Tuberculosis in pregnancy
Authors
Lloyd N Friedman, MD
Lynn T Tanoue, MD Section Editors
C Fordham von Reyn, MD
Charles J Lockwood, MD Deputy Editor
Elinor L Baron, MD, DTMH
Last literature review version 18.2: May 2010 | This topic last updated: January 19, 2010 (More)
INTRODUCTION — Prenatal care presents a unique opportunity for evаluation and management of latent and active tuberculosis (TB) in pregnant women [1]. Routine tuberculin skin test (TST) screening is not indicated for all pregnant women. However, individuals with an increased risk of tuberculosis may seek medical care only during pregnancy (such as foreign born individuals within five years of immigration from TB endemic countries or individuals with HIV infection). (See "Epidemiology of tuberculosis".)
The pathogenesis of tuberculosis infection and disease in pregnant women is similar to that in nonpregnant women [2,3]. There is no firm evidence that the risk of new infection or reactivation of tuberculosis in pregnant women is significantly different from matched controls. However, tuberculosis in pregnant women can present insidiously, since symptoms of malaise and fatigue may be attributed to pregnancy rather than disease [4]. In addition, during pregnancy it can be difficult to recognize weight loss. (See "Microbiology and pathogenesis of tuberculosis".)
Since pregnancy has not been shown to increase the risk of TB, the epidemiology of TB in pregnancy is a reflection of the general incidence of disease [5]. This also is true in HIV-infected women, as shown in a group of predominantly HIV-infected pregnant women in New York City during 1991 to 1992, where the rate of TB was 94.8 per 100,000 deliveries [6].
Issues related to diagnosis and treatment of latent TB infection and active TB disease in pregnant women will be reviewed here. Issues related to the management of latent and active TB in nonpregnant patients are discussed in detail separately. (See "Diagnosis of latent tuberculosis infection in adults" and "Diagnosis of tuberculosis in HIV-seronegative patients" and "Treatment of tuberculosis in HIV-seronegative patients".)
LATENT TB — Pregnancy has not been shown to influence the pathogenesis of TB or the likelihood of progression from latent to active disease, nor has it been shown to affect the response to treatment [7,8].
Diagnosis — Routine testing for latent tuberculosis in pregnant women is not indicated. Testing should be performed during pregnancy only if there is an indication for prompt treatment of latent tuberculosis infection (LTBI); a decision to test presupposes a decision to treat promptly if the test is positive. However, contact with the health system during pregnancy is an opportunity to identify patients at risk for LTBI who should be evаluated further following pregnancy. Appropriate groups for testing include those at high risk for progression of LTBI to active disease, especially those who are significantly immunocompromised (eg, HIV infection, immunosuppressive therapy) or those who have been infected with TB recently [9]. (See "Diagnosis of latent tuberculosis infection in adults".)
If feasible, performing the TST before pregnancy is preferred; this allows opportunity for counseling about the risk of becoming pregnant while on therapy [10]. If treatment for LTBI is initiated and the patient becomes pregnant subsequently, therapy should be continued [11]. In the absence of major risk factors for progression to active infection during pregnancy, testing and treatment for LTBI in those for whom targeted testing is indicated should be delayed until three months after delivery to minimize risk of adverse drug effects. (See 'Toxicity and monitoring' below.)
Diagnostic tools for latent tuberculosis include tuberculin skin testing (TST) and interferon gamma release assays (IGRAs). Tuberculin skin testing can be performed safely in pregnant women, and pregnancy does not alter the response to the TST [9,12]. Definitions of positive skin tests are outlined in the Table (table 1). Interferon gamma release assays are also safe in pregnancy and would be expected to be as effective for diagnosis of LTBI in pregnancy as in other circumstances, although they have not been evаluated formally in the setting of pregnancy, and there is no definitive recommendation for their use [13,14]. (See "Diagnosis of latent tuberculosis infection in adults", section on 'Interferon gamma release assays'.)
