumonia occurs most often cella in the United States has resulted in a sharp decline in the rate of in the third trimester, and the infection is likely to be severe.52,68,69 The death from varicella. However, varicella vaccine is not recommended maternal mortality rate for varicella pneumonia may be as high as for use in pregnancy. The overall decline in incidence of adult varicella 35% to 40%, compared with 11% to 17% for nonpregnant individu- infection because of childhood vaccination will likely result in a als.52,69 Although one review reported a decreased mortality rate, with decreased incidence of varicella infection and varicella pneumonia only three deaths among 28 women with varicella pneumonia,68 during pregnancy. another study documented a maternal mortality rate of 35%.52 A study73 assessed the risk of congenital varicella syndrome and However, a later report documented 100% survival among 18 gravidas other birth defects in offspring of women who inadvertently received with varicella pneumonia who were treated with acyclovir.51 In this varicella vaccine during pregnancy or within 3 months of conception. report, there was one intrauterine fetal death at 25 weeks’ gestation in Fifty-eight women received their first dose of varicella vaccine during a woman with varicella. In one report of 312 pregnancies, there was the first or second trimester. No cases (0%) of congenital varicella no increase in the number of birth defects and no consistent pattern syndrome were identified among 56 live births (CI, 0 to 15.6). Among of congenital abnormalities. In another report, 17 other infants were the prospective reports of live births, five congenital anomalies were delivered beyond 36 weeks, and there was no evidence of neonatal identified in the susceptible cohort or the sample population as a varicella.51 whole. The investigator suggested that although the numbers in the Varicella pneumonia usually manifests 2 to 5 days after the onset study were small, the results should provide some reassurance to health of fever, rash, and malaise and is heralded by the onset of pulmonary care providers and women with inadvertent exposure before or during symptoms, including cough, dyspnea, pruritic chest pain, and hemop- pregnancy. tysis.52 The severity of the illness may vary from asymptomatic radio- graphic abnormalities to fulminant pneumonitis and respiratory Pneumocystis jiroveci failure (Fig. 45-4).52,70 Infection with the HIV virus significantly increases the risk for pulmo- All gravidas with varicella pneumonia should be aggressively treated nary infection. S. pneumoniae and H. influenzae are the most com- with antiviral therapy and admitted to the intensive care unit for close monly isolated organisms.73 One report74 also identified Pseudomonas observation or intubation if indicated. Acyclovir, a DNA polymerase aeruginosa as a significant cause of bacterial pneumonia in HIV- inhibitor, should be started. The early use of acyclovir was associated infected individuals. Pneumocystis pneumonia, an AIDS-defining with an improved hospital course after the 5th day and a lower mean illness, occurs more frequently when the helper T-cell count (CD4+) is temperature, lower respiratory rate, and improved oxygenation.52 less than 200 cells/mm3. Pneumocystis jiroveci pneumonia (PJP), for- Treatment with acyclovir is safe in pregnancy. Among 312 pregnancies, merly designated Pneumocystis carinii pneumonia (PCP), is the most there was no increase in the number of birth defects and no consistent common of the serious opportunistic infections in pregnant women infected with HIV.75,76 P. jiroveci is the number one cause of pregnancy- associated AIDS deaths in the United States.77 Initial reports of PJP in pregnancy described a 100% maternal mortality rate.47,75,78-80 However, in a 2001 review of 22 cases of PJP in pregnancy, the mortality rate was 50% (11 of 22 patients).81 However, the mortality rate is still higher than that reported for HIV-infected nonpregnant individuals.81 In that series, respiratory failure developed in 13 patients, and 59% required mechanical ventilation. The survival rate of gravidas requiring mechan- ical ventilation was 31%. In this series, maternal and fetal outcomes were better in cases of PJP that occurred during the third trimester of pregnancy. A high index of suspicion is necessary when gravidas at risk for HIV infection present with symptoms such as weight loss, fatigue, fever, tachypnea, dyspnea, and nonproductive cough.75 The onset of disease can be insidious, including