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TB and Pregnancy

PCCSU Volume 25, Lesson 32

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

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PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center 
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine 
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison


By Aditi Mathur, MD; Beth Hott, MD; and Ghada Bourjeily, MD, FCCP

Dr. Mathur is a Pulmonary and Critical Care Fellow at Yale University School of Medicine, Department of Internal Medicine in New Haven, Connecticut. Dr. Holt works in the Women's Medicine Collaborative in the Department of Medicine at The Miriam Hospital in Providence, Rhode Island. Dr. Bourjeily is Assistant Professor of Medicine at Warren Alpert Medical School of Brown University, Department of Medicine at The Miriam Hospital in Providence, Rhode Island.

Drs. Mathur, Holt, and Bourjeily have disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this lesson.

Objectives

  1. Understand the global impact of TB on women of childbearing age.
  2. Be able to identify pregnant women at risk for TB.
  3. Be able to identify pregnant women who require immediate treatment for latent TB.
  4. Be able to identify pregnant women who require work-up and treatment of active TB.
  5. Know the diagnostic modalities available for diagnosis and the impact of pregnancy on diagnostic modalities.

Key Words: infertility; lactation; pregnancy; tuberculosis

Abbreviations: AAP = American Academy of Pediatrics; AFB = acid-fast bacilli; ACOG = American College of Gynecologists; ART = antiretroviral therapy; CDC = Centers for Disease Control and Prevention; CFP-10 = culture filtrate protein-10; ESTAT-6 = early secreted antigen target-6; FGTB = female genital tuberculosis; FDA = Food and Drug Administration; HSG = hysterosalpingogram; IGRA = interferon gamma release assay; IVF = in vitro fertilization; INH = isoniazid; LTBI = latent tuberculosis infection; MDR-TB = multidrug resistant tuberculosis; PCR = polymerase chain reaction; PZA = pyrazinamide; TST = tuberculin skin testing; WHO = World Health Organization

Introduction

Since the World Health Organization (WHO) declared TB a global emergency in 1994, there have been increasing efforts to identify and curtail the deleterious effects of this infectious disease. One population that deserves particular attention during this time is women of childbearing age. In this group, TB is among the top three leading causes of mortality worldwide1 and a major cause of infertility.2 There are an estimated 10 million orphaned children as a result of TB deaths among parents.3 Given that mothers are the primary caregivers in most cultures, targeting mothers for prevention and early therapy may help prevent disease transmission.

Many women throughout the world may only have access to health care during pregnancy and immediately postpartum. This gives providers caring for pregnant women a major role in screening and identifying women at risk for developing TB. Because they have the most experience with TB treatment, pulmonologists and infectious disease specialists must work closely with obstetricians so that latent and active TB infection are swiftly treated and the rare opportunity during which many women have access to health care is not lost.

This article discusses the diagnostic and treatment challenges unique to the perinatal period with additional discussion of newer diagnostic modalities and their application in the pregnant population. Infertility caused by extrapulmonary TB and the impact of assistive reproductive technology are also discussed.

Epidemiology of TB

TB continues to be one of the leading causes of mortality worldwide from an infectious disease; in 2010, there were 8.8 million cases globally.3 Of these, it is estimated that nearly 1.4 million people succumbed to the disease. In the late 20th century, global travel increased and the HIV epidemic spread throughout the world, changing the epidemiology of TB. In the 1990s, TB incidence was on the rise in sub-Saharan Africa, where it became one of the top three causes of death in women of childbearing age.4 Worldwide, approximately 13% of adults diagnosed with TB had HIV; this statistic was more than double in certain African nations.5 TB incidence was also on the rise in Eastern European countries that were formerly part of the Soviet Union, possibly because of economic decline and substandard health services. More than 10% of TB cases in Estonia, Latvia, and parts of Russia were found to be due to multidrug resistant TB (MDR-TB) (TB that is resistant to isoniazid [INH] and rifampin).6 Despite the increasing incidence of TB in Africa and Eastern Europe, half of all TB cases in the world still arose in Asia, specifically China, India, and Indonesia.7,8

The highest-growing population diagnosed with TB in the 1990s was women of childbearing age. As the incidence of TB increased in this population, so did the number of pregnant women infected with TB. The incidence of TB in pregnant women in New York City increased from 12.4 cases per 100,000 deliveries from 1985 to 1990 to 95 cases per 100,000 deliveries from 1991 to 1992.9,10 In South Africa, TB was the third-leading cause of maternal mortality (15%), trailing behind sepsis (34%) and hypertensive disorders of pregnancy (25%). Coinfection with HIV was noted in 75% of cases.

