Queensland Tuberculosis Control Centre

GUIDELINES FOR TREATMENT OF TUBERCULOSIS IN PREGNANCY

The decision to treat tuberculosis in pregnancy must take into account the potential risks to mother and foetus from medication, and the benefits to mother, foetus and community of adequate treatment. It is widely considered that the benefits of treating tuberculosis in pregnancy outweigh any risk of treatment. Untreated tuberculosis represents a far greater hazard to a pregnant woman and her fetus than does treatment of the disease CDC (2003, 62)

INTERNATIONAL GUIDELINES
The British Thoracic Society (www.brit-thoracic.org.uk), International Union Against Tuberculosis and Lung Disease (www.iuatld.org) and the World Health Organisation (www.who.int) all support the use of standard first-line drug regimens in pregnant women with tuberculosis. The Centers for Disease Control (USA) (www.cdc.gov) does not specifically endorse the use of pyrazinamide in pregnancy, citing the absence of detailed teratogenicity data, but states that it can probably be used safely during pregnancy. An alternative 9(E)HR regimen is endorsed by the CDC.

EFFECTS OF TUBERCULOSIS ON PREGNANCY

Maternal tuberculosis has been associated with an increased risk of spontaneous abortion, perinatal mortality, small for gestational age and low birth weight in some studies. Outcome is unfavourably influenced by delays in diagnosis or treatment, along with disease other than that in lymph nodes (Ormerod, 2001). Congenital tuberculosis is a rare complication of in utero tuberculosis infection as a result of maternal haematogenous spread. Congenital tuberculosis is difficult to diagnose as it is seldom distinguishable from other neonatal or congenital infections. Symptoms usually arise in the second or third weeks' post-partum. Hepatosplenomegaly, respiratory distress and fever are common, and chest radiography is almost universally abnormal (Ormerod, 2001).

FIRST-LINE DRUGS
Isoniazid: (Pregnancy Category A). Recommended for use in pregnancy. As isoniazid may be associated with an increased risk of hepatotoxicity in pregnant women, symptoms should be assessed, and it is recommended by some that liver function tests be performed fortnightly during the first two months of treatment, and monthly thereafter (Bothamley, 2001). Isoniazid given for treatment of latent tuberculosis (chemoprophylaxis) is considered safe, and is recommended especially where the risk of developing disease is higher, such as with HIV coinfection or with a history of recent contact (Bothamley, 2001). Pyridoxine: Pyridoxine supplementation is recommended for all pregnant women taking isoniazid as deficiency is more likely in pregnant women than in the general population (CDC 2003, 62; Bothamley 2001). The Queensland Tuberculosis Control Centre recommends the routine use of pyridoxine in all patients taking isoniazid. Rifampicin: (Pregnancy Category C). Bleeding attributed to hypoprothrominaemia has been reported in infants and mothers following the use of rifampicin in late pregnancy. The use of rifampicin is indicated in pregnant women with tuberculosis, with the recommendation that vitamin K be given to both the mother and the infant postpartum if rifampicin is used in the last few weeks of pregnancy (Bothamley 2001). Ethambutol: (Pregnancy Category A). Recommended for use in pregnancy.
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Pyrazinamide: (Pregnancy Category n/a only available on SAS). There are no reports of foetal malformations attributable to pyrazinamide, although there are additionally no animal or epidemiological studies reported to support the safety of this drug in pregnancy. The absence of such safety data is the reason that the CDC (USA) guidelines do not endorse pyrazinamide in pregnancy. Its use is supported by other tuberculosis authorities, including the IUATLD and the BTS. To date, there are no reports of significant adverse events from the use of this drug in the treatment of TB in pregnant women despite the fact that the drug is used as part of the standard regimen in many countries. However, additionally, insufficient data are available about the number of pregnant women treated for TB in these many settings. If the treating doctor elects not to use pyrazinamide, a nine-month regimen containing isoniazid and rifampicin throughout (supplemented by ethambutol until drug susceptibility results are available) is recommended.