normal radiographic findings, and it can then proceed to rapid deterioration.75 When the chest radiograph is positive, it typically exhibits bilateral alveolar disease in the perihilar regions and lower lung fields (Fig. 45-5), which can progress to include the entire parenchyma.75 Diagnosis can be accomplished by means of sputum silver stains, bronchial aspiration, or bronchoscope-directed biopsy.82 Lung biopsy is recommended for definitive diagnosis.78 Therapy for PJP in pregnancy includes trimethoprim-sulfamethox- azole (TMP-SMX), which is a category C drug. Gravidas with a history of PJP, a CD4+ lymphocyte count of less than 200/mm3, or oral pha- FIGURE 45-4 Varicella pneumonia. The chest radiograph ryngeal candidiasis should receive prophylaxis.83 TMP-SMX is the drug demonstrates bilateral nodular and interstitial pneumonia of varicella of choice and may provide cross protection against toxoplasmosis pneumonia. and other bacterial infections.84 The usual dose is one double-strength
  • 8. 934 CHAPTER 45 Respiratory Diseases in Pregnancy Pneumocystis pneumonia with TMP-SMX in HIV-infected adults, including pregnant women and patients receiving highly active anti- retroviral therapy, should begin when the CD4+ cell count is less than 200 cells/mm3 or there is a history of oropharyngeal candidiasis. Pro- phylaxis should be discontinued when the CD4+ cell count increases to more than 200 cells/mm3 for a period of 3 months. Tuberculosis in Pregnancy Tuberculosis kills more than 1 million women per year worldwide, and it is estimated that 646 million women and girls are already infected with tuberculosis. In women between 15 and 44 years old in developing countries, tuberculosis is the third most common cause of morbidity and mortality combined, and tuberculosis kills more women than any other infectious disease, including malaria and AIDS. Case-notification rates from countries with a high prevalence of tuberculosis suggest that tuberculosis may be less common among females.86 Epidemiologic information shows differences between men and women in prevalence of infection, rate of progression from infec- tion to disease, incidence of clinical disease, and mortality resulting from tuberculosis. Seventy percent more smear-positive male than female tuberculosis patients are diagnosed every year and reported to the World Health Organization.86 Differences between males and females have also been shown in the development and outcome of FIGURE 45-5 Pneumocystis jiroveci pneumonia (PJP). Bilateral active disease, with female cases having a higher progression from alveolar disease is consistent with PJP pneumonia. infection to disease and a higher case-fatality rate.87 The conclusion of a research workshop on gender and tuberculosis was that a com- bination of biologic and social factors is responsible for these tablet (150 mg/m2 of TMP and 750 mg/m2 of SMX given three times differences.86 each week). Adverse reactions such as drug allergy, nausea, fever, neu- The incidence of tuberculosis in the United States began to decline tropenia, anemia, thrombocytopenia, and elevated transaminase levels in the early part of the 20th century and fell steadily until 1953, when have been reported in 20% to 30% of nonpregnant individuals receiv- the introduction of isoniazid led to a dramatic decrease in the number ing TMP-SMX therapy.84 Complete blood cell count with a differential of cases, from 84,000 cases in 1953 to 22,255 cases in 1984.88 However, cell count and liver function tests should be obtained every 6 to 8 weeks since 1984, there have been significant changes in tuberculosis morbid- to monitor for toxicity. Other regimens used for prophylaxis for indi- ity trends. From 1985 through 1991, reported cases of tuberculosis viduals with intolerance to TMP-SMX include aerosolized pentami- increased by 18%, representing approximately 39,000 more cases than dine (300 mg every month by Respirgard II nebulizer) or dapsone expected had the previous downward trend continued. This increase (100 mg once daily). Hussain and colleagues85 found that the survival results from many factors, including the HIV epidemic, deterioration rate for patients treated with SMX alone was 71% (5 of 7 patients) and in the health care infrastructure, and more cases among immigrants.88,89 that the rate with SMX and steroids was 60% (3 of 5 patients); the Between 1985 and 1992, the number of tuberculosis cases among overall survival rate for both groups was 66.6% (8 of 12 patients). The women of childbearing age