Patients with positive LTBI screening results (table 1) must undergo clinical evаluation to rule out active tuberculosis. This includes evаluation for symptoms (eg, fever, cough, weight loss) and radiographic examination of the chest (with appropriate shielding). (See "Diagnosis of latent tuberculosis infection in adults", section on 'Interferon gamma release assays'.)
Treatment — Testing and treatment for latent tuberculosis infection should be pursued during pregnancy only if there is an indication for prompt management of LTBI (usually in recent infection or immunocompromised hosts); a decision to test presupposes a decision to treat promptly if the test is positive (even during the first trimester). Therefore, patients appropriately targeted for LTBI screening with positive TST results should initiate treatment during pregnancy [9]. If treatment for LTBI is initiated prior to pregnancy for the usual indications noted in the CDC statement [9], and the patient becomes pregnant subsequently, therapy should be continued [11]. (See 'Diagnosis' above and "Diagnosis of latent tuberculosis infection in adults".)
However, if a skin test has been performed in the absence of an indication for prompt LTBI management and is positive, a chest radiograph should be performed. Delaying therapy is appropriate for patients with positive TST in the absence of a major risk factor for progression to active disease, ie, recent infection or immunosuppression. Therapy may be initiated three months after delivery to minimize concern for hepatitis in the postpartum period. If treatment for LTBI is deferred until after delivery, repeat evаluation for active disease, including chest x-ray, should be performed to confirm that active tuberculosis did not develop in the intervening time between diagnosis and treatment. (See 'Toxicity and monitoring' below.)
Adherence may suffer when patients identified with LTBI during pregnancy delay treatment. In a study evаluating 393 women with LTBI during pregnancy who delayed treatment until the postpartum period, only 42 percent attended a follow up visit in the TB clinic, and only 18 percent completed treatment [15]. Therefore, close follow-up is required.
The regimen of choice for treatment of LTBI is isoniazid (5 mg/kg up to 300 mg daily) for nine months (table 2). This should be combined with pyridoxine supplementation (25 mg daily) [9]. Minor interruptions in therapy are acceptable, so long as 270 doses are completed within 12 months. A six month regimen of daily isoniazid also provides protection but is less desirable, although in the setting of difficulty with adherence, providers may prefer to concentrate efforts in ensuring six months of therapy [9].
Another choice for treatment of LTBI is rifampin (daily for four months) (table 2) [9]. Rifampin should be used for patients who are intolerant of INH or who are presumed to have infection with INH-resistant, rifampin-sensitive strains of TB. It may also be useful in the setting of difficulty with adherence. (See "Diagnosis of latent tuberculosis infection in adults".)
Toxicity and monitoring — Pregnancy and the early postpartum period may confer increased risk for isoniazid hepatotoxicity [16-19]. Among 3681 pregnant and postpartum women with LTBI, isoniazid was associated with a 2.5-fold increase in fulminant hepatitis and a fourfold increase in mortality compared with nonpregnant women, although these data did not reach statistical significance [16].
Pregnant and postpartum women should have pre-treatment liver transaminases and bilirubin function tests and, if normal, isoniazid can be started with follow up symptom evаluations, and exams every month. Initially LFTs should be obtained every month for at least two months until shown to remain within normal limits. The evаluation of pregnant and postpartum women receiving LTBI treatment (either isoniazid or rifampin) also should include testing for HIV, hepatitis B and C, and a general evаluation for chronic liver disease, alcohol use, and exposure to other hepatotoxins. If there is a mild elevation of transaminases, more frequent monitoring may be necessary until stability is established.
Patients should receive explicit instructions to stop therapy immediately and contact their healthcare provider upon the development of any symptoms that are consistent with hepatitis. Isoniazid should be discontinued if the patient is symptomatic and the ALT is more than three times the upper limit of normal [20]. It should be discontinued in asymptomatic patients when the ALT is more than five times the upper limit of normal [20].
