second approach involves using adjusted-dose subcutaneous heparin or enoxaparinthroughout pregnancy. We recommend dosage regimens as outlined in Table 36.5,with acknowledgment of the paucity of data supporting these recommendations.Given the controversies outlined above, with their ensuing medicolegal implications,the patient must be involved in this choice and thoroughly informed of the risksand benefits of either approach.

Further reading

ACC/AHA Guidelines for the Management of Patients with Valvular Heart Disease: a Reportof the American College of Cardiology/American Heart Association Task Force on PracticeGuidelines (Committee on Management of Patients with Valvular Heart Disease). J Am CollCardiol 1998;32:1486.

APPCR Panel and Scientific Roundtable. Anticoagulation and enoxaparin use in patients withprosthetic heart valves and/or pregnancy. Clin Cardiol Consensus Rep 2002;3(9).

Avila WS, Rossi EG, Ramires JA, et al. Pregnancy in patients with heart disease: experiencewith 1,000 cases. Clin Cardiol 2003;26:135.

Clark SL. Structural cardiac disease in pregnancy. In: Clark SL, Cotton DB, Phelan JP, eds.Critical care obstetrics, 3rd edn. Boston: Blackwell Scientific, 1997.

Gei AF, Hankins GD. Cardiac disease and pregnancy. Obstet Gynecol Clin North Am2001;28:465.

Hung L, Rahimtoola SH. Prosthetic heart valves and pregnancy. Circulation 2003;107:1240.Ramsey PS, Ramin KD, Ramin SM. Cardiac disease in pregnancy. Am J Perinatol

2001;18:245.Ray P, Murphy GJ, Shutt LE. Recognition and management of maternal cardiac disease in

pregnancy. Br J Anaesth 2004;93:428.Reimold SC, Rutherford JD. Valvular heart disease in pregnancy. N Engl J Med 2003;349:52.Rout CC. Anesthesia and analgesia for the critically ill parturient. Best Pract Res Clin Obstet

Gynecol 2001;15:507.

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37 Maternal pulmonary disorderscomplicating pregnancySteven L. Clark and Calla Holmgren

Pregnant women are afflicted by the same respiratory ailments as nonpregnantwomen, but these conditions are complicated by the physiologic alterations of preg-nancy. Certain lung diseases, such as asthma, are common in women of childbear-ing age and may often be seen in pregnant women. Asthma and other pulmonarydiseases may first manifest during pregnancy or change their course during gesta-tion. Respiratory illness can affect both maternal and fetal outcomes during preg-nancy. Pharmacologic treatment of lung disease can be undertaken to minimizeadverse effects to both mother and fetus.

Handbook of Clinical Obstetrics: The Fetus & Mother, Third EditionE. Albert Reece, John C. Hobbins

Copyright © 2007 by Blackwell Publishing Ltd

Diagnostic techniques

History and physical examinationIf the patient has been pregnant in the past, the presence of respiratory symptomsduring the previous pregnancy should be noted and compared with the patient’susual respiratory symptoms when not pregnant.

Dyspnea is the most common respiratory complaint during pregnancy, with asmany as 60–70% of previously normal women having this symptom at some timeduring pregnancy. The complaint usually begins in the first or second trimester butis most prevalent at term. It is not usually due to underlying lung disease, butappears to result from the subjective perception of hyperventilation that normallyaccompanies pregnancy. As the woman acclimatizes to this new sensation, her per-ception of dyspnea is reduced, and the dyspnea stabilizes as the pregnancy pro-gresses. Unlike pathologic dyspnea, symptoms do not increase with exertion.

Arterial blood gasesIn a normal pregnant female, arterial blood gas measurements will usually show acompensated respiratory alkalosis due to maternal hyperventilation. The pH gen-erally ranges from 7.40 to 7.47, and the partial pressure of arterial carbon dioxideis 25–32mmHg. The partial pressure of arterial oxygen (PaO2) may be as high as106mmHg in early pregnancy, decreasing during pregnancy but remaining at100mmHg, or slightly higher, at term.

Calculating the O2 content of blood requires a knowledge of the amount of O2

dissolved in the blood, the maximum amount of O2 able to be carried per gram ofhemoglobin, the hemoglobin concentration, and the O2 saturation of hemoglobin.

O2 content = [(hemoglobin [Hb] (g/dL) × 1.39mLO2/g Hb) × (O2 saturation)] + [(0.003mL O2/100mL of blood)

× PaO2 (mmHg)]

Mismatching of ventilation and perfusion is responsible for most of the defectivegas exchange in pulmonary diseases. The adequacy of alveolar gas exchange can beassessed by calculating the alveolar–arterial O2 tension gradient and, if the alveolarO2 tension (PAO2) greatly exceeds the PaO2, then alveolar gas exchange is abnormal.Ideal PaO2 is calculated as follows:

PaO2 = FIO2 × (PB − 47) − PaCO2/0.8

FIO2, fractional percentage of inspired O2; PB, barometric pressure; 47, water vaporpressure; PaCO2, arterial blood tension of carbon dioxide; 0.8, respiratory quotient.

Because most acute lung diseases are accompanied by an increased (A–a) O2 gra-dient, the gradient should be assessed with the pregnant patient in the upright posi-tion and should be considered abnormal if it exceeds 25mmHg. Blood gas analysisshould be accompanied by calculation of the gradient because, given the usualdecreased Pco2 in pregnancy, on casual observation, a “normal” PaCO2 can be seeneven with an abnormally increased (A–a) O2 gradient.

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Pulmonary function testsThe enlarging fetus and the increased concentration of circulating hormones duringpregnancy account for the changes in pulmonary function seen with gestation (Table 37.1). The hyperventilation of pregnancy is characterized by an increaseddepth of breathing (tidal volume increased from 450 to 600mL) and not a higherrespiratory rate.