increased by 40%.90 One report described investigators concluded that PJP has a more aggressive course during tuberculosis-complicated pregnancies in 94.8 cases per 100,000 pregnancy, with increased morbidity and mortality.85 However, treat- deliveries between 1991 and 1992.91 ment with SMX compared with other therapies may result in improved The emergence of drug-resistant tuberculosis has become a serious outcome. They also caution that withholding appropriate PJP prophy- concern. In New York City in 1991, 33% of tuberculosis cases were laxis may adversely affect maternal and fetal outcomes.85 resistant to at least one drug, and 19% were resistant to isoniazid and PJP is a devastating opportunistic infection in pregnant women rifampin. Multidrug resistance is an additional problem. Many centers who are infected with HIV. The maternal mortality rate is extremely advocate directly observed therapy in the treatment of multidrug- high, and prophylaxis with TMP-SMX is indicated during the antepar- resistant disease. Pregnancy complicates treatment of multidrug- tum period for individuals with a CD4+ cell count less than 200/mm3 resistant tuberculosis for the following reasons: or a history of oropharyngeal candidiasis and for individuals with a prior history of PJP infection. Initiation of therapy during the ante- Several antimycobacterial drugs are contraindicated during partum period can also prevent the rare occurrence of perinatally gestation. transmitted PJP.84 When a gravida is demonstrating symptoms consis- Patients and physicians may fear the effects of chest tent with a possible infection, a diligent search should be conducted to radiography on the fetus. quickly identify PJP as the cause of pneumonia. When PJP is untreated, Untreated, infectious, multidrug-resistant tuberculosis may be the maternal mortality rate can approach 100%. In summary, PJP vertically and laterally transmitted.92 pneumonia remains a dreaded complication of HIV infection and an AIDS-defining illness. There is a very high maternal and fetal mortality In one report,92 three patients had disease resulting from rate when PJP complicates pregnancy. Primary prophylaxis against multidrug-resistant M. tuberculosis, and one had disease resulting from
  • 9. CHAPTER 45 Respiratory Diseases in Pregnancy 935 multidrug-resistant Mycobacterium bovis. Only one patient began Women with a positive PPD skin test result must be evaluated for retreatment during pregnancy because her organism was susceptible active tuberculosis with a thorough physical examination for extrapul- to three antituberculosis drugs that were considered nontoxic to the monary disease and a chest radiograph after they are beyond the first fetus. Despite concern about teratogenicity of the second-line antitu- trimester.54 Symptoms of active tuberculosis include cough (74%), berculosis medications, careful timing of treatment initiation resulted weight loss (41%), fever (30%), malaise and fatigue (30%), and hemop- in clinical cure for the mothers, regardless of some complications tysis (19%).97 Individuals with active pulmonary tuberculosis may have because of chronic tuberculosis or therapy. In this series, all infants radiographic findings, including adenopathy, multinodular infiltrates, were born healthy and remained free of tuberculosis.92 cavitation, loss of volume in the upper lobes, and upper medial retrac- tion of hilar markings (Fig. 45-6). The finding of acid-fast bacilli in early morning sputum specimens confirms the diagnosis of pulmo- Diagnosis nary tuberculosis. At least three first-morning sputum samples should Most gravidas with tuberculosis in pregnancy are asymptomatic. All be examined for the presence of acid-fast bacilli. If sputum cannot be gravidas at high risk for tuberculosis (Table 45-1) should be screened produced, sputum induction, gastric washings, or diagnostic bron- with subcutaneous administration of intermediate-strength purified choscopy may be indicated. protein derivative (PPD). If anergy is suspected, control antigens such Extrapulmonary tuberculosis occurs in up to 16% of cases in the as candidal, mumps, or tetanus toxoids should be used.93 The sensitiv- United States; however, the pattern may occur in 60% to 70% of all ity of the PPD is 90% to 99% for exposure to tuberculosis. The tine patients with AIDS.98 Extrapulmonary sites include lymph nodes, test should not be used for screening because of its low sensitivity. bone, kidneys, intestine, meninges, breasts, and endometrium. Extra- The onset of the recent