How to manage Anti-Tuberculosis Therapy (ATT)-induced liver injury in pregnancy?

Management of ATT-Induced Liver Injury in Pregnancy

Immediate Action

Stop all hepatotoxic anti-tuberculosis drugs immediately and initiate a non-hepatotoxic regimen consisting of streptomycin and ethambutol until liver function normalizes. 1

• Discontinue isoniazid, rifampin, and pyrazinamide as soon as drug-induced liver injury (DILI) is identified 1
• Start streptomycin and ethambutol (15-20 mg/kg daily) as bridging therapy while awaiting normalization of liver enzymes 1
• Critical caveat: Streptomycin carries risk of congenital deafness (approximately 1 in 6 exposed infants) and should be avoided if possible, but the immediate threat of untreated tuberculosis to both mother and fetus may justify short-term use until drug reintroduction can begin 2, 3

Monitoring During Acute Phase

• Monitor liver function tests (ALT, AST, bilirubin) at least twice weekly during the acute injury phase 1
• Continue monitoring until ALT normalizes to less than 3 times the upper limit of normal 4
• Assess for signs of fulminant hepatic failure: encephalopathy, coagulopathy, rapidly rising bilirubin 5
• If fulminant hepatic failure develops, immediate transfer to a transplant center is required, as artificial liver support systems may serve only as a bridge to transplantation 5

Sequential Drug Reintroduction Protocol

Once liver enzymes normalize, reintroduce anti-tuberculosis drugs sequentially, starting with isoniazid first:

Step 1: Isoniazid Reintroduction

• Begin isoniazid at 50 mg/day 1
• Increase to full dose (300 mg/day) after 2-3 days if no reaction occurs 1
• Add pyridoxine 25 mg/day for all pregnant women taking isoniazid to prevent neuropathy 2
• Monitor ALT weekly for the first 2 weeks, then every 2 weeks for 2 months 1

Step 2: Rifampin Reintroduction

• Add rifampin only after 2-3 days of full-dose isoniazid without adverse reaction 1
• Start at 75 mg/day, increase to 300 mg after 2-3 days 1
• Further increase to 450 mg (if <50 kg) or 600 mg (if >50 kg) after another 2-3 days 1
• Continue weekly ALT monitoring 1

Step 3: Pyrazinamide Consideration

• Pyrazinamide should generally be avoided in pregnancy after DILI 1
• If absolutely necessary, start at 250 mg/day, increase to 1.0 g after 2-3 days, then to 1.5 g (<50 kg) or 2.0 g (>50 kg) 1
• However, given the hepatotoxic profile and pregnancy status, alternative regimens without pyrazinamide are strongly preferred 2

Alternative Treatment Regimens After DILI

If pyrazinamide cannot be tolerated (most common scenario after DILI in pregnancy):

• Use isoniazid, rifampin, and ethambutol for 2 months, followed by isoniazid and rifampin for 7 months (total 9 months) 2, 1

If isoniazid cannot be tolerated:

• Use rifampin, ethambutol, and a fluoroquinolone for 12 months 1
• Note: Fluoroquinolones have limited safety data in pregnancy but may be necessary for drug-resistant tuberculosis 3

If rifampin cannot be tolerated:

• This represents a more challenging scenario requiring expert consultation
• Consider isoniazid and ethambutol with extended duration, though efficacy is reduced 2

Criteria for Stopping Reintroduction

Halt drug reintroduction and revert to non-hepatotoxic regimen if:

• ALT rises to >3 times upper limit of normal with hepatitis symptoms (nausea, vomiting, abdominal pain, jaundice) 4
• ALT rises to >5 times upper limit of normal even without symptoms 4
• Any signs of hepatic decompensation develop 4

Special Pregnancy Considerations

• Pregnancy itself increases risk of isoniazid hepatotoxicity, particularly in the postpartum period 6, 7
• Recent data suggest pregnancy-related DILI is more severe than in non-pregnant women of childbearing age 7
• The U.S. Drug-Induced Liver Injury Network recommends deferring isoniazid for latent tuberculosis to the postpartum period whenever feasible 7
• However, active tuberculosis must be treated during pregnancy as untreated disease poses greater risk to mother and fetus than the medications 2, 3

Obstetric Monitoring

• Perform fetal ultrasound surveillance throughout treatment, as case reports document potential fetal complications including ventriculomegaly in severe maternal DILI cases 5
• Monitor for preterm labor, as tuberculosis and its treatment are associated with increased preterm birth risk 3
• Coordinate care with maternal-fetal medicine specialists 5

Critical Pitfalls to Avoid

• Never continue hepatotoxic drugs once DILI is identified, even if tuberculosis is severe—switch to non-hepatotoxic regimen immediately 1
• Do not reintroduce multiple drugs simultaneously—sequential reintroduction is essential to identify the causative agent 1
• Do not use streptomycin beyond the acute bridging period due to ototoxicity risk to the fetus 2, 3
• Avoid pyrazinamide reintroduction in pregnancy after DILI unless absolutely no alternative exists, as it is the most hepatotoxic first-line agent and has limited teratogenicity data 2
• Do not delay treatment of active tuberculosis due to pregnancy—untreated tuberculosis carries higher maternal and fetal mortality than the medications 2, 3