A woman with a respiratory disease that is unlikely to deteriorate during preg-nancy, an FEV1 greater than 1L, and no dyspnea at rest can undertake pregnancysafely.

Radiographic testingIf at any time during pregnancy, the health of the mother or fetus would be compromised by failure to perform a radiologic examination, the examinationshould be performed. Irradiation in utero may increase the risk of childhood

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Table 37.1 Pulmonary parameters.

Lung volumes Description

Tidal volume (TV) The volume of air inhaled or exhaled with each normal breath

Residual volume (RV) The volume of air remaining in the lungs after a vital capacity maneuver

Inspiratory reserve volume (IRV) The maximal additional volume of gas that can be inhaled after a tidal breath is inhaled

Expiratory reserve volume (ERV) The maximal volume of gas that can be exhaled after a tidal breath is exhaled

Total lung capacity (TLC) The volume of air in the lungs at maximal inspiration

Vital capacity (VC) The maximum amount of air that can be exhaledafter a maximal inspiration to TLC

Inspiratory capacity (IC) The maximal volume of gas that can be inspiredfrom the resting expiratory level

Functional residual capacity (FRC) The volume of air remaining in the lungs after atidal volume exhalation

Forced vital capacity (FVC) The volume of air exhaled during a rapid forcedexpiration starting at full inspiration

Other measurements made by spirometryForced expiratory volume in 1 s (FEV) The volume of air expelled in 1s during a forced

expiration starting at full inspirationMinute ventilation (MV) The amount of air exhaled per minute, measured

under resting conditionsPeak expiratory flow rate (PEFR) The peak rate (L/min) of a forceful expiration of

a vital capacity

leukemia and other malignancies by 40–50%. Taking into account the greatestoncogenic risk, the overall risk of any adverse effect from exposure to 1 rad is esti-mated to be 0.1%, a risk that is thousands of times smaller than the risks of spon-taneous abortion, malformation, or genetic disease. Fetal exposure to less than 5 radis considered to be insufficient reason to recommend the termination of a desiredpregnancy.

When chest radiographs are performed in the pregnant patient, normal findingsdiffer from those seen in nonpregnant women of childbearing age. The diaphragmmay be elevated 4cm at term, but there will be a compensatory increase in antero-posterior diameter. There is an increase in the subcostal angle from 68.5° to 103.5°from early to late pregnancy. Also, lung marking may be increased, giving a falseimpression of mild congestive heart failure. Postpartum pleural effusions may notbe a normal occurrence.

Maternal–fetal oxygen exchangeIn a woman with no pulmonary disease who is breathing room air, arterial bloodtypically has a PaO2 of 91mmHg and a PCO2 of 36mmHg. In the fetal umbilicalvein, a simultaneous blood gas typically shows a PO2 of 32mmHg and a PCO2 of50mmHg. Increases in the concentration of inspired O2 result in the expected risein O2 tension in the maternal arteries, but not in large increases in the O2 tensionof the fetal umbilical veins. Nevertheless, even a small increase in the oxygen contentcan result in a significant increase in oxygen transfer to the fetus. This occurs becauseof the high maternal perfusion rate of the uterus, the enhanced avidity of fetal hemo-globin for oxygen, and the leftward shift in the fetal oxyhemoglobin dissociationcurve. However, the fetus is sensitive to large shifts in oxygen delivery, caused by afall in cardiac output and, with complete interruption of oxygen supply to the umbil-ical vein, the fetus has only a 2- to 4-min oxygen reserve.

Maternal alkalosis can result in decreased fetal oxygen tensions because ofreduced uterine blood flow due to hypocarbia-induced vasoconstriction of uterinearteries, on account of the mechanical effects of hyperventilation causing decreasedmaternal venous return, and because of a shift in the maternal oxyhemoglobin dis-sociation curve to the left, thereby impairing oxygen transfer to the fetus. In thestudies by Wulf and colleagues (1972), fetal oxygen delivery was compromised whenmaternal pH exceeded 7.6 and PCO2 was 15 mmHg, values unlikely to be reachedin acute asthma.

Asthma

Asthma, or reversible narrowing of the large or small airways, is the most commonobstructive lung disease affecting women of childbearing age, occurring in 0.4–1.3%of pregnant women.

The effect of asthma on the outcome of pregnancyMost asthmatics experience pregnancy with few ill effects and, in general, there are

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no striking differences between the outcome of pregnancy in asthmatics comparedwith a control population. Nevertheless, severe and inadequately managed asthmacan be associated with increased maternal and fetal complications, such as enhancedmaternal and fetal mortality, a slight increase in the incidence of premature births,stillbirth, low birthweight babies, and subsequent neurologic abnormalities in theoffspring. No differences in the frequency of multiple births or congenital malfor-mations or in the infants’ Apgar scores have been seen in the children of asthmaticmothers.

The effect of pregnancy on the course of asthmaAsthma worsens during pregnancy in slightly more than one-third of patients,improves in slightly more than one-third of patients, and remains unchanged in one-third of patients. The change in asthma course associated with pregnancyusually reverts to the prepregnancy course within 3 months after delivery, and the course of asthma tends to be similar in a given woman during subsequent pregnancies.

Clinical presentationClassically, two clinical patterns of asthma have been recognized. One group, theso-called extrinsic asthmatics, develops asthma at a young age, has a family historyof atopy, may have other atopic manifestations (skin and nasal allergies), and hasevidence of immunoglobulin (Ig)E-mediated response along with blood and sputumeosinophilia. Attacks are often seasonal and precipitated by well-defined allergens.The second group, the “intrinsic asthmatics,” develops asthma later in life, has nofamily history of asthma or atopy, has no evidence of IgE-mediated bronchospasm,uncommonly has eosinophilia, but may have severe asthma that is difficult to treat.The intrinsic asthmatic is sensitive to environmental irritants, and acute exacerba-tions are often triggered by viral respiratory illness. Other clinical patterns includethe triad of chronic asthma, a history of nasal polyps and pansinusitis, and the devel-opment of significant reductions in airflow rates following ingestion of aspirin ornonsteroidal anti-inflammatory drugs. In these patients, bronchospasm developswithin minutes to hours, and symptoms may be severe or even life-threatening. Exercise-induced asthma is another common variant and is characterized by thedevelopment of bronchospasm following discontinuation of exercise in patients whomay or may not have chronic asthmatic symptoms.

