Pulmonary tuberculosis in pregnancy

FIFTH PRIZE MANUSCRIPT

PULMONARY TUBERCULOSIS IN PREGNANCY Quynh T. Vo, MD, William Stettler, MD, and Kathleen Crowley, MD

Tuberculosis (TB) was once a formidable public health hazard but is now less feared because of the development of an armamentarium of effective drugs. The incidence of TB had been declining for decades until recently when the number of cases of TB began to rise. The most obvious reasons for this trend were the rising rate of human immunodeficiency virus infection and the development of multiple drug–resistant TB. The largest percentage increase in TB cases occurred among persons 25 to 44 years of age; many of them are women. A number of these women will first be diagnosed with TB infection during pregnancy. It is important for the clinician to be aware of the impact of TB on this population. Patients must be screened as recommended by the Centers for Disease Control and Prevention because it is important to quickly diagnose TB. Prompt and effective therapy will benefit the mother and the neonate. This article reviews the diagnosis, prevention, and treatment regimens of TB in pregnancy, as well as the effects on the HIV patient, the neonate, and breastfeeding. Prompt recognition and treatment of TB infection will ensure that the rates of TB cases decline. (Prim Care Update Ob/Gyns 2000;7:244 –249 © 2000 Elsevier Science Inc. All rights reserved.)

From the John Peter Smith Hospital, Department of Ob-Gyn, Fort Worth, Texas.

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Tuberculosis (TB) has been found in the bones of prehistoric man, been observed in mummies, and been written about by Galen and Hippocrates. The topic of concern and controversy for centuries, TB was once the leading cause of death in civilized countries. Advancements in the diagnosis and treatment, along with better living conditions, had caused the rate of TB to decline. Between 1953 and 1985, the number of TB cases in the United States declined 6% per year.1 In recent years, there has been a worldwide resurgence of TB. In the United States, the number of cases of TB began to rise in the mid-1980s; this upward trend continued until 1992. In 1997, according to the Centers for Disease Control and Prevention (CDC),2 there were 19,855 cases of TB reported in the United States, an overall decrease of 26% from 1992, when the number of cases had peaked.2 However, the number of cases among foreign-born persons has increased by 6% during this same period.3 This reemergence of TB has led to a decrease in the average age of patients with TB, many of whom are in their reproductive years. A number of these women will be diagnosed with TB infection during pregnancy. The human immunodeficiency virus (HIV) epidemic has been a major cause of the resurgence of TB in the United States. Other factors, including immigration from highrisk areas, increasing poverty and homelessness, deterioration in the health care infrastructure, and the development of multiple drug–

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resistant organisms have brought TB back as a significant public health issue. Once a disease of the elderly, TB is becoming more prevalent among younger individuals. Between 1985 and 1992, the largest percentage increase (54%) in TB cases occurred in persons 25 to 44 years of age.1 The rate of TB in pregnant women ranges from .1% to 1.9%.4,5 With the recent rise in TB coupled, with the trend for childbearing in later years, these percentages may rise. Currently, the purified protein derivative (PPD) skin test is the standard screening test for TB. However, it is not routinely ordered during pregnancy, instead being obtained only in the presence of significant suspicion or risk factors. One half to two thirds of pregnant women with TB are asymptomatic.6 The increasing incidence of infection, especially the asymptomatic infections, is raising the question as to whether guidelines for the diagnosis, prevention, and treatment of TB infection in women of reproductive age should be reevaluated. Historically, pregnancy was once thought to have deleterious effects on the course of TB. Abortion was prescribed for pregnant women manifesting pulmonary TB. The effects of pregnancy on tuberculosis have since been studied extensively, and accumulated data from numerous studies now confirm that pregnancy does not alter the course of TB.6,7 Pregnancy does not reactivate latent infection, although recent converters have a much higher risk of developing active disease.7,8 Pregnancy also does not appear to

PII S1068-607X(00)00053-6

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PULMONARY TUBERCULOSIS Table 1. Recommended TB Screening in High-Risk Groups Category At increased risk for exposure

At increased risk of disease once infected

stimulate the development of active disease in the asymptomatic infected patient, those with positive PPD results and without clinical or radiographic evidence of disease.8 There is conflicting evidence on the outcome of pregnancy complicated by TB. Some authors report no adverse perinatal outcomes,8 yet other authors report that TB is associated with prematurity, small for gestational age, and low birth weights.9,10 These adverse outcomes were observed in cases with late diagnosis, inadequate treatment, and advanced disease. With the development of effective treatment in pregnant women with TB, most authors agree that adverse perinatal effects can be reverted by early diagnosis and treatment.

