REVIEW ARTICLE

Tuberculosis and Pregnancy

G.C. Khilnani

Department of Medicine, All India Institute of Medical Sciences, New Delhi, India

ABSTRACT
As tuberculosis (TB) is prevalent all over the world and affects all ages, its management during
pregnancy and lactation is of special importance. It affects the health of both mother and the
infants. There are many constraints in the diagnosis of TB in pregnancy including hazards of
radiography. Treatment of tuberculosis requires a careful selection of drugs and avoiding agents,
which are unsafe during pregnancy. Untreated TB cases risk to both mother and infant. Most
of the antituberculosis drugs are secreted in breast milk but the concentrations are sub-
therapeutic. INH prophylaxis is a serious consideration for infants born to mothers with active
pulmonary TB. Congenital TB, although rare, is a definite entity and needs to be recognized.

Key words : Pregnancy, Tuberculosis, INH-prophylaxis.

[Indian J Chest Dis Allied Sci 2004; 46 : 105-111]

INTRODUCTION Limitations in the diagnosis of tuberculosis

during pregnancy, safety of antituberculosis
The diagnosis of tuberculosis (TB) in therapy and the need for prophylaxis must be in
pregnancy is of utmost importance to both the the knowledge of all the physicians giving care
mother and the fetus since untreated disease to pregnant women.
carries much greater risk to both. TB is a major
health problem all over the world. One third of
the world’s population and approximately 50% HISTORICAL OVERVIEW AND
of Indian adults are infected with Mycobacterium EXTENT OF THE PROBLEM
tuberculosis1,2. It is expected that the incidence of
tuberculosis among pregnant women would be TB in pregnant women has been a topic of
as high as in general population. Considering concern and controversy since the days of
the high prevalence of this disease in many Hippocrates 3 . Before the age of effective
developing countries including India, a large chemotherapy, the role of pregnancy in the
number of pregnant women can be expected to reactivation and progression of TB was
suffer from TB. The clinical and laboratory intensely debated. Till the beginning of the
diagnosis, and therapy during pregnancy and fourteenth century, increased abdominal
post partum period, deserve special attention. pressure in pregnancy was believed to help
Also untreated pulmonary tuberculosis in a close the tuberculous cavities and indeed a
pregnant women would be a definite risk for German physician recommended that young
transmission of disease to the new born. women with TB marry and become pregnant to
[Received October 29, 2002; accepted after revision : September 22, 2003]
Correspondence and reprints request: Dr G.C. Khilnani, Additional Professor, Department of Medicine, All India
Institute of Medical Sciences, New Delhi-110 029; Tele.: 91-11-26593488; Telefax: 91-11-26588663;
E-mail: <gckhil@hotmail.com>.
106 Tuberculosis and Pregnancy
slow the disease progression4. However, in 1850,
Grisolle demonstrated that TB worsened in
pregnancy 5 and until 1950’s many experts
recommended therapeutic abortion for women
with TB. In 1953, Hedvall, in a controlled study
found an equal number of women with
tuberculosis who benefited and those who
worsened during pregnancy6. Schaefer, in 1975,
demonstrated that the rate of progression of TB
was not significantly different in pregnant
women as compared to non-pregnant controls7.
By the middle of the twentieth century, there
was an increased concern regarding the
progression of TB in the post partum period. It
was thought that the descent of the diaphragm
after parturition leads to changes in the
intrathoracic pressure accompanied by
hormonal fluctuations, nutritional deprivation
and altered immunity leading to increased
susceptibility to pulmonary tuberculosis 8,9.
There are no national statistics available
regarding incidence of TB in pregnant women.
However, the same is judged by the prevalence
of tuberculosis in women of child bearing age in
the community. In studies conducted in two
urban hospitals in New York, the incidence of
TB in pregnant women was 12.4 cases per 105
births from 1985 to 1990 and 94.8 cases per 105
births from 1991-92 10. There are significant
ethnic differences in incidence of tuberculosis in
the United States. CDC Atlanta reported that the
incidence of TB was 5.2 times higher in non-
white (29.6/105 population) as compared to that
in American whites (5.7/105 population)11, 12. It
was also reported that the number of cases
among non-whites peaked between 25-34 years
of age which is important period of child
bearing age. No Indian data are available.
However, considering the high prevalence of
