Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e14
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8
Respiratory disease in pregnancy Niharika Mehta, MD, Assistant Professor of Medicine *, Kenneth Chen, MD, Assistant Professor of Medicine and Ob Gyn, Erica Hardy, MD, MMSc, Assistant Professor of Medicine and Ob Gyn, Raumond Powrie, MD, Professor of Medicine and Ob Gyn Warren Alpert Medical School of Brown University, Providence, RI, USA
Keywords: respiratory pregnancy asthma pneumonia ARDS smoking cessation
Many physiological and anatomical changes of pregnancy affect the respiratory system. These changes often affect the presentation and management of the various respiratory illnesses in pregnancy. This article focuses on several important respiratory issues in pregnancy. The management of asthma, one of the most common chronic illnesses in pregnancy, remains largely unchanged compared to the nonpregnant state. Infectious respiratory illness, including pneumonia and tuberculosis, are similarly managed in pregnancy with antibiotics, although special attention may be needed for antibiotic choices with more pregnancy safety data. When mechanical ventilation is necessary, consideration should be given to the maternal hemodynamics of pregnancy and fetal oxygenation. Maintaining maternal oxygen saturation above 95% is recommended to sustain optimal fetal oxygenation. Cigarette smoking has known risks in pregnancy, and current practice guidelines recommend offering cognitive and pharmacologic interventions to pregnant women to assist in smoking cessation. © 2015 Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Medicine, Women and Infants Hospital of Rhode Island, 101 Dudley Street, Providence, RI 02905, USA. E-mail address: [email protected] (N. Mehta). http://dx.doi.org/10.1016/j.bpobgyn.2015.04.005 1521-6934/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mehta N, et al., Respiratory disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.005
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N. Mehta et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e14
Physiologic changes in the respiratory system with pregnancy Pregnancy is associated with profound anatomical, physiological, and biochemical changes, which affect the different organ systems variably. Changes begin soon after fertilization and continue throughout gestation. Many of these adaptations occur in response to hormonal or mechanical stimuli, and they can either be misinterpreted as disease or mask a compromised status. For example, progesterone-mediated vasodilation can lead to increased mucosal vascularity and edema, presenting as rhinitis and causing an increased prevalence of epistaxis in pregnancy. On the other hand, because pregnancy is typically associated with lower levels of carbon dioxide (PaCO2) than the normal nonpregnant state, a finding of “normal” PaCO2 level in arterial blood gases may indicate impending respiratory failure, and this should prompt the clinician to consider intubation. Mechanical changes to the respiratory system during pregnancy result from several adaptations the body undergoes to accommodate the growing uterus in the abdomen. Understandably, the diaphragm is elevated by about 4e5 cm past its original position [1]. The clinical implication of this change is that a higher approach might be necessary while performing a thoracentesis on a pregnant woman. There is also an increase in the chest wall circumference and the anteroposterior diameter, resulting from hormoneinduced relaxation of ligaments connecting the ribs to the sternum leading to an outward flare of the lower ribs. There is anecdotal experience to suggest that this leads to a mechanical stress on the lower ribs predisposing pregnant women to stress fractures from even minor trauma such as coughing [2,3]. Pregnancy has a major effect on lung volumes. It is associated with a 30e50% increase in tidal volume (TV), which occurs at the expense of the functional residual capacity (FRC) (FRC ¼ residual volume (RV) þ expiratory reserve volume (ERV)) [4]. While the respiratory rate is not increased, minute ventilation (product of respiratory rate and TV) is increased, leading to a higher PaO2 in the maternal circulation (104e108 mmHg or 13.8e14.3 kPa) and a reduction in PaCO2 from 35-e40 mmHg (4.6e5.3 kPa) in the nonpregnant state to 27e32 mmHg (3.6e4.2 kPa) in pregnancy [1]. Despite the changes in TV and FRC, spirometry remains unchanged in pregnancy. Therefore, abnormal spirometry results should be attributed to underlying respiratory illness and not to pregnancy itself [5]. The lower PaCO2 in the maternal circulation results in a state of chronic respiratory alkalosis (pH 7.4e7.45), which is compensated for by an increase in renal excretion of bicarbonate, leading to a reduced serum bicarbonate level of 18e21 mmol/L [4]. This has both advantages and disadvantages for the expectant mother. On the one hand, lower bicarbonate levels shift the hemoglobin oxygen dissociation curve to the right, so that the affinity of maternal hemoglobin to oxygen is reduced, thereby facilitating the transfer of oxygen to the fetus. On the other hand, this reduction in bicarbonate results in a lower buffering capacity, which makes the pregnant woman particularly susceptible to acidosis [4]. Approach to dyspnea in pregnancy Shortness of breath is a common complaint in pregnancy, with over two-thirds of pregnant women experiencing some form of it during the gestation period. An increasing abdominal girth or weight gain alone are not enough to explain the symptoms as many women experience it in early gestation before such changes have occurred. Dyspnea of pregnancy refers to a commonly encountered condition in pregnancy in which women describe a sense of “air hunger” or a “need to take a deep breath intermittently.” All too often, the patient will report that the shortness of breath was first noticed while conversing, because she cannot complete her sentence without pausing for a breath. Progesterone-induced stimulation of the respiratory center in the brain, necessary for the increase in TV with pregnancy, is thought to be the possible mechanism of this. By the third trimester, the majority of women will report some decrease in exercise tolerance most likely resulting from mechanical changes associated with weight gain and decreased venous return. When a pregnant woman complains of dyspnea, distinguishing between underlying disease and normal pregnancy-related dyspnea can be a difficult diagnostic problem. While the differential diagnosis of dyspnea in general includes a myriad of conditions, the list of conditions of particular importance in pregnancy is relatively small. Table 1 describes these causes, clinical features characteristic for the condition, and a brief summary of possible investigations and interventions. Please cite this article in press as: Mehta N, et al., Respiratory disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.005