An acute attack of asthma is usually heralded by the clinical triad cough, wheez-ing, and dyspnea. Dyspnea may be interpreted as a tightness in the chest. Attacksoften occur at night. Usually, there is a history of exposure to a specific allergen,physical exertion, a viral respiratory tract infection, or emotional excitement preceding the onset of an exacerbation, and the patient will often have a history ofsimilar episodes in the past.

Physical examination during an exacerbation reveals audibly harsh respirations,inspiratory and expiratory wheezing with a prolonged expiratory phase, tachypnea,tachycardia, and mild systolic hypertension. The lungs are overinflated, and the

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anterior–posterior diameter of the thorax is increased beyond that typically expectedin pregnancy. With increased duration and severity of an attack, the accessory res-piratory muscles become visibly active, and the patient may develop a paradoxicalpulse, both signs of severe respiratory compromise.

The chest radiograph during an acute attack usually shows hyperinflation of thelungs with a small, elongated heart. The chest film may be necessary to excludecomplications such as pneumothorax, pneumomediastinum, cardiomegaly, pneu-monia, mucoid impaction, or bronchopulmonary aspergillosis, but only when theseconditions are suspected on clinical grounds.

Laboratory studies are nonspecific. A complete blood count often displays a mildto moderate eosinophilia that may be reduced or absent if the patient has beentaking corticosteroids. Life-threatening risks can be avoided by careful and routinemedical attention during pregnancy and by early pharmacologic intervention duringan exacerbation. The clinical hallmarks of cough, wheezing, and dyspnea do notcorrelate in any predictable way with lung function. Thus, if the patient can performa forced expiration, the FEV1 or the peak expiratory flow rate (PEFR) should beused to assess the severity and progress of airway obstruction. Carbon dioxide reten-tion begins to occur at an FEV1 of approximately 750mL (about 25% of the pre-dicted value), and a PEFR of less than 100L/min is thought to be associated withan increased risk of a potentially fatal attack. With severe asthma, accessory muscleuse and pulsus paradoxicus may be seen, suggesting that the FEV1 is less than 25%of normal.

Pharmacology of asthma therapyBecause asthma is an airways disease, inhalation therapy is generally preferable tosystemic treatment. Aerosolized medications deliver the drug directly to the airways,minimizing systemic side-effects. Inhaled β2-agonists are usually sufficient therapyfor mild, intermittent asthma. If symptoms disappear and pulmonary function nor-malizes with inhaled β2-agonists, they can be used indefinitely as needed. However,their use on a daily basis, or even more often than three times a week, usually indi-cates a need for anti-inflammatory therapy.

Inhaled anti-inflammatory agents are the primary therapy for moderate asthma.Choices include cromolyn sodium or inhaled corticosteroids, which provide effec-tive asthma control with minimal side-effects at the recommended doses. Suppres-sion of symptoms and PEFR improvement are often not maximal until 2–4 weeksof treatment. A spacer, used to bypass the oropharynx during the administration ofaerosolized medication, should be considered not only to reduce oropharyngeal can-didiasis but also to improve respiratory tract penetration and reduce systemic effects.

A short tapering course of oral corticosteroids is indicated when asthma is notcontrolled by a combination of bronchodilators, cromolyn sodium, and inhaled cor-ticosteroids. Such deterioration of asthma may be characterized by a reduction inPEFR of 20% or more from normal values that fails to respond to inhaled bron-chodilators, by greater intolerance of exercise, or by the development of nocturnalsymptoms. At the end of this course, oral corticosteroids can be stopped; if asthma

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symptoms do not recur and pulmonary functions remain normal, no additional oralsteroid therapy is necessary. However, if this “burst” of prednisone does not controlsymptoms, is effective for fewer than 10 days, or must be repeated frequently, thepatient needs additional therapy. Prolonged use of high doses of oral corticosteroidsmay be associated with increased risk of gestational diabetes and maternal adrenalinsufficiency.

Leukotriene modifiers, such as montelukast (Singulair) and zafirlukast (Accolate),are available for the treatment of asthma. The cysteinyl leukotrienes (LTC4, LTD4,and LTE4) are produced by way of arachidonic acid metabolism and are releasedby mast cells and eosinophils. They then bind to leukotriene receptors in the humanairway, causing airway edema, smooth muscle contraction, and altered cellularactivity. Leukotriene modifiers bind to these leukotriene receptors, inhibiting theactions of leukotriene at the level of the mast cell and eosinophil. These medica-tions are pregnancy category B and may be continued during pregnancy. Sustainedrelease theophylline or a long-acting oral agonist once a day in the evening may behelpful for the patient with primarily nocturnal symptoms. Otherwise, oral theo-phylline is generally not used in current clinical practice.

Therapy of acute asthma attacksSeveral risk factors for fatal asthma have been identified, and these include the following:• a history of intubation for asthma;• two or more hospitalizations for asthma within 1 year;• three or more emergency room visits for asthma within 1 month;• recent withdrawal from systemic corticosteroids;• history of syncope or seizure associated with an asthmatic attack;• previous admission to a hospital intensive care unit for asthma;• coexisting psychiatric disease or psychosocial problems.

An acute attack of asthma should be managed aggressively, and the patient should be evaluated carefully for possible hospital admission (Table 37.2). Inapproximately 10–15% of pregnancies complicated by asthma, the patient may

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Table 37.2 Prophylactic evaluation and management of the asthmatic.