The start of the 21st century has seen the beginning of a slow decline in the incidence of TB and a decrease in TB mortality by 40%. While this is encouraging, the high incidence among young women and those co-infected with HIV requires physician vigilance; knowledge about the disease process remains crucial for continued treatment and eradication of the disease. In 2010, TB remained among the three greatest causes of death in women of childbearing age.1

Diagnosis

The biggest barrier in diagnosing TB during pregnancy is simply acknowledging it as a possibility and overcoming the barrier of concern for fetal harm.11 Failure to gain weight during pregnancy may be the only clue to toward diagnosis.

If active TB is suspected based on a history of cough for 2 or more weeks, previous history of TB, contact with infected person or failure to gain weight, the issue should be further investigated with three sputum collections for acid-fast bacilli (AFB) smear and culture, chest radiography, and histological exam of available tissues such as liver and lymph nodes.12 Pulmonary TB is the most common form of maternal TB, accounting for about 85% of all cases.13 Chest radiography should not be delayed and can be performed with lead shielding of the abdominal area. Chest radiographs expose the fetus to a minimal amount of radiation in the range of 0.001 rads. The amount of radiation considered justifiable in pregnancy is in the range of five to 10 rads.14 Chest radiographs may reveal pulmonary infiltrates, cavitation, bronchiectasis, and/or pleural effusion.

Placental and endometrial tissue samples can also be analyzed immediately postpartum,15 but the diagnostic work-up should never be delayed until delivery. Just as in the nonpregnant population, drug susceptibility testing should be performed on smear and culture positive samples, but results may not be available for several weeks. If obtainable, a rapid automated molecular test for TB and assessment of rifampin resistance using a polymerase chain reaction (PCR) assay should be pursued for quick detection of resistance. Genetic probes, which detect drug resistance to rifampin, are very suggestive of MDR-TB. Rifampin monoresistance is rare; thus, rifampin resistance is a marker for MDR-TB in greater than 90% of cases.16

Pregnancy may also be a good time to screen for latent TB infection (LTBI) given potentially improved compliance and frequent scheduled visits. Screening in pregnant women is no different than for any other patient. Studies in which the same patients were tested during and after pregnancy have demonstrated that pregnancy has no effect on cutaneous tuberculin hypersensitivity.17,18 Tuberculin skin testing (TST) is considered valid and safe throughout pregnancy. No teratogenic effects of testing during pregnancy have been documented.19

Within the last few years, there have been development and widespread use of interferon gamma release assays (IGRA) using Mycobacterium. TB antigens culture filtrate protein-10 (CFP-10) and early secreted antigen target-6 (ESTAT-6).20 This test has been used as an alternative to TST screening, particularly in patients who have received the Bacillus Calmette-Guérin vaccine. The sensitivity and specificity of this test has been published to be 89% and 98% respectively.21 While several IGRAs are approved by the US Food and Drug Administration (FDA) and widely used, controversial results exist in pregnant women22,23 and the test is not yet validated or approved for use in this population; thus, a TST remains the test of choice for now.24

In summary, pregnant women at high risk for acquiring LTBI (Table 1) should be screened with a TST, which is established to be safe during pregnancy.


Table 1Patients at Risk for Acquiring LTBI

Patients at risk for acquiring LTBI63
HIV infected
Close contacts of person known or suspected of having active TB
Injection drug users
Employees of health-care and correctional facilities
Recently arrived foreign born of high-TB-incidence countries
Patients with medical risk factors known to increase risk of TB disease

Treatment

Safety Issues
Prescribing in pregnancy is complicated by fear of fetal harm. Teratogenicity studies are difficult to perform for many reasons. Ethical issues complicate the design of such studies. Analyses need to take into consideration the baseline risk of congenital malformations of about 2% to 3%. In addition, even established teratogenic drugs cause malformations in only a small percentage of patients exposed and therefore, large-scale studies are usually needed to establish drug safety. In addition, drug safety studies need to tease out whether the malformation is due to exposure to the drug, the disease, or to baseline risk.