Etiology TB is caused by Mycobacterium tuberculosis. It is an aerobic, acid-fast bacterium that is slow growing and sensitive to heat but resistant to desiccation. The organism is known to survive for a long period of time in dried sputum. The bacteria gains entry into the lungs via aerosolized droplets. An inflammatory reaction, called a primary complex or a Ghon complex, develops in the lung parenchyma. These complexes are small lesions that may heal spontaneously or may progress to caseVolume 7, Number 6, 2000

Group Health care workers Homeless individuals Poverty stricken, inner city residents Immigrants from high-prevalence countries Intravenous drug users Residents of health care facilities, shelters, prisons Immunosuppressed patients, including HIV Malnutrition Patients with chronic debilitating disease, including diabetes Children

ation necrosis with signs and symptoms of pulmonary tuberculosis. TB can affect any organ system, but 90% of cases will affect the lungs.11

Clinical Manifestations Although pregnancy does not alter the clinical presentation of TB, early disease and symptoms may mimic the physiologic changes that occur in pregnancy. These nonspecific symptoms include an increase in the respiratory rate, malaise, and fatigue. Constitutional symptoms of TB include weight loss, fever, night sweats, anorexia, cough, and sputum production. Hemoptysis is usually a later finding because it is associated with progressing TB lesions, cavitation, or necrotizing pneumonitis. Associated chest pains are signs of pneumonitis, pleurisy, pericarditis, or occasionally, pneumothorax. Yet surprisingly, as many as 50% to 75% of pregnant patients with pulmonary TB are asymptomatic.7 Once TB is suspected, a careful history should be obtained. One should inquire about past or present exposure to TB, a history of a positive PPD or abnormal chest radiograph, and immigration from a high-risk area (Mexico, the Philippines, Vietnam). Certain ethnic backgrounds (Asians, African-Americans, Hispanics, Native Americans) have

an increased incidence of TB. Previous pulmonary disease, such as pleurisy or pneumonia, a history of diabetes, alcoholism, or malnutrition should raise the suspicion of possible TB exposure. The physical exam may reveal clues suggestive of TB. Scattered rhonchi, rales, and wheezes are common findings in pulmonary TB.

Evaluation Approximately 10% of all women are PPD test positive.6 This number is substantially increased in the high-risk groups listed in Table 1. Significantly, the CDC recommends the PPD test as part of the routine evaluation in these groups. Currently, screening all pregnant patients with the PPD tuberculin test is not considered routine care, although testing is indicated in the patient with known or suspected exposure to TB or with symptoms of TB and for those in the high-risk group. The initial screening test for TB is the PPD tuberculin (Mantoux) test. This test is considered safe and reliable in pregnancy,8 and pregnancy does not appear to interfere with the application and interpretation of the test.4,6 The PPD involves the intradermal injection of .1 mL of 5 tuberculin unit–strength purified protein derivative into the forearm. The test is interpreted 48 –72 hours after injection. The PPD is 90%–99% sensitive in detection of active TB in immunocompetent, well-nourished individuals.6,8 Because this test involves activation of the reticuloendothelial system, anergy can occur in patients who have AIDS or other immunosuppressive conditions. Moreover, a negative PPD tuberculin test is found in as many as 55% of immunosuppressed patients with active TB.12 Therefore, placing a control, such as mumps or candida, at the time of the PPD is recommended. In a PPD-negative patient with signs and symptoms consistent with TB, a 245

VO ET AL Table 2. CDC Recommendations for PPD Interpretation PPD Size

Considered Positive

ⱖ15 mm ⱖ10 mm

Low-risk patients Intravenous drug abusers known to be HIV negative Residents of health care facilities, shelters, prisons Health care workers Immigrants from high-prevalence countries Certain minorities (Hispanics, blacks) Patients with diabetes Patients with renal failure Postgastrectomy or intestinal bypass patients Patients with certain hematological and reticuloendothelial diseases Immunosuppressed patients Silicosis patients Malnourished patients (10% below ideal body weight) Chronic alcoholic patients Patients with known or suspected HIV infection Patients with recent close contact with an active case Patients with clinical or radiographic evidence of TB