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Asthma in pregnancy Asthma is the most common chronic medical illness to complicate pregnancy, affecting between 6% and 12% of all pregnancies [6e8]. It is often undiagnosed and, even when recognized, may be undertreated. Pregnancy provides an opportunity to diagnose asthma and to optimize the treatment of women already known to have asthma. The course of asthma is typically unpredictable in pregnancy, and studies have suggested that about one-third of patients improve, one-third remain the same, and a third worsen [9,10]. Factors contributing to improvement may be the pregnancy-associated rise in serum cortisol and/or the increase in progesterone, which acts as a potent smooth muscle relaxant. Acute asthma in labor is unlikely because cortisol levels at term are around four times the prepregnancy levels [11]. Women whose symptoms improve during the last trimester of pregnancy may experience a postpartum flare-up. Factors contributing to worsening include the increased incidence of gastroesophageal reflux disease (GERD) and gestational rhinitis, which leads to postnatal drip [12]. Deterioration in disease control is commonly caused by a reduction or even complete cessation of medications due to patient fears about their safety, although this aspect has reduced significantly in recent years [13]. Caseecontrol studies have shown that well-controlled pregnant asthmatic patients do not have a significantly higher rate of adverse outcomes than women without asthma [14,15]. Women with documented frequent exacerbations are more likely to have miscarriages [16], and suboptimal control appears to be associated with low birth weight and intrauterine growth restriction. Chronic or intermittent maternal hypoxemia is usually offered as the explanation for the above, although it should be noted that the majority of women with even poorly controlled asthma are unlikely to have chronic hypoxia to the degree that would explain these obstetric outcomes. The National Asthma Expert Panel Report [17] classifies asthma severity into four categories: intermittent, mild persistent, moderate persistent, and severe persistent. Patients within each category can be classified as well controlled, not well controlled, or poorly controlled. This classification is very useful in directing appropriate management with step therapy. The first step in the management is establishing the diagnosis of asthma. The next step is the identification and avoidance of triggers. Identification and treatment of GERD, sinus disease, and allergic or gestational rhinitis will help control symptoms. Compliance and proper use of medications are paramount. Monitoring peak flows, reviewing inhaler techniques on a regular basis, and the provision and adherence to an asthma management plan have all been shown to reduce the frequency and severity of asthma exacerbations. The National Asthma Education and Prevention Program (NAEPP) published guidelines on the pharmacological management of pregnant patients with asthma in 2004 [18] after reviewing extensive Table 1 Approach to dyspnea. Causes of dyspnea Dyspnea of pregnancy
Clinical characteristic
Need to take a deep breath intermittently, or inability to get a deep enough breath Asthma/airways Dyspnea with chest tightness or disease wheezing Cardiac disease Myocardial/valvular dysfunction: progressive orthopnea or orthopnea with paroxysmal nocturnal dyspnea. Often present at end of second trimester or in early postpartum period when fluid shifts occur Arrhythmia Sudden onset and cessation, associated sensation of palpitations or chest discomfort Venous Sudden onset, any trimester. May thromboembolism have associated DVT features
Helpful investigations
Interventions
None
Reassurance
Spirometry, pre- and postbronchodilator Echocardiogram
Inhaled beta agonists ± inhaled steroids Diuretics, beta-blockers as indicated. ACE inhibitors contraindicated in pregnancy
Electrocardiogram, Holter or event monitor
Beta-blockers, calcium channel blockers
Computerized tomography Anticoagulation with injectable pulmonary angiogram, V/Q heparins in pregnancy, warfarin in the postpartum period. scan, lower-extremity Dopplers
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Table 2 Asthma management in pregnancy: Stepwise approach to preferred treatments (Ref. [18]). Step 1 (mild intermittent) Step 2 (mild persistent) Step 3 (moderate persistent, daily symptoms) Step 4 (Severe persistent, continual symptoms, frequent nocturnal symptoms)
No daily medication needed. Short-acting inhaled beta2-agonists (albuterol: ®Ventolin and ®Proair) as needed for symptoms Low-dose inhaled corticosteroids Low-dose inhaled corticosteroids plus long-acting beta2-agonist OR medium-dose inhaled corticosteroids High-dose inhaled corticosteroids plus long-acting inhaled beta2-agonist and, if needed, systemic steroids
data on the fetal safety of all the available drugs. Table 2 summarizes a stepwise approach to the management of asthma. Mild intermittent asthma should be managed with an inhaled short-acting “reliever” (beta-agonist) medication as required (step 1). If this usage exceeds once daily, regular inhaled anti-inflammatory medication with a steroid “preventer” inhaler should be commenced (step 2). The next step in therapy is either the addition of a long-acting reliever or an increase in the dose of inhaled steroid (step 3). Further steps involve a trial of additional therapies such as leukotriene receptor antagonist (step 4). If all of the above measures fail to achieve adequate control, then frequent or continuous use of oral steroids becomes necessary (step 5). It is vital that any woman who is still smoking be advised to cease immediately as this undoubtedly acts as a major trigger factor. All of the above medications have been shown to be safe in pregnancy and lactation. This should be emphasized in preconception