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Tuberculosis disease (active tuberculosis) in pregnancy

Tuberculosis disease (active tuberculosis) in pregnancy
Literature review current through: Jan 2024.
This topic last updated: Dec 01, 2022.

INTRODUCTION — Tuberculosis (TB) terminology is inconsistent in the literature (table 1) [1]. The following terms are used in this discussion:

Tuberculosis infection (newer term for latent tuberculosis)

Tuberculosis disease (newer term for active tuberculosis)

Prenatal care presents a unique opportunity for evaluation and management of TB infection and TB disease among individuals with risk of TB who may not otherwise present for medical care.

Organizations with published guidance for management of TB include the United States Centers for Disease Control and Prevention (CDC), the United States National Tuberculosis Controllers Association (NTCA), the United States Department of Health and Human Services (DHHS), the American Thoracic Society (ATS), the Infectious Disease Society of America (IDSA), and the World Health Organization (WHO) [2-7].

Issues related to diagnosis and treatment of TB disease in pregnant patients will be reviewed here, for TB that is presumed or demonstrated to be susceptible to isoniazid and/or rifampin.

Issues related to diagnosis and treatment of TB infection in pregnant patients are discussed separately. (See "Tuberculosis infection (latent tuberculosis) in pregnancy".)

TERMINOLOGY — Tuberculosis terminology is inconsistent in the literature [1]. Relevant terms are defined in the table (table 1).

NATURAL HISTORY OF TB IN PREGNANCY — Tuberculosis infection is caused by inhalation of viable bacilli, which may persist in a clinically inactive state (known as TB infection [TBI]) or progress to TB disease.

Individuals with TBI are asymptomatic and not contagious. Latent TB bacilli remain viable and may reactivate, causing symptomatic TB disease, which can be transmitted via airborne spread.

Postpartum patients with TB disease can transmit infection to their infants; this is discussed further below. (See 'Controlling transmission' below.)

Maternal TB disease may be associated with congenital infection by hematogenous dissemination via the placenta; this is very rare. (See "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis".)

CLINICAL MANIFESTATIONS — Pregnant patients with pulmonary TB have the same clinical manifestations as nonpregnant patients; these may include fever, cough, weight loss, night sweats, and malaise. Pulmonary TB disease may be transmitted via airborne spread.

TB in pregnant patients can present insidiously since malaise and fatigue may be attributed to pregnancy rather than disease [8-13]. In addition, during pregnancy, it can be difficult to recognize weight loss. (See "Pulmonary tuberculosis: Clinical manifestations and complications".)

DIAGNOSIS — Diagnostic evaluation for TB disease is warranted in the setting of clinical suspicion for TB disease, based on clinical manifestations and epidemiologic factors (such as exposure to a known or suspected case, residence in or travel to an endemic area).

The approach to diagnosis for TB disease in pregnant patients is the same as in nonpregnant individuals; it consists of clinical history (including epidemiologic assessment) and physical examination followed by chest radiography (with appropriate shielding to protect the fetus) [14]. Chest imaging suggestive of pulmonary TB should prompt submission of three sputum specimens (coughed or induced) for acid-fast bacilli smear and culture as well as at least one sputum specimen for Mycobacterium tuberculosis nucleic acid amplification testing. (See "Diagnosis of pulmonary tuberculosis in adults".)

A positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA) supports a diagnosis of TB infection but, in the absence of other evidence, is not sufficient for diagnosis of TB disease. In addition, a negative TST or IGRA result does not rule out TB disease.

Diagnosis of TB disease should prompt evaluation for HIV infection. (See "Screening and diagnostic testing for HIV infection".)

TREATMENT

Whom to treat — Treatment of TB in the setting of pregnancy should be initiated if the suspicion of TB disease is moderate to high (such as a positive sputum acid-fast bacilli smear, positive sputum nucleic acid amplification test, or cough and upper lobe infiltrate in an individual with relevant risk factors). (See "Epidemiology of tuberculosis", section on 'Risk factors'.)

TB disease in pregnancy is associated with adverse maternal and fetal outcomes; untreated TB disease represents a greater hazard to the mother and fetus than antituberculous therapy [15].

Other principles for treatment of TB disease in pregnant patients are the same as for nonpregnant patients. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection".)

Clinical approach

Initial treatment regimen

Patients without HIV infection – The regimen for empiric treatment of presumed drug-susceptible TB disease during pregnancy in the United States consists of isoniazid, rifampin, and ethambutol administered for two months, followed by isoniazid and rifampin for seven months, for a total of nine months of treatment [5,16-18]. If the results of drug susceptibility studies are available and the isolate is known to be susceptible to isoniazid and rifampin, ethambutol may be discontinued after one month.

Pyrazinamide is not absolutely necessary as part of a first-line regimen for TB disease. Detailed teratogenicity data are not available for this agent, so it is often excluded from TB treatment for pregnant patients in the United States; some favor its use for patients with severe and/or extrapulmonary TB [5,19]. In contrast with United States practice, pyrazinamide is recommended by the World Health Organization as part of a standard regimen for treatment of TB in pregnant patients [20].

