Question:

Dear Sir/Madam,

I am writing to you due to a serious problem that I have just recently learned about. I am a 25-year-old student of medicine and in mid-September I discovered that I had fallen ill of tuberculosis. I immediately started treatment with the combination of isoniazid, rifampicin, pyrazinamid and ethambutol. As of today I have been taking this combination for 6 weeks.

Unfortunately, I have also just found out that I am 15-days pregnant. I can provide a date so accurate because I have a very good feel over my own body and I am 100% sure about the exact moment of ovulation and implantation even. Normally I would continue treatment with pyrazinamid for 2 more weeks but at the moment I learned about the pregnancy (4 days ago = 11th day of pregnancy) I decided to exclude it from the combination.

I have read information about the medicines included in the combination ad found out the following:

ethambutol —> OK. pyrazinamid —> Not known. No data on humans. No tests on animals had been conducted. Advised against in pregnancy. isoniazid —> Not proved as teratogenic in humans. Teratogenic indeed in rodents. Assumed OK. rifampicin —> Not proved as teratogenic in humans. Teratogenic indeed in rodents. Assumed OK.

Even letting alone the fact that both latter substances have been found teratogenic in rodents (treated with proportional doses to the ones used in humans) I have however found about cases when pregnant women treated with rifampicin had spontaneous abortions and gave birth to children with congenital malformations. [“In a preliminary report, nine malformations occurred among the children of 229 women exposed to the drug. (Three had defects of the central nervous system, and three had skeletal reduction defects.)” Author: Kenneth Hartigan-Go, M.D. Department of Pharmacology UP College of Medicine Manila, Philippines Tel: 63-2-5218251 Fax: 63-2-407168 Date: January 1990]

Therefore, I would like to ask you for any information (statistic or research data preferably) that could serve as evidence for or against the use of rifampicin/isoniazid/pyrazinamid in pregnant women due to their teratogenic effect on the human fetus. Should you posess no such data, I shall be truly grateful for any advice based on your experience with similar cases, particularly the results of such pregnancies and information about cases of congenital malformations (cleft palate, spina bifida) as well as malfunctions discovered post partum, in developing children.

May I just add that I would appreciate a prompt reply. Thank you for your time and consideration,

Yours sincerely,

Answer:

The use of any medications during pregnancy requires a careful consideration of the potential risks and benefits of the therapy. Tuberculosis is a serious bacterial infection. Patients receiving prompt and adequate treatment when the disease is discovered have a survival rate of around 90%, while those left untreated have mortality rates of up to 60%. The severity of disease when discovered and the resistance pattern of the bacteria to available agents will determine how aggressively a physician should treat the patient. The Sanford Guide to Antimicrobial Therapy recommends three-drug therapy with Isoniazid, rifampin and ethambutol for 9 month in pregnant patients. The Red Book 2000 Report of the American Academy of Pediatrics Committee on Infectious Disease recommends prompt initiation of therapy with a combination of isoniazid, rifampin and ethambutol for at least 6 months to protect both the mother and the developing fetus. A good source of information regarding the use of medicines during pregnancy is Drugs in Pregnancy and Lactation by Briggs, Freeman and Jaffe. This book should be available in any well-supplied medical school library. Monographs for the four drugs you mention are available in this text. With the exception of pyrizinamide, for which little information is available, the other three first tier medications for TB appear to be well tolerated with little evidence of significant teratogenic risk. The book provides further details. Pyrizinamide may need to be added to the three-drug regimen if evidence of bacterial persistence is present. Resistance patterns for mycobacterium tuberculum in your area may dictate changes to standard regimens. Both isoniazid and rifampin have been associated with an increased risk of bleeding in the newborn. To prevent this adverse effect, prophylactic use of Vitamin K1 (phytonadione) should be administered to the mother during labor. These are general recommendations for treatment of TB during pregnancy. TB treatment should be individualized to achieve the best results. Consult with your physician regarding your pregnancy and how this may affect your care.

 This response was prepared in part by Vadooda Hassam Pharm.D. candidate at the University of Toledo College of Pharmacy.

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