About three decades ago, the FDA introduced a classification of fetal risks due to pharmaceuticals that divides drugs into category A, B, C, D, or X based on available human and animal safety data. Although this classification is most helpful for drugs in categories A and X, it may be less valuable in other categories given a few drawbacks to this classification system. Teratogenicity may be species specific, and safety in animal studies does not automatically establish safety in humans. In addition, teratogenicity (category X) and clear drug safety (category A) in humans have been established in a very small proportion of drugs, and the majority of drugs end up falling in categories, such as B (animal studies have failed to show a risk and there are no adequate human data) or C (animal studies have shown a risk but there are no adequate human data). In reality, many of the category C or D drugs are used on a regular basis, and some category B drugs are avoided when possible. Another major limitation to the FDA classification is that it does not usually take into account the risk of the untreated disease on the fetus, the mother, and the public in diseases that represent a public concern, such as TB. In many cases, when the risk of the untreated disease outweighs the risk of teratogenicity, clinicians must use their judgment and appropriately counsel the expecting family about risks and benefits. For instance, a clinician may hesitate to prescribe a category B drug to treat a common cold but unwaveringly initiate therapy with a category C or D drug for a life-threatening condition. In some circumstances, clinicians may decide to obtain signed consent from the family. Detailed reviews on basic principles of prescribing in pregnancy have been recently published.25,26

With this information in mind, prescribing medications to treat latent or active TB should take these issues into consideration.

Treatment of LTBI in Pregnancy
As many women seek medical care only during pregnancy, obstetricians have a unique opportunity to assist in the battle against TB by detecting those with active and latent forms of TB.27 TST should be performed in pregnant women at risk for TB. If the TST is positive and active disease has been ruled out based on a lack of symptoms and a review of chest radiograph, then a confident diagnosis of LTBI can be made. The risk of progression from LTBI to TB disease is 10% over an immunocompetent person’s lifetime. In those with both LTBI and untreated HIV infection, the risk is 7% to 10% each year.28 The Centers for Disease Control and Prevention (CDC) recommend treatment with INH in patients with LTBI at high risk for developing active disease—defined in Table 2—regardless of pregnancy status. INH dosed at 300 mg per day and pyridoxine dosed at 25 mg per day is recommended for 9 months.29 INH does not appear to carry an increased risk of fetal malformations, childhood malignancies, miscarriages, or perinatal deaths.30


Table 2Risk Factors for TB Reactivation

Risk factors for TB reactivation29
HIV disease
Immunocompromised status
Close recent contact with a patient with active TB
Recent skin test conversion (within 2 years)

For pregnant women who are not considered high risk, the CDC and American College of Gynecologists (ACOG) advise delaying treatment to the postpartum period.31 This recommendation stems from a 1989 study that suggested an increased risk of INH-induced hepatitis during pregnancy. The study reported a 2.5-fold increase in the risk of INH hepatitis among their pregnant patients compared to a control group of nonpregnant women. However, this result was not statistically significant and rates of fatal hepatitis were extremely low in both groups (two case fatalities in the study population versus one case fatality in the control population).32 The study also lacked a concurrent control group, failed to specify clinical monitoring practices, and used prophylactic treatment for longer than currently recommended (12 months rather than 9 months). More recently, a decision analysis of antepartum versus postpartum INH treatment of LTBI found that antepartum treatment led to the fewest cases of TB within the cohort (1,400 versus 1,800 per 100,000) and that both antepartum and postpartum INH treatment led to a significant reduction in active TB cases compared to no treatment at all.33

In summary, pregnant women with LTBI at high risk for reactivation of disease should receive INH treatment in conjunction with pyridoxine. Their liver function tests should be checked before initiating treatment and then routinely thereafter up to the immediate postpartum period (3 months).31,34 While there is no consensus on how often transaminases should be monitored, we recommend checking liver function tests every 2 weeks for the first 8 weeks of treatment and then monthly until treatment ceases. Given the theoretical increased risk of hepatitis during pregnancy, the CDC and ACOG currently recommend delaying treatment of LTBI for pregnant women who are not at high risk for reactivation until after delivery and the postpartum period. Given that only a small number of patients actually return for a follow-up TB visit postpartum, many public health experts question whether delaying treatment is in the best interest of the patient.