SECOND- LINE DRUGS

Streptomycin: (Pregnancy Category n/a only available on SAS). Streptomycin has a well established association with foetal ototoxicity and IS NOT RECOMMENDED for the treatment of tuberculosis in pregnant women. Fluoroquinolones: (Pregnancy Category B3 for Ciprofloxacin, Gatifloxacin, Moxifloxicin and Norfloxacin). There is no evidence of increased incidence of abnormalities in babies of mothers treated with fluoroquinolones. Animal studies of ciprofloxacin suggest that there is a risk of damage to articular cartilage and subsequent juvenile arthritis with short courses of treatment, and the possibility of joint damage with longer courses of treatment used for tuberculosis must be seriously considered (Bothamley, 2001). Fluoroquinolones should only be used in pregnant women with tuberculosis where the benefits of treatment are judged to outweigh the potential risks and the decision to use such drugs in this setting should only be made after discussion with clinicians experienced in the management of TB. Amoxycillin/Clavulanic Acid (pregnancy category B1). There is no evidence of teratogenicity in animal studies. Amoxycillin/clavulanic acid has been used in late pregnancy as prophylaxis in women with prolonged rupture of membranes without any problems documented, but there is limited experience with its use in the first trimester. There is only likely to be a minor role for amoxycillin/clavulanic acid in the treatment of pregnant women with MDR-TB where insufficient alternatives are available (Bothamley 2001). MDR-TB should only be treated after close consultation with clinicians experienced in the management of TB. Para-Aminosalicylic Acid (PAS) (Pregnancy Category n/a only available on SAS). There is insufficient animal and human safety data relating to the use of PAS in pregnancy. It has been associated with a slightly higher incidence of limb and ear abnormalities in one report involving 123 patients taking PAS with other anti-TB drugs (Bothamley, 2001). However, an increased risk of congenital defects has not been found in other studies. PAS should not be used to treat TB in pregnant women unless the benefit/risk ratio (after discussion with a clinician experienced in the management of difficult TB cases) is favourable. Amikacin (Pregnancy Category D). There is concern that all aminoglycosides are potentially nephrotoxic and ototoxic to the foetus and their use IS NOT RECOMMENDED in tuberculosis in pregnant women. Maternal drug levels do not appear to correlate with foetal safety (MIMS 2003). Use of aminoglycosides in pregnancy should only be as a last resort after due consideration of the risks and benefits (WHO 2003) and close discussion with experts in the clinical management of TB. Capreomycin (Pregnancy Category C). There is evidence of teratogenicity in studies where capreomycin was given to pregnant rats. Capreomycin is generally contraindicated in pregnancy and should only be used following consideration of its risks and benefits (MIMS 2003, WHO 2003) in consultation with an expert in the clinical management of TB. Ethionamide and Prothionamide (Pregnancy category n/a only available on SAS). These drugs have been shown to be teratogenic in animal studies and their use IS NOT RECOMMENDED in pregnancy (Ormerod 2001).
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Cycloserine (Pregnancy Category n/a only available on SAS). There is no evidence of teratogenicity in rats, but there is insufficient study in humans to confirm the safety of cycloserine in pregnancy. Its use should only be considered where the benefits outweigh the potential risks (MIMS 2003) after discussion with an expert in the clinical management of TB.

TREATMENT OF TUBERCULOSIS IN WOMEN WHO ARE BREASTFEEDING

There is general consensus that although small concentrations of anti-tuberculosis drugs are excreted in breast milk, treatment for tuberculosis is not a contraindication to breastfeeding. It is also important to note that the concentrations of TB drugs in breast milk are so low that they cannot be relied upon for treatment of the infant. If an infant requires treatment for active disease or primary prophylaxis, the weight-based guidelines for children should be followed in selecting a suitable treatment regimen. In general, mothers with fully drug susceptible pulmonary TB can continue breast feeding their infants providing the infant has been given appropriate antimycobacterial cover (isoniazid, if no evidence of disease in the infant, or full treatment if active TB disease cannot be excluded.) Explanation of Pregnancy Categories (MIMS 2003) Category
Category A

Explanation
Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed Drugs that have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals[1] have not shown evidence of an increased occurrence of foetal damage Drugs that have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals[1] are inadequate or may be lacking, but available data show no evidence of an increased occurrence of foetal damage Drugs that have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals[1] have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans Drugs that, owing to their pharmacological effects, have caused, or may be suspected of causing harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible Drugs that have caused, are suspected to have caused, or may be expected to cause an increased incidence of human foetal malformations, or irreversible damage. These drugs may also have adverse pharmacological effects Drugs that have such a high risk of causing permanent damage to the foetus that they should not be used in pregnancy, or when there is a possibility of pregnancy

Category B1

Category B2

Category B3

Category C

Category D

Category X

Note: For drugs in categories B1, B2 and B3, human data are lacking or inadequate and sub-categorisation is therefore based on available animal data. The allocation of a B category does not imply greater safety than the C category. Drugs in category D are not absolutely contraindicated in pregnancy (e.g. anticonvulsants). Moreover, in some cases the D category has been assigned on the basis of `suspicion'. Due to legal considerations in this country, sponsor companies have, in some cases, applied a more restrictive category than can be justified on the basis of available data. In some cases there may be discrepancies between the official product information appearing in MIMS Annual and the information in the Medicines in Pregnancy booklet due to the lead times involved in printing. [1] Animal studies submitted in support of new drug applications must conform to the Australian Guidelines for the Registration of Drugs - Volume 1, Prescription and other specified Drug Products, 2nd Edition.
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References: Bothamley G (2001) Drug Treatment for Tuberculosis during Pregnancy: Safety Considerations Drug Safety 24(7):553-65 British Thoracic Society (1998) Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998 Thorax 53:536-48 Centers for Disease Control (2003) Treatment of Tuberculosis MMWR 52(RR-11):1-77 Enarson DA, Rieder HL, Arnadottir T and Trbucq A (2000) Management of Tuberculosis: A Guide for Low Income Countries IUATLD, Paris 5th Ed. MIMS Online (2003) accessed electronically via http://ckn.health.qld.gov.au in January 2006. Ormerod P (2001) Tuberculosis in pregnancy and the puerperium Thorax 56:494-9 World Health Organisation (2003) Treatment of Tuberculosis: Guidelines for National Programs WHO, Geneva 3rd Ed

Queensland Tuberculosis Control Centre

26 June 2006