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Tuberculosis and Pregnancy: Update on an Old Nemesis Fidelma B. Rigby, MD, Louisiana State University Medical Center, New Orleans Infect Med 17(4):284-288, 2000. © 2000 Cliggott Publishing, Division of SCP Communications Abstract and Introduction Abstract Mycobacterium tuberculosis infection occurs most frequently during the childbearing years. Altered immune response during pregnancy causes unusual manifestations of tuberculosis (TB). Heightened awareness of the risk of TB in pregnant patients is important. Skin testing on all pregnant women and strategic efforts to identify active disease are key steps to successful treatment. Chemoprophylaxis during pregnancy should be considered in patients with recent purified protein derivative (PPD) conversion or known TB exposure. In patients older than 35 years, the risk of isoniazid hepatitis usually rules out chemoprophylaxis. Since active TB during pregnancy often presents with minimal symptoms, careful monitoring of all PPDpositive patients is required. Introduction Pregnancy during infection with Mycobacterium tuberculosis requires special attention because of altered immunity associated with pregnancy and because of neonatal care issues. Tuberculosis (TB), once the leading cause of death in Western countries, reemerged as a concern in the late 1980s and early 1990s as a result of multiple factors, including lack of public health funding and the HIV epidemic. With a re-awakening of the medical community to the dangers of the epidemic, steps were taken that led to a decline in the number of cases reported by the mid-1990s. Nevertheless, vigilance -- including routine screening of high-risk populations -- is required to ensure that this downward trend continues. Approximately one third of the world's population is infected with M tuberculosis. The greatest disease burden is during the childbearing years of 15 to 49, with 80% of all deaths from TB occurring in this group.[1] Worldwide, TB is the number one infectious cause of death among women, killing more than 1 million women each year. TB currently is responsible for more deaths annually than all other causes of maternal morbidity combined.[1] In communities in which TB is endemic, pregnant women are at high risk, especially for infection with resistant organisms. Interaction Between TB and Pregnancy Risk to the Pregnancy The influence of TB on the outcome of pregnancy, as well as the influence of pregnancy on the course of the infection, has long been debated. Pregnancy has been variously reported to improve, worsen, or have no effect on TB. In the early 1800s, some authorities believed the enlarging uterus would place pressure on the lungs, collapse open cavities, and thus improve outcomes for pregnant women with TB.[2] Induced abortion was recommended from the mid-19th century into the first half of the 20th century. Studies done during the 1950s suggested that the postpar-tum period was associated with increased rates of relapse.[2,3] However, development of effective therapy for TB has reduced the potential detrimental effect of this disease on the gravid patient. There is general agreement that appropriately treated TB does not worsen the outcome of pregnancy. In addition, pregnancy does not appear to increase progression to active TB.[4] However, as reports from other countries indicate, untreated active TB is a significant risk to maternal health. Therefore, pregnancy in patients with untreated active TB should be considered high-risk.[5] Pregnancy and TB Symptoms Pregnant patients with active TB often have few of the typical TB symptoms. Between 20% and 67% of pregnant patients presenting with pulmonary TB are unaware of their disease and have no significant symptoms.[6-8] Even mothers of children born with congenital TB often have unremarkable symptoms.[9-12] TB Screening During Pregnancy Studies indicate that routine skin test screening of all pregnant women is appropriate. The goal is to discover dormant infection and asymptomatic disease and to lower the incidence of congenital or infantile TB. A review of TB diagnosis in Rhode Island from 1987 to 1991 found that pregnant women with TB were most likely to be identified through routine screening and to be asymptomatic.[6] Mantoux Test The initial screening test for TB is an intradermal skin test using purified protein derivative (PPD). There is no evidence that this test is detrimental to the fetus or mother.[13] There is also no evidence that the immunosuppression found in pregnancy leads to false-negative results. Prior vaccination with BCG can complicate the interpretation of the Mantoux test. The main indication for BCG vaccination in this country is for PPD-negative children who are at high risk for infection from family members[14] or for patients who cannot be properly monitored or given prophylactic treatment.