or early pregnancy counseling, so that women do not self-cease important antiinflammatory inhaled therapy. Pregnant women with asthma should be asked about a history of aspirin sensitivity before being advised to take low-dose aspirin (e.g., preeclampsia prophylaxis or antiphospholipid antibody syndrome). If the patient is identified as having GERD, treatment with a proton pump inhibitor or histamine H2 blocker should be instituted. In the management of an acute exacerbation, tachypnea and raised PaCO2 level (above the normal pregnancy range) should prompt the suspicion of impending respiratory failure. The early use of noninvasive ventilation (NIV) and/or intubation should be considered in these cases [19]. With regard to fetal testing, a routine third-trimester ultrasound can be considered in a woman with well-controlled asthma with appropriate growth in the fundal height. The NAEPP Working Group recommends serial ultrasounds starting at 32 weeks of gestation in women with suboptimally controlled asthma and women with moderate to severe asthma [18]. If the growth is not appropriate, fetal testing should be started. Testing may include non-stress testing (NST), biophysical profiles (BPP), and/or umbilical artery Doppler flow studies. The frequency of such testing would depend on the severity of the patient's asthma or on the degree of growth restriction. It is advisable to administer stress dose steroids at the time of labor and delivery to patients who have been on prolonged systemic steroids during the pregnancy [20]. Both prostaglandin E2 and oxytocin can be used as induction agents. The use of 15-methyl prostaglandin F2-alpha to treat life-threatening postpartum hemorrhage may be unavoidable, but it should be used with caution in women with asthma as it can cause bronchospasm. Fentanyl is preferred to morphine and meperidine, both of which can release histamine and result in bronchoconstriction. Epidural anesthesia is advised as it reduces oxygen consumption and minute ventilation, as well as reducing the possibility of requiring general anesthesia if an emergency cesarean section is indicated during labor. During the postpartum period, women should be counseled to continue on the same asthma medications to reduce the likelihood of a flare-up. All of the drugs discussed above can be safely used during lactation. Breast-feeding should be encouraged as it appears to reduce the likelihood of the offspring developing asthma and other atopies [21], most likely due to the delay in introduction of cow's milk.
Pneumonia in pregnancy Pregnant patients are susceptible to the same respiratory diseases as the nonpregnant patient, and for the most part they should be treated similarly. Pneumonia is the most common cause of fatal nonPlease cite this article in press as: Mehta N, et al., Respiratory disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.005
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obstetric infection in the pregnant patient [22]. Peripartum risk factors such as delivery by cesarean section can increase the risk of hospital admission for pneumonia in the postpartum period [23]. Pneumonia in pregnancy can also lead to an increased likelihood of a complicated delivery compared to pregnancies in which infection is absent [24]. Pregnant patients have several characteristics specific to pregnancy predisposing them to an increased incidence and risk of complications from pneumonia [24e27]. These include immunologic changes such as altered T lymphocyte immunity; maternal physiologic changes such as increased oxygen consumption, increase in lung water, and elevation of the diaphragm; and the higher likelihood of aspiration during labor and delivery. Coexisting illness or habits may also increase the risk of pneumonia in the peripartum period such as smoking, underlying lung disease such as asthma, cystic fibrosis, HIV infection, or immunosuppressive therapy for other chronic conditions. The etiologies of pneumonia in pregnancy are similar to those in the nonpregnant host, and often no etiologic agent is identified [28]. Bacterial, viral (with the risk of secondary bacterial infection), fungal, and mycobacterial etiologies are all possible. Like the nonpregnant host, common bacterial pathogens in community-acquired pneumonia include Streptococcus pneumoniae, Haemophilus influenzae, as well as atypical bacterial pathogens such as Legionella species, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. Staphylococcus aureus (including methicillin-resistant strains) is also a possible cause of pneumonia, and it can be associated with a secondary infection after an influenza illness. Health-careassociated organisms are less common and are usually present in those with other comorbidities, including cystic fibrosis [25]. Pneumocystis jirovecii should be considered in a pregnant woman with human immunodeficiency syndrome (HIV), especially with a low CD4 cell count. Viral agents include influenza and rarely varicella. Up to 9% of primary cases of varicella during pregnancy can be complicated by pneumonia [29]. Fungal etiologies such as coccidiomycosis are rare. The clinical presentation in pregnant women with pneumonia is similar to that in nonpregnant women. Fever, cough, dyspnea, and hypoxia are part of the common presentation. Some experts advise that the inpatient and ICU admission criteria for pregnant woman should be liberalized, as there is a decreased ability to tolerate hypoxia in the pregnant patient [24]. Potential indications for ICU admissions, according to the American Thoracic Society/Infectious Disease Society of America, include but are not limited to the need for mechanical ventilation, septic shock requiring vasopressors, respiratory rate of >30 breaths per minute, PaO2/FiO2 ratio 70 mmHg or 9.3 kPa; equivalent to oxygen saturation 95%) using oxygen supplementation to avoid fetal effects of maternal hypoxia. Noninvasive positive pressure ventilation (NIPPV) can improve oxygenation when supplemental oxygen has failed,
Table 5 Diagnostic tests indicated in the obstetric patient with ARDS. 1 2 3 4 5 6 7
Complete blood count (CBC): Rule out anemia as a contributing factor Creatinine and blood urea nitrogen(BUN): Rule out renal failure PTT, fibrinogen, and fibrinogen degradation products(FDP): Look for evidence of amniotic fluid embolism AST, uric acid, and urinalysis (in addition to abovementioned CBC and creatinine): Look for evidence of preeclampsia Blood and urine cultures in all patients with fever Urine drug screen: Look for evidence of cocaine or narcotics as a cause Echocardiogram: Rule out underlying cardiac cause for pulmonary edema or evidence of cardiac compromise in preeclampsia