ⱖ5 mm

chest radiograph is warranted, especially if she is in one of the high-risk groups. The CDC recommendation for PPD interpretation is presented in Table 2. A positive PPD indicates either infection or disease. According to the American Thoracic Society, infection is defined as a positive PPD without evidence of active, clinical disease. Infection is a state in which the tubecule bacillus has become established but produces no symptoms, radiological abnormalities, or recoverable bacilli on culture or body fluids.4 Active TB is defined as a proliferation of the organisms, either from a recent exposure or a reactivation, causing signs and symptoms of active disease. The chance that a patient with a positive PPD will subsequently develop the disease is 5%–10%,6 provided his or her immune system is intact. In patients with human immunodeficiency virus (HIV), lymphoproliferative malignancies, immunosuppression from medications, diabetes, postgastrectomy states, or malnourishment, the chance is higher. A false-positive PPD can be found in the patient who has been vaccinated with the Bacille Calmette Guerin (BCG) vaccination. The clinician must inquire about prior vaccination in all PPD-positive pa246

tients, especially those from highrisk countries in which the vaccine is commonly administered. As the cell-mediated immunity from the vaccination diminishes over time, it is unpredictable. The CDC has recommended disregarding a history of BCG administration when interpreting the PPD.13 In an asymptomatic patient with a positive result, it is recommended to obtain a thorough history, perform a complete physical exam, and order a shielded chest radiograph.11 Appropriate shielding of the abdomen limits fetal radiation to less than 0.3 mrads.7 Significantly, the benefit derived from an indicated chest radiograph outweighs the risk from the low-dose radiation. The chest radiograph consistent with TB is categorized as primary TB or reactivation TB. Primary TB is associated with changes from the patient’s initial exposure to TB, whereas reactivation TB is associated with the changes from the expression of the disease many years after the initial exposure and containment of the TB organism. If the chest radiograph indicates TB, the patient is considered infected, and she should be placed on chemoprophylaxis to prevent development of disease. The diagnosis of TB should be confirmed with sputum cultures.

The usual collection method is to ask the patient to cough productively on awakening each morning for 3 days. The secretions that have pooled overnight will give the highest yield of organisms. If the patient cannot produce sputum, it may be induced with inhalation of hypertonic saline through a nebulizer. The patient who is unable to produce any sputum may be a candidate for gastric aspiration. If these methods fail, the patient should be considered for fiberoptic bronchoscopy with lavage, brushing, and possible biopsy. Although a sputum stain that reveals acid-fast bacteria is highly suspicious for TB, culture and sensitivity tests should also be performed. Therapy must be initiated promptly while waiting for the culture results, which can take 2 weeks or more.

Treatment Pregnant patients who should receive chemoprophylaxis include 1) patients who have recently converted within the last 2 years; these newly infected patients are at a 4% risk in each of the first 2 years of developing active disease;6 2) PPD reactors living with or having close contact with people with active disease; and 3) PPD reactors with immunosuppression: patients on longterm corticosteroid therapy or who have diabetes or AIDS. The CDC recommendation for prophylaxis for tuberculosis in pregnancy is included in Table 3. Untreated tuberculosis represents a far greater hazard to a pregnant woman and her fetus than does treatment; therefore, in a patient diagnosed with active disease, therapy must be initiated immediately. The success of treatment depends on several factors: 1) the culture and sensitivity of the organisms, 2) treatment with multiple drugs to which the organism is sensitive, and 3) administration of the drugs for a Prim Care Update Ob/Gyns

PULMONARY TUBERCULOSIS Table 3. Treatment of TB in Pregnancy Diagnostic Information

Treatment

Active TB

INH, 300 mg PO qd; rifampin, 600 mg PO qd; pyridoxine, 50 mg qd; and (initially) ethambutol, 2.5 gm PO qd, for 6 to 9 months INH, 300 mg PO qd and pyridoxine, 50 mg PO qd, after the first trimester for 6 to 9 months INH, 300 mg PO qd and pyridoxine, 50 mg PO qd, after delivery for 6 to 9 months INH, 300 mg qd and pyridoxine, 50 mg PO qd, after delivery for 12 months Not treated unless documented conversion within last 2 years