[15] Although BCG vaccination can cause a false-positive PPD test result, the most recent guidelines from the CDC note that the interpretation of the skin test should not be influenced, since the effect of the BCG vaccine wears off at a variable rate. Furthermore, despite being immunized, these persons are still at risk for active TB. Chest X-Ray Film A chest radiograph should be obtained when the PPD test is positive. Appropriate shielding will limit fetal radiation exposure to less than 0.3 mrads and should not harm the fetus.[13] HIV-negative women older than 35 who have a normal radiograph and have not had a PPD conversion within the preceding 2 years require no treatment. Figure 1 outlines the approach to further workup and treatment of the pregnant patient with a positive PPD test. Figure 1. Workup of the pregnant patient with a positive PPD test Chemoprophylaxis During Pregnancy The risk of hepatitis from isoniazid (INH) prophylaxis is thought to outweigh the benefits of treatment in most HIV-negative persons older than 35. However, pregnant women age 35 and older who have PPD conversion within 2 years of being tested should be treated with INH for 6 months after delivery. Similar treatment is recommended for PPD-positive women younger than 35 with no recent exposure. Some public health units are delaying treatment postpartum for 3 to 6 months because of a slightly increased risk of postpartum hepatitis from INH treatment.[16] Women with recent exposure should be treated for 6 months following the first trimester.[3] Problems arise when the recent exposure involves a multidrug-resistant organism. There is no current chemoprophylaxis regimen that is without risk to the fetus.[3,17] The CDC recommends ethambutol (EMB) with pyrazinamide (PZA) or a fluoroquinolone (ciprofloxacin or ofloxacin) for 6 to 12 months for nonpregnant persons.[3] Of these alternatives, the PZA regimen has less known risk to the fetus (ciprofloxacin has been implicated in limb reduction defects in animal studies), but because of inadequate available teratogenic data, PZA has not been used during pregnancy in the United States. INH should be given after the first trimester of pregnancy if the patient has had a recent exposure to TB. Half of the TB cases that develop post-PPD conversion will occur within 1 year. In addition, Miller and Miller[3] recommend INH prophylaxis after the first trimester for HIV-positive women who are PPD-positive. Diagnosis of Active TB Diagnosis of active TB in pregnant patients is similar to that in other patients, with the caveat that, as noted above, a significant percentage of pregnant patients with TB will have minimal symptoms and no awareness of their disease. In the Rhode Island review mentioned earlier, minimal radiographic findings (no fibrotic changes, no cavities, and only minimal infiltrates or pleural disease) were found in pregnant women with TB.[6] The diagnosis of active TB is confirmed by culture. Sputum should be sent for immediate acid-fast bacillus smear and culture. The first morning sputum is thought to contain the highest concentration of mycobacteria. For patients with dry coughs, hypertonic saline can be inhaled through a nebulizer to induce sputum or, alternatively, aspiration of gastric contents through a nasogastric tube can be performed. If these steps are unsuccessful, bronchoscopy may be necessary to obtain tissue for culture and sensitivity.[3] Growth of the mycobacteria can take up to 6 weeks. The development of newer technologies, such as radiometric culture techniques, genetic probes, high-pressure liquid chromatology, and monoclonal antibody testing, are greatly accelerating identification and susceptibility testing.[18,14] Only those laboratories with experience in testing for mycobacteria should be used. TB Treatment During Pregnancy Treatment of TB during pregnancy requires consideration for the developing fetus. In all cases, proper medical treatment of the mother is of benefit to the fetus if the treatment is carefully planned to minimize the risk of congenital anomalies. Therapeutic abortion is not indicated. Guidelines for the management of TB during pregnancy have been issued by the American Thoracic Society (ATS).[14] The guidelines have evolved as the number of drug-resistant cases has increased. Recommendations for initial therapy should be based on an assessment of the M tuberculosis strains and pattern of resistance in the community. Although it is vital that accurate sputum samples and cultures be obtained, empiric therapy should be started while awaiting laboratory findings. If there is believed to be no significant resistance in the M tuberculosis strain, then INH and rifampin (RMP) are used as first-line therapy. If there is low suspicion of resistance, then EMB should be added, while a highly resistant strain would prompt the consideration of PZA.