Other side effects of isoniazid include rashes, neuropsychiatric disturbances including depression, mania, and memory loss, pellagra, peripheral neuritis, and seizures [21].
Adverse effects due to rifampin include hepatitis, thrombocytopenia, hemolytic anemia, and fever and rash. (See "Rifampin and other rifamycins" and 'First line drugs' below.)
ACTIVE TB — Pregnancy has not been shown to influence the pathogenesis of TB or the likelihood of progression from latent infection to active disease, nor has it been shown to affect the response to treatment [7,8]. Active maternal infection can lead to congenital infection by hematogenous dissemination via the placenta, although congenital infection is very rare. (See 'Congenital and neonatal TB' below.)
Clinical manifestations — Pregnant patients with pulmonary tuberculosis typically have the same clinical manifestations as nonpregnant patients. However, tuberculosis in pregnant women can present insidiously, since malaise and fatigue may be attributed to pregnancy rather than disease [19]. In addition, during pregnancy it can be difficult to recognize weight loss. In the setting of extrapulmonary disease symptoms may be especially vague and the diagnosis can be significantly delayed [22-24]. (See "Clinical manifestations of pulmonary tuberculosis".)
Diagnosis — The evаluation for active tuberculosis in pregnant women should proceed as in nonpregnant individuals, including chest X-ray, with appropriate protection of the fetus [25]. evаluation for extrapulmonary disease should be guided by clinical symptoms and/or radiographic findings. Diagnosis of TB also should prompt evаluation for HIV infection. (See "Diagnosis of tuberculosis in HIV-seronegative patients" and "Primary HIV-1 infection: Diagnosis and treatment".)
TREATMENT OF ACTIVE TB — Treatment of tuberculosis in the setting of pregnancy should be initiated if the suspicion of active disease is moderate to high (such as a persistent upper lobe infiltrate and cough in a high-risk individual and/or a positive AFB smear or nucleic acid amplification test), since untreated disease represents a greater hazard to the mother and fetus than antituberculous therapy. The principles of treatment of active tuberculosis in HIV-seronegative pregnant patients are the same as for nonpregnant patients, except for the exclusion of certain medications [26]. HIV-positive patients are discussed in detail separately, and decisions about therapy in these individuals should be made in consultation with an expert. (See "Treatment of tuberculosis in HIV-seronegative patients" and "Treatment of pulmonary tuberculosis in the HIV-infected patient".)
The approach to treatment also includes consideration of issues related to transmission, including separation of mother from newborn in certain circumstances. (See 'Controlling transmission' below.)
First line drugs — The initial treatment regimen (for presumed drug sensitive disease) for active TB during pregnancy in the United States typically consists of isoniazid, rifampin and ethambutol administered for two months followed by isoniazid and rifampin for seven months, for a total of nine months [3,7,14,26,27]. If the results of drug sensitivity studies are available and the organism is known to be susceptible to isoniazid and rifampin, then ethambutol may be discontinued after one month.
Pyrazinamide is not absolutely necessary as part of a first line regimen, and because of limited safety data, it is not used routinely for pregnant women in the United States. However, pyrazinamide is recommended by the World Health Organizations as part of a standard regimen for treatment of TB in pregnant women [28,29]. In circumstances such as HIV coinfection, tuberculous meningitis, very extensive disease, and any form of drug resistance, it would be prudent to consider the use of pyrazinamide [14,30]. The absence of pyrazinamide from the treatment regimen results in a treatment duration of nine months instead of six months.
Steroids for manifestations such as meningitis and pericarditis should be used as discussed separately [26]. (See "Central nervous system tuberculosis" and "Tuberculous pericarditis".)
