Tuberculosis infection (latent tuberculosis) in pregnancy

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 (TBI) among individuals with risk of TB who may not otherwise present for medical care.

Organizations with published guidance for diagnosis and management of TBI 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) [2-6].

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

Issues related to the management of TB disease in pregnant patients are discussed separately. (See "Tuberculosis disease (active tuberculosis) in pregnancy".)

Issues related to TB in children are discussed separately. (See "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis" and "Tuberculosis disease in children: Treatment and prevention" and "Tuberculosis infection (latent tuberculosis) in children".)

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

NATURAL HISTORY OF TB IN PREGNANCY — TBI is caused by inhalation of viable bacilli, which may persist in a clinically inactive state (known as TBI, or latent TBI) or progress to TB disease. While we continue to expand our understanding of the dynamic and continuous spectrum of TBI to TB disease, for the purposes of this discussion we define TBI as presence of evidence for TB infection, in the absence of clinical, radiographic, or microbiological evidence of TB disease [7].

Individuals with TBI are asymptomatic and not infectious. TB bacilli remain viable and may reactivate, causing active symptomatic TB disease, which can be transmitted via airborne spread. The natural history of TB is discussed further separately. (See "Tuberculosis: Natural history, microbiology, and pathogenesis".)

Pregnancy has not been definitively proven to influence the pathogenesis of TB or the likelihood of progression from TB infection to active disease, nor has it been shown to affect the response to treatment [8]. However, multiple cohort studies have found higher incidence of TB disease among pregnant and/or postpartum individuals compared with nonpregnant individuals:

●One study including more than 192,000 pregnant people in the United Kingdom between 1996 and 2008 noted a higher incidence of TB diagnosis among postpartum individuals compared with nonpregnant individuals (incidence rate ratio [IRR] 1.95, 95% CI 1.24-3.07) but no significant increase in the incidence of TB diagnosis during pregnancy (IRR 1.29, 95% CI 0.82-2.03) [9]; the authors hypothesized these observations may have been due in part to delays in diagnosis of TB disease.

●In another study of more than 649,000 people ages 14 to 49 years who gave birth in Sweden between 2005 and 2013, an increased incidence of TB disease during pregnancy (IRR 1.4, 95% CI 1.1-1.7) and during the first six months postpartum (IRR 1.9, 95% CI 1.5-2.5) was observed, compared with nonpregnant periods [10].

SCREENING FOR TB INFECTION

Whom to test — Testing asymptomatic patients for TBI during pregnancy is warranted for patients with significant risk factors for TB and progression to TB disease during pregnancy [4,11]; these include:

●Pregnant patients with recent contact with a patient with infectious active respiratory TB.

●Pregnant patients with human immunodeficiency (HIV) infection.

●Pregnant patients with other significant immunosuppression – This includes patients receiving medications such as corticosteroids (≥15 mg/day of prednisone for ≥1 month), immunosuppressive therapy, or tumor necrosis factor-alpha inhibitors as well as patients with major immunocompromising conditions (eg, lymphoma, leukemia, head and neck cancer, solid organ transplant).

Issues related to indications for TBI screening are discussed further separately. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)", section on 'Indications for TBI testing'.)

A positive test for TBI (see below) should prompt an evaluation for TB disease (see 'Diagnostic evaluation after positive test' below); pregnant patients with TB disease should be treated immediately. (See "Tuberculosis disease (active tuberculosis) in pregnancy".)

If TB disease is excluded, decisions regarding timing of treatment for TBI are based on individual circumstances. (See 'Treatment' below.)

For patients with TB risk factors not included above, TBI treatment can be delayed until two to three months after delivery to minimize risk of adverse drug effects related to treatment. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

If indicated, TBI testing prior to pregnancy is preferred (if feasible); this allows opportunity for counseling about the risk of becoming pregnant with TBI as well as the potential opportunity to treat TBI before pregnancy [12].

How to test — The diagnosis of TBI is established by demonstrating an immune response to Mycobacterium tuberculosis antigens and excluding TB disease. (See "Tuberculosis disease (active tuberculosis) in pregnancy".)