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Table 6 Salient features in the management of ARDS in pregnancy. 1 Supplemental oxygen to maintain maternal oxygen saturation above 95% 2 Consider intubation for PaO2 45 mmHg on 100% oxygen 3 Look for precipitating causes listed in Table 4 in addition to sepsis, massive transfusion, aspiration of gastric contents, or trauma 4 Appropriate diagnostic testing as listed in Table 5 5 Immediate discontinuation of tocolytic therapy where applicable 6 Fluid restriction 7 IV furosemide 10e20 mg 8 IV antibiotics if infection suspected 9 Echocardiogram to rule out cardiac cause for pulmonary edema 10 Afterload reduction with sodium nitroprusside, hydralazine (if patient undelivered), and ACE inhibitors or angiotensin receptor blockers (ARBs) in the postpartum patient
and in severe cases mechanical ventilation may be necessary. Later in this chapter, the principles of mechanical ventilation in pregnant patients are discussed in more detail. The care of a critically ill obstetric patient obviously demands a multidisciplinary involvement, to ensure the well-being of the maternalefetal unit. Fetal assessments as appropriate, depending upon gestational age, should take place early and regularly in the course of the illness. Plans for possible delivery, which will depend upon the gestational age, maternal status, and available facilities for supporting a preterm infant, should be drafted. Whether delivery has a positive impact on maternal condition in patients with ARDS is unclear. While there are numerous case reports in which the fetus remained undelivered despite maternal respiratory failure and intubation, most case series in the literature suggest that mothers with ARDS in the third trimester rarely stay pregnant for more than a few days [38,39,42]. For the most part, patients with ARDS secondary to chorioamnionitis, placental abruption, amniotic fluid embolism, and preeclampsia need immediate delivery, while those with pyelonephritis or varicella pneumonia can often recover without delivery. The high rates of adverse fetal outcomes do support expeditious delivery for maternal ARDS after 28 weeks of gestation. Scarce literature exists to guide the decision regarding the mode of delivery. Although vaginal delivery may not be tolerated in a woman with ARDS due to increased oxygen consumption, cesarean delivery results in fluid shifts and blood loss that are both larger and more rapid than with vaginal delivery and this may present a greater physiologic stress [45]. Until further data are available, the decision for the mode of delivery should be based on standard obstetric indications.
Ventilatory support in pregnancy Obstetric admissions to the ICU are fortunately uncommon. When they do occur, hypertensive disorders of pregnancy and hemorrhage remain the most common causes [46]. However, respiratory illness necessitating an ICU level of care are also seen, and ventilator support may become necessary in these patients. NIV refers to positive pressure ventilation delivered to the patient without the need for endotracheal intubation. NIV has not been studied well in the obstetric population. Theoretically, an increased risk of aspiration due to lower resting gastroesophageal sphincter tone and suboptimal ventilation due to pregnancy-associated airway edema can occur. However, more evidence is mounting towards the successful use of this modality in pregnancy [47], and short trials of NIV may be attempted in the pregnant patient prior to endotracheal intubation, particularly if assisted ventilation for a prolonged period of time is not anticipated. Endotracheal intubation in pregnancy is technically difficult. The incidence of failed intubation among the pregnant population is estimated to be up to eight times that of the nonpregnant population [48]. Several factors complicate endotracheal intubation in pregnancy, including airway edema, increased oxygen consumption, and anatomic changes such as increased weight and breast size. Key points to remember in airway intubation of the pregnant woman include airway assessment even in Please cite this article in press as: Mehta N, et al., Respiratory disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.005
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urgent intubations, preoxygenation prior to intubation attempt, keeping each attempt brief and interspersed with brief periods of bag-mask ventilation, being vigilant for the possibility of aspiration, and having the most experienced provider perform the intubation. Indications for mechanical ventilation in pregnancy remain the same as that of nonpregnant patients, which include progressive or unremitting hypoxia, respiratory acidosis, maternal fatigue, and altered mental status [49]. Care should be taken to interpret arterial blood gases in light of normal pregnancy-associated physiologic changes. Ventilator strategies in pregnant patients do not differ much from nonpregnant patients but the maternal hemodynamics of pregnancy and fetal oxygenation should be taken into consideration. For example, hypotension can normally result in late gestation from inferior vena cava (IVC) compression when the pregnant patient is placed in the supine position. This can be further exaggerated by the addition of positive pressure ventilation, which leads to an increase in intrathoracic pressure and a drop in venous return. Placing the patient in the left lateral decubitus position or tilting her to the left by placing a wedge under the right hip might be helpful strategies. Maternal hypoxia can result in significant fetal compromise; therefore, maintaining maternal oxygenation is paramount. Expert opinion favors keeping maternal PaO2 above 70 mm Hg to avoid deleterious effects on the fetus [20]. Continuous fetal monitoring should be initiated when there is an acute change in the maternal respiratory status. Permissive hypercapnea in pregnancy is controversial [50]. Fetal hypercapnea may be associated with fetal acidosis and a shift in the oxyhemoglobin curve, leading to impaired oxygenation in the fetus. When possible, maternal PaCO2 should be kept in the normal pregnancy range (28e32 mmHg).