[19] The drugs used to treat TB in pregnant patients are listed in Table 1. INH has been used extensively during pregnancy. It inhibits the activity of the enzyme mycolate synthetase, is bacteriostatic and bactericidal, and penetrates tissue well.[3] Its major side effect is an increased risk of hepatitis in patients older than 35. There is also a risk of peripheral neuropathy because of the drug's interference with pyridoxine metabolism. These risks are increased in patents with prior histories of hepatitis, alcohol abuse, or conditions that predispose to neuropathy (diabetes, malnutrition, and uremia).[3] Multiple studies have examined the use of INH during pregnancy, with the general consensus that any potential side effects (such as CNS malfunctions and increased seizure activity) can be significantly reduced by supplementing with 50 mg/d of pyridoxine.[17] Liver function tests (LFTs) should be ordered before initiation of therapy and monthly thereafter in high-risk patients. Elevations of LFTs up to 3 to 4 times normal can occur in some asymptomatic patients and do not necessitate stopping therapy. However, clinical signs of chemical hepatitis, such as jaundice or an enlarged or tender liver, require stopping the drug. There is usually prompt resolution of the symptoms and LFT elevations.[20] RMP is a bactericidal agent that penetrates well into tissues and inhibits DNAdependent RNA polymerase in mycobacteria. A number of side effects may be associated with RMP (Table 1). Its mechanism of action has raised concerns about possible effects on the fetus. One study found a statistically insignificant increase in limb reduction defects[21]; no studies have found significant increases in birth defects between RMP and control groups. RMP significantly enhances the P-450 oxidizing system and therefore decreases the half-life of a number of medications, including oral contraceptives. The effect of RMP on the metabolism of other drugs taken concurrently should be reviewed before its use. RMP also gives an orange color to body secretions, including urine and tears, which can alter the tint of contact lenses.[3] EMB has a low toxicity profile with the exception of retrobulbar neuritis, which is probably dosage- and duration-related. Blurred vision and central scotomata occur before changes in acuity or color perception.[3] This drug has been used extensively during pregnancy without noted fetal abnormalities.[17,22] PZA is recommended by the CDC for treatment of resistant TB in nonpregnant patients. It is excreted primarily in the urine and the dosage needs to be adjusted in patients with renal insufficiency. Because of a lack of teratogenicity data, the ATS and most authors do not recommend routine use during pregnancy. Davidson[23] and Miller and Miller,[3] however, note that it has been used during pregnancy around the world without significant adverse effects reported. Indeed, it is recommended for use during pregnancy by most international organizations.[19] Davidson and Miller and Miller therefore feel it can be given safely for the treatment of TB that is highly suspected to be multidrug-resistant. Streptomycin (SM) is another anti-TB drug occasionally used in the nonpregnant patient. Its use during pregnancy is limited because of reports of increased cranial nerve VIII damage in the fetus after exposure.[17,19,22] Its ototoxic effects occur in all 3 trimesters. Kanamycin and capreomysin are also contraindicated during pregnancy because of similar possible ototoxic effects. Para-aminosalicylic acid, cycloserine, and ethionamide use is limited during pregnancy chiefly because of maternal side effects.[3] Therefore, multidrug therapy in pregnant women with active TB should include INH and RMP with the addition of EMB in resistant cases. PZA is not routinely recommended at this time. Therapy should continue for 9 months. Breast-feeding may often continue safely, because of the low concentrations of the therapeutic agents in breast milk.[2,16] Issues of Compliance Compliance with therapy is essential for successful treatment of TB. Many regimens have been devised to increase patient compliance. The most promising of these is directly observed therapy (DOT). This modality uses a twice-weekly dosing program and helps provide incentives (including education, bus tokens, and close case followup) to help with patient compliance. Communities that have used this approach to treatment have noted significant declines in the number of cases of TB.[23] Pregnancies complicated by highly resistant organisms and/or AIDS require special consideration. In these cases, combinations of 4 or 5 drugs may be necessary, including drugs such as SM, which is not normally recommended during pregnancy. Consideration should be giv-en to initial treatment in a hospital setting followed by closely supervised DOT.[3] TB in Neonates Congenital TB in neonates is potentially serious, with morbidity and mortality approaching 50%.[24] Fortunately, it is relatively rare, with fewer than 200 cases reported in the English literature.