tuberculosis epidemic stimulated the need pulmonary tuberculosis appears to be rare in pregnancy.99 Extrapul- for rapid diagnostic tests using molecular biology methods to detect monary tuberculosis that is confined to the lymph nodes has no effect M. tuberculosis in clinical specimens. Two direct amplification tests on obstetric outcomes, but tuberculosis at other extrapulmonary have been approved by the FDA, the Mycobacterium tuberculosis Direct sites does adversely affect the outcome of pregnancy.100 Jana and col- (MTD) Test (Gen-Probe, San Diego, CA) and the Amplicor Mycobac- leagues100 documented that tuberculosis lymphadenitis did not affect terium tuberculosis (MTB) Test (Roche Diagnostic Systems, Branch- the course of pregnancy, labor, or perinatal outcome. However, com- burg, NJ). Both tests amplify and detect M. tuberculosis 16S ribosomal pared with control women, the 21 women with tubercular involvement DNA.94 When testing acid-fast stained smear–positive respiratory of other extrapulmonary sites had higher rates of antenatal hospitaliza- specimens, each test has a sensitivity of greater than 95% and a speci- tion (24% versus 2%; P < .0001), infants with low Apgar scores (≤6) ficity of essentially 100% for detecting the M. tuberculosis complex.95,96 soon after birth (19% versus 3%; P = .01), and low-birth-weight When testing acid-fast stained smear–negative respiratory specimens, (<2500 g) infants (33% versus 11%; P = .01). Rarely, mycobacteria the specificity 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 TABLE 45-1 HIGH-RISK FACTORS FOR TUBERCULOSIS Human immunodeficiency virus infection Close contact with persons known or suspected to have tuberculosis Medical risk factors known to increase risk for disease if infected Birth in a country with high tuberculosis prevalence Medically underserved status Low income Alcohol addiction Intravenous drug use Residency in a long-term care facility (e.g., correctional FIGURE 45-6 Chest radiograph of pulmonary tuberculosis. institutions, mental institutions, nursing homes and facilities) Radiographic findings may include adenopathy, multinodular Health professionals working in high-risk health care facilities infiltrates, cavitation, loss of volume in the upper lobes, and upper medial retraction of hilar markings.
  • 10. 936 CHAPTER 45 Respiratory Diseases in Pregnancy invade the uteroplacental circulation, and congenital tuberculosis resulted in a marginal increase in life expectancy because of the pre- results.49,90,101 The diagnosis of congenital tuberculosis is based on one vented isoniazid-related hepatitis and deaths, compared with no treat- of the following factors90: ment or postpartum treatment. Antepartum treatment was the least expensive.104 Isoniazid should be accompanied by pyridoxine (vitamin Demonstration of primary hepatic complex or cavitating B6) supplementation (50 mg/day) to prevent the peripheral neuropa- hepatic granuloma by percutaneous liver biopsy at birth thy that is associated with isoniazid treatment. Women with an Infection of the maternal genital tract or placenta unknown or prolonged duration of PPD positivity (>2 years) should Lesions seen in the first week of life receive isoniazid (300 mg/day) for 6 to 9 months after delivery. Isonia- Exclusion of the possibility of postnatal transmission by a zid prophylaxis is not recommended for women older than 35 years thorough investigation of all contacts, including attendants who have an unknown or prolonged PPD positivity in the absence of active disease. The use of isoniazid is discouraged in this group because of an increased risk for hepatotoxicity. Isoniazid is associated with Prevention hepatitis in pregnant and nonpregnant adults. However, monthly Most gravidas with a positive PPD result in pregnancy are asymptom- monitoring of liver function tests may prevent this adverse outcome. atic and have no evidence of active disease; they are classified as infected Among individuals receiving isoniazid, 10% to 20% will develop mildly without active disease. The risk of progression to active disease is elevated values detected on liver function tests. These changes resolve highest in the first 2 years of conversion. It is important to prevent the after the drug is discontinued.105 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 Treatment positive PPD result and no evidence of active disease, the recom- The gravida with active tuberculosis should be treated initially with mended prophylaxis is isoniazid (300 mg/day), starting after the