Available tests to detect the immune response to TB antigens include the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs). Both tests evaluate cell-mediated immunity. The TST measures immune sensitization (type IV or delayed-type hypersensitivity) to mycobacterial protein antigens that occurs following exposure to (and infection by) mycobacteria, while IGRAs measure the release of interferon-gamma following stimulation by antigens unique to M. tuberculosis. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

Both TST and IGRAs can be performed safely in pregnant patients, and either test may be used [11,13-20]. Some data suggest that both of these tests may be affected by pregnancy [18-20].

Definitions of positive TST are summarized in the table (table 2). Additional issues related to TST and IGRA interpretation, including causes of false-negative and false-positive tests, are discussed separately. (See "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults" and "Use of the tuberculin skin test for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)

Diagnostic evaluation after positive test — Patients with a positive TST or IGRA must undergo clinical evaluation to rule out TB disease. This includes evaluation for symptoms (eg, fever, cough, weight loss [or lower than expected weight gain for pregnancy]) and radiographic examination of the chest (with appropriate shielding), regardless of gestational age. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)", section on 'Excluding TB disease'.)

Patients with a positive TST or IGRA with no evidence of TB disease may be presumed to have TBI and should be managed as discussed below.

CLINICAL MANIFESTATIONS — Patients with TBI are asymptomatic and not infectious. There is no risk for vertical transmission of TBI.

TREATMENT

General principles — Our approach consists of shared decision-making; this includes discussion about the risks and benefits of TB preventive therapy during pregnancy relative to the risk of progression to TB disease during pregnancy and the early postpartum period. Pregnant people with HIV residing in higher TB incidence settings are at higher risk of developing TB than those residing in lower-incidence settings; therefore, the discussion should take into account the risk of developing of TB disease.

All patients diagnosed with TBI prior to pregnancy and started on treatment for an appropriate indication should continue TBI treatment during pregnancy; the regimen should be modified (if necessary) to a regimen suitable for pregnancy, described below [11,21].

For patients with significant immunosuppression (apart from HIV infection, which is discussed below), the decision to treat during pregnancy or defer until after delivery should be based on individual clinical circumstances including the degree of immunosuppression.

Patients without HIV infection

Timing of treatment — Our approach to timing of TBI treatment in pregnant patients without HIV infection is as follows (algorithm 1):

●Positive screening test for TBI

•Recent exposure to a patient with active respiratory TB – We initiate TBI treatment promptly during pregnancy (even during the first trimester), given increased risk of progression to TB disease after a recent exposure. (See 'Selecting a regimen' below.)

•Recent (within two years) conversion of a test for TB infection from negative to positive – We initiate TBI treatment promptly during pregnancy (even during the first trimester), given increased risk of progression to TB disease due to presumed recent infection. (See 'Selecting a regimen' below.)

•No recent exposure to a patient with untreated active respiratory TB and no recent TB infection test conversion

-Presence of immunosuppression (see 'Whom to test' above) – We initiate TBI treatment promptly during pregnancy (even during the first trimester), given increased risk of progression to TB disease due to immunosuppression. (See 'Selecting a regimen' below.)

-Absence of immunosuppression – We defer TBI treatment until two to three months after delivery [2], to minimize the risk of adverse drug effects and adverse pregnancy outcomes associated with TBI treatment during pregnancy [22-24]. In such cases, close follow-up is required [25]. After delivery, such patients should have follow-up evaluation for active disease (including chest radiograph) to confirm that TB disease did not develop in the interval since diagnosis of TBI and the time that treatment for TBI begins. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)", section on 'Excluding TB disease' and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection".)

●Negative screening test for TBI

•Recent exposure to a patient with active respiratory TB

-Presence of immunosuppression – We initiate TBI treatment promptly during pregnancy (even during the first trimester), given increased risk of progression to TB disease. (See 'Selecting a regimen' below.)

-Absence of immunosuppression – No role for TBI treatment at this time. However, the patient should be retested 10 weeks after the last infectious exposure to see if they have become infected.

Selecting a regimen

●Available regimens - Regimens for treatment of TBI in pregnancy include (table 3) [2]:

•Rifampin (daily for four months; abbreviation 4R)

•Isoniazid and rifampin (daily for three months; abbreviation 3HR)

•Isoniazid (daily for nine or six months; abbreviation 9H or 6H)

For treatment of pregnant patients with TBI in the absence of HIV infection, we suggest a rifamycin-based regimen over isoniazid monotherapy given shorter treatment duration, higher rates of treatment completion, and decreased risk of hepatotoxicity.

