PENTAMIDINE

Drugs in Pregnancy and Lactation.

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Name: PENTAMIDINE
Class: Anti-infective
Risk Factor:    CM

Fetal Risk Summary

Pentamidine is an antiprotozoal agent indicated for the treatment of pneumonia caused by Pneumocystis carinii, a common opportunistic infection in patients suffering from human immunodeficiency virus (HIV) disease. The mechanism of action of this agent is not fully known. In vitro tests have indicated that pentamidine inhibits the synthesis of DNA, RNA, phospholipids, and proteins, and it may be a folic acid antagonist by inhibiting dihydrofolate reductase (1,2).

Pentamidine was not teratogenic in pregnant rats treated with doses similar to those used in humans (3). However, these doses were embryocidal when administered during embryogenesis (3). Significant placental transfer was observed in rats administered pentamidine in late pregnancy (4). By the 12th hour, fetal brain tissue concentrations of pentamidine were statistically similar to the maternal serum levels achieved 2 hours after the dose.

In an experiment using in vitro perfused human placentas, the placental transfer of pentamidine in humans was undetectable with therapeutic maternal concentrations of approximately 2 µg/mL (5). The level of sensitivity of the high-performance liquid chromatography method was 0.05 µg/mL. When peak concentrations of pentamidine on the maternal side were increased to approximately 14 µg/mL, fetal levels were consistently 0.2 µg/mL at 30 minutes. Pentamidine did concentrate in placental tissue at all drug levels studied, but the clinical significance of this to placental function is unknown (5).

In contrast to the above, a study published in 1995 used a more sensitive test to document the placental transfer of pentamidine at about 33 weeks' gestation (6). A 21-year-old HIV-infected woman received pentamidine, 200 mg (3.4 mg/kg) IV daily, for 7 days before a cesarean section. A maternal serum sample, drawn 8 hours after her seventh dose, was 0.0813 µg/mL (free base). The pentamidine concentration in the cord blood sample, obtained 16.5 hours after the dose, was 0.0132 µg/mL.

The U.S. Centers for Disease Control and Prevention (CDC) recommends aerosolized pentamidine as one of two treatment regimens for prophylaxis against P. carinii in persons infected with HIV (7,8). However, because the safety of this treatment has not been established in human pregnancies, the CDC advises against this use in pregnant women (7,8). Others have cited information from the manufacturer that the use of aerosolized pentamidine is contraindicated in pregnancy (9).

A 1988 Reference cited a concern that pregnant health care workers involved in the care of patients treated with aerosolized pentamidine might be at risk for fetal harm (10). An estimation of this risk, based on a pharmacokinetic model, was published in 1994 (11). The maximum exposure of health care workers, at two different hospitals, to aerosolized pentamidine was estimated to be 1.7 and 9.8 µg/kg/day (IV equivalent). The authors then calculated the embryolethal and teratogenic IV-equivalent Reference doses, based on pregnant rat data, to be 0.08 and 4 µg/kg/day, respectively. Comparison of the estimated actual exposures to the predicted toxic levels led to the conclusion that improvement was needed in the methods used to reduce pentamidine exposure of health care workers (11).

An argument favoring the use of pentamidine in the pregnant patient with active P. carinii pneumonia, when other treatment regimens had failed, was put forth in a 1987 article (12). Moreover, this same source, in a 1990 Reference, argued that the availability of aerosolized pentamidine for prophylaxis should be disclosed to the pregnant HIV-seropositive patient “as part of the informed consent process” (13). This latter position is strengthened by the in vitro data cited above relating to the placental transfer of the agent. Because aerosolized pentamidine results in very low systemic concentrations, fetal exposure to the drug by this route is probably minimal and below the level of detection.