first isoniazid (300 mg/day) combined with rifampin (600 mg/day) (Table trimester and continuing for 6 to 9 months.54 Under base-case assump- 45-2).106 Resistant disease results from initial infection with resistant tions in a Markov decision-analysis model, the fewest cases of tuber- strains (33%) or can develop during therapy.107 The development of culosis within the cohort occurred with antepartum treatment (1400 resistance is more likely in individuals who are noncompliant with per 100,000), compared with no treatment (3300 per 100,000) or therapy. If resistance to isoniazid is identified or anticipated, 2.5 g of postpartum treatment (1800 per 100,000).104 Antepartum treatment ethambutol per day should be added, and the treatment period should PPD positive (without prior treatment) CXR CXR normal abnormal or other evidence of active disease Respiratory No respiratory symptoms Three morning sputum samples symptoms for smear/cx “High risk” Old conversion Three morning or conversion 2 years or 1st sputum samples for within 2 years positive PPD Workup Workup smear/cx or workup for extrapulmonary TB Antepartum If 35 years, INH/B6 postpartum If 35 years, Immediate INH/B6 postpartum antepartum INH/B6 3 drug Workup Workup therapy Immediate If 35 years, antepartum postpartum 3 drug INH/B6 therapy FIGURE 45-7 Algorithm for the management of a patient with a positive purified protein derivative (PPD) result. In women with known conversion within the past 2 years to a positive PPD result and no evidence of active disease, the recommended prophylaxis is 300 mg of isoniazid per day, starting after the first trimester and continuing for 6 to 9 months. B6, pyridoxine; cx, culture; CXR, chest radiograph; INH, isoniazid, TB, tuberculosis.
  • 11. CHAPTER 45 Respiratory Diseases in Pregnancy 937 TABLE 45-2 ANTITUBERCULOSIS DRUGS Drug Dosage Route Daily Dose Weekly Dose Major Adverse Reactions First-Line Drugs (for Initial Treatment) Isoniazid PO, IM 10 mg/kg, up to 300 mg 15 mg/kg, up to 900 mg Hepatic enzyme elevation, peripheral neuropathy hepatitis, hypersensitivity Rifampin PO 10 mg/kg, up to 600 mg 10 mg/kg, up to 600 mg Orange discoloration of secretions and urine; nausea, vomiting, hepatitis, febrile reaction, purpura (rare) Pyrazinamide PO 15-30 mg/kg, up to 2 g 50-70 mg/kg, twice Hepatotoxicity, hyperuricemia, arthralgias, rash, gastrointestinal upset Ethambutol PO 15 mg/kg, up to 2.5 g 50 mg/kg Optic neuritis (decreased red-green color discrimination, decreased visual acuity), rash Streptomycin IM 15 mg/kg, up to 1 g 25-30 mg/kg, up to 1 g Ototoxicity, nephrotoxicity Second-Line Drugs (Daily Therapy) Capreomycin IM 15-30 mg/kg, up to 1 g Auditory, vestibular, and renal toxicity Kanamycin IM 15-30 mg/kg, up to 1 g Auditory and renal toxicity, rare vestibular toxicity Ethionamide PO 15-20 mg/kg, up to 1 g Gastrointestinal disturbance, hepatotoxicity, hypersensitivity p-Amino-salicylic acid PO 150 mg/kg, up to 1 g Gastrointestinal disturbance, hypersensitivity, hepatotoxicity, sodium load Cycloserine PO 15-20 mg/kg, up to 1 g Psychosis, convulsions, rash IM, intramuscularly; PO, orally. be extended to 18 months.108 Ethambutol is teratogenic in animals; tive maternal sputum cultures.54 Infants of women with multidrug- however, this effect has not been seen in humans. resistant tuberculosis should probably be placed with an alternative The most common side effect of ethambutol therapy is optic neu- caregiver until there is no evidence of active disease in the mother. ritis. Streptomycin should be avoided during pregnancy because it is The newborn should also receive BCG vaccine and isoniazid prophy- associated with cranial nerve VIII damage in neonates.109 Antitubercu- laxis.92 Active tuberculosis in the neonate should be treated appropri- lous agents not recommended for use in pregnancy include ethion- ately with isoniazid and rifampin immediately on diagnosis or with amide, streptomycin, capreomycin, kanamycin, cycloserine, and multiagent therapy if drug-resistant organisms are identified. Infants pyrazinamide.54 However, case reports documenting the use of these and children who are at high risk for intimate and prolonged exposure antituberculous agents in pregnancy revealed no adverse fetal or neo- to untreated or ineffectively treated persons should receive the BCG natal effects. There were no congenital abnormalities, and pregnancy vaccine.110 outcomes for the individuals treated were good. Untreated tuberculosis In summary, high-risk gravidas should be screened for tuberculosis