Patients on regimens including isoniazid should also receive pyridoxine supplementation (25 to 50 mg daily) given to reduce the risk of isoniazid-induced peripheral neuropathy.

●Efficacy for rifamycin-based regimens – Support for use of 4R and 3HR in pregnancy is based on extrapolation of data from studies in nonpregnant patients. Among nonpregnant adults, 4R has been shown to be noninferior to isoniazid (daily for nine months) for prevention of TB disease; it is also associated with a higher rate of treatment completion and lower rate of hepatotoxicity [26]. 3HR has similar efficacy and hepatotoxicity to that of isoniazid administered for six months [27]. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection", section on 'Rifampin (4R)' and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection", section on 'Isoniazid and rifampin (3HR)'.)

Neither the three-month weekly isoniazid and rifapentine (abbreviation 3HP) regimen nor the one-month daily isoniazid and rifapentine (abbreviation 1HP) regimen are recommended for individuals who are pregnant or expecting to become pregnant during the treatment period, due to limited safety data for rifapentine in pregnancy [28]. One clinical trial evaluating the pharmacokinetics and safety of 3HP in 50 pregnant patients (including 20 with HIV on efavirenz-based antiretroviral therapy [ART]) did not identify any drug-related serious adverse events [29].

●Efficacy for isoniazid monotherapy – If isoniazid is used, we favor daily administration for nine months given its established efficacy based on data in nonpregnant patients. Isoniazid daily for six months provides some protection; in the setting of difficulty with adherence, providers may prefer to concentrate efforts in ensuring six months of therapy. This approach is favored by the World Health Organization (WHO). However, regimens shorter than nine months should not be used for patients with fibrotic lesions on chest radiograph. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection", section on 'Isoniazid monotherapy'.)

●Rifamycin nitrosamine impurities – In August 2020, the US Food and Drug Administration (FDA) announced detection of nitrosamine impurities in samples of rifampin [30]. Some such compounds have been implicated as possible carcinogens in long-term animal studies, with toxicity largely related to cumulative exposure. Because the risks from TB appear to be greater than those from cancer, and the risks for serious toxicity such as isoniazid-induced hepatitis may be substantial with alternative regimens, the United States Centers for Disease Control and Prevention (CDC) and FDA recommend the use of rifampin continue for treatment of TBI. This should be done only following individual patient discussion of benefits, risks, and alternatives, which may include deferral of treatment altogether.

Patients with HIV infection

Settings with TB transmission <500 per 100,000

Timing of treatment — Our approach to management of TBI in pregnant patients with HIV infection is as follows (algorithm 2):

●Recent exposure to a patient with untreated active respiratory TB – We initiate TBI treatment promptly during pregnancy (even during the first trimester), given increased risk of progression to TB disease after a recent exposure. (See 'Selecting a regimen' below and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)", section on 'Individuals with recent exposure (close and casual contacts)'.)

●Recent (within two years) conversion of a test for TB infection to positive – We initiate TBI treatment promptly during pregnancy (even during the first trimester), given increased risk of progression to TB disease. (See 'Selecting a regimen' above.)

●No recent exposure to a patient with untreated active respiratory TB and no recent TB infection test conversion

•Patients with HIV infection on antiretroviral therapy – We defer TBI treatment until two to three months after delivery; this approach is in alignment with the CDC guidelines, which recommend treatment can be delayed for two to three months in pregnancy for patients at lower risk of progression to TB disease [2], and the Department of Health and Human Services guidelines for people with HIV, which state that treatment may be delayed until after delivery [4].