Tuberculosis in pregnancy Worldwide, every year, over one billion tuberculosis (TB) infections, nine million new cases, and approximately 1.7 million deaths are estimated to occur [51]. An individual with latent TB has a 5% risk of active disease within the first 2 years, and a subsequent 5% lifetime risk of disease. HIV coinfection significantly increases the risk of active TB to 5e10% per year, highlighting the importance of evaluating for TB exposure and latent disease in those with HIV infection. TB is also one of the leading causes of mortality in reproductive-age women [52]. In 2012, an estimated 2.9 million women had TB illness and 410,000 women died [58]. Of the TB deaths in HIVinfected individuals, 50% were in women. The African and Southeast Asian regions accounted for 68% of the TB cases in women, and almost 90% of the TB deaths in women were in Africa. More than half of the estimated TB cases in women went undetected compared to
Contents lists available at ScienceDirect
Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn
8
Respiratory disease in pregnancy Niharika Mehta, MD, Assistant Professor of Medicine *, Kenneth Chen, MD, Assistant Professor of Medicine and Ob Gyn, Erica Hardy, MD, MMSc, Assistant Professor of Medicine and Ob Gyn, Raumond Powrie, MD, Professor of Medicine and Ob Gyn Warren Alpert Medical School of Brown University, Providence, RI, USA
Keywords: respiratory pregnancy asthma pneumonia ARDS smoking cessation
Many physiological and anatomical changes of pregnancy affect the respiratory system. These changes often affect the presentation and management of the various respiratory illnesses in pregnancy. This article focuses on several important respiratory issues in pregnancy. The management of asthma, one of the most common chronic illnesses in pregnancy, remains largely unchanged compared to the nonpregnant state. Infectious respiratory illness, including pneumonia and tuberculosis, are similarly managed in pregnancy with antibiotics, although special attention may be needed for antibiotic choices with more pregnancy safety data. When mechanical ventilation is necessary, consideration should be given to the maternal hemodynamics of pregnancy and fetal oxygenation. Maintaining maternal oxygen saturation above 95% is recommended to sustain optimal fetal oxygenation. Cigarette smoking has known risks in pregnancy, and current practice guidelines recommend offering cognitive and pharmacologic interventions to pregnant women to assist in smoking cessation. © 2015 Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Medicine, Women and Infants Hospital of Rhode Island, 101 Dudley Street, Providence, RI 02905, USA. E-mail address: [email protected] (N. Mehta). http://dx.doi.org/10.1016/j.bpobgyn.2015.04.005 1521-6934/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mehta N, et al., Respiratory disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.005
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Physiologic changes in the respiratory system with pregnancy Pregnancy is associated with profound anatomical, physiological, and biochemical changes, which affect the different organ systems variably. Changes begin soon after fertilization and continue throughout gestation. Many of these adaptations occur in response to hormonal or mechanical stimuli, and they can either be misinterpreted as disease or mask a compromised status. For example, progesterone-mediated vasodilation can lead to increased mucosal vascularity and edema, presenting as rhinitis and causing an increased prevalence of epistaxis in pregnancy. On the other hand, because pregnancy is typically associated with lower levels of carbon dioxide (PaCO2) than the normal nonpregnant state, a finding of “normal” PaCO2 level in arterial blood gases may indicate impending respiratory failure, and this should prompt the clinician to consider intubation. Mechanical changes to the respiratory system during pregnancy result from several adaptations the body undergoes to accommodate the growing uterus in the abdomen. Understandably, the diaphragm is elevated by about 4e5 cm past its original position [1]. The clinical implication of this change is that a higher approach might be necessary while performing a thoracentesis on a pregnant woman. There is also an increase in the chest wall circumference and the anteroposterior diameter, resulting from hormoneinduced relaxation of ligaments connecting the ribs to the sternum leading to an outward flare of the lower ribs. There is anecdotal experience to suggest that this leads to a mechanical stress on the lower ribs predisposing pregnant women to stress fractures from even minor trauma such as coughing [2,3]. Pregnancy has a major effect on lung volumes. It is associated with a 30e50% increase in tidal volume (TV), which occurs at the expense of the functional residual capacity (FRC) (FRC ¼ residual volume (RV) þ expiratory reserve volume (ERV)) [4]. While the respiratory rate is not increased, minute ventilation (product of respiratory rate and TV) is increased, leading to a higher PaO2 in the maternal circulation (104e108 mmHg or 13.8e14.3 kPa) and a reduction in PaCO2 from 35-e40 mmHg (4.6e5.3 kPa) in the nonpregnant state to 27e32 mmHg (3.6e4.2 kPa) in pregnancy [1]. Despite the changes in TV and FRC, spirometry remains unchanged in pregnancy. Therefore, abnormal spirometry results should be attributed to underlying respiratory illness and not to pregnancy itself [5]. The lower PaCO2 in the maternal circulation results in a state of chronic respiratory alkalosis (pH 7.4e7.45), which is compensated for by an increase in renal excretion of bicarbonate, leading to a reduced serum bicarbonate level of 18e21 mmol/L [4]. This has both advantages and disadvantages for the expectant mother. On the one hand, lower bicarbonate levels shift the hemoglobin oxygen dissociation curve to the right, so that the affinity of maternal hemoglobin to oxygen is reduced, thereby facilitating the transfer of oxygen to the fetus. On the other hand, this reduction in bicarbonate results in a lower buffering capacity, which makes the pregnant woman particularly susceptible to acidosis [4]. Approach to dyspnea in pregnancy Shortness of breath is a common complaint in pregnancy, with over two-thirds of pregnant women experiencing some form of it during the gestation period. An increasing abdominal girth or weight gain alone are not enough to explain the symptoms as many women experience it in early gestation before such changes have occurred. Dyspnea of pregnancy refers to a commonly encountered condition in pregnancy in which women describe a sense of “air hunger” or a “need to take a deep breath intermittently.” All too often, the patient will report that the shortness of breath was first noticed while conversing, because she cannot complete her sentence without pausing for a breath. Progesterone-induced stimulation of the respiratory center in the brain, necessary for the increase in TV with pregnancy, is thought to be the possible mechanism of this. By the third trimester, the majority of women will report some decrease in exercise tolerance most likely resulting from mechanical changes associated with weight gain and decreased venous return. When a pregnant woman complains of dyspnea, distinguishing between underlying disease and normal pregnancy-related dyspnea can be a difficult diagnostic problem. While the differential diagnosis of dyspnea in general includes a myriad of conditions, the list of conditions of particular importance in pregnancy is relatively small. Table 1 describes these causes, clinical features characteristic for the condition, and a brief summary of possible investigations and interventions. Please cite this article in press as: Mehta N, et al., Respiratory disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.005