TB, it is expected that TB in pregnancy would be
at least as common as in the general population.
EFFECT OF TUBERCULOSIS ON
PREGNANCY AND CHILD BIRTH
With the advent of effective chemotherapy,
most studies have demonstrated that tuber-
culosis does not increase complications of
G.C. Khilnani
childbirth13, 14. There is no statistically significant
increase in congenital malformations in children
born to mothers with tuberculosis though
prematurity, fetal growth retardation, low birth
weight and increased perinatal mortality have
been commonly reported15. The clinical presen-
tation of tuberculosis in the pregnant women is
similar to that in the non-pregnant patients.
Cough, weight loss, fever, fatigue and hemop-
tysis are the usual features. Other features like
lethargy, abdominal distension, irritability and
skin lesions may also be seen16.
Extrapulmonary tuberculosis is also fairly
common and has been observed in 20% of
cases 17. Lymphadenitis is the most common
form of extrapulmonary tuberculosis reported
and has no adverse effect on the maternal and
fetal outcome. Other forms of extrapulmonary
tuberculosis such as intestinal, spinal, endome-
trial and meningeal tuberculosis are associated
with an increased frequency of maternal
disability, fetal growth retardation and infants
with low apgar scores 18. Patients co-infected
with HIV have a greater incidence of
extrapulmonary tuberculosis. Multi-drug
resistant tuberculosis (MDR-TB) should be as
common during pregnancy as in the non-
pregnant patients although this is not
documented. However, pregnant mothers with
MDR-TB have increased risk of neonatal
complications and the mother herself has more
advanced disease with more extensive
radiographic changes and longer sputum
conversion times.
CONGENITAL TUBERCULOSIS
Congenital tuberculosis is rare and less than
300 cases have been reported in literature19.
During pregnancy, TB may infect the placenta or
the female genital tract. The fetus may be
infected, either, hematogenously through the
umbilical vein and a primary focus develops in
the liver with involvement of the periportal
lymph nodes and the tubercle bacilli infect the
lung secondarily. Alternatively, the fetus may be
infected by aspiration or ingestion of amniotic
fluid that has been contaminated by hemato-
2004; Vol. 46 The Indian Journal of Chest Diseases & Allied Sciences
genous dissemination of tuberculosis through
placenta. At times, the fetus has multiple pri-
mary foci in the gut or the lungs20. The criteria of
diagnosis of congenital TB are21: Lesions in the
1st week of life, primary hepatic complex or
caseating hepatic granulomas, and tuberculous
infection of the placenta or the maternal genital
tract. Evaluation of the possibility of post-natal
transmission is also important.
Symptoms and signs of congenital
tuberculosis usually begin within the 2nd or 3rd
weeks of life and are often nonspecific.
Hepatosplenomegaly and respiratory distress
occur most often followed by fever and
lymphadenopathy. Abdominal distension,
lethargy, irritability, ear discharge and skin
lesions have also been reported21. Radiographic
abnormalities appear later. Tuberculin skin test
in usually negative initially and may become
positive within 4-6 weeks. Sputum is difficult to
obtain from infants. However, tubercular bacilli
are easily cultured from gastric aspirates 22.
Direct smears from the middle ear, bone marrow
and tracheal aspirates may also show acid-fast
bacilli (AFB). A maternal history of exposure to
tuberculosis is important for suspecting this
disease.
Mortality rate in congenital tuberculosis is
very high and approaches nearly 50 percent.
Delay in diagnosis contributes to high risk of
mortality20,23. Since congenital tuberculosis is
rare, no therapeutic trials have determined the
optimal treatment, however, several regimens
have been evaluated and published20,23-26. A six-
month course of isoniazid (INH), rifampicin(R),
pyrazinamide (PZA) and streptomycin for two
months and biweekly (R and H) for four months
has shown good results with a relapse of only
one percent and no deaths from the disease.
There are case reports of successful treatment
with INH, PZA and streptomycin; INH and
streptomycin; INH, rifampicin and
pyrazinamide 23, 27, 28
. Streptomycin (20-30 mg/kg
body weight/day) can be used safely in infants
but is contraindicated in pregnant women.
Accepted mode of treatment is INH (10-15 mg/
kg body weight/day), rifampicin (10-20 mg/kg
body weight/day) and pyrazinamide (15-30
mg/kg body weight/day) and either
107
streptomycin or ethambutol (15-25 mg/kg body
weight/day) for the first two months followed
by INH and rifampicin for 4-10 months21.
DIAGNOSIS OF TUBERCULOSIS IN