This approach to defer treatment until after delivery is supported by a 2019 study demonstrating more frequent adverse pregnancy outcomes among pregnant patients in eight countries with high TB incidence treated with isoniazid during pregnancy than among patients treated three months after delivery [23]. The study included more than 900 participants with HIV (CD4 count 351 to 670 cells/mm³ on antiretroviral therapy [ART]) randomly assigned to initiate TBI treatment with isoniazid immediately during pregnancy or defer treatment until 12 weeks after delivery. Patients in the first trimester and those with recent TB exposure were excluded. Mothers and infants were followed for 48 weeks after delivery. The incidence of TB was comparable between the groups (0.60 versus 0.59 per 100 person-years); however, the composite adverse pregnancy outcome (stillbirth or spontaneous abortion, low birth weight, preterm delivery, or congenital anomalies) was observed more frequently among patients in the immediate treatment group than in the deferred group (23.6 versus 17.0 percent; difference 6.7, 95% CI 0.8-11.9). The rate of hepatotoxicity was similar between the groups (6.2 versus 7.2 percent; relative difference -1.0, 95% CI -4.3 to 2.3). The risk of adverse pregnancy outcomes associated with isoniazid appears to be impacted by gestational age at exposure, with earlier exposure more associated with adverse pregnancy outcomes.

Our approach to management of pregnant patients with HIV differs from the WHO 2020 TBI statement, which favors TBI treatment during pregnancy, regardless of recent exposure [5].

•Patients with HIV infection not on antiretroviral therapy – We initiate ART promptly; the risk of progression from TBI to TB disease in individuals on ART is significantly decreased [4,31]. Issues related to management of ART in pregnancy are discussed separately. (See "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings".)

Data to guide TBI management for pregnant patients with HIV who are not on ART are limited, and there is no consensus on the optimal approach. Pregnant people with HIV should receive ART, for their own health as well as for reducing the risk of perinatal HIV transmission.

Pending further study, we favor initiation of TBI treatment during pregnancy for all patients with HIV who are not on ART; other experts favor initiation of TBI treatment during pregnancy only for those with CD4 count ≤200 cells/mm³ (with deferral of treatment until two to three months after delivery for those with CD4 count >200 cells/mm³) [32].

Selecting a regimen — In settings with TB disease incidence <500 per 100,000, pregnant patients with HIV may be treated with the same TBI regimens as for pregnant patients without HIV infection (see 'Selecting a regimen' above); however, special consideration must be given to potential drug-drug interactions for patients receiving ART, especially with rifamycins. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection", section on 'Drug interactions: ART and rifamycins'.)

Settings with TB transmission ≥500 per 100,000 — In settings with high TB transmission (incidence ≥500 per 100,000) (table 4), the WHO recommends that people with HIV and a positive or unknown test for TB infection be treated with isoniazid for at least 36 months [31]; however, the regional TB transmission level is not always known. In general, we support the use of extended isoniazid (≥36 months) for settings with high TB incidence. This is discussed further separately. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection", section on 'Settings with high TB transmission rates (≥500 per 100,000)'.)

MONITORING DURING TREATMENT

●Adverse effects − Pregnancy and the early postpartum period may confer increased risk for isoniazid-induced hepatotoxicity [22,33-35]. Other side effects of isoniazid include rashes, neuropsychiatric disturbances including depression, mania, memory loss and/or psychosis, pellagra, peripheral neuritis, and seizures.

Adverse effects due to rifampin include hepatitis, thrombocytopenia, hemolytic anemia, fever, and rash. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)

●Baseline evaluation − Pregnant patients and postpartum patients within three months of delivery should have baseline liver function testing (serum transaminases and bilirubin) prior to initiation of TBI treatment. 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 − In addition, 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 [36]. 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.

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 is not contraindicated among patients on treatment for TBI with first-line agents [37]. The small concentrations of isoniazid and rifampin found in breastmilk do not produce toxic effects in the nursing infant [6,11,38,39]. As such, these small concentrations also do not provide effective treatment for TBI in a nursing infant. Breastfed infants whose mothers are taking isoniazid do not require pyridoxine supplementation (unless the infant is also receiving isoniazid themselves) [37]. Rifamycins can cause orange discoloration of body fluids including breastmilk, which is expected and considered harmless to patients and their nursing infants.

Decisions about breastfeeding with second-line agents should be made in consultation with an expert. (See "Treatment of drug-resistant pulmonary tuberculosis in adults".)

PATIENTS WISHING TO AVOID OR TERMINATE PREGNANCY — Rifamycins are potent inducers of hepatic metabolism of hormonal contraceptives (specifically progestin-only pills, combined hormonal contraception [pill, patch, ring], and implants), which can lead to significant reductions in concentrations (and therapeutic failure). In addition, rifamycins may decrease the concentrations of mifepristone (used in medication abortions) reducing its effectiveness. This effect can last up to two weeks after rifamycin discontinuation.