has been associated with higher morbidity and mortality rates among and treated appropriately with isoniazid prophylaxis for infection pregnant women. The management of the gravida with multidrug- without overt disease and with dual antituberculous therapy for active resistant tuberculosis should be individualized. The patient should be disease. The newborn also should be screened for evidence of tuber- counseled about the small risk of teratogenicity and understand that culosis. Proper screening and therapy will lead to a good outcome for the risk of postpartum transmission of tuberculosis to the infant may the mother and infant in most cases. be higher among those born to patients with drug-resistant tubercu- losis. In patients with active disease at the time of delivery, separation of the mother and newborn should be accomplished to prevent infec- tion of the newborn. Asthma in Pregnancy Women who are being treated with antituberculous drugs may Asthma may be the most common potentially serious medical condi- breastfeed. Only 0.75% to 2.3% of isoniazid and 0.05% of rifampin are tion to complicate pregnancy.111 Asthma is characterized by chronic excreted into breast milk. Ethambutol excretion into breast milk is also airway inflammation with increased airway responsiveness to a variety minimal. However, if the infant is concurrently taking oral antituber- of stimuli and airway obstruction that is partially or completely culous therapy, excessive drug levels may be reached in the neonate, reversible.111 Approximately 4% to 8% of pregnancies are complicated and breastfeeding should be avoided. Breastfed infants of women by asthma.112,113 The prevalence and morbidity rates for asthma are taking isoniazid should receive a multivitamin supplement that increasing, although the mortality rate has decreased in recent years. includes pyridoxine.54 Neonates of women taking antituberculous Insight into the pathogenesis of asthma has changed with the rec- therapy should have a PPD skin test at birth and again when 3 months ognition that airway inflammation occurs in almost all cases. The old. Infants born to women with active tuberculosis at the time of medical management for asthma emphasizes treatment of airway delivery should receive isoniazid prophylaxis (10 mg/kg/day) until inflammation to decrease airway responsiveness and prevent asthma maternal disease has been inactive for 3 months as evidenced by nega- symptoms.
  • 12. 938 CHAPTER 45 Respiratory Diseases in Pregnancy Diagnosis Effects of Asthma on Pregnancy The enlarging uterus elevates the diaphragm about 4 cm, reducing the Existing studies on the effects of asthma on pregnancy have had incon- functional residual capacity. However, there are no significant altera- sistent results in regard to maternal and perinatal outcomes. For tions in forced vital capacity, peak expiratory flow rate (PEFR), or example, asthma has been associated with increased perinatal mortal- forced expiratory volume in 1 second (FEV1) in normal pregnancies. ity,117 hyperemesis gravidarum,118 hemorrhage,112,118,119 hypertension or Shortness of breath at rest or with mild exertion is common and is preeclampsia,118-125 preterm birth,118,122,123,126-128 hypoxia at birth,118 low often referred to as physiologic dyspnea of pregnancy. Asthma is char- birth weight,118,129 increased cesarean section,119,121,122,126,129 small- acterized by paroxysmal or persistent symptoms, including breathless- for-gestational-age status or intrauterine growth restriction,122,123,130 ness, chest tightness, cough, and sputum production. The diagnosis of gestational diabetes,119,126 and anomalies.122 asthma is based on a history of symptoms and results of spirometry. In contrast, asthma has not been associated with prematur- Patients with asthma have improved FEV1 after administration of a ity,112,117,129-132 malformations,112,118,121,123,131 birth injury,118 increased short-acting, inhaled β2-agonist and increased sensitivity to inhaled perinatal mortality,118 reduced gestational age,120,121,133-135 reduced mean methacholine, although this test is not usually performed during birth weight,120,121,129,134-136 perinatal death,119,121,131,135,137 low Apgar pregnancy. score,121 neonatal respiratory difficulty,121 antepartum or postpartum In 2004, the National Asthma Education and Prevention Program hemorrhage,123,129,133 perinatal complications,124,129 gestational hyper- (NAEPP) Working Group on Asthma and Pregnancy114 defined mild tension or preeclampsia,126,130,131,138 intrauterine