PREGNANT WOMEN
A careful history is mandatory in high-risk
cases in the antenatal period. History of
exposure and symptoms should be obtained
and in case of suspicion a tuberculin skin test
should be carried out. If tuberculin skin test is
greater than 10 mm of induration, a chest
radiograph should be obtained in a
symptomatic patient with proper abdominal
screening (shielding). In an asymptomatic
patient, the chest radiograph should be delayed
until the 12 th week of gestation. Routine
screening with radiography is not indicated
because of low yield and possible hazards.
There has been some debate in literature about
the sensitivity of tuberculin test during
pregnancy and earlier reports suggested that
tuberculin sensitivity might be diminished in
pregnancy 29. However, well controlled trials
have found no significant difference30. Tubercu-
lin test is deemed a safe and useful method for
screening tuberculosis infection in pregnancy
and should be used in women with symptoms
and signs of tuberculosis. Pregnant women with
diabetes or HIV, women employed in hospitals,
old age homes, prisoners and those belonging to
low socio-economic status are other candidates
for tuberculin test. Women who are infected
with HIV may have a diminished or negative
tuberculin reaction and therefore an area of
5 mm or greater induration in an HIV positive
patient is considered positive31.
TREATMENT OF PREGNANT WOMEN
WITH ACTIVE TUBERCULOSIS
The indications for treatment of active
tuberculosis in a pregnant women are the same
as for a non-pregnant women. Treatment should
be initiated without delay. Review of published
data reveals that INH is safe during pregnancy.
Although it crosses the placental barrier, it is not
108 Tuberculosis and Pregnancy
teratogenic even when administered in the first
trimester32. Only one percent incidence of abnor-
malities was reported in infants of mothers
treated with INH, which falls below the 1.2-6%
incidence of fetal malformations cited in the
population at large. The rate of congenital
malformations in infants who received
rifampicin was 3.35% in a study and included
limb reduction, CNS lesions and hemorrhagic
complications postulated to be due to inhibition
of DNA dependent RNA polymerase 32 .
However, the incidence falls within the safety
limits and hence rifampicin is also considered to
be safe. Ethambutol is the next commonly used
drug in pregnancy with an incidence of
malformations reported at two percent.
Although it was feared that ethambutol might
interfere with ophthalmological development,
this was not observed in doses of 15-25 mg/kg
body weight/day 32 . Pyrazinamide, the
bactericidal drug used in most first line
regimens, does not have sufficient studies to
ensure its safety during pregnancy. Although
some international organizations recommend its
use, it may be avoided due to inadequate data
on teratogenecity 31. Streptomycin has been
proved to be potentially teratogenic throughout
pregnancy causing fetal malformations and
eighth nerve paralysis with deficits ranging
from mild hearing loss to bilateral deafness.
Other aminoglycosides including kanamycin,
amikacin and capreomycin are also contrain-
dicated during pregnancy.
With the emergence of MDR-TB and HIV-
associated TB; pregnant women may sometimes
need to be treated with second line drugs, the
safety of which is unfortunately not well
established. Para-aminosalicylic acid (PAS) was
commonly used in conjunction with INH
during the 1950’s and 60’s and did not appear to
increase the malformations in infants but causes
gastrointestinal side effects, which were difficult
to tolerate during pregnancy. Little is known
about the safety of cycloserine, ethionamide or
fluoroquinolones like ciprofloxacin and
ofloxacin during pregnancy. There are no
existing guidelines for the treatment of pregnant
women with drug resistant tuberculosis and it
has been suggested that elective abortion may
G.C. Khilnani
be considered while treating a pregnant women
with MDR-TB33.
ERH is a safe regimen. Pyrazinamide should
be avoided and streptomycin should be
discontinued if the patient becomes pregnant.
There is no indication for therapeutic abortion
except if MDR-TB is established. A contact study
should be considered on case-to-case basis. In
the post partum period it is important to look
for drug induced hepatitis, which is common in
these patients.
TREATMENT OF TB IN LACTATING
WOMEN
The safety of breast-feeding is an important
issue. Several studies have measured the
concentration of ATT drugs in breast milk34-37.
INH concentration peaks three hours after
ingestion and reaches a concentration of 16.6
mg/l with a 300 mg dose 34. Rifampicin has a