Treatment of Active TB in Pregnancy
Active TB at any point during pregnancy increases maternal and neonatal morbidity; thus, treatment should not be delayed once a diagnosis of active TB infection has been made. The use of three of the four commonly used first-line drugs (INH, rifampin, and ethambutol) is justified in pregnancy with no reports of associated human fetal malformations.35 Pyrazinamide (PZA) is not well-studied in pregnancy but is regarded as safe and the WHO and the International Union Against Tuberculosis and Lung Disease support its use during pregnancy as part of an initial four-drug regimen for 2 months followed by an additional 4 months of INH and rifampin. Due to insufficient safety data for PZA, the CDC does not endorse its use during pregnancy.29 If PZA is not included in the initial regimen, then treatment is prolonged for a total of 9 months instead of 6 months.29 In areas in which drug resistance is high and a four-drug regimen is usually warranted, the addition of PZA is likely justified.

INH, rifampin, and PZA all carry a small risk of clinical hepatitis. The risk of INH-induced hepatitis is quoted to be around 0.6%. It increases to 2.7% if the patient is concomitantly on rifampin.11 Ethambutol carries a risk of ocular toxicity, mainly in the form of retrobulbar neuritis, which is generally reversible and related to the dose and duration of treatment. There have been no reports of visual problems in children born to mothers taking ethambutol during pregnancy.36

Routine prenatal care for women receiving TB treatment should include careful attention to symptoms such as flulike illness or nonspecific gastrointestinal upset. Liver function tests must be obtained prior to treatment and immediately if the pregnant patient develops fever, malaise, loss of appetite, nausea, vomiting, or jaundice. Otherwise, transaminases and bilirubin levels need to be monitored routinely during pregnancy and up to 3 months postpartum.31 A protocol that includes bimonthly liver function testing for the first 2 months of treatment followed by monthly testing thereafter is a reasonable approach.34 All potential hepatotoxic drugs need to be stopped if transaminases or bilirubin levels are three to five times the upper limit of normal.30

The diagnosis of MDR-TB or the need for second-line anti-infective agents due to serious adverse effects from first-line agents poses a challenge to the treating clinician. Second-line agents are considered more toxic than first-line drugs and clinical experience in pregnancy is lacking (Table 3). The injectable aminoglycoside streptomycin should be avoided, if possible, during pregnancy due to a clear association with fetal hearing loss from damage to cranial nerve eight.37,38 Based on safety profiles, it is difficult to offer a multidrug second-line regimen with similar safety and efficacy profiles of first-line agents. Pregnant women with active MDR-TB must be extensively counseled regarding the potential maternal and fetal risks associated with second-line agents and untreated disease, and they must be cared for by a multidisciplinary team.