Patients on rifamycins who are using these forms of contraception should receive counseling regarding use of alternative methods. (See "Contraception: Counseling and selection" and "Emergency contraception".)

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

●Natural history of TB in pregnancy − (See 'Natural history of TB in pregnancy' above.)

•Natural history − Tuberculosis (TB) infection (TBI) is caused by inhalation of viable bacilli, which may persist in an inactive state (known as TB infection or latent TBI) or progress to TB disease. Individuals with TBI are asymptomatic and not contagious. Latent TB bacilli remain viable and may reactivate, causing active symptomatic TB disease, which can be transmitted via airborne spread.

•Influence of pregnancy − Pregnancy has not been definitively proven to influence the pathogenesis of TB or the likelihood of progression from latent infection to active disease; however, multiple cohort studies have found higher incidence of TB disease among postpartum individuals compared with nonpregnant individuals.

●Whom to test – Screening for TBI during pregnancy should be pursued for patients with significant risk factors for progression to active disease during pregnancy; these include patients with recent contact with a patient with untreated active respiratory TB, patients with HIV, and patients with other significant immunosuppression. (See 'Whom to test' above.)

●How to test – Diagnostic tools for TBI include tuberculin skin testing (TST) and interferon-gamma release assays (IGRAs). Definitions of positive TST are summarized in the table (table 2). Patients with a positive TST or IGRA must undergo clinical evaluation to rule out TB disease; this includes evaluation for symptoms (eg, fever, cough, weight loss [or, in pregnancy, lower than expected weight gain]) and radiographic examination of the chest (with appropriate shielding), regardless of gestational age. (See 'How to test' above and 'Diagnostic evaluation after positive test' above.)

●Treatment approach − The potential risks of adverse pregnancy outcomes associated with TB preventive therapy during pregnancy must be weighed against the potential risks of progression to TB disease during pregnancy and the early postpartum period. Pregnant people with HIV residing in higher TB incidence settings are at higher risk of developing TB than those residing in lower-incidence settings; thus, discussion about the benefits and risks of initiating versus delaying to postpartum should take into account the risk of developing of TB disease. (See 'General principles' above.)

•Patients without HIV − Our approach is summarized in the algorithm (algorithm 1). For most pregnant patients without HIV, we suggest deferral of TBI treatment until two to three months after delivery (Grade 2C). We suggest initiation of treatment promptly during pregnancy (even in the first trimester) for patients with recent contact with a patient with untreated active respiratory TB, recent TBI test conversion, or significant immunosuppression (Grade 2C). (See 'Patients without HIV infection' above.)

•Patients with HIV in low-TB transmission settings – Our approach is summarized in the algorithm (algorithm 2). For most pregnant patients with HIV on antiretroviral therapy (ART) in low-TB transmission settings, we suggest deferral of TBI treatment until two to three months after delivery (Grade 2C). We suggest initiation of treatment promptly during pregnancy (even during the first trimester) for patients with recent contact with a patient with untreated active respiratory TB, recent TBI test conversion, or patients who are not on ART (Grade 2C). (See 'Patients with HIV infection' above.)

-Regimen selection – For treatment of patients in the preceding two categories, we suggest a rifamycin-based regimen over isoniazid monotherapy (Grade 2C), given the efficacy, favorable treatment completion rates, and relatively low hepatotoxicity rates of rifamycin-based regimens (table 3). (See 'Selecting a regimen' above and 'Settings with TB transmission <500 per 100,000' above.)

Consideration must be given to potential drug-drug interactions for patients receiving ART and rifamycins. In addition, nitrosamine contamination must be considered in the risk-benefit analysis for any rifampin-based regimen. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection", section on 'Drug interactions: ART and rifamycins'.)

•Patients with HIV in high-TB transmission settings − For pregnant patients with HIV in high-TB transmission settings (table 4), we suggest TBI treatment during pregnancy with daily isoniazid for 36 months (Grade 2C). (See 'Settings with TB transmission ≥500 per 100,000' above.)

●Monitoring − Issues related to baseline evaluation and monitoring are summarized above. (See 'Monitoring during treatment' above.)

●Breastfeeding − Issues related to breastfeeding during TBI treatment are summarized above. (See 'Breastfeeding' above.)