Pregnancy and MDR-TB

1. Pregnancy and MDR-TB Session 7

2. Tuberculosis infection during pregnancy • TB disease occurs in a small but definite percentage of pregnant woman. • Relative immuno-compromise may allow latent infection to progress to active TB disease. • Pregnant women with active TB have a higher risk of complications (pre-eclampsia, vaginal hemorrhage and fetal loss).

3. Options for treatment of TB during pregnancy • Need to consider risks and benefits for the mother and fetus. • Option 1: Stop or delay MDR-TB treatment • Can be considered if TB disease is not an immediate threat to the health of the patient or if TB is diagnosed in the late stages of pregnancy. • Option 2: Terminate the pregnancy • May be considered in cases that require injectable agents for cure. • Option 3: Continue treatment while pregnant • Treatment is challenging but not contraindicated. • There is minimal data about the safety of second-line anti-tuberculous agents during pregnancy.

4. Pregnancy and MDR-TB Retrospective review of 3089 patients started on MDR-TB treatment from July 1996 to December 2005 in Peru: • 1033 (33.4%) of these patients were women of child‐bearing age (age, 15–45 years); • 38 (3.6%) were reported to be pregnant while receiving treatment for MDR‐TB; • 14 women experienced no changes in their treatment regimen during pregnancy; • MDR‐TB treatment was suspended after determination of pregnancy for 14 (36.8%) women; and • 13 women (34.2%) subsequently resumed treatment after discussion with a physician a median of 1.9 weeks (IQR, 1.0–4.6 weeks) after suspension of treatment. Palacios E, Dallman R, Muñoz M, et al. Drug-resistant tuberculosis and pregnancy: treatment outcomes of 38 cases in Lima, Peru. Clin Infect Dis 2009;48(10):1413-9.

5. Treatment outcomes Palacios E, Dallman R, Muñoz M, et al. Drug-resistant tuberculosis and pregnancy: treatment outcomes of 38 cases in Lima, Peru. Clin Infect Dis 2009;48(10):1413-9.

6. Children • Follow‐up data were available for 26/38 children. • 2 children were treated for latent TB (IPT per NTP protocol); • 1 child was treated successfully for active MDR-TB at 19 months of age based on the DST of the mother; • 1 child died of pneumonia shortly after birth (no TB involvement was reported); • 25 children are currently healthy, including those who were treated for latent or active TB; and • 2 children have minor health problems: • 1 child was born with testicular malformation (unlikely to be related to exposure to second-line TB drugs in utero; • 1 child has idiopathic growth retardation but has otherwise remained healthy. Palacios E, Dallman R, Muñoz M, et al. Drug-resistant tuberculosis and pregnancy: treatment outcomes of 38 cases in Lima, Peru. Clin Infect Dis 2009;48(10):1413-9.

7. Timing of Treatment Initiation • Ideally avoid treatment during the first trimester. • If the clinical state is severe enough to pose a threat to the life of the patient, consider treatment during the first trimester. • Start treatment during the second or third trimester so that the patient will be smear and culture negative at the time of giving birth.

8. Safety Classification of Medications During Pregnancy • A = safety established in human studies. • B = safety presumed based on animal studies. • C = safety uncertain; no human or animal studies reveal an adverse effect. • D = safety uncertain; evidence of risk but use is justified in certain circumstances.

9. Isoniazid • Safety class C • Experience with patients suggests safety • Pyridoxine (vitamin B6) should be used during pregnancy

10. Rifampicin • Safety class C • Experience with patients suggests safety

11. Ethambutol • Safety class B • Experience with pregnant patients suggests safety

12. Pyrazinamide • Safety class C • Formal studies are limited but there is much clinical experience

13. Streptomycin • Safety class D • Documented toxicity to the developing fetal ear (8-11%). Toxicity is higher in the first trimester. • Risks and benefits should be carefully considered. • Use should be limited to severe cases when clinical status and drug resistance warrants use.

14. Kanamycin, Amikacin • Safety class D • Documented fetal ototoxicity • With use of KM, 2.3% • Risks and benefits should be carefully considered.

15. Capreomycin • Safety class C • Less ototoxicity in adults compared with the aminoglycosides. • If the risk of morbidity or mortality from TB during pregnancy is high, it is preferable to use CM in place of an aminoglycoside.

16. Fluoroquinolones • Safety class C • No documented teratogenic effects in human studies. Mean duration given 2-4 weeks. • In 240 pregnant patients, no congenital effects observed. • Data regarding the prolonged use in pregnant patients is limited, but benefits likely outweigh risks.

17. Ethionamide • Safety class C • Animal studies (high doses); • 2 studies of 47 cases and 1 of 70 cases without adverse effects; • In another study, 7 of 23 children had congenital malformations. • The use is controversial given the mixed data; if an adequate regimen cannot be constructed without it, the use of ethionamide is justified. • Given its gastrointestinal side effects, nausea and vomiting during pregnancy may be aggravated.

18. Cycloserine • Safety class C • Few studies in pregnant patients • Animal studies do not document toxicity

19. PAS • Safety class C • No data to show teratogenicity

20. Breastfeeding • First-line medications have a variable concentration in breast milk. • Injectables not absorbed by infant (minimal possibility of toxicity for breastfeeding infant). • Effects of other medications during breastfeeding unknown. • Advise mother that breastfeeding is not prohibited but she should consider the risks and benefits of the decision.

21. Family Planning • Of 38 Peruvian women who received MDR-TB therapy while pregnant: • 3 patients (7.9%) were pregnant at the initiation of MDR‐TB therapy and had been pregnant for a median of 8.2 months (IQR, 7.3–8.2 months). • 35 patients (92.1%) became pregnant while receiving treatment; these patients became pregnant a median of 9.7 months (IQR, 4.4–17.0 months) after treatment initiation. Palacios E, Dallman R, Muñoz M, et al. Drug-resistant tuberculosis and pregnancy: treatment outcomes of 38 cases in Lima, Peru. Clin Infect Dis 2009;48(10):1413-9.

22. Recommendations • The best way to deal with MDR-TB and pregnancy is to prevent it. • All women of child-bearing age should be offered a reliable method of family planning by the health care worker providing MDR-TB treatment (integrated family planning). • A “reliable method” excludes abstinence and condoms. • Depo-Provera can be provided at 3 month intervals during the clinic visit.

23. Recommendations • Provide individualized care based on risks and benefits to the patient and fetus. • The patient should be involved in therapeutic decisions. • If pregnancy occurs during treatment and the patient is stable, treatment can be deferred until the second trimester unless there is clinical deterioration.

24. Recommendations • During the first 20 weeks of pregnancy, avoid the injectable if possible. • Exception: if the risk of morbidity or mortality is high, an injectable agent should be used (preferably CM). • There is limited evidence, but clinical experience has shown that cycloserine, fluoroquinolones, and PAS may be used in pregnant patients.

25. Recommendations • Ethionamide and prothionamide • Some cases of congenital fetal defects; • Not enough data to confirm the safety or risks of these medications. • Use pyridoxine (vitamin B6) in all pregnant patients. • Breastfeeding is permissible, however the risks and benefit should be discussed with the patient.