⫹PPD, recent seroconversion ⫹PPD, no evidence of active disease ⫹PPD, abnormal chest radiograph, inactive disease ⫹PPD, ⬎35 years of age

sufficient duration and frequency to assure a cure.7 Of the first-line agents for TB, isoniazid (INH), rifampin, and ethambutol are considered safe during pregnancy (Table 4). These antituberculosis agents do cross the placenta and are well distributed in the amniotic fluid.12 With the increasing incidence of drug-resistant cases, guidelines published by the CDC should be followed. The recommended treatment regimen for

the pregnant patient consists of at least INH and rifampin (Table 3). In addition, ethambutol is recommended initially until sensitivities show that INH and rifampin are effective. An alternative regimen consists of INH and rifampin two or three times weekly after an initial 1 to 3 months of daily dosages. This regimen has been shown to be efficacious in the nonpregnant patient and may be helpful in the poorly compliant patient. Although this

regimen decreases the total amount of antimicrobial therapy to the mother and her fetus, its efficacy has not been well studied in the pregnant population. The rate of relapse in the general population with this regimen is 3%.6 Therapy should be tailored appropriately after the results of sputum culture and sensitivities are available. Monthly sputum should be obtained, and therapy should be continued for at least 3 months after cultures are negative. Other agents commonly used for TB in the nonpregnant population include Pyrazinamide, streptomycin, ethionamide, kanamycin, capreomycin, para-amino salicylic acid, and cycloserine. Although para-amino salicylic acid is approved in pregnancy, it is difficult to tolerate because of gastrointestinal side effects, especially for the pregnant patient. The benefits of the other agents do not outweigh their risk in pregnancy, and possible adverse effects in the fetus have not been studied adequately. These agents should only be used in cases

Table 4. Antituberculosis Agents, Side Effects, Use in Pregnancy and Lactation Drug Name

Maternal Side Effect

Fetal Effects

Isoniazid

Hepatitis, GI distress, seizures, peripheral neuropathy, hypersensitivity reactions

Safe

Safe

Rifampin

Hepatitis, GI distress, febrile reactions, purpura, orange secretions, accelerates the metabolism of many medications Retrobulbar neuritis—blurred vision, central scotomata, red-green discrimination difficulty GI distress, rash, arthralgias, hyperuricemia, hepatitis Ototoxicity, nephrotoxicity GI distress, postural hypotension, CNS depression, hepatotoxicity, hypersensitivity Ototoxicity, nephrotoxicity Ototoxicity, nephrotoxicity, eosinophilia, transient proteinuira GI distress, myxedema, hepatitis, sodium load CNS disturbances, psychosis, seizures, drowsiness

May cause central nervous system toxicity if pyridoxine not supplemented None reported

Safe

Safe

None reported

Safe

Safe

Lack of data

Unknown

Avoid

Ototoxicity None established

Safe Unknown

Avoid Avoid

None established None established

Safe Unknown

Avoid Avoid

None established

Unknown

Safe

None established

Yes

No

Ethambutol Pyrazinamide Streptomycin Ethionamide Kanamycin Capreomycin Paraaminosalicylic acid Cycloserine

BF

P

BF ⫽ breastfeeding compatible; P ⫽ use in pregnancy

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VO ET AL Table 5. Dosages of Drugs Commonly Used to Treat TB Drug

Daily Dose (mg/kg)

Intermittent Dose, mg/kg

Isoniazid

5

15, 2–3 times/wk

Rifampin

10

10, 2–3 times/wk

Ethambutol

15–25

Pyrazinamide

15–30

50, 2 times/wk 25–30, 3 times/wk 50–70, 2 times/wk

Streptomycin

15

Ethionamide Kanamycin Capreomycin Para-amino salicylic acid Cycloserine

15–20 15–30 15–30 150

50–70, 3 times/wk 25–30, 2 times/wk 25–30, 3 times/wk Not recommended 15–30, 2–3 times/wk 15–30, 2–3 times/wk Not recommended