Take a careful history, including severity of asthma and identifiable precipitantsBaseline pulmonary function tests and PEFRsVaccinate against influenzaOptimize dosage and frequency of medicationsPatient counseling

Appropriate exerciseAvoidance of precipitantsInstruction on early recognition of wheezing and need for prompt intervention

require hospitalization for status asthmaticus, a condition characterized by refrac-tory airway obstruction with failure to resolve after appropriate treatment. A quicksearch for a precipitating event and questioning about prior and current corticos-teroid use are part of the initial history. Then examination of pulse, blood pressure,respiratory rate, pulsus paradoxus, and FEV1 and/or peak expiratory flow is indi-cated. A pulse of more than 120/min, respiratory rate of more than 30/min, pulsusparadoxus more than 18mmHg, peak expiratory flow less than 120L/min, moder-ate to severe dyspnea, accessory muscle use, and severe wheezing at the time of pres-entation are all signs of potentially life-threatening disease and probably indicate aneed for acute hospitalization.

The emergency management of acute, severe asthma in pregnancy involves severalinitial steps:1 Administer O2 to maintain a PaO2 as near normal as possible but at least above60mmHg or O2 of at least 95%.2 Perform baseline arterial blood gases, continuous pulse oximetry, and intensivefetal monitoring for late second- or third-trimester fetuses.3 Obtain baseline pulmonary function tests (FEV or PEFR).4 Administer an inhaled beta-agonist, such as albuterol, 2.5mg in 2–3mL of diluentwith a pressure-driven nebulizer, every 20min for up to three doses. Alternatively,terbutaline sulfate, 0.25mg, is administered subcutaneously every 20–30min for upto three doses.

In an emergency setting, epinephrine (0.3mL of 1:1000 dilution) can be givensubcutaneously with serial injections leading to cumulative improvements in airwayfunction. This therapy should be avoided in patients with marked hypertension (sys-tolic BP > 200mmHg) or in those patients with an irregular pulse.

Further management is based on clinical response and improvements in pul-monary function testing. If these maneuvers improve the PEFR to more than 70%of baseline, the patient may be discharged, often with a short course of oral corti-costeroids. For a PEFR that is 40–70% of baseline, the beta-agonist therapy is con-tinued (at intervals as frequent as every hour in patients without heart disease) andmethylprednisolone, 80mg every 6h, is initiated. If the initial response results in aPEFR less than 40% of baseline, the patient should be admitted to the hospital. APEFR of less than 25% or PCO2 of more than 35mmHg suggests imminent respi-ratory failure. The patient should be admitted to an intensive care unit. Intubationmay be necessary if deterioration continues. In a patient with a viable fetus(> 24 weeks), it may be prudent to employ external fetal monitoring to ensure adequate oxygen delivery to the fetus.

Other obstructive lung disorders

Severe emphysema due to α1-antitrypsin deficiency and cystic fibrosis (CF) can occurin women of childbearing age. Care of these patients is primarily supportive, withattention to the physiologic parameters of lung function and oxygenation discussed earlier.

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A National Institutes of Health study followed 129 pregnancies in CF patientsand found only 86 viable infants, leading the investigators to conclude that CFpatients have greatly increased fetal wastage. In the study, there were six sponta-neous abortions, 25 therapeutic abortions, and 11 perinatal deaths. Ten of the peri-natal deaths occurred in infants born at less than 37 weeks’ gestation. Prematurelabor occurred in 26 of the 129 pregnancies, and infant mortality was 18% within24 months of delivery. The authors recommended that pregnancy be avoided unlessthe potential CF mother was clinically healthy. Published studies relate the severityof maternal disease at the onset of pregnancy more than the effects of CF on preg-nancy to outcomes. Factors such as pancreatic insufficiency, nutritional status, andlow Taussig score were predictors of poor prognosis in pregnancy. Any woman withpulmonary hypertension should not undertake pregnancy. A reasonable set of guide-lines is to advise against pregnancy in any CF patient with a vital capacity of lessthan 50% of predicted, hypoxemia, pulmonary hypertension, or pancreatic insuffi-ciency. The absence of pancreatic insufficiency may identify a subgroup more ableto tolerate pregnancy. A recent study showed that women with CF, after adjustingfor demographic differences, who became pregnant did not have worse survival.

Bronchial drainage, antibiotic therapy, prophylactic immunization (includingannual influenza vaccine administration), and optimal nutritional and psychosocialcare are essential components in the care of the CF patient contemplating pregnancy.

Aspiration of stomach contents

The aspiration of low-pH liquid stomach contents into the tracheobronchial tree,with subsequent chemical pneumonitis, was first described in women undergoinglabor and delivery. This syndrome is most likely to develop if aspirated material hasa pH of less than 2.5, but some reports suggest that some degree of respiratory dys-function can occur even if the pH of the aspirate is higher. Other syndromes thatcan result from aspiration are bronchial obstruction by an aspirated foreign bodyand bacterial pneumonia from aspiration of oropharyngeal bacteria.

Immediate clinical illness may appear if the aspiration is massive, but typicallythere is generally a delay of at least 6–8h before the first appearance of signs andsymptoms such as bronchospasm, tachycardia, hypotension, tachypnea, cyanosis,and frothy pink sputum. Diagnosis is facilitated by having a high index of suspi-cion in the postpartum patient with respiratory distress.

Treatment of acid aspiration is supportive with O2 and mechanical ventilation ifneeded. If aspiration is observed, endotracheal suctioning should be performed, butsaline lavage is not indicated and may even serve to spread the acid to uninvolvedareas. Bronchodilators may be used to control bronchospasm, and the prophylac-tic use of broad-spectrum antibiotics should be considered. Corticosteroids havebeen used in the treatment of witnessed gastric aspiration, but are of unprovenbenefit.

