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 subtherapeutic. 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
The 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 many developing 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 tuberculosis during 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 Hippocrates 3 . Before the age of effective chemotherapy, 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

[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>.

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slow the disease progression4. However, in 1850, Grisolle demonstrated that TB worsened in pregnancy 5 and until 1950s 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 nonwhite (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.

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 presentation of tuberculosis in the pregnant women is similar to that in the non-pregnant patients. Cough, weight loss, fever, fatigue and hemoptysis 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, endometrial 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 nonpregnant 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-

EFFECT OF TUBERCULOSIS ON PREGNANCY AND CHILD BIRTH

With the advent of effective chemotherapy, most studies have demonstrated that tuberculosis does not increase complications of

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genous dissemination of tuberculosis through placenta. At times, the fetus has multiple primary 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 sixmonth 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 23, 27, 28 pyrazinamide . 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 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. Tuberculin 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 abnormalities 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 contraindicated during pregnancy. With the emergence of MDR-TB and HIVassociated 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 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 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 administered 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

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months. However, there is a significant risk of hepatotoxicity, which is more during the postpartum 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 prophylaxis 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 maximum during the first two years. (b) Close contacts of person with active tuberculosis. (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 conversion and/or a recent exposure to close contact with active tuberculosis and immunosuppression 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.

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 mothers 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 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 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 untreated 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 unsuspected and untreated during pregnancy and the disease is generally well advanced. If tuberculosis is diagnosed and treated appropriately, the prognosis for both mother and child is excellent.

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INH PROPHYLAXIS FOR INFANT BORN TO WOMEN WITH ACTIVE TUBERCULOSIS

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