• Isoniazid is considered acceptable for use in pregnancy and is not considered to be a human teratogen, although the risk of hepatitis and peripheral neurotoxicity may be increased in the peripartum period [26,27,31,32]. In general, the benefit of isoniazid (given its importance for treatment of active TB) justifies the potential risk to the fetus. Pyridoxine (25 mg/day) should be administered to pregnant women receiving isoniazid (and to their breastfeeding infants, even if the infant is not receiving isoniazid therapy) [9,26].
• Rifampin is considered acceptable for use in pregnancy; rare cases of fetal abnormalities and hemorrhagic disease have been reported [9,11,26,32,33]. Rifabutin often is used as an alternative to rifampin in patients with HIV infection on antiretroviral medications. There is insufficient safety information relating to the use of rifapentine in pregnancy (category C). (See "Treatment of pulmonary tuberculosis in the HIV-infected patient".)
• Ethambutol is considered acceptable for use in pregnancy [26,31,32].
• Pyrazinamide is not universally considered acceptable for use in pregnancy; the adverse effects of pyrazinamide in pregnancy are not certain. Because detailed teratogenicity data are not available for this agent, it is not used routinely for pregnant women in the United States since it is not absolutely necessary as part of a first line regimen [8,26].
Dosing regimens for treatment of tuberculosis are outlined separately. (See "Treatment of tuberculosis in HIV-seronegative patients".)
Second line drugs — Pregnant women with drug resistant tuberculosis or who have difficulty taking first line drugs should be managed in consultation with an expert in treating tuberculosis. In the setting of monoresistance it may be acceptable to treat with first line drugs during pregnancy, especially if a determination is made that it is acceptable to use pyrazinamide.
In the setting of resistance to multiple agents, there may be no choice but to use a regimen with some potential toxicity to the fetus; women should be counseled accordingly. There have been multiple cases in which mothers with MDR-TB have been treated with second line agents and delivered at term; most of these babies were delivered without evidence of adverse effects [34-37].
Agents to avoid — Streptomycin (category D) is a known teratogen; it interferes with inner ear development and may cause congenital deafness [32]. Among 40 pregnant women treated with streptomycin, 17 percent of the babies had eighth nerve damage with deficits ranging from mild hearing loss to bilateral deafness [38]. Given this risk and the availability of effective and less toxic alternatives, streptomycin should NOT be used for treatment of TB in pregnancy.
Kanamycin (category D) and amikacin (category D) presumably share this potential for toxicity and should NOT be administered in pregnancy, although there is little specific information on the fetal effects of these drugs. Capreomycin (category C), which is assumed to have eighth nerve and renal toxicity in fetuses, also should be avoided.
Agents to consider — These agents should be used in pregnancy only when there are no suitable alternatives for treatment (eg, due to drug resistance or adverse effects of safer agents) and only in consultation with an expert in the treatment of tuberculosis.
• The adverse effects of cycloserine (category C) in pregnancy are unproven. This agent crosses the placenta and should be used for pregnant women only where there are no suitable alternatives [32].
• The adverse effects of PAS (para-aminosalicylic acid) (category C) in pregnancy are not certain. There appears to be no evidence for teratogenicity among babies whose mothers received isoniazid with PAS [27,32]. PAS should be used in pregnancy only where there are no suitable alternatives.
• Ethionamide (category C) crosses the placenta and is teratogenic in laboratory animals [32]. It should be used in pregnancy only when there are no suitable alternatives.
• The fluoroquinolones (category C) have been associated with arthropathies and should be used in pregnancy only where there are no suitable alternatives [32].
Follow up — Treatment should be administered by directly observed therapy (DOT). To improve adherence and to evаluate for drug toxicity, patients should be seen and examined every month. An expert in tuberculosis should be consulted for interruptions longer than two weeks or for sporadic adherence, especially within the first two months of treatment [26]. (See "Adherence to tuberculosis treatment".)