Prophylaxis of aspiration should always be undertaken in the pregnant patientundergoing surgery, with antacids given during labor to raise the gastric pH to more

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than 2.5 and thus reduce the chance of a dangerous aspiration. Adverse pulmonaryreactions may result from aspirating antacid particles; thus, the use of nonparticu-late agents is preferred. Various combinations of oral nonparticulate antacids andH2-receptor blockers have been advocated as a convenient prophylactic regimen forpatients about to undergo elective or emergency Cesarean section, but no particu-lar combination appears to be clearly superior. Additional prophylactic measuresinclude limiting oral intake to essential medications once labor is started, nasogas-tric evacuation of a distended stomach, selection of regional anesthesia when possible, use of a cuffed endotracheal tube, and use of cricoid pressure during intubation.

Respiratory infections

Bacterial pneumoniaPneumonia of all etiologies is a relatively common cause of maternal mortality. Ithas been reported in 0.1–0.84% of all pregnancies, with a mortality rate of3.5–8.6%, although antibiotics and modern obstetric care have improved the prog-nosis. Streptococcus pneumoniae is the most common infectious agent implicatedin antepartum pneumonia, and other common bacterial pathogens includeMycoplasma pneumoniae and Haemophilus influenzae. Legionella pneumoniae andListeria monocytogenes have rarely been reported to cause respiratory failure inpregnancy.

Pneumococcal pneumonia classically begins with the abrupt onset of shakingchills, fever, pleuritic chest pain, cough productive of purulent sputum, and short-ness of breath. The physical examination often shows signs of consolidation, suchas dullness to percussion, tactile fremitus, and egobronchophony. A chest radio-graph usually reveals evidence of lobar consolidation, but bronchopneumonia mayalso occur. Laboratory examination may reveal a polymorphonuclear leukocytosisin the range of 12000 to 25000 cells/mL, but a normal white blood cell count canalso be seen, especially in patients with overwhelming infection and bacteremia. Asputum specimen for culture and Gram’s stain should generally be obtained andmay demonstrate Gram-positive encapsulated cocci in pairs and short chains. Bloodcultures are positive in approximately 20–30% of patients and should be collectedbefore the administration of antibiotics.

Although penicillin U has long been considered the antibiotic of choice, recentevidence suggests that penicillin nonsusceptibility is found in nearly 40% of strainsof Streptococcus pneumoniae causing disease in adults. Given this, any gravidpatient thought to have bacterial pneumonia should be admitted to hospital andstarted on a third-generation cephalosporin and a macrolide (e.g., azithromycin)until sputum culture reveals the causal organism and sensitivities. Once established,antibiotic treatment can be tailored to the responsible organism. This will typicallylead to defervescence within 48h. Once the patient is afebrile for 48h, parenteralantibiotic therapy can be discontinued and oral cephalosporin continued for10–14 days.

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Mycobacterium pneumoniae produces symptoms similar to a viral infection, witha flu-like syndrome, interstitial infiltrates, and alveolar filling. Because tetracyclineis relatively contraindicated in pregnancy, erythromycin is the drug of choice.Haemophilus influenzae pneumonia may have a gradual rather than an abrupt onsetand may be clinically indistinguishable from S. pneumoniae. It is infrequently seenin young adults unless the patient has a history of chronic obstructive lung diseaseor is an alcoholic. The chest radiograph may show either bronchial or lobar con-solidation, and pleural effusions are common. Again, because the occurrence ofampicillin resistance may be significant, the patient should be managed as statedabove with susceptibility testing performed on all culture isolates and antibiotictherapy tailored appropriately.

InfluenzaIn a review of all deaths due to influenza from 1957 through 1960, 1–11% occurredin pregnant patients. These deaths were concentrated late in the third trimester andearly puerperium and were more likely to occur with increased maternal age.However, because earlier studies were based on the clinical diagnosis of influenza,the conclusion that pregnancy predisposes to infection or to an enhanced severityof illness is controversial.

Influenza usually begins abruptly with systemic symptoms, such as headache, fever,chills, myalgia, and malaise accompanied by an upper respiratory illness. In anuncomplicated case, complaints of a sore throat and cough may persist for a week ormore. Physical findings may be minimal, but injection of the mucous membranes anda postnasal discharge can be seen along with mild cervical adenopathy. The chestexamination may be normal but can reveal rhonchi, wheezes, and scattered rales.Occasionally, the disease can progress rapidly to fulminant cardiopulmonary failure,or it can be complicated by secondary bacterial or mixed viral–bacterial pneumoniainvolving Streptococcus, Staphylococcus, or H. influenzae.

Amantadine, an oral antiviral agent active against influenza A, can be used ther-apeutically and prevents 70–90% of experimentally produced and natural infec-tions. It is not effective in treating infections due to influenza B. If used within 48 hof the onset of symptoms, amantadine shortens the duration of the illness by up to50%, reduces fever, and hastens the resumption of normal activities. If given con-comitantly with an influenza vaccine, it can protect the patient for the 2–3 weeksnecessary for immunity to develop during exposure to an epidemic. Other antivi-rals, zanamivir and osteltamivir, may reduce the duration of uncomplicatedinfluenza A and B. No clinical study has been conducted regarding the safety or effi-cacy of any of these antiviral medications during pregnancy.

Although influenza virus can cross the placenta, it has not been isolated from fetalblood, and transplacental passage does not appear to cause congenital defects. Fetalabnormalities, such as circulatory defects, central nervous system malformations,cleft lip, and childhood cancer, have been attributed to influenza, but most investi-gators have concluded that no influenza-induced congenital syndrome exists.Influenza vaccine may be administered appropriately in pregnant women in any

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trimester with standard indications for such immunization. Because increased mor-tality from infections usually occurs late in pregnancy, vaccination can often bedelayed until the middle of the second trimester if necessary.