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Asthma in pregnancy Asthma is the most common chronic medical illness to complicate pregnancy, affecting between 6% and 12% of all pregnancies [6e8]. It is often undiagnosed and, even when recognized, may be undertreated. Pregnancy provides an opportunity to diagnose asthma and to optimize the treatment of women already known to have asthma. The course of asthma is typically unpredictable in pregnancy, and studies have suggested that about one-third of patients improve, one-third remain the same, and a third worsen [9,10]. Factors contributing to improvement may be the pregnancy-associated rise in serum cortisol and/or the increase in progesterone, which acts as a potent smooth muscle relaxant. Acute asthma in labor is unlikely because cortisol levels at term are around four times the prepregnancy levels [11]. Women whose symptoms improve during the last trimester of pregnancy may experience a postpartum flare-up. Factors contributing to worsening include the increased incidence of gastroesophageal reflux disease (GERD) and gestational rhinitis, which leads to postnatal drip [12]. Deterioration in disease control is commonly caused by a reduction or even complete cessation of medications due to patient fears about their safety, although this aspect has reduced significantly in recent years [13]. Caseecontrol studies have shown that well-controlled pregnant asthmatic patients do not have a significantly higher rate of adverse outcomes than women without asthma [14,15]. Women with documented frequent exacerbations are more likely to have miscarriages [16], and suboptimal control appears to be associated with low birth weight and intrauterine growth restriction. Chronic or intermittent maternal hypoxemia is usually offered as the explanation for the above, although it should be noted that the majority of women with even poorly controlled asthma are unlikely to have chronic hypoxia to the degree that would explain these obstetric outcomes. The National Asthma Expert Panel Report [17] classifies asthma severity into four categories: intermittent, mild persistent, moderate persistent, and severe persistent. Patients within each category can be classified as well controlled, not well controlled, or poorly controlled. This classification is very useful in directing appropriate management with step therapy. The first step in the management is establishing the diagnosis of asthma. The next step is the identification and avoidance of triggers. Identification and treatment of GERD, sinus disease, and allergic or gestational rhinitis will help control symptoms. Compliance and proper use of medications are paramount. Monitoring peak flows, reviewing inhaler techniques on a regular basis, and the provision and adherence to an asthma management plan have all been shown to reduce the frequency and severity of asthma exacerbations. The National Asthma Education and Prevention Program (NAEPP) published guidelines on the pharmacological management of pregnant patients with asthma in 2004 [18] after reviewing extensive Table 1 Approach to dyspnea. Causes of dyspnea Dyspnea of pregnancy
Clinical characteristic
Need to take a deep breath intermittently, or inability to get a deep enough breath Asthma/airways Dyspnea with chest tightness or disease wheezing Cardiac disease Myocardial/valvular dysfunction: progressive orthopnea or orthopnea with paroxysmal nocturnal dyspnea. Often present at end of second trimester or in early postpartum period when fluid shifts occur Arrhythmia Sudden onset and cessation, associated sensation of palpitations or chest discomfort Venous Sudden onset, any trimester. May thromboembolism have associated DVT features
Helpful investigations
Interventions
None
Reassurance
Spirometry, pre- and postbronchodilator Echocardiogram
Inhaled beta agonists ± inhaled steroids Diuretics, beta-blockers as indicated. ACE inhibitors contraindicated in pregnancy
Electrocardiogram, Holter or event monitor
Beta-blockers, calcium channel blockers
Computerized tomography Anticoagulation with injectable pulmonary angiogram, V/Q heparins in pregnancy, warfarin in the postpartum period. scan, lower-extremity Dopplers
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Table 2 Asthma management in pregnancy: Stepwise approach to preferred treatments (Ref. [18]). Step 1 (mild intermittent) Step 2 (mild persistent) Step 3 (moderate persistent, daily symptoms) Step 4 (Severe persistent, continual symptoms, frequent nocturnal symptoms)
No daily medication needed. Short-acting inhaled beta2-agonists (albuterol: ®Ventolin and ®Proair) as needed for symptoms Low-dose inhaled corticosteroids Low-dose inhaled corticosteroids plus long-acting beta2-agonist OR medium-dose inhaled corticosteroids High-dose inhaled corticosteroids plus long-acting inhaled beta2-agonist and, if needed, systemic steroids
data on the fetal safety of all the available drugs. Table 2 summarizes a stepwise approach to the management of asthma. Mild intermittent asthma should be managed with an inhaled short-acting “reliever” (beta-agonist) medication as required (step 1). If this usage exceeds once daily, regular inhaled anti-inflammatory medication with a steroid “preventer” inhaler should be commenced (step 2). The next step in therapy is either the addition of a long-acting reliever or an increase in the dose of inhaled steroid (step 3). Further steps involve a trial of additional therapies such as leukotriene receptor antagonist (step 4). If all of the above measures fail to achieve adequate control, then frequent or continuous use of oral steroids becomes necessary (step 5). It is vital that any woman who is still smoking be advised to cease immediately as this undoubtedly acts as a major trigger factor. All of the above medications have been shown to be safe in pregnancy and lactation. This should be emphasized in preconception or early pregnancy counseling, so that