As noted above, careful clinical monitoring for hepatitis is especially important for pregnant and postpartum women; pre-treatment liver transaminases and bilirubin function tests followed by monthly liver enzyme testing should be obtained, and patients should be instructed to call immediately if any symptoms or signs of hepatitis occur. In general, isoniazid should be discontinued for the same indications as for treatment of LTBI. (See 'Toxicity and monitoring' above.)
BREAST FEEDING — Breast feeding is not contraindicated if the mother is being treated for active TB or LTBI with usual first line agents, since the small concentrations of these drugs in breast milk do not produce toxic effects in the nursing infant (ie, approximately 20 percent or less of a normal newborn infant dose) [9,26,32,39].
All infants receiving isoniazid (either via breast milk or as directed therapy) should receive supplemental pyridoxine. If the infant already is receiving isoniazid therapy, then breast feeding will increase the infant's total daily exposure to INH. There are no specific recommendations concerning this or other antituberculous drugs, and it would be difficult to make accurate adjustments of the daily dose to compensate for the amount received in the breast milk.
Breast feeding in the setting of rifabutin or fluoroquinolones is not recommended [26,32]. Decisions about breast feeding with other second-line agents should be made in consultation with an expert. Decisions regarding choice of these agents should be individualized in consultation with an expert [32].
CONGENITAL AND NEONATAL TB — Congenital TB is very rare; a 1980 review noted that only 24 cases had been described in the literature since the introduction of isoniazid in 1952 [40]. Congenital TB is associated with maternal HIV infection, tuberculous endometritis and miliary tuberculosis [26]. The index of suspicion should be increased in regions with high prevаlence of both maternal HIV and tuberculosis [41]. It can occur hematogenously via the placenta and umbilical vein or by fetal aspiration (or ingestion) of infected amniotic fluid [7]. Clinical manifestations of congenital TB include respiratory distress, fever, hepatomegaly, splenomegaly, poor feeding, lethargy, irritability, low birth weight, and low APGAR scores [40,42]. Clinical evаluation of the infant in the setting of suspected congenital TB should include routine evаluation in addition to lumbar puncture and evаluation of the placenta with histologic examination (including acid fast bacillus [AFB] staining) and AFB culture [31]. The tuberculin skin test in the infant most often is negative.
Neonatal TB develops following exposure of an infant to his or her mother's aerosolized respiratory secretions. This is more common than congenital TB, and diagnosis of neonatal TB can lead to identification of previously unrecognized diagnosis of TB in the mother [43]. Clinical evаluation of the infant and the mother should be pursued as outlined in detail separately (see "Diagnosis of tuberculosis in HIV-seronegative patients").
The mortality in the setting of congenital and neonatal TB is about 50 percent [7,40].
CONTROLLING TRANSMISSION — If a mother has established or suspected active pulmonary TB at the time of delivery, she and the infant should be separated until both have been fully evаluated [31]. The same is true for household contacts of the infant.
If both the mother (or household contact) and infant are found to have active TB and both are started on treatment, separation is not necessary as long as both adhere to treatment. The mother (or household contact) should wear a mask until no longer infectious.
If the mother (or household contact) has active TB disease, and the infant has a positive skin test (in the absence of evidence for active disease), the mother should be treated for active disease and the infant should be treated for latent TB infection. Separation is not necessary as long as both adhere to treatment. The mother (or household contact) should wear a mask until no longer infectious.
If the mother (or household contact) has TB but the infant does not have active TB or a positive skin test, the mother should be treated for active disease and the infant should be treated for LTBI for three to four months, at which time a skin test should be repeated. If the repeat skin test is positive, the infant should be reevаluated for active TB, and a full course of treatment for either latent or active TB should ensue, based on the result of the reevаluation. If the repeat skin test is negative, and the mother is no longer contagious, the infant's LTBI treatment may be discontinued. Separation is not necessary as long as both adhere to treatment; the mother (or household contact) should wear a mask until she is no longer infectious.