The use of aerosolized and IV pentamidine during gestation in women with HIV infection has been described (14,15,16 and 17) . A 1992 abstract described the use of aerosolized pentamidine, 300 mg/month, in 15 women during the 2nd and 3rd trimesters (14). No significant effects on the course of pregnancy or on the fetus or newborn were observed. The second Reference reported five pregnancies (six fetuses, one set of twins) that were treated with aerosolized pentamidine, zidovudine, and other drugs (15). One woman was treated throughout her 39-week gestation, one from 10 to 39 weeks' gestation, and three during the 2nd and 3rd trimesters. The outcomes of the exposed pregnancies included one growth-retarded infant, one with albinism, one with congenital cytomegalovirus infection, and three normal infants. The latter two References described IV pentamidine in five women (16) and aerosolized drug in nine (16,17). No adverse fetal effects of the drug were reported.

Breast Feeding Summary

Because systemic concentrations achieved with aerosolized pentamidine are very low, breast milk levels of the drug after administration via this route are probably nil. However, no reports of lactating women administered pentamidine by any route (IM, IV, or by inhalation) have been located.

References

  1. Product information. Pentam. Lyphomed, Inc. 1991.
  2. Drake S, Lampasona V, Nicks HL, Schwarzmann SW. Pentamidine isethionate in the treatment of Pneumocystis carinii pneumonia. Clin Pharm 1985;4:507–16.
  3. Harstad TW, Little BB, Bawdon RE, Knoll K, Roe D, Gilstrap LC III. Embryofetal effects of pentamidine isethionate administered to pregnant Sprague-Dawley rats. Am J Obstet Gynecol 1990;163:912–6.
  4. Little BB, Harstad TH, Bawdon RE, Sobhi S, Roe DA, Knoll KA, Ghali FE. Pharmacokinetics of pentamidine in Sprague-Dawley rats in late pregnancy. Am J Obstet Gynecol 1991;164:927–30.
  5. Fortunato SJ, Bawdon RE. Determination of pentamidine transfer in the in vitro perfused human cotyledon with high-performance liquid chromatography. Am J Obstet Gynecol 1989;160:759–61.
  6. Schwebke K, Fletcher CV, Acosta EP, Henry K. Pentamidine concentrations in a mother with AIDS and in her neonate. Clin Infect Dis 1995;20:1569–70.
  7. Anonymous. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. MMWR 1989;38 (Suppl 5):1–9.
  8. Anonymous. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. JAMA 1989;262:335–9.
  9. Sarti GM. Aerosolized pentamidine in HIV; promising new treatment for Pneumocystis carinii pneumonia. Postgrad Med 1989;86:54–69.
  10. Conover B, Goldsmith JC, Buehler BA, Maloley BA, Windle ML. Aerosolized pentamidine and pregnancy. Ann Intern Med 1988;109:927.
  11. Ito S, Koren G. Estimation of fetal risk from aerosolized pentamidine in pregnant healthcare workers. Chest 1994;106:1460–2.
  12. Minkoff HL. Care of pregnant women infected with human immunodeficiency virus. JAMA 1987;258:2714–7.
  13. Minkoff HL, Moreno JD. Drug prophylaxis for human immunodeficiency virus-infected pregnant women; ethical considerations. Am J Obstet Gynecol 1990;163:1111–4.
  14. Nana D, Tannenbaum I, Landesman S, Mendez H, Moroso G, Minkoff H. Pentamidine prophylaxis in pregnancy (abstract). Am J Obstet Gynecol 1992;166:387.
  15. Sperling RS, Stratton P, O'Sullivan MJ, Boyer P, Watts DH, Lambert JS, Hammill H, Livingston EG, Gloeb DJ, Minkoff H, Fox HE. A survey of zidovudine use in pregnant women with human immunodeficiency virus infection. N Engl J Med 1992;326:857–61.
  16. Stratton P, Mofenson LM, Willoughby AD. Human immunodeficiency virus infection in pregnant women under care at AIDS clinical trials centers in the United States. Obstet Gynecol 1992;79:364–8.
  17. Gates HS Jr, Barker CD. Pneumocystis carinii pneumonia in pregnancy. A case report. J Reprod Med 1993;38:483–6.

Index