15–20

Not recommended

where primary agents are contraindicated or where there have been failures of the recommended agents. Therapeutic agents used for TB are associated with many adverse side effects. A thorough history should be obtained and baseline laboratory studies ordered as necessary before beginning therapy. Monitoring should be individualized as to type and frequency, depending on the agents used. Drug therapy should be dosed according to CDC guidelines as summarized in Table 5. The patient must be thoroughly educated on appropriate drug dosages and on the common symptoms of drug toxicity for their regimen (Table 5). Patients should also be instructed to report adverse side effects immediately. Another prophylaxis agent for TB is the BCG vaccination. The BCG remains controversial despite many years of use worldwide. It is primarily used in countries with higher rates of TB and is rarely used in the United States. The efficacy of the vaccine is questionable, and its effectiveness has ranged from 0 – 80%.6 The cell-mediated immunity also diminishes over time and therefore is unpredictable. The vaccination is recommended in certain 248

Usual Dose 300 mg PO, qd 900 mg PO, 2–3 times/week 600 mg PO, qd 600 mg PO, 2–3 times/week 2–2.5 g PO, qd 4 g PO, 2 times/wk 2 g PO, qd; 4 g PO, 2 times/ wk; 3 g PO, 3 times/wk 1 g qd, 1.5 g 2–3 times/wk 1 g PO, qd 1 g qd, 2–3 times/wk 1 g qd, 2–3 times/wk 10–12 g PO, qd 1 g PO, qd

instances: 1) PPD-negative infants and children who are at a high risk for exposure, 2) PPD-negative children who are exposed to patients who have INH and rifampin-resistant TB, and 3) infants and children in areas where the incidence of TB is ⬎1% per year and surveillance programs are unfeasible.

Breastfeeding Breastfeeding should not be discouraged in nursing mothers treated with antituberculosis drugs. Studies of drug concentration in breast milk demonstrate the levels to be too low to adversely affect the infant.6 The percentages of the therapeutic dose of antituberculosis agents that potentially may be delivered to the nursing infant range from .05% to 28%.5 Currently, INH, rifampin, ethambutol, and streptomycin (first-line agents) and kanamycin and cycloserine (second-line agents) are the only agents considered by the American Academy of Pediatrics to be compatible with breast feeding; the other agents are questionable because of a lack of studies. In infants being treated for TB, it is important to use the correct

therapeutic dosages because drug concentration in breast milk is not adequate for prevention or treatment of TB.

Effects of TB on the Neonate Active TB poses a significant risk to the neonate, because there is the potential for transmission in utero, as well as for acquiring TB postpartum, the latter being more frequent. Congenital TB is a rare entity but one that may increase in frequency with the HIV epidemic. TB can be transmitted by various routes during pregnancy, such as chorioamnionitis, which can spread the tubercle bacilli to the fetus or neonate at the time of delivery. Another route is hematogenous; this occurs via the infected placenta through the umbilical vein and into the fetal liver. Also, aspiration of infected amniotic fluid at the time of birth is another potential route for infection. In a pregnant woman who is known or suspected to have TB, the placenta should be examined for evidence of TB, and acid-fast bacilli stains, cultures, and histological examination should be ordered. Signs of congenital TB can present by the second or third week of life, but median age at presentation is 24 days.14 Signs and symptoms are nonspecific and include respiratory distress, fever, failure to thrive, lethargy, irritability, and hepatosplenomegaly. Most infants will have an initial negative PPD but an abnormal chest radiograph. The diagnosis of congenital TB requires a culture-proven disease present at birth or within a few days of birth; in addition, the primary tuberculous complex must be present in the neonatal liver. Mortality in untreated infants is as high as 38% overall, and 22% in those that were treated.14 Prompt recognition and institution of treatment is essential for a successful recovery. The neoPrim Care Update Ob/Gyns

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nate born to a mother with active TB should be separated from the mother until she is bacteriologically negative and the infant has been started on INH prophylaxis (10 mg/kg per day for at least 3 months). As many as 50% of the infants born to mothers with active disease will develop active disease during the first year of life if INH prophylaxis is not given. Another option mentioned previously is the BCG vaccine. Vaccination of the infant should be considered in cases of INH noncompliance. In the neonate with TB, it is essential to begin appropriate therapy as soon the diagnosis is suspected and cultures have been obtained. The drug regimen for the infant is similar to those for the adult; at least INH and rifampin for 9 months. Other alternative regimens include INH with rifampin for 6 months and the addition of PZA for the initial 2 months. Twice-weekly regimens are also available. The infant of a breastfeeding mother who is also being treated must be carefully monitored for signs and symptoms of drug toxicity from the additional amount in the breast milk.