Table 3Pregnancy and Lactation Safety of Antituberculous Agents

First-Line Agents Safety Lactation
INHa,b It is considered unlikely to cause substantial effect on fetus but data are limited to fair. Experimental animal studies suggest potential adverse effects to the embryo related to associated vitamin B6 deficiency. Pyridoxine supplementation is recommended to avoid risk of neurotoxicity (25 mg/day). Small amounts of INH are excreted in breast milk. Suggest taking INH right after breastfeeding to avoid peak levels. Pyridoxine supplementation is recommended.
Rifampina,b Experimental animal studies are conflicting, but human experience suggests that the drug is unlikely to pose substantial teratogenic risk; however, data are insufficient to state that there’s no risk. The manufacturer does not recommend breastfeeding because of tumorigenicity observed in animal studies; however, the CDC and American Academy of Pediatrics (AAP) do not consider rifampin a contraindication to breastfeeding.
Ethambutola,b There is an unlikely risk of teratogenicity to a child born after exposure to Ethambutol. Only one case report of ophthalmic abnormalities in infant exposure to three first-line drugs in utero. The manufacturer suggests use during breastfeeding only if benefits to the mother outweigh the possible risk to the infant. Exposure to the infant is low and does not produce toxicity; breastfeeding should not be discouraged.
PZAb,c Teratogenic effects have not been observed in animal reproduction studies, but quality and quantity of data are very limited. Although not recommended as the initial treatment regimen by the CDC, the use of PZA during pregnancy is recommended by the WHO in high-incidence countries.64 Low concentrations of PZA have been detected in breast milk; concentrations are less than maternal plasma concentration.65 AAP has not reviewed.
Second-Line Agents Safety in Pregnancy Lactation
Streptomycina,b Risk of deafness minimal too small but risk estimated by limited data Excreted in small amounts into breast milk
Amikacina,b There are very limited data and concern for risk of ototoxicity and nephrotoxicity. This may be used in serious infections if benefit outweighs the risk. Due to pregnancy-induced physiologic changes such as volume of distribution and increased renal clearance, some pharmacokinetic parameters may be altered. It is excreted into breast milk in trace amounts but not absorbed when taken orally. Drug is not reviewed by AAP.
Capreomycinc,d It is shown to be teratogenic in some animal studies. No human safety data are available. Excretion in breast milk is unknown.
Clofaziminea,b Unlikely to result in a substantial risk of teratogenicity; small risk cannot be excluded. Limited data are available. Levels in milk are moderate to high. Reddish discoloration of milk and infant may occur. Effect on nursing infant is unknown.
Cycloserinea,b No safety data available Considered compatible by AAP
Dapsoneb,c Per the manufacturer, it is not shown to have an increased risk of congenital anomalies when given during all trimesters of pregnancy. Several reports have described adverse effects in the newborn after in utero exposure, including neonatal hemolytic disease, methemoglobinemia, and hyperbilirubinemia. Teratogenicity data are limited; a small risk cannot be excluded but a high risk is unlikely. It is excreted in breast milk and can be detected in the serum of nursing infants. Hemolytic anemia has been reported in a breastfed infant. Breastfeeding is not recommended by the manufacturer due to the potential for carcinogenicity observed in animal studies and the potential for hemolysis in the neonate, especially if there is a family history of G6PD deficiency. WHO considers the drug unsafe, but AAP considers it compatible with breastfeeding.
Ethionamidea,c Teratogenic effects were observed in animal studies. Some human case reports of central nervous system defects after in-utero exposure exist; causality has not been established. Data are limited. Excretion in breast milk is unknown.
Para-Aminosalicylic Acidb,d Very limited data; risk undetermined Insufficient data to make a recommendation per WHO
Fluoroquinolonesa,b Safety in pregnancy has not been established for any of the quinolones, but studies of babies born to women exposed to norfloxacin or ciprofloxacin during the first trimester have not identified any increased teratogenic risk. In one prospective case-control study comparing 200 women exposed to fluoroquinolones and 200 women exposed to known nonembryotoxic antibiotics, there were no differences in birth defects, spontaneous abortions, prematurity, or fetal distress but a higher rate of therapeutic abortions, suggesting that concerns about teratogenic risks may exceed the actual risks. Animal studies show that fluoroquinolones are toxic to developing cartilage. Small doses are found in breast milk with some reports of uniformly stained greenish teeth in breastfed, exposed infants. Clinical significance of exposure is unclear. However, AAP considers the drug compatible with breastfeeding.
Other Agents    
Pyridoxinea,b Available evidence suggests safe use during pregnancy Pyridoxine is secreted in milk in direct proportion to the maternal intake and concentrations in milk vary in reported studies. Pyridoxine is a normal component of a diet. Inhibition of lactation at doses >600 mg/day are possible when taken immediately postpartum.66
Dexamethasonea,c Adverse events have been observed with corticosteroids in animal reproduction studies. Dexamethasone crosses the placenta and is partially metabolized to an inactive metabolite by placental enzymes. Due to its positive effect on stimulating fetal lung maturation, the injection is often used in patients with premature labor (24 to 34 weeks’ gestation). Some studies have shown an association between first trimester systemic corticosteroid use and oral clefts and possibly growth retardation. Excretion in breast milk is unknown, possibly low.

a. Crosses the placenta
b. Excreted in breast milk
c. Data about excretion in breast milk not available
d. Data about crossing the placenta not available

Micromedex Mitromedex Getaway.
http://www.thomsonhc.com/micromedex2/librarian Accessed February 21, 2013; Hale Publishing, LP. Medications and Mothers’ Milk.
http://www.medsmilk.com/menu.html Accessed February 21, 2013; American Academy of Pediatrics: Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human breast milk. Pediatrics. 108;776-789: 2001.


Available safety data of second-line drugs are summarized in Table 3. There are published case reports in which pregnant women with MDR-TB have been safely treated with second-line drugs.39-42 However, these small numbers certainly do not establish drug safety.

In summary, treatment of active TB should not be delayed in pregnant women. Three of the four first-line agents are not known to be teratogenic. Second-line agents are not well-studied in pregnancy; nonetheless, treatment of MDR-TB during pregnancy should not be postponed.

