Tuberkulosis and Pregnancy

8/12/2019 Tuberkulosis and Pregnancy

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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]

[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: .

INTRODUCTIONThe diagnosis of tuberculosis (TB) in

pregnancy is of utmost importance to both the

mother and the fetus since untreated disease

carries much greater risk to both. TB is a major

health problem all over the world. One third of

the worlds population and approximately 50%

of Indian adults are infected with Mycobacterium

tuberculosis1,2. It is expected that the incidence of

tuberculosis among pregnant women would be

as high as in general population. Considering

the high prevalence of this disease in manydeveloping countries including India, a large

number of pregnant women can be expected to

suffer from TB. The clinical and laboratory

diagnosis, and therapy during pregnancy and

post partum period, deserve special attention.

Also untreated pulmonary tuberculosis in a

pregnant women would be a definite risk for

transmission of disease to the new born.

Limitations in the diagnosis of tuberculosisduring pregnancy, safety of antituberculosis

therapy and the need for prophylaxis must be in

the knowledge of all the physicians giving care

to pregnant women.

HISTORICAL OVERVIEW AND

EXTENT OF THE PROBLEM

TB in pregnant women has been a topic of

concern and controversy since the days of

Hippocrates3. Before the age of effectivechemotherapy, the role of pregnancy in the

reactivation and progression of TB was

intensely debated. Till the beginning of the

fourteenth century, increased abdominal

pressure in pregnancy was believed to help

close the tuberculous cavities and indeed a

German physician recommended that young

women with TB marry and become pregnant to


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Tuberculosis and Pregnancy G.C. Khilnani 106

slow the disease progression4. However, in 1850,

Grisolle demonstrated that TB worsened in

pregnancy5and until 1950s many experts

recommended therapeutic abortion for women

with TB. In 1953, Hedvall, in a controlled studyfound 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 theintrathoracic pressure accompanied by

hormonal fluctuations, nutritional deprivation

and altered immunity leading to increased

susceptibility to pulmonary tuberculosis8,9.

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 1991-9210. 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

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 havebeen 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

cases17. 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 scores18. 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-


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2004; Vol. 46 The Indian Journal of Chest Diseases & Allied Sciences 107

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 orcaseating 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 2ndor 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 aspirates22.

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

pyrazinamide23, 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

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 abdominalscreening (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

pregnancy29. 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


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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 thepopulation 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 polymerase32.

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/day32. 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 teratogenecity31. Streptomycin has been

proved to be potentially teratogenic throughoutpregnancy 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) wascommonly used in conjunction with INH

during the 1950s and 60s 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

be considered while treating a pregnant women

with MDR-TB33.

ERH is a safe regimen. Pyrazinamide should

be avoided and streptomycin should bediscontinued 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 dose34. Rifampicin has a

peak milk concentration of 10-30 mg/l with a

600 mg dose35. No information on the

concentration of ethambutol in breast milk has

been published. Streptomycin reaches a

concentration of 1.3 mg/l thirty minutes afterinjection 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-feedingmother 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


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months. However, there is a significant risk of

hepatotoxicity, which is more during the post-

partum period38. In view of the same, all the

pregnant women to be put on INH prophylaxis

should have baseline liver function tests beforestarting 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 contactwith 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

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 themother 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 mothers sputum

becomes negative for AFB and the baby is

tuberculin negative. If the infant is tuberculin

positive then INH prophylaxis should be givenfor a total period of six months after ruling out

active tuberculosis40. There is a recommendation

that if the mother is suffering from MDRTB,

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

effect41-43. BCG is contraindicated in HIV

positive children.

It is important to make an early diagnosis of

tuberculosis infection and disease in a pregnantwoman. 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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Tuberkulosis and Pregnancy