Management of tuberculosis during pregnancy

Tuberculosis predominantly affects the younger population. Females in the child bearing age group have high risk of acquiring tuberculosis especially in endemic areas like south Asia and Africa. A known TB patient may become pregnant or tuberculosis may be acquired after the pregnancy status is known. Pregnancy does not increase the risk of acquiring tuberculosis. 

Symptoms
Can present with the usual symptoms like productive cough, fever, weight loss, hemoptysis
Can be asymptomatic or present atypically
Symptoms of TB fatigue, dyspnea etc can be confused and wrongly attributed to that of pregnancy
Failure to gain weight during pregnancy should alert the physician to consider tuberculosis as one of differential
High index of suspicion is needed to consider TB as one of the possibilities in pregnancy and initiate investigations.
In some cases mothers are diagnosed only after the neonate is diagnosed with tuberculosis.
Higher proportion of extrapulmonary TB can also occur in pregnancy

Diagnostic Investigations
Sputum – Smear for Acid Fast Bacilli (AFB) and AFB culture
Mantoux
Chest X ray with appropriate shield to protect the fetus (preferably after the first trimester).

Effect of untreated TB on pregnancy outcomes
Increased incidence of pre-eclampsia
Increased incidence of vaginal bleeding
Acute fetal distress
Early fetal death
Prematurity
Low birth weight
Small for date
Low APGAR score
Increased perinatal death
Increased maternal death especially if HIV co-infection is present
Transmission of tuberculosis to the neonate

Rationale for treatment during pregnancy
Untreated TB causes more serious complications to the mother and fetus than the ATT related adverse effects. Treatment is important to prevent transmission to fetus/infant and improves pregnancy outcomes.
TB may worsen in the mother if left untreated
TB may spread to her contacts

ATT and adverse effect in pregnancy

First line drugs
Isoniazid – Higher risk of hepatitis in pregnancy. The dose of pyridoxine may be increased to 50mg/day to avoid neurotoxicity in fetus and mother. Isoniazid is considered as relatively safe drug that has been used extensively in pregnancy. Can cause neonatal seizures if pyridoxine is not given. 
Rifampicin – Can be used safely in pregnancy.
Ethambutol – Animal studies showed teratogenicity. Has been used in pregnancy and so far no fetal organ malformations have been reported. Can cause retrobulbar neuritis if used after birth in neonate
Pyrazinamide – Animals studies are limited. If pyrazinamide is used the ATT regimen is for 6 months. If it is not used the treatment needs to be continued for 9 months. Widely used in pregnancy and so far no significant adverse effect noted. 
Streptomycin – Should not be used in pregnancy as it causes vestibular damage in fetus. Children born to mothers treated with streptomycin have hearing impairment and deafness.

Second line drugs
The information regarding the adverse effects of second line drugs in pregnancy is limited.
Amikacin, Kanamycin and Capreomycin - have the theoretical adverse effect of ototoxicity similar to streptomycin.
Ethionamide - known to be teratogenic and can also cause premature labour
Aminoglycosides - cause both nephrotoxicity and ototoxicity
Quinolones cause developmental anomalies of bones
Rifabutin - known to cause congenital defects in animal studies
Rifapentine - can cause bleeding in pregnancy
Limited data is available for cycloserine, PAS, thiacetazone, clofazimine, clarithromycin
Clarithromycin is associated with adverse fetal outcomes
Clofazimine can result in bronze discoloration of infant skin.

Treatment

Active Tuberculosis
The treatment is similar to the non-pregnant state except streptomycin should not be used. Treatment should be commenced as soon as the diagnosis if made to reduce the perinatal complications related to TB. Isoniazid, Rifampicin, ethambutol and pyrazinamide have been used widely and does not cause significant adverse complications in pregnancy related outcomes. Since the risk of pyrazinamide is unknown, some suggest a regimen of Isoniazid, Rifampicin, ethambutol for 2 months followed by 7 months of isoniazid and rifampicin. Pyrazinamide if used is helpful in rapid sputum conversion.  