Risk to the Fetus—Breastfeeding, Rates of Fetal Transmission, and Mortality

Active TB can be transmitted to the infant is several ways. Hematogenous spread of the tubercle bacilli can infect the placenta, which can lead to dissemination of disease through the umbilical vein. Aspiration of infected amniotic fluid or TB endometritis can cause congenital infection. Postnatal infection can also occur; distinction of postnatal infection from congenital TB may be difficult.

Neonates born to women with active pulmonary TB are significantly more likely to be of low birth weight and at a greater risk of being born premature and being small for date.43,44 Infants born to infected mothers should immediately be evaluated for signs of disease. Actively infected newborns may have an abnormal chest radiograph at birth, respiratory distress, fever, poor feeding, hepatosplenomegaly, or lethargy. If there is evidence of active infection, TB treatment should be promptly initiated. The infant should be separated from the mother if she is actively infectious. If the newborn does not display signs of active infection and an initial chest radiograph is normal, INH treatment with pyridoxine supplementation should be initiated and TST should be done at birth and at 3-month intervals. When neonatal TB is suspected, a work-up should be done that includes placental histologic and microbiologic examination, HIV testing, chest radiograph, and a lumbar puncture.45 A TST is rarely positive at birth but if it is greater than 5 mm at any 3-month serial follow-up, a thorough investigation for pulmonary and extrapulmonary TB should be pursued. If active disease is found, then two additional medications should be added to the INH regimen.46 In contrast, if the TST is negative at 6 months of age, the mother’s sputum smear is negative, and no symptoms of infection are present, then INH can be stopped in the infant. If the TST is positive at 6 months but a thorough evaluation for active TB is negative, then INH should be continued for a total of 9 months.47

Mothers who are not actively infectious with negative sputum smears should not be discouraged from breastfeeding their infant. The TB pathogen is not found in breast milk except in rare cases of TB mastitis. The only word of caution regarding breastfeeding is that anti-TB drugs are secreted in human breast milk at low concentrations but are not enough to treat the newborn. If the infant is also receiving treatment, there is a potential for increased toxicity from the additional, albeit small, amount of medication received in feedings.

TB of the Genital Tract and Infertility, Emerging Issues With In Vitro Fertilization

Female genital tuberculosis (FGTB) is thought to be an uncommon type of extrapulmonary TB that can lead to infertility. It is difficult to ascertain the incidence of this type of TB in the general population because it requires knowledge and high suspicion on the part of the practitioner. Even then it is difficult to accurately diagnose. Among women presenting to infertility clinics in the United States, less than 1% were recorded as having FGTB.48,49 In contrast, the incidence among women presenting to infertility clinics in Nigeria, South Africa, and India is upwards of 10%.50,51

FGTB is usually a secondary complication of a primary TB infection located at a site other than the genital system. It is estimated that around 10% of women with pulmonary TB also have coexisting FGTB, although it usually remains silent. After initial infection at the primary site, mycobacteria spread hematogenously or lymphatically and initially invade the fallopian tubes. From this site, the bacteria spread to the endometrium, ovaries, and rarely the cervix and vagina. In women with abdominal TB, spread to the genital system can occur by direct contact. Rarely, FGTB can spread by sexual contact.52

Women presenting to infertility clinics with risk factors for TB should undergo diagnostic evaluation including chest radiography, TST or IGRA, and evaluation of the gynecologic tract. While a positive AFB culture from the genital tract is considered the gold standard in diagnosing FGTB, demonstration of granulomas by histopathology is also strongly suggestive of FGTB and considered adequate for its diagnosis. With the recent availability of TB PCR assays,16 recovering DNA specimens from multiple sites during gynecologic endoscopy is considered strongly suggestive of the diagnosis.53

AFB are seldom recovered from endometrial biopsies, menstrual fluid, or vaginal/cervical brushings. Hysterosalpingogram (HSG) adds valuable information in the investigation of FGTB. Findings raising suspicion for the disease include: calcifications in the adnexal areas, obstruction of the fallopian tube in the zone of transition between the isthmus and the ampulla, beading of the fallopian tubes, and endometrial adhesions and/or obliteration of the endometrial cavity.54

If the HSG is abnormal, diagnosis requires endoscopic evaluation (laparoscopy-hysteroscopy),55 which may reveal tubercles on the peritoneum; tubo-ovarian masses; pelvic adhesions; and various fallopian tube abnormalities, including hydrosalpinx, pyosalpinx, beaded tubes, and loss of patency.50 In chronic disease, there may be obliteration of the uterine cavity from adhesions and shrunken, blocked fallopian tubes that may be fixed to the ovaries. Biopsies for histopathology, AFB culture, and PCR assays should be obtained from multiple sites.