TB in the HIV-Infected Pregnant Woman The overall prevalence of TB coinfection in HIV-infected individuals ranges from 5% to 35%.6 The progression from infection to fulminant disease can occur within months in the HIV-positive patient. Also, infection with HIV has been recognized as a major risk factor for the development of active TB in persons with latent TB infection.9 HIV-positive pregnant patients with a positive PPD should receive the standard prophylaxis with INH and pyridoxine for 12 months. The patients with active disease should

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receive treatment with INH, rifampin, and ethambutol for 9 –12 months or until sputum cultures have been negative for 6 months. It is important that therapy begin immediately and aggressively due to the potential for rapid progression. Close monitoring for adverse drug effects is required because there is an increased rate of such in HIVinfected patients on protease inhibitors. These agents increase the serum level of rifampin, leading to possible drug toxicity, whereas the rifampin accelerates the metabolism of the protease inhibitors, resulting in subtherapeutic levels.

Conclusion The diagnosis of TB in pregnancy can be difficult to recognize because of the low index of suspicion by clinicians, as well as lack of routine screening. Diagnosing TB in pregnancy is challenging; the early symptoms often mimic the normal physiologic changes of pregnancy. Moreover, the majority of pregnant women found to have TB are asymptomatic. The HIV epidemic has placed importance on the rapid diagnosis and treatment of TB, and the increasing rate of multi-drug– resistant organisms emphasizes the need for adequate and appropriate treatment. Although only about 1% of reproductive age women are skin test positive, the high-risk groups have a higher percentage. The clinician should screen the pregnant patient for the risk factors discussed. In these individuals, the routine use of the PPD skin test is recommended and reasonable to aid in early diagnosis, prevention, and treatment. Notably, prompt treatment and prevention of TB is needed to ensure that the number of cases of TB continues to decline.

References 1. Huebner RE, Castro KG. The changing face of tuberculosis. Ann Rev Med 1995;46:47–55. 2. Centers for Disease Control and Prevention. Tuberculosis morbidity— United States, 1997. MMWR 1998; 47:253–7. 3. LeMasters CZ. Treatment of pulmonary tuberculosis. Lippincott’s Prim Care Pract 1999;3:55–58. 4. Hamadeh MA, Glassroth J. Tuberculosis and pregnancy. Chest 1992; 101:1114 –20. 5. Tran JH, Montakantikul P. The safety of antituberculosis medications during breastfeeding. J Hum Lactation 1998;14:337– 40. 6. Medchill MT, Gillum M. Diagnosis and management of tuberculosis during pregnancy. Obstet Gynecol Surv 1989;44:81– 4. 7. Miller KS, Miller JM Jr. Tuberculosis in pregnancy: interactions, diagnosis, and management. Clin Obstet Gynecol 1996;39:120 – 42. 8. Gillum MD, Maki DG. Tuberculin testing, BCG in pregnancy. Infect Control Hosp Epidemiol 1988;9: 119 –21. 9. Figueroa-Damian R, ArredondoGarcia JL. Pregnancy and tuberculosis: influence of treatment on perinatal outcomes. Am J Perinatol 1998;15:303– 6. 10. Jana N, Vasishta K, Jindal SK, Khunnu B, Ghosh K. Perinatal outcomes in pregnancies complicated by pulmonary tuberculosis. Int J Gynaecol Obstet 1994;44:119 –24. 11. Maccato ML. Pneumonia and pulmonary tuberculosis in pregnancy. Obstet Gynecol Clin North Am 1989;16:417–30. 12. Brost BC, Newman RB. The maternal and fetal effects of tuberculosis therapy. Obstet Gynecol Clin North Am 1997;24:659 –73. 13. Centers for Disease Control and Prevention. Core Curriculum on Tuberculosis, 3rd ed. Atlanta. U.S. Department of Health and Human Services, 1994. 14. Cantwell MF, Shelhab ZM, Costello AM, et al. Brief report: congenital tuberculosis. N Engl J Med 1994; 330:1051– 4. Address correspondence and reprint requests to Q. T. Vo, MD, John Peter Smith Hospital, 1500 S. Main Street, Fort Worth, TX 76104.

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