Viral pneumoniaOther life-threatening viral pneumonias can develop in the pregnant patient, including varicella pneumonia, which may accompany chickenpox and can rangefrom a mild to a rapidly fatal illness. In pregnancy, varicella is rare, but if pneumonia develops, mortality is high, ranging from 30% to 40% in some series. In addition, varicella pneumonia has been associated with an increased incidence of premature labor. Maternal varicella infection in any trimester of preg-nancy can be associated with infrequent, but possibly lethal, congenital anomalies.If the maternal infection occurs within 5 days of delivery, the infant is at risk offatal disseminated infection. Given the high mortality rate associated with varicellapneumonia occurring in pregnancy and the lack of demonstrated human fetal tox-icity, it is recommended that any gravid patient with varicella pneumonia be admitted to hospital for parenteral therapy with acyclovir. The dose is 500mg/m2

every 8h and should be continued until the symptoms of the illness resolve. Animportant consideration of varicella pneumonia during pregnancy is the issue ofprevention. Patients considering pregnancy should be questioned regarding theirhistory of varicella and, if unsure, titers should be drawn to confirm immunity. If the patient is not immune, then the varicella vaccine can be given prior to pregnancy. If the patient is not immune, but exposed to varicella peripartum, many authors have recommended the administration of varicella zoster immuneglobulin.

Fungal pneumoniaCryptococcus neoformans, Blastomyces dermatitidis, and Sporothrix schenckii haverarely been reported as causing serious respiratory infection in pregnancy. The clin-ical course and outcome are generally the same in pregnant and nonpregnantpatients. It has been estimated that coccidioidomycosis occurs in less than one ofevery 1000 pregnancies. However, infection in pregnancy, particularly during thesecond and third trimesters, increases the rate of disseminated infection from 0.2%to more than 20%. It has been suggested that 17β-estradiol has a stimulatory effecton the fungus and may be responsible for the increased risk of dissemination associated with pregnancy. Maternal mortality rate from disseminated coccid-ioidomycosis approaches 100%, a rate approximately twice that seen in nonpreg-nant patients. Dissemination is associated with increased fetal prematurity andmortality.

Amphotericin B has been used to treat cryptococcoses, blastomycosis, and dis-seminated coccidioidomycosis in pregnancy. It crosses the placenta and can be foundin both amniotic fluid and fetal blood. Although use in pregnancy has not been wellstudied, normal, full-term infants have been born to patients who received ampho-

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tericin B in the first trimester. Its use is associated with anemia; thus, serial hemat-ocrits must be followed.

Pneumocystis carinii pneumoniaPneumocystis carinii pneumonia is the most common opportunistic infection affecting the lungs of patients with acquired immunodeficiency syndrome (AIDS).It can be confused with atypical mycobacterial infection, cryptococcoses, and histoplasmosis.

There are several case reports of P. carinii pneumonia (PCP) complicating preg-nancy and evidence to suggest that PCP has a more aggressive course during preg-nancy, with increased morbidity and mortality. The treatment of choice in pregnantwomen with AIDS and P. carinii pneumonia is trimethoprim-sulfamethoxazole(SXT). Concomitant use of steroids is controversial. Studies of in utero exposure toSXT failed to show an increase in prematurity, hyperbilirubinemia, or kernicterus.Patients should be monitored for drug toxicity, such as rash, fever, neutropenia,thrombocytopenia, and hepatitis. Nausea and vomiting may occur and can exacer-bate hyperemesis gravidarum.

In patients who cannot tolerate trimethoprim-sulfamethoxazole, pentamidinemay be required because of the life-threatening risk of withholding treatment fromthe mother. If pentamidine is used, the mother should be closely monitored for hypo-glycemia. Aerosolized pentamidine, because of poor systemic absorption anddecreased systemic side-effects, has been advocated as safe, effective prophylaxis forP. carinii pneumonia. Prophylaxis against PCP with trimethoprim-sulfamethoxazoleis known to be very effective, with rates of prevention of 90–95%. Given this, inpregnant patients with known human immunodeficiency (HIV)-positive status, pro-phylaxis should be strongly considered.

Amniotic fluid embolism

Amniotic fluid embolus (AFE) is a devastating, pregnancy-specific condition, inwhich both maternal and fetal death is the most probable outcome. It is one of theprincipal causes of maternal death in developed countries. There is direct supportfor the anaphylactoid nature of this condition, based on marked clinical similaritiesbetween a large series of patients with AFE and patients with both septic and ana-phylactic shock.

Clinically, AFE manifests by the sudden development of hypoxia, hypotension, orcardiac arrest and disseminated intravascular coagulation (DIC). All components ofthe full AFE syndrome are not invariably present. AFE occurs as fetal tissue enters thematernal circulation and incites the reaction described above, probably via the releaseof various endogenous mediators. This most commonly occurs during labor but, insusceptible maternal–infant pairs, it has clinical onset at the time of Cesarean section.

The diagnosis of AFE is a clinical one based on physiologic manifestations andmust be made after the exclusion of other conditions, such as myocardial infarction

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and pulmonary thromboembolism. The presence of a consumptive coagulopathy,although not required for the diagnosis of AFE, supports its diagnosis because acuteconsumptive coagulopathy in obstetrics is limited to AFE and placental abruption.Because some fetal debris is commonly found in the maternal circulation, the pres-ence or absence of histologic pulmonary findings is not sufficient by itself to makethe diagnosis of AFE, nor does its absence rule this syndrome out in the presenceof appropriate clinical manifestations.

There is currently no way to predict or prevent AFE. Treatment of the mother issupportive, and involves the administration of O2 in response to clinical hypoxia,preload and inotropic support of falling blood pressure, and blood componentreplacement for DIC with clinical hemorrhage. With the development of lethalcardiac dysrhythmia, standard basic and advanced cardiac life support protocolsshould be instituted.

In the presence of maternal cardiac arrest, maternal survival without profoundneurologic impairment is rarely achieved. However, a clear relationship existsbetween arrest-to-delivery interval and neonatal outcome. Thus, expeditious peri-mortem Cesarean section should be initiated on the diagnosis of maternal cardiacarrest, regardless of its etiology, assuming the gestation has advanced to the pointof fetal viability.