If a decision is made to include pyrazinamide, the treatment duration can be shortened from nine months to six months in most patients [5].

The rifapentine-moxifloxacin-based four-month regimen has not been studied in pregnant patients and should not be used in this population [21,22].

Patients with HIV infection – In general, the approach to antituberculous therapy for pregnant patients with HIV infection is the same as for pregnant patients without HIV infection. However, careful attention to drug interactions is critical. For patients on rifampin-based TB treatment, only a limited number of antiretroviral medications within a limited number of drug classes can be coadministered, due to drug interactions that adversely affect HIV treatment efficacy. Such cases should be managed in consultation with an expert in TB and HIV drug interactions. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy", section on 'Drug interactions'.)

Drug dosing – Dosing regimens for treatment of TB are summarized separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection".)

Tailoring treatment – Drug susceptibility data should be reviewed when available, and treatment should be adjusted if needed. Issues related to treatment of drug-resistant TB in pregnancy are discussed separately. (See "Treatment of drug-resistant pulmonary tuberculosis in adults", section on 'Pregnant patients'.)

Directly observed therapy – Treatment should be administered by directly observed therapy using patient-centered case management wherever possible. (See "Adherence to tuberculosis treatment".)

Treatment interruptions – Treatment interruptions longer than two weeks, suspected or confirmed drug resistance, or sporadic adherence should prompt consultation with an expert in tuberculosis. Nonadherence within the first two months of treatment generally warrants restarting treatment from the beginning [5]. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection".)

Adverse effectsIsoniazid, rifampin, and ethambutol are generally considered by experts to be acceptable for use in pregnancy [5,23,24].

Isoniazid – Use of isoniazid may be associated with increased risk of hepatitis and peripheral neurotoxicity in the peripartum period, especially in Hispanic or African American individuals [5,10,18,23-27]. In general, the benefit of isoniazid (given its importance for treatment of TB disease) justifies the potential risk. Pyridoxine should be administered to pregnant patients receiving isoniazid and to their breastfeeding infants (even if the infant is not receiving isoniazid therapy) [5,28].

Other side effects of isoniazid include rashes, neuropsychiatric disturbances including depression, mania, memory loss and/or psychosis, pellagra, peripheral neuritis, and seizures.

Rifamycins

-Adverse effects – Adverse effects due to rifampin include hepatitis, thrombocytopenia, hemolytic anemia, fever, and rash. Use of rifampin also has been associated with rare cases of fetal abnormalities and hemorrhagic disease [5,23,28,29]. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)

-Nitrosamine impurities – The US Food and Drug Administration (FDA) has reported detection of nitrosamine impurities in samples of rifampin [30,31]. Both the United States Centers for Disease Control and Prevention (CDC) and the FDA recommend that rifampin continue to be used for treatment of TB disease because the risks from TB appear to be greater than those from cancer related to nitrosamine impurities. Until these recommendations change, we favor continued use of rifampin for treatment of TB disease if acceptable to the patient, as the risk of not taking rifampin likely outweighs any potential risk from nitrosamine impurities.

-Alternative agentsRifabutin often is used as an alternative to rifampin in patients with HIV infection on antiretroviral medications and may be used in pregnancy in consultation with an expert. Excess nitrosamine impurities have not been detected in rifabutin. Rifapentine should not be used in pregnancy, as there is insufficient safety information.

Monitoring during treatment

Baseline testing – Pregnant patients and postpartum patients within three months of delivery should have baseline liver function testing (serum transaminases and bilirubin) prior to initiation of treatment for TB infection or TB disease. Additional evaluation should include testing for HIV and hepatitis B and C as well as general evaluation for chronic liver disease, alcohol use, and exposure to other hepatotoxins.

Monitoring during treatment – In the absence of evidence for underlying liver disease, initiation of antituberculous drugs should be followed by monthly evaluation for symptoms of hepatitis, clinical examination, and liver function testing. In the setting of liver disease or abnormal liver function tests, more frequent monitoring may be warranted.

Patient education – Patients on antituberculous drugs should be educated about the symptoms of hepatitis and instructed to stop the medication should such symptoms occur and to seek prompt evaluation of symptoms to reduce risk for progression to severe disease [32]. Symptoms include anorexia, nausea, vomiting, dark urine, icterus, rash, persistent paresthesias of the hands and feet, persistent fatigue, weakness or fever lasting three or more days, abdominal pain (particularly right upper quadrant discomfort), easy bruising or bleeding, or arthralgias.

Regimen adjustments – Issues related to regimen adjustments and hepatotoxicity should be addressed as discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection", section on 'Regimen adjustments for drug intolerance'.)

BREASTFEEDING — Breastfeeding may be encouraged after at least two weeks of treatment for TB disease [24]. The small concentrations of first-line antituberculous drugs (isoniazid, rifampin, ethambutol, and pyrazinamide) in breast milk do not produce toxic effects in the nursing infant [5,23,28,33]. Exclusively breastfed infants receiving isoniazid (either via breast milk or as directed therapy) should receive supplemental pyridoxine.

