Risk Factor: CM
Class: Anti-infectives/ Antimalarials
Fetal Risk Summary
Pyrimethamine is a folic acid antagonist (inhibitor of dihydrofolate reductase) used in combination with other agents primarily for the treatment and prophylaxis of malaria, but also for toxoplasmosis. Shepard reviewed 15 studies that evaluated the reproductive effects of pyrimethamine in rats, mice, and hamsters (1). Malformations in fetal rats included cleft palate, mandibular hypoplasia, limb defects, and neural tube defects. In some cases, the teratogenic dose was similar to the human dose. At slightly higher doses in rats, pyrimethamine caused chromosomal aberrations such as trisomy or chromosomal mosaicism (1).
A 1993 study found in pregnant rats and mice that oral folic acid potentiated the embryotoxicity of pyrimethamine, but that decreased embryotoxicity was observed when folic acid was given intraperitoneally (2). The mechanism of the increased toxicity appeared to be reduced plasma levels of 5-methyltetrahydrofolic acid in the dams. 5-Methyltetrahydrofolic acid is the principal active folate in plasma and it undergoes a large amount of enterohepatic circulating (2). Folic acid inhibited the absorption of the active folate from the intestine.
Reproduction studies, reported by the manufacturer, revealed teratogenicity in rats, hamsters, and miniature pigs (3). In rats, oral doses 7 times the human dose for chemoprophylaxis of malaria (HDCM) or 2.5 times the human dose for toxoplasmosis (HDT), caused cleft palate, brachygnathia, oligodactyly, and microphthalmia. Meningocele was seen in hamsters, given doses 170 times the HDCM or HDT, and cleft palate occurred in miniature pigs at 5 times the HDCM or HDT (3).
Antimalarial agents, including pyrimethamine, are used routinely during pregnancy because the risks from the disease far outweigh the risks to the fetus from drug therapy (see Proguanil for a discussion on the maternal and fetal risks of malaria during pregnancy).
Although some folic acid antagonists are human teratogens (e.g., see Methotrexate), this does not seem to occur with pyrimethamine (4,5,6,7,8,9 and 10). One case report, however, did describe a severe defect of the abdominal and thoracic wall (exteriorization of the heart, lungs, and most of the abdominal viscera) (possible variant of ectopia cordis) and a missing left arm in an infant exposed to the drug (11). The woman had been treated with chloroquine, 100 mg/day, plus a combination of dapsone (100 mg) and pyrimethamine (12.5 mg) (Maloprim) on postconception days 10, 20, and 30. However, an association between the drug and the defect has been questioned (12,13). Moreover, most studies describing the use of pyrimethamine in pregnant women for the treatment or prophylaxis of malaria have found the drug to be relatively safe and effective (13,14,15,16,17,18,19,20,21,22,23,24,25,26,27 and 28), although some recommend avoiding the drug during the 1st trimester (24).
Two reviews of toxoplasmosis (Toxoplasma gondii) in pregnancy were published in 1994 (29,30). Pyrimethamine, in combination with sulfadiazine, was recommended in both as the most effective treatment after the infection had reached the fetus. No fetal adverse effects of this therapy have been observed.
In spite of the animal study above that described increased embryotoxicity after oral folic acid, if pyrimethamine is used during pregnancy, folic acid (5