Venous air embolism

Venous air embolism may account for as many as 1% of maternal deaths, with riskfactors being the performance of surgery, intravenous infusions, and central venouscatheter placement. However, because the venous sinuses of the uterus are particu-larly susceptible to the entry of air during pregnancy, air embolism can occur duringnormal labor, delivery of a placenta previa, criminal abortions using air, orogenitalsex, and insufflation of the vagina during gynecologic procedures. Maternal mor-tality associated with a clinically significant event exceeds 90% in untreated cases.The severity of a venous air embolism depends on the amount and rate of air entry.Small amounts of venous air are clinically undetectable, but accidental bolus injec-tions of 100–300mL3 of air have been reported to be fatal. However, there arereports of patients surviving infusions of up to 1600mL3.

Embolization of a large bolus of venous air to the right ventricle results in mechan-ical obstruction to the forward flow of blood in the pulmonary artery outflow tract.In addition, the pumping action of the right ventricle acting on blood and air mayproduce platelet damage and fibrin formation, resulting in fibrin emboli that lodge inthe pulmonary vascular bed. Maldistribution of pulmonary blood flow may result inischemia or hyperperfusion, with the hyperperfused areas being susceptible to devel-oping interstitial and alveolar edema. Areas that are initially ischemic may alsobecome abnormally permeable once perfusion is restored. Paradoxical embolizationcan occur if there is an atrial septal defect, resulting in arterial ischemia or occlusion.

The patient initially presents with a feeling of faintness, dizziness, fear of impend-ing doom, dyspnea, cough, diaphoresis, and substernal chest pain. Physical exami-

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nation may reveal a state of altered consciousness, cyanosis, tachypnea, wheezing,tachycardia, hypotension, elevated jugular venous pressure, gallop rhythm, and anevanescent “mill wheel” or “waterwheel” murmur heard over the precordium. Para-doxical embolism may be evidenced by bubbles in the retinal arterioles, marble-likeskin (air in the superficial dermal vessels), and possibly stroke or myocardial infarc-tion. A blood gas test characteristically reveals hypoxemia, and there may be anassociated metabolic acidosis. Chest radiography may occasionally demonstrate airin the right side of the heart or the main pulmonary artery, and the electrocardio-gram may show signs of right heart strain, ischemia, or arrhythmia.

Therapy must be instituted promptly, and the patient should be placed in the leftlateral decubitus position to minimize obstruction to the right ventricular outflowtract.

Administration of 100% O2 promotes removal of nitrogen from the air bubble andresults in more rapid absorption of the embolus. Nitrous oxide is highly soluble and,in a patient receiving general anesthesia, it should be discontinued because it canincrease the size of the air embolus. In the presence of cardiovascular collapse, closedchest compression and aspiration of air from the right side of the heart via venouscatheterization or transthoracic puncture have been suggested, although actualimproved survival of pregnant women so treated has not been demonstrated. Hyperbaric O2 may be useful in the setting of cerebral venous air embolism, and anticoagulation has been suggested to minimize the formation of fibrin microem-boli. Mechanical ventilation may be necessary to treat permeability pulmonaryedema.

Adult respiratory distress syndrome

Adult respiratory distress syndrome (ARDS) is the final common pathway of patho-physiologic changes occurring in the lungs as a consequence of a variety of acutebodily insults that reach the lung directly or via the vasculature. Clinically, patientspresent with marked respiratory distress, tachypnea, hypoxemia refractory to O2

therapy, “stiff’ noncompliant lungs that require high pressures to achieve inflation,and diffuse bilateral interstitial and alveolar infiltrates on chest radiograph. Thecentral pathophysiologic event in ARDS is injury to the alveolar–capillary mem-brane, either directly or via mediators delivered by the pulmonary vasculature,which results in increased vascular permeability and noncardiogenic pulmonaryedema. Severe hypoxemia results from both increased shunting of unoxygenatedblood and impaired ventilation and perfusion matching in the alveoli, with an arte-rial PO2 of typically less than 50–60mmHg despite an inspired O2 concentration of60% or more. To make the diagnosis of ARDS, chronic pulmonary disease and leftheart failure (cardiogenic pulmonary edema) must be excluded, and an appropriateprecipitating event should be present. Right heart catheterization is often requiredto demonstrate that the pulmonary capillary hydrostatic pressure is not elevated,but the data thus obtained should be assessed in the light of the expected decreasein colloid oncotic pressure during pregnancy and in the immediate postpartum

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period. Mortality in patients with ARDS continues to exceed 50%, a figure that hasremained fairly constant over the last 20 years.

In the pregnant patient, ARDS can be associated with many of the factors thatcomplicate pregnancy and delivery including septicemia, AFE, aspiration of stomachcontents, eclampsia, septic abortion, venous air embolism, abruptio placentae, bloodtransfusion (with white blood cell agglutination in the pulmonary circulation), deadfetus syndrome (with DIC), drug overdose (narcotics, barbiturates, aspirin), fatembolism (after long bone fracture), hemorrhagic shock, seizures, and overwhelm-ing pneumonia (Table 37.3).

Clinical presentationClinically, the patient with ARDS of any etiology may go through four clinicalstages:1 injury;2 apparent stability;3 respiratory insufficiency;4 terminal stage.

The initial injury may occur without outward clinical signs and usually lasts for6h or more. Next, the patient develops dyspnea associated with rapid shallowbreathing and a persistent cough. Approximately 12–24h after injury, the chest radi-ograph may begin to show bilateral infiltrates that coalesce into a diffuse haze, rep-resenting perivascular fluid accumulation, interstitial edema, and alveolar edema.

Therapy of ARDSCorticosteroids, in doses up to several grams of methylprednisolone over 24h, havebeen widely used in the treatment of full-blown ARDS without good evidence that

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Table 37.3 Causes of ARDS in pregnant women.