growth restriction,126,131 intermittent, mild persistent, moderate persistent, and severe persistent increased cesarean section,112,132,137 low birth weight,121,132,133,136,137 gesta asthma according to daytime and nighttime symptoms (e.g., wheezing, tional diabetes,112,124 or respiratory distress syndrome.112 cough, dyspnea) and objective tests of pulmonary function. The most Many of these studies have methodologic inadequacies, including commonly used pulmonary function parameters are the PEFR and low power, variable inclusion criteria, little or no information regard- FEV1. The NAEPP guidelines suggest classifying asthma severity in ing asthma management or control, and time frames that do not reflect patients not on symptom-controlling drugs and asthma control in current management. Some positive findings may result from non- patients on symptom-controlling medications (Table 45-3).115 Preg- existent or inadequate control for confounders such as oral corticoste- nant patients with mild asthma according to symptoms and pulmo- roid treatment, ethnicity, smoking status, obesity, socioeconomic nary function who nonetheless required regular medications to control status, and hypertension. Another potential explanation for inconsis- their asthma are similar to those with moderate asthma with respect tencies is that most of these studies did not classify asthma severity. to asthma exacerbations; those requiring regular systemic corticoste- Classification of asthma severity has important clinical implications in roids to control asthma symptoms were similar to severe asthmatics regard to asthma morbidity and tailoring optimal treatment regi- with respect to exacerbations.116 mens.139,140 Asthma medications and poor asthma control leading to hypoxia may explain some of these observations.141 Some data support a relationship between poor asthma control, as indicated by hospital- Effects of Pregnancy on Asthma ization for exacerbations or decreased FEV1 values, and low birth Asthma has been associated with considerable maternal morbidity. In weight and low ponderal index.137,141,142 Studies have shown that women a large, prospective study of pregnant women, those with mild asthma with more severe asthma may have the greatest risk for complications had an exacerbation rate of 12.6% and hospitalization rate of 2.3%; during pregnancy,122,126,127,143 whereas better-controlled asthma is those with moderate asthma had an exacerbation rate of 25.7% and associated with decreased risks.131,144,145 Poor control of asthma during hospitalization rate of 6.8%; and severe asthmatics had an exacerba- pregnancy may be caused by the physician’s reluctance to prescribe tion rate of 51.9% and hospitalization rate of 26.9%.116 The effects of medications during pregnancy. Women with asthma significantly pregnancy on asthma vary. In a large, prospective study, 23% improved reduce their medications, especially inhaled and rescue corticosteroids, and 30% became worse during pregnancy.116 One of the most impor- during the first trimester.146 tant conclusions of this study is that pregnant women with mild or There is considerable consistency among prospective studies of even well-controlled asthma should be monitored by PEFR and FEV1 the effects of asthma during pregnancy. Eight prospective studies testing during pregnancy. reporting maternal and neonatal outcomes with at least 100 subjects TABLE 45-3 CLASSIFICATION OF ASTHMA SEVERITY AND CONTROL IN PREGNANT PATIENTS Well Controlled* Not Well Controlled* Very Poorly Controlled* Signs and Symptoms Intermittent† Mild Persistent† Moderate Persistent† Severe Persistent† Symptom frequency/short-acting ≤2 days per week >2 days per week, Daily symptoms Throughout the day β-agonist use but not daily Nighttime awakening ≤2 times per month >2 times per month >1 time per week ≥4 times per week Interference with normal activity None Minor limitation Some limitation Extremely limited FEV1 or peak flow (percent >80% >80% 60-80% <60% predicted/personal best) *Asthma control: assess in patients on long-term-control medications to determine whether step-up, step-down, or no change in therapy is indicated. † Asthma severity: assess severity for patients who are not on long-term-control medications, see Table 45-7 to determine starting controller therapy based on severity. FEV1, forced expiratory volume in 1 second.