[9] These numbers, however, reflect, in part, the difficulty of confirming a congenital case, which often requires organ biopsy. Signs and symptoms are nonspecific but may include respiratory distress, fever, hepatosplenomegaly, lethargy, lymphadenopathy, and irritability. Other signs of TB in neonates include abdominal distention, ear discharge, and skin lesions.[25-28] An abnormal chest radiograph is not a consistent finding, and a positive PPD test result is even less common. When an infant is born to a PPD-positive mother, separation of mother and infant is rarely indicated.[8] Possible exceptions would include a mother infected with multidrug- resistant organisms or a contagious family member known to be noncompliant with treatment. BCG vaccination of the infant can be considered if separation is not an option in these cases. Tables Table 1. Drugs for treatment of tuberculosis in pregnancy Drug Dosage form Daily dose (mg/k g) Maximum Biweekl dose: y dose daily/biweek (mg/kg) ly Side effects Comments Ethambutol Tablets: 100 mg, 400 mg 15 - 25 50 2.5 g/4 g Optic neuritis Follow with eye examinatio ns before start of therapy, then periodically (monthly if dosage is > 15 mg/kg/d) Isoniazid Tablets: 100 mg, 400 mg 10 - 20 20 - 30 PO or PO or IM IM 300 mg/900 mg Hepatitis, neuropathy Pretherapy and monthly liver function tests Pyrazinami de Tablets: 500 mg 20 - 40 50 2 g/3 g Hepatitis, arthralgias Not approved for use during pregnancy Rifampin Capsule s, syrup: 150 mg, 300 mg Streptomyci Vials: n 1 g, 4 g 10 - 20 10 - 20 600 mg/600 mg Hepatitis, blood dyscrasias May alter oral contracepti ve dosing 20 - 40 20 - 40 -- Ototoxicity, Fetal nephrotoxici toxicity ty References 1. Connolly M, Nun P. Women and tuberculosis. World Health Stat Q. 1996;49:115-119. 2. Snider D. Pregnancy and tuberculosis. Chest. 1984;86:105-135. 3. Miller KS, Miller JM. Tuberculosis in pregnancy: interactions, diagnosis, and management. Clin Obstet Gynecol. 1996;39:120-142. 4. Espinal M, Reingold AL, Lavandera M. Effect of pregnancy on the risk of developing active tuberculosis. J Infect Dis. 1996;173:488-491. 5. Jana N, Vasishta K, Jindal SK, et al. Perinatal outcome in pregnancies complicated by pulmonary tuberculosis. Int J Gynaecol Obstet. 1994; 44:119124. 6. Carter EJ, Mates S. Tuberculosis during pregnancy: the Rhode Island experience, 1987 to 1991. Chest. 1994;106:1466-1470. 7. Wilson EA, Thelin TJ, Dilts PV. Tuberculosis complicated by pregnancy. Am J Obstet Gynecol. 1973;115:526-529. 8. Vallejo JG, Starke JR. Tuberculosis and pregnancy. Clin Chest Med. 1992;13:693-707. 9. Nemir RL, O'Hare D. Congenital tuberculosis. Am J Dis Child. 1985;139:284287. 10. Niles RA. Puerperal tuberculosis with death of infant. Am J Obstet Gynecol. 1982;144:131-132. 11. Gogus S, Sanal O, Osmanlioglu G. Neonatal tuberculosis. Pediatr Pathol. 1993;13:299-304. 12. Rosenfield EA, Hageman JR, Yogev R. Tuberculosis in infancy in the 1990's. Pediatr Clin North Am. 1993;40:1087-1103. 13. Medchill MT, Gillum M. Diagnosis and management of tuberculosis during pregnancy. Obstet Gynecol Surv. 1989;44:81-84. 14. American Thoracic Society. Diagnostic standards and classification of tuberculosis. Am Rev Respir Dis. 1990;142:725-735. 15. Centers for Disease Control and Prevention. Use of BCG vaccines in the control of tuberculosis: a joint statement by the ACIP and the Advisory Committee for elimination of tuberculosis. MMWR. 1988;37:663-675. 16. Riley L. Pneumonia and tuberculosis in pregnancy. Infect Dis Clin North Am. 1997;11:119-133. 17. Holdiness MR. Teratology of the antituberculosis drugs. Early Hum Dev. 1987;15:61-74. 18. Centers for Disease Control and Prevention. Tuberculosis morbidity -- United States, 1995. MMWR. 1996;45:365-370. 19. American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med. 1994;149: 13591374. 20. Starke JR. Tuberculosis. An old disease but a new threat to the mother, fetus, and neonate. Clin Perinatol. 1997;24:107-127. 21. Myianthopoulos NC, Chung CS. Congenital malformations in singletons: epidemiologic survey. Birth Defects. 1974;10:1-58. 22. Snider DE, Layde PM, Johnson MW, et al. Treatment of tuberculosis during pregnancy. Am Rev Respir Dis. 1980;122:65-79. 23. Davidson PT. Treating tuberculosis: what drugs, for how long? Ann Intern Med. 1990; 112:393-394. 24. Chaulk CP, Moore-Rice K, Rizzo R, et al. Eleven years of community-based directly observed therapy for tuberculosis. JAMA. 1995;274:945-951. 25. Nolan TE. Tuberculosis: a threat to women's health. Female Patient. 1993;18:21-28. 26. Cantwell MF, Shehab ZM, Costello AM. Brief report: congenital tuberculosis. N Engl J Med. 1994;330:1051-1054. 27. Hageman J, Shulman S, Schreiber M. Congenital tuberculosis: critical reappraisal of clinical findings and diagnostic procedures. Pediatrics. 1980;66:980-984. 28. Bate TW, Sinclair RE, Robinson MJ. Neonatal tuberculosis. Arch Dis Child. 1986;61:512-514.