women do not self-cease important antiinflammatory inhaled therapy. Pregnant women with asthma should be asked about a history of aspirin sensitivity before being advised to take low-dose aspirin (e.g., preeclampsia prophylaxis or antiphospholipid antibody syndrome). If the patient is identified as having GERD, treatment with a proton pump inhibitor or histamine H2 blocker should be instituted. In the management of an acute exacerbation, tachypnea and raised PaCO2 level (above the normal pregnancy range) should prompt the suspicion of impending respiratory failure. The early use of noninvasive ventilation (NIV) and/or intubation should be considered in these cases [19]. With regard to fetal testing, a routine third-trimester ultrasound can be considered in a woman with well-controlled asthma with appropriate growth in the fundal height. The NAEPP Working Group recommends serial ultrasounds starting at 32 weeks of gestation in women with suboptimally controlled asthma and women with moderate to severe asthma [18]. If the growth is not appropriate, fetal testing should be started. Testing may include non-stress testing (NST), biophysical profiles (BPP), and/or umbilical artery Doppler flow studies. The frequency of such testing would depend on the severity of the patient's asthma or on the degree of growth restriction. It is advisable to administer stress dose steroids at the time of labor and delivery to patients who have been on prolonged systemic steroids during the pregnancy [20]. Both prostaglandin E2 and oxytocin can be used as induction agents. The use of 15-methyl prostaglandin F2-alpha to treat life-threatening postpartum hemorrhage may be unavoidable, but it should be used with caution in women with asthma as it can cause bronchospasm. Fentanyl is preferred to morphine and meperidine, both of which can release histamine and result in bronchoconstriction. Epidural anesthesia is advised as it reduces oxygen consumption and minute ventilation, as well as reducing the possibility of requiring general anesthesia if an emergency cesarean section is indicated during labor. During the postpartum period, women should be counseled to continue on the same asthma medications to reduce the likelihood of a flare-up. All of the drugs discussed above can be safely used during lactation. Breast-feeding should be encouraged as it appears to reduce the likelihood of the offspring developing asthma and other atopies [21], most likely due to the delay in introduction of cow's milk.
Pneumonia in pregnancy Pregnant patients are susceptible to the same respiratory diseases as the nonpregnant patient, and for the most part they should be treated similarly. Pneumonia is the most common cause of fatal nonPlease cite this article in press as: Mehta N, et al., Respiratory disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.005
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obstetric infection in the pregnant patient [22]. Peripartum risk factors such as delivery by cesarean section can increase the risk of hospital admission for pneumonia in the postpartum period [23]. Pneumonia in pregnancy can also lead to an increased likelihood of a complicated delivery compared to pregnancies in which infection is absent [24]. Pregnant patients have several characteristics specific to pregnancy predisposing them to an increased incidence and risk of complications from pneumonia [24e27]. These include immunologic changes such as altered T lymphocyte immunity; maternal physiologic changes such as increased oxygen consumption, increase in lung water, and elevation of the diaphragm; and the higher likelihood of aspiration during labor and delivery. Coexisting illness or habits may also increase the risk of pneumonia in the peripartum period such as smoking, underlying lung disease such as asthma, cystic fibrosis, HIV infection, or immunosuppressive therapy for other chronic conditions. The etiologies of pneumonia in pregnancy are similar to those in the nonpregnant host, and often no etiologic agent is identified [28]. Bacterial, viral (with the risk of secondary bacterial infection), fungal, and mycobacterial etiologies are all possible. Like the nonpregnant host, common bacterial pathogens in community-acquired pneumonia include Streptococcus pneumoniae, Haemophilus influenzae, as well as atypical bacterial pathogens such as Legionella species, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. Staphylococcus aureus (including methicillin-resistant strains) is also a possible cause of pneumonia, and it can be associated with a secondary infection after an influenza illness. Health-careassociated organisms are less common and are usually present in those with other comorbidities, including cystic fibrosis [25]. Pneumocystis jirovecii should be considered in a pregnant woman with human immunodeficiency syndrome (HIV), especially with a low CD4 cell count. Viral agents include influenza and rarely varicella. Up to 9% of primary cases of varicella during pregnancy can be complicated by pneumonia [29]. Fungal etiologies such as coccidiomycosis are rare. The clinical presentation in pregnant women with pneumonia is similar to that in nonpregnant women. Fever, cough, dyspnea, and hypoxia are part of the common presentation. Some experts advise that the inpatient and ICU admission criteria for pregnant woman should be liberalized, as there is a decreased ability to tolerate hypoxia in the pregnant patient [24]. Potential indications for ICU admissions, according to the American Thoracic Society/Infectious Disease Society of America, include but are not limited to the need for mechanical ventilation, septic shock requiring vasopressors, respiratory rate of >30 breaths per minute, PaO2/FiO2 ratio 70 mmHg or 9.3 kPa; equivalent to oxygen saturation 95%) using oxygen supplementation to avoid fetal effects of maternal hypoxia. Noninvasive positive pressure ventilation (NIPPV) can improve oxygenation when supplemental oxygen has failed,
Table 5 Diagnostic tests indicated in the obstetric patient with ARDS. 1 2 3 4 5 6 7
Complete blood count (CBC): Rule out anemia as a contributing factor Creatinine and blood urea nitrogen(BUN): Rule out renal failure PTT, fibrinogen, and fibrinogen degradation products(FDP): Look for evidence of amniotic fluid embolism AST, uric acid, and urinalysis (in addition to abovementioned CBC and creatinine): Look for evidence of preeclampsia Blood and urine cultures in all patients with fever Urine drug screen: Look for evidence of cocaine or narcotics as a cause Echocardiogram: Rule out underlying cardiac cause for pulmonary edema or evidence of cardiac compromise in preeclampsia