  • 13. CHAPTER 45 Respiratory Diseases in Pregnancy 939 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 Management Approaches mild or moderate asthma can have excellent maternal and perinatal The ultimate goal of asthma therapy during pregnancy is to maintain outcomes (Table 45-4). These findings do not contradict the possibility adequate oxygenation of the fetus by prevention of hypoxic episodes that suboptimal control of asthma during pregnancy is associated with in the mother. Other goals include achievement of minimal or no increased risk to the mother or infant.145 Lower FEV1 values during maternal symptoms day or night, minimal or no exacerbations, no pregnancy are significantly associated with increased risks for low birth limitations of activities, maintenance of normal or near-normal pul- weight and prematurity.148 The two largest studies indicate that classi- monary function, minimal use of short-acting β2-agonists, and minimal fication of asthma severity with therapy tailored according to asthma or no adverse effects from medications. Consultation or comanage- severity can result in excellent perinatal and maternal outcomes.144,145 ment with an asthma specialist is appropriate for evaluation of the role This generally confirms the findings of two earlier and smaller pro- of allergy and irritants, complete pulmonary function studies, or eval- spective cohort studies131,133 in which asthma was managed by asthma uation of the medication plan if there are complications in achieving specialists. the goals of therapy or the patient has severe asthma. A team approach There are important caveats when interpreting this literature. Pro- is helpful if more than one clinician is managing the asthma and the spective studies have tended to find fewer significant adverse associa- pregnancy. The effective management of asthma during pregnancy tions, possibly because of better asthma surveillance and treatment. relies on four integral components: objective assessment, trigger The excellent maternal and perinatal outcomes were achieved at centers avoidance, patient education, and pharmacologic therapy. that tended to actively manage asthma during pregnancy. Women who enroll in research studies tend to be more compliant and better moti- Objective Measures for Assessment vated than the general public. The lack of finding more adverse out- and Monitoring comes among women with severe asthma may also be a function of Subjective measures of lung function by the patient or physician the relatively small numbers of this cohort and the resulting lack of provide an insensitive and inaccurate assessment of airway hyperre- power to find adverse outcomes that were statistically significant. sponsiveness, airway inflammation, and asthma severity. The FEV1 Nonetheless, these prospective studies are reassuring in their consensus value after a maximal inspiration is the single best measure of pulmo- of good pregnancy outcomes among women with asthma. However, nary function. When adjusted for confounders, a mean FEV1 less than they do not suggest that asthma should be considered to be a benign 80% of the predicted value has been significantly associated with condition, because active asthma management was a part of these increased preterm delivery at less than 32 weeks and less than 37 weeks studies and might have positively influenced outcomes. and with a birth weight less than 2500 g.148 However, measurement of TABLE 45-4 PROSPECTIVE COHORT STUDIES REPORTING OBSTETRIC AND NEONATAL OUTCOMES Stenius- Stenius- Schatz Aarniala and Dombrowski Bracken et al, Aarniala et al, Mihrshani Jana et al, Teramo, Minerbi-Codish et al, 2004145 2003144 et al, 1996133 1995131 et al, 2003124 1995137 1988121 et al, 1998132 Outcomes (N = 1739) (N = 872) (N = 504) (N = 486) (N = 340) (N = 182) (N = 181) (N = 101) Preterm, < 32 No NR NR NR NR NR NR NR weeks Preterm, < 37 No (yes if No (yes if oral No No No No NR No weeks severe) steroids) Preeclampsia No No (yes if daily No No No NR Yes No symptoms) Cesarean delivery Yes (if NR Yes (if NR No No Yes No moderate elective) or severe) Gestational No (yes if NR No No NR NR No No diabetes severe) Small for No No (yes if daily NR No NR NR NR No gestational age symptoms) Malformation No NR No No NR No NR No Antenatal NR NR No NR NR No No NR hemorrhage Postnatal No NR NR NR NR NR NR NR hemorrhage RDS/HMD No NR NR No NR NR No NR NEC No NR NR No NR NR NR NR Perinatal death No NR No No NR No No NR NICU admission No NR No NR No NR No NR HMD, hyaline membrane disease; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; No, no significant association; NR, not reported; RDS, respiratory distress syndrome; Yes, significantly increased.