If a diagnosis of FGTB is made, treatment should be promptly initiated. In many cases, despite effective treatment, infertility is irreversible because the disease is usually caught in late stage. Even if pregnancy occurs, large numbers of them are ectopic. If the uterine cavity is patent, in vitro fertilization (IVF) is considered safe after TB treatment.56

With the widespread availability and popularity of IVF, many women with infertility due to unrecognized FGTB are undergoing egg retrieval and embryo implantation.57 As a result, there have been multiple case reports in the literature of TB reactivation after IVF procedures.58 Presumably, harvesting ova can lead to disruption and dissemination of TB tubercles from the genital tract. Hematogenous spread of these tubercles has led to cases of military TB after IVF procedures.59 There have also been cases of TB ovarian abscesses and congenital TB due to reactivation of disease after IVF.

Treatment of TB With HIV Coinfection

Coinfection with TB and HIV is a major cause of maternal and fetal morbidity and mortality in high HIV-prevalent settings. Treatment of active TB infection and HIV can lead to improved maternal-fetal outcomes but may be associated with immune reconstitution syndrome, drug-drug interactions, noncompliance because of multiple medications, and overlapping toxicities.

As discussed earlier, women with HIV and LTBI infection during pregnancy should receive INH immediately and not delay treatment until the postpartum period. A physician experienced in treating coinfection and the medication interactions that can occur should evaluate women who have active TB and HIV coinfection during pregnancy. The WHO recommendation for treatment of TB in pregnant women with HIV is to treat for a minimum course of 9 months instead of 6 months. Both the WHO and CDC recommend an initial four-drug regimen including PZA.29,60 Antiretroviral therapy (ART) is initiated in the first trimester if needed for maternal well-being but can be delayed to the second trimester if necessary only for perinatal transmission prevention; they should not be delayed beyond 28 weeks of gestation.61 Treating clinicians need to be aware of drug-drug interaction in pregnant women treated with antituberculous and ART.

While women with smear negative TB are encouraged to breastfeed, this is not the case with TB and HIV coinfection, where women should be encouraged to exclusively formula feed since HIV can be transmitted through breast milk.

Conclusion

Great strides have been made in the understanding and treatment of TB in pregnant women. In the early 19th century, immediate marriage and pregnancy were recommended for women with “consumption,” or active TB, because the gravid uterus was believed to apply pressure to the lungs and compress TB cavities. This view drastically changed in the mid-19th century and therapeutic abortion was recommended for pregnant women with active TB because pregnancy was felt to have a harmful effect on the infection.19 Fortunately, the health-care community now recognizes that pregnancy probably neither increases nor decreases a woman’s risk of developing TB, although a recent study suggests a higher incidence of TB in the postpartum period.62 Active TB requires immediate treatment regardless of pregnancy. Currently, treatment of LTBI in pregnancy is dictated by whether the woman falls into a high-risk category of disease reactivation.

Since Robert Koch first saw the TB bacilli under a microscope, numerous antibiotics to kill or delay growth of this bacterium have been developed; unfortunately, dangerous drug resistance has also developed. While current experience does not show evidence of teratogenicity or fetal harm with the use of first-line agents during pregnancy, use of second-line agents during the peripartum period is largely unchartered territory and requires further understanding and research. Certainly, the HIV epidemic and the interaction between the two infectious diseases is also an important area of study.

New diagnostic modalities such as TB-PCR, rapid drug resistance testing, and IGRAs have been some of the major strides made in the battle against this vicious disease process, although the latter requires further testing in the pregnant population.

Along with improvement in diagnostic testing, medical advancement has also allowed women with previous FGTB a chance at conception with the advent of IVF. This procedure appears to be safe with the caveat that it is pursued after appropriate treatment of the disease because there is emerging evidence that egg retrieval and embryo implantation may lead to reactivation and, at times, hematogenous dissemination of disease.


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