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