CONTROLLING TRANSMISSION — Mothers with untreated pulmonary TB disease can transmit infection to their infants. Therefore, patients with known or suspected TB disease at the time of delivery should be separated from the infant until both have been evaluated [24] (see "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis' and "Diagnosis of pulmonary tuberculosis in adults"):

If both the mother and infant have pulmonary TB disease (implying congenital TB, which is very rare), both should be started on treatment. The infant and mother need not be separated as long as both are adherent; the mother should wear a mask until no longer contagious. (See "Tuberculosis disease in children: Treatment and prevention".)

If the mother has drug-susceptible pulmonary TB disease and the infant has a positive skin test (in the absence of evidence for TB disease), the mother should be treated for TB disease and the infant should be treated for TBI. The infant and mother need not be separated as long as both are adherent; the mother should wear a mask until no longer contagious. (See "Tuberculosis infection (latent tuberculosis) in children".)

If the mother has drug-susceptible pulmonary TB disease and the infant has no evidence of TB infection or disease, the mother should be treated for TB disease and the infant should be treated for TB infection for three to four months. The infant and mother need not be separated as long as both are adherent; the mother should wear a mask until no longer contagious.

After three to four months of treatment, the infant should have a repeat skin test. If the mother has drug-susceptible TB and has been adherent to treatment and has shown clinical, radiographic, and microbiologic improvement, at this point the mother should have been noncontagious (and the infant should have had no TB exposure) for at least 10 weeks:

If the infant's repeat skin test is positive, the infant should be reevaluated for TB disease (see "Tuberculosis infection (latent tuberculosis) in children" and "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis"). The infant should receive a full course of treatment for either TB infection or TB disease, based on the result of the reevaluation. The infant and mother need not be separated as long as both are adherent.

If the infant's repeat skin test is negative, the infant need not continue treatment for TB infection. The infant and mother need not be separated as long as the mother is adherent.

If the mother is still contagious, both mother and infant warrant further investigation in conjunction with expert consultation. (See "Treatment of drug-resistant pulmonary tuberculosis in adults" and "Tuberculosis infection (latent tuberculosis) in children" and "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis".)

Bacille Calmette-Guérin (BCG) vaccination should not be given during pregnancy for prevention of TB since it is a live vaccine. Issues related to BCG vaccination are discussed further separately. (See "Prevention of tuberculosis: BCG immunization and nutritional supplementation".)

Issues related to controlling transmission in the setting of drug-resistant TB warrant expert consultation. General issues related to TB transmission and control are discussed further separately. (See "Tuberculosis transmission and control in health care settings".)

OUTCOMES — Outcomes for TB in pregnancy may be worse among patients with HIV infection; in one study including 80 pregnant patients with HIV and TB and 155 pregnant patients with HIV but not TB, those with TB had higher rates of preeclampsia, their infants had higher rates of mortality and low birth weight, and 12 percent of these infants were born with TB [34].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of tuberculosis".)

SUMMARY AND RECOMMENDATIONS

Clinical manifestations – Pregnant patients with pulmonary tuberculosis (TB) have the same clinical manifestations as nonpregnant patients; these may include fever, cough, weight loss, night sweats, and malaise. TB in pregnant patients can present insidiously, since malaise and fatigue may be attributed to pregnancy rather than disease. In addition, it can be difficult to recognize weight loss during pregnancy. (See 'Clinical manifestations' above.)

Diagnosis – The approach to diagnosis of TB disease in pregnant patients is the same as in nonpregnant individuals; it consists of clinical history (with epidemiologic assessment) and physical examination, followed by chest radiography (with appropriate shielding to protect the fetus). Chest imaging suggestive of pulmonary TB should prompt submission of three sputum specimens (coughed or induced) for acid-fast bacilli smear and culture as well as at least one sputum specimen for Mycobacterium tuberculosis nucleic acid amplification testing. (See 'Diagnosis' above.)

Treatment – (see 'Clinical approach' above):

Antituberculous regimen – We suggest that the initial regimen for treatment of TB disease in pregnancy (for presumed drug-susceptible disease) consists of isoniazid, rifampin, and ethambutol administered for two months, followed by isoniazid and rifampin for seven months, for a total of nine months (Grade 2C).

Use of pyrazinamide – Pyrazinamide is not absolutely necessary as part of a first-line regimen and is not used routinely for treatment of pregnant patients in the United States because of limited safety data; some favor its use for patients with severe and/or extrapulmonary TB. In contrast with United States practice, pyrazinamide is recommended by the World Health Organization as part of a standard regimen for treatment of TB in pregnant patients.

Monitoring – Pregnant patients and postpartum patients within three months of delivery should have baseline liver function testing (serum transaminases and bilirubin) prior to initiation of treatment. In the absence of evidence for underlying liver disease, initiation of antituberculous drugs should be followed by monthly evaluation for symptoms of hepatitis, clinical examination, and liver function testing. In the setting of liver disease or abnormal liver function tests, more frequent monitoring may be warranted. (See 'Monitoring during treatment' above.)

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