peak milk concentration of 10-30 mg/l with a
600 mg dose 35 . No information on the
concentration of ethambutol in breast milk has
been published. Streptomycin reaches a
concentration of 1.3 mg/l thirty minutes after
injection of a 1 gm dose38. There is consensus
that breast-feeding should not be discouraged.
ATT drugs should be taken preferably after
breast-feeding and the next feed could be a
bottle-feed. Drug concentration in breast milk is
low and has no therapeutic value. If both the
mother and infant are taking INH, the drug may
reach supratherapeutic doses and in such
circumstances bottle-feeding is recommended.
Supplemental pyridoxine should be adminis-
tered to an infant on INH or if the breast-feeding
mother is taking INH because pyridoxine
deficiency may cause seizures in the newborn.
INH PROPHYLAXIS IN PREGNANT
WOMEN
Preventive therapy with INH is highly
effective and there is no teratogenic risk in
pregnant women treated with standard dosages
(Maximum dose 300 mg/day) for 6 to 12
2004; Vol. 46 The Indian Journal of Chest Diseases & Allied Sciences
months. However, there is a significant risk of
hepatotoxicity, which is more during the post-
partum period 38. In view of the same, all the
pregnant women to be put on INH prophylaxis
should have baseline liver function tests before
starting prophylactic therapy and the same
should be repeated every month and as and
when symptoms suggestive of hepatitis
develop. Pyridoxine should be given to these
women to decrease the risk of INH induced
neuropathy39.
It is recommended that in pregnant women
with positive tuberculin test, therapy with INH
should be delayed until after delivery if the
chest radiograph is normal. However, in certain
situations it is advisable to give INH prophy-
laxis during pregnancy. These include :
(a) Recent converters : If there is documented
tuberculin conversion within preceding two
years. This is based on the fact that chances
of a person with tuberculin conversion
developing active tuberculosis are maxi-
mum during the first two years.
(b) Close contacts of person with active tubercu-
losis.
(c) If the woman is immunocompromized (e.g.,
HIV seropositivity).
In the areas with high endemicity for
tuberculosis, the tuberculin positivity in general
population is high. For example, in India
approximately 50% of adult population is
tuberculin positive2. Therefore, in such areas a
tuberculin positivity should not be taken as
indication for INH prophylaxis. However, in the
event of a documented recent tuberculin conver-
sion and/or a recent exposure to close contact
with active tuberculosis and immunosu-
ppression would be indications for INH
prophylaxis. The usual dose of INH is 5 mg/kg
body weight with a maximum dose of 300 mg/
day.
INH PROPHYLAXIS FOR INFANT
BORN TO WOMEN WITH ACTIVE
TUBERCULOSIS
Tuberculin positive mother without active
109
tuberculosis dose not pose any risk to the
newborn. Also, if a pregnant woman with active
pulmonary tuberculosis is sputum negative
during the last three months of gestation, the
risk to infant is negligible there. However, if the
mother is not documented to be sputum
negative or if she is sputum positive, then the
infant needs evaluation for active tuberculosis
with chest radiograph and examination of
gastric aspirate or sputum for AFB. If there is no
evidence of active tuberculosis, the infant
should receive INH prophylaxis for three
months until after the mother’s sputum
becomes negative for AFB and the baby is
tuberculin negative. If the infant is tuberculin
positive then INH prophylaxis should be given
for a total period of six months after ruling out
active tuberculosis40. There is a recommendation
that if the mother is suffering from MDR–TB,
then INH prophylaxis has no role and hence
should not be given. In such cases, the infant
should receive BCG vaccination. BCG
vaccination has been shown to have a protective
effect 41-43 . BCG is contraindicated in HIV
positive children.
It is important to make an early diagnosis of
tuberculosis infection and disease in a pregnant
woman. Tuberculosis in pregnancy is as
common as in the non-pregnant women. Better
results are obtained in women known to have
tuberculosis before the onset of pregnancy and
who have been treated, as compared to untrea-
ted patients with active tuberculosis. The
poorest results have been shown to occur in
patients in whom tuberculosis is first discovered
in the puerperium, since it has been unsus-
pected and untreated during pregnancy and the
disease is generally well advanced. If tubercu-
losis is diagnosed and treated appropriately, the
prognosis for both mother and child is excellent.
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