Latent Tuberculosis
Latent tuberculosis during pregnancy can be treated with isoniazid. Since the risk of hepatitis due to isoniazid is increased during pregnancy, some experts suggest that treatment for latent TB can be withheld till the pregnancy is over and then treatment can begin. The usefulness of treating latent TB in high endemic countries is not clear. But if the mother is co-infected with HIV infection, the risk of latent TB becoming active TB is high and it such instances the latent TB should be treated.

MDR-TB
Multi drug resistance is resistance to the first line drugs Rifampicin and Isoniazid. MDR-TB is difficult to treat in pregnancy as many of the second line drugs are less effective but more toxic. Individualized treatment regimens (ITR) are used for patient with MDR-TB. Information regarding the teratogenicity of these drugs is not fully studied. But several case reports have suggested successful treatment for MDR-TB during pregnancy. All MDR-TB patients of child bearing age should be counseled regarding possible adverse effects of second line drugs on fetus and if possible to plan pregnancy after the completion of therapy. Some experts suggest delaying the treatment till the second trimester as the maximum risk of teratogenicity occurs in the first trimester. Although withholding the treatment in the first trimester resulted in less toxic exposure, higher rates of TB related complications were noted.

TB with HIV in pregnant women
All pregnant females with TB should be screened for HIV and vice versa. Active tuberculosis may result in placental inflammation and can facilitate the intrauterine transmission of HIV from the mother to child. Hence increased mother to child transmission of HIV is noted if the mother is suffering from active tuberculosis. HIV positive pregnant female with tuberculosis depending on the clinical situation should be treated with both ATT and HAART. But combining both regimens is complex and possibly lead to drug-drug interactions and increased toxicities. Rifampicin interacts with protease inhibitors and the drug levels can decrease to ineffective range. But HAART is essential to reduce the vertical transmission of HIV. Individualized treatement should be formulated based on the clinical situation of the patient.  Pyrazinamide should be used as it benefits outweigh unknown adverse effects in HIV positive pregnant women.

Treatment of neonate
Neonatal tuberculosis is difficult to diagnose. The neonate can acquire TB through trans-placental route, aspiration or ingestion of amniotic fluid/cervicovaginal secretions. Transmission can also occur during breast feeding, from a common household contact eg. Father and airborne transmission from mother in postnatal period. The child should be examined for perinatal tuberculosis. Investigations done are gastric aspirate, nasopharngeal aspirate for smear and culture of AFB. The infant disease is predominantly smear negative but culture positive. Chest radiography should be taken. Other specimens like lymph node biopsy, urine, tracheal aspirate can also be used. The placenta can also be examined for tuberculous lesions. Mantoux is not useful due to immunological immaturity. The utility of newer tests based on interferon gamma release assays have not be fully studied for use in neonatal population. If the mother has active tuberculosis, then the infant should be given isoniazid prophylaxis (5 mg/kg) with pyridoxine supplementation for 6 months or isoniazid plus rifampicin for 3 months. If TB is detected, multi drug regimen of ATT should be given. Ethambutol should be avoided in infants as it may cause retrobulbar neuritis. BCG vaccination should be given to the infant as it protects against disseminated TB and TB meningitis. The infant should be monitored for a period of 1 to 2 years with repeat TST and chest x ray if needed. 

Breast feeding
Ideally the mother and the neonate should be separated till the sputum conversion but it is not practically feasible in developing countries. Hence breast feeding can be continued, the only contraindication being tuberculous breast abscess. The ATT drug levels are lower in the breast milk and do not harm the infant.

Compliance to therapy
Non-compliance to medications can be high in pregnancy due to parental concerns about adverse effects of drugs on the fetus, toxicity and side effects like nausea. The patient should be counselled and involved in decision to treat and explained the rationale for drug treatment during pregnancy.

Infertility
Improved fertility outcome are seen in women with genital tuberculosis when treated with the anti-TB drugs.

Rifampicin and Contraception
The rifampicin can interact with the oral contraceptive medication and make them ineffective. Hence patients on rifampicin should be advised alternative methods of contraception.

References

http://www.ncbi.nlm.nih.gov/pubmed/12684912
http://www.ncbi.nlm.nih.gov/pubmed/14998501
http://www.ncbi.nlm.nih.gov/pubmed/18823726
http://www.ncbi.nlm.nih.gov/pubmed/17414128