Abruption Intra-abdominal abscessAir embolism Intrauterine fetal demiseAmniotic fluid embolism Lung contusionAspiration Nonthoracic traumaBacterial pneumonia PancreatitisBlood transfusion Preeclampsia, eclampsiaCarcinogenesis PyelonephritisDiabetic ketoacidosis SeizureDrugs Septic abortionFat embolism SepticemiaFractures ShockFungal and Pneumocystis carinii pneumonia Tocolytic therapyHead trauma TuberculosisInhaled toxin Uremia

they are effective. However, although corticosteroids have not been shown to beeffective in treating “early ARDS,” there is some evidence to suggest that their usein the management of “late ARDS” is useful. The use of corticosteroids and mineralocorticoids to treat patients who are in shock that might be caused by oraccompanied by adrenal insufficiency is warranted. Surfactant, a complex substancecontaining phospholipids and apoproteins, is used to treat RDS in prematureinfants, but there are some data to suggest that, when instilled by way of bron-choscopy, it may be useful in the treatment of ARDS. Efforts to identify pharma-cologic agents effective in enhancing lung repair or blocking mediators of lung injuryin ARDS have been largely unsuccessful. Nonsteroidal anti-inflammatory drugs,such as ibuprofen, meclofenamate, and indomethacin, have been studied in vitroand in animals and have shown some promise.

Reversible causes of ARDS, such as occult intra-abdominal or pelvic abscesses,should be sought because early surgical intervention and antimicrobial therapy maybe life-saving. Patients with abruptio placentae, dead fetus syndrome, and septicabortion often have accompanying DIC. These patients should undergo delivery ofthe fetus or evacuation of the uterus as soon as the coagulopathy has been addressedand the patient is surgically stable.

Mechanical ventilation in ARDSVentilator therapy should be instituted when refractory hypoxemia is present andshould be considered at the earliest recognition of ARDS-related symptoms to ensurefetal well-being. With correction of hypoxemia and respiratory alkalosis, fetal O2

delivery can often be maintained at an adequate level. Pregnant patients with ARDSshould be placed in the left lateral decubitus position, with the right buttock andhip elevated approximately 15°, or with the uterus manually displaced to the left,to maximize venous return. Continuous external fetal heart monitoring should beinstituted when appropriate, and pulse oximetry can permit continuous monitoringof arterial oxygenation. Periodic blood gas determinations should be obtained tocheck acid–base status.

If the maternal arterial O2 saturation cannot be maintained at or above 90%,with an FIO2 of 0.6 or less, then positive end-expiratory pressure (PEEP) should beadded. Despite the lack of any clear evidence that its use improves mortality rates,PEEP is almost universally employed because it improves oxygenation and canreduce O2 needs below potentially toxic concentrations. PEEP recruits atelectaticareas for gas exchange that would otherwise collapse during expiration and whichare difficult to expand due to the loss of surfactant and structural derangements.The result is an increase in systemic arterial O2 tension and in the lung’s FRC andcompliance. The use of PEEP is not without pitfalls, however, as it can overdistendalveoli, thereby decreasing compliance and increasing the risk of pneumothorax.The most important adverse effect is to decrease cardiac output by impeding venousreturn to the right side of the heart, particularly when the blood volume is low. Anoptimal PEEP has been defined as a level that increases oxygenation without sig-nificantly reducing cardiac output and, consequently, O2 delivery.

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Further reading

Ahmad H, Mehta NJ, et al. Pneumocystis carinii pneumonia in pregnancy. Chest 2001;120(2):666–671.

Anon. Influenza vaccination and treatment during pregnancy. ACOG Committee Opin 2004;305:1125–1126.

Barth W. Asthma in pregnancy. In: Clark SL, Cotton DB, Hankins GDV, Phenlan J, eds.Critical care obstetrics, 3rd edn. Malden, MA: Blackwell Science, 1997.

Benedetti TJ, Valle R, et al. Antepartum pneumonia in pregnancy. Am J Obstet Gynecol1982;144(4):413–417.

Cheek TG, Gutsche BB. Maternal physiologic alterations during pregnancy. In: Shnider SH,Levinson G, eds. Anesthesia for obstetrics. Baltimore: Williams & Wilkins; 1984:3.

Clark SL, Hankins GD, et al. Amniotic fluid embolism: analysis of the national registry. AmJ Obstet Gynecol 1995;172(4 Pt 1):1158–1167; discussion 1167–1169.

Fowler MJ Jr, Thomas CE, et al. Diffuse cerebral air embolism treated with hyperbaric oxygen:a case report. J Neuroimaging 2005;15(1):92–96.

Gardner MO, Doyle NM. Asthma in pregnancy. Obstet Gynecol Clin North Am 2004;31(2):385–413, vii.

Mabie WC, Barton JR, et al. Adult respiratory distress syndrome in pregnancy. Am J ObstetGynecol 1992;167(4 Pt 1):950–957.

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38 Diabetes mellitus in pregnancyCarol J. Homko, Zion Hagay, and E. Albert Reece

Diabetes mellitus is a heterogeneous disorder characterized by hyperglycemia, whichis a result of relative or absolute insulin deficiency. It is estimated that diabetes mel-litus affects approximately 4 million women of childbearing age in the United States.

Classification

Diabetes during pregnancy is still generally classified using the original system proposed by Priscilla White almost 40 years ago. White’s classification relates theonset of diabetes, its duration, and the degree of vasculopathy to the outcome ofpregnancy. Practically speaking, women with pregnancies complicated by diabetesmellitus may be separated into one of two groups:1 Gestational diabetes: women with carbohydrate intolerance of variable severity,

with onset or first recognition during the present pregnancy.2 Pregestational diabetes: women known to have diabetes before pregnancy.

Table 38.1 presents the classifications that include these two groups.