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Table 6 Salient features in the management of ARDS in pregnancy. 1 Supplemental oxygen to maintain maternal oxygen saturation above 95% 2 Consider intubation for PaO2 45 mmHg on 100% oxygen 3 Look for precipitating causes listed in Table 4 in addition to sepsis, massive transfusion, aspiration of gastric contents, or trauma 4 Appropriate diagnostic testing as listed in Table 5 5 Immediate discontinuation of tocolytic therapy where applicable 6 Fluid restriction 7 IV furosemide 10e20 mg 8 IV antibiotics if infection suspected 9 Echocardiogram to rule out cardiac cause for pulmonary edema 10 Afterload reduction with sodium nitroprusside, hydralazine (if patient undelivered), and ACE inhibitors or angiotensin receptor blockers (ARBs) in the postpartum patient
and in severe cases mechanical ventilation may be necessary. Later in this chapter, the principles of mechanical ventilation in pregnant patients are discussed in more detail. The care of a critically ill obstetric patient obviously demands a multidisciplinary involvement, to ensure the well-being of the maternalefetal unit. Fetal assessments as appropriate, depending upon gestational age, should take place early and regularly in the course of the illness. Plans for possible delivery, which will depend upon the gestational age, maternal status, and available facilities for supporting a preterm infant, should be drafted. Whether delivery has a positive impact on maternal condition in patients with ARDS is unclear. While there are numerous case reports in which the fetus remained undelivered despite maternal respiratory failure and intubation, most case series in the literature suggest that mothers with ARDS in the third trimester rarely stay pregnant for more than a few days [38,39,42]. For the most part, patients with ARDS secondary to chorioamnionitis, placental abruption, amniotic fluid embolism, and preeclampsia need immediate delivery, while those with pyelonephritis or varicella pneumonia can often recover without delivery. The high rates of adverse fetal outcomes do support expeditious delivery for maternal ARDS after 28 weeks of gestation. Scarce literature exists to guide the decision regarding the mode of delivery. Although vaginal delivery may not be tolerated in a woman with ARDS due to increased oxygen consumption, cesarean delivery results in fluid shifts and blood loss that are both larger and more rapid than with vaginal delivery and this may present a greater physiologic stress [45]. Until further data are available, the decision for the mode of delivery should be based on standard obstetric indications.
Ventilatory support in pregnancy Obstetric admissions to the ICU are fortunately uncommon. When they do occur, hypertensive disorders of pregnancy and hemorrhage remain the most common causes [46]. However, respiratory illness necessitating an ICU level of care are also seen, and ventilator support may become necessary in these patients. NIV refers to positive pressure ventilation delivered to the patient without the need for endotracheal intubation. NIV has not been studied well in the obstetric population. Theoretically, an increased risk of aspiration due to lower resting gastroesophageal sphincter tone and suboptimal ventilation due to pregnancy-associated airway edema can occur. However, more evidence is mounting towards the successful use of this modality in pregnancy [47], and short trials of NIV may be attempted in the pregnant patient prior to endotracheal intubation, particularly if assisted ventilation for a prolonged period of time is not anticipated. Endotracheal intubation in pregnancy is technically difficult. The incidence of failed intubation among the pregnant population is estimated to be up to eight times that of the nonpregnant population [48]. Several factors complicate endotracheal intubation in pregnancy, including airway edema, increased oxygen consumption, and anatomic changes such as increased weight and breast size. Key points to remember in airway intubation of the pregnant woman include airway assessment even in Please cite this article in press as: Mehta N, et al., Respiratory disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.005
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urgent intubations, preoxygenation prior to intubation attempt, keeping each attempt brief and interspersed with brief periods of bag-mask ventilation, being vigilant for the possibility of aspiration, and having the most experienced provider perform the intubation. Indications for mechanical ventilation in pregnancy remain the same as that of nonpregnant patients, which include progressive or unremitting hypoxia, respiratory acidosis, maternal fatigue, and altered mental status [49]. Care should be taken to interpret arterial blood gases in light of normal pregnancy-associated physiologic changes. Ventilator strategies in pregnant patients do not differ much from nonpregnant patients but the maternal hemodynamics of pregnancy and fetal oxygenation should be taken into consideration. For example, hypotension can normally result in late gestation from inferior vena cava (IVC) compression when the pregnant patient is placed in the supine position. This can be further exaggerated by the addition of positive pressure ventilation, which leads to an increase in intrathoracic pressure and a drop in venous return. Placing the patient in the left lateral decubitus position or tilting her to the left by placing a wedge under the right hip might be helpful strategies. Maternal hypoxia can result in significant fetal compromise; therefore, maintaining maternal oxygenation is paramount. Expert opinion favors keeping maternal PaO2 above 70 mm Hg to avoid deleterious effects on the fetus [20]. Continuous fetal monitoring should be initiated when there is an acute change in the maternal respiratory status. Permissive hypercapnea in pregnancy is controversial [50]. Fetal hypercapnea may be associated with fetal acidosis and a shift in the oxyhemoglobin curve, leading to impaired oxygenation in the fetus. When possible, maternal PaCO2 should be kept in the normal pregnancy range (28e32 mmHg).
Tuberculosis in pregnancy Worldwide, every year, over one billion tuberculosis (TB) infections, nine million new cases, and approximately 1.7 million deaths are estimated to occur [51]. An individual with latent TB has a 5% risk of active disease within the first 2 years, and a subsequent 5% lifetime risk of disease. HIV coinfection significantly increases the risk of active TB to 5e10% per year, highlighting the importance of evaluating for TB exposure and latent disease in those with HIV infection. TB is also one of the leading causes of mortality in reproductive-age women [52]. In 2012, an estimated 2.9 million women had TB illness and 410,000 women died [58]. Of the TB deaths in HIVinfected individuals, 50% were in women. The African and Southeast Asian regions accounted for 68% of the TB cases in women, and almost 90% of the TB deaths in women were in Africa. More than half of the estimated TB cases in women went undetected compared to