If the mother has known or suspected pulmonary drug resistant TB and the newborn does not have evidence of active or latent infection, they should remain separated until the mother is not infectious. Routine BCG vaccination at birth is warranted in countries where tuberculosis is endemic (special considerations apply for children born to HIV infected mothers as discussed separately; (see "BCG vaccination"). In countries where BCG administration is not routine, BCG immunization should be considered for the infant of a mother with tuberculosis in consultation with an expert in TB. (See "BCG vaccination".)
BCG vaccination should not be administered during pregnancy for prevention of tuberculosis since it is a live vaccine. (See "BCG vaccination".)
SUMMARY AND RECOMMENDATIONS
• Pregnancy is not a risk factor for TB and has not been shown to influence the pathogenesis of TB or the likelihood of progression from latent infection to active disease. However, maternal infection can lead to congenital infection or neonatal infection. In addition, TB in pregnant women can present insidiously since symptoms of malaise and fatigue may be attributed to pregnancy rather than infection. (See 'Introduction' above.)
• Screening for latent TB infection (LTBI) should be performed during pregnancy only for those women at high risk for progression from latent to active disease (eg, women who have been infected recently and those who have HIV or are otherwise significantly immunocompromised) (table 1). (See 'Latent TB' above and "Diagnosis of latent tuberculosis infection in adults".)
• Treatment of LTBI is reserved for pregnant women at high risk for progression of LTBI to active disease, such as recent infection, HIV infection, or immunosuppression. In these circumstances, we recommend isoniazid for treatment of LTBI (table 2) (Grade 1B). We use daily therapy for nine months; for patients with difficulties related to adherence, six months duration and/or twice weekly directly observed therapy are alternatives. (See 'Latent TB' above.)
• We recommend that the initial treatment regimen for active TB in pregnancy (for presumed drug susceptible disease) consist of isoniazid, rifampin and ethambutol administered for two months, followed by isoniazid and rifampin for seven months for a total of nine months (table 2) (Grade 1B). Pyrazinamide is not absolutely necessary as part of a first line regimen, and because of limited safety data, it is not used routinely for pregnant women in the United States. However, pyrazinamide is recommended by the World Health Organizations as part of a standard regimen for treatment of TB in pregnant women. It may be important to consider in the setting of HIV coinfection, tuberculous meningitis, extensive disease, and drug resistance. (See 'Treatment of active TB' above.)
• We recommend NOT using streptomycin, kanamycin, amikacin or capreomycin for treatment of TB in pregnancy (Grade 1A). Streptomycin is a known teratogen that interferes with eighth nerve development and may cause congenital deafness. Kanamycin and amikacin presumably share this potential for toxicity, and although they are also aminoglycosides, there is little specific information on the fetal effects of these drugs. Capreomycin is assumed to have eighth nerve and renal toxicity. (See 'Agents to avoid' above.)
• The following agents may be useful when there are no suitable alternatives, but should be considered in consultation with an expert in treating TB: rifabutin, cycloserine, PAS (para-aminosalicylic acid), ethionamide and fluoroquinolones. (See 'Agents to consider' above.)
• Breast feeding is not contraindicated in mothers being treated for active TB or LTBI with standard first line agents, since the small concentrations of these drugs in breast milk do not produce toxic effects in the nursing infant. Supplemental pyridoxine should be administered to breastfeeding mothers receiving isoniazid as well as to their infants, even if the infant is not taking isoniazid therapy. Patients receiving treatment for drug resistant TB with second line agents should not breast feed. (See 'Breast feeding' above.)
• Congenital TB is very rare and most often associated with maternal HIV infection or maternal miliary or uterine TB. Neonatal TB is more common than congenital tuberculosis, and diagnosis can lead to identification of a previously unrecognized diagnosis of TB in the mother. The mortality of untreated congenital and neonatal TB is about 50 percent. (See 'Congenital and neonatal TB' above.)
• Issues related to separation of mother and infant for controlling transmission are as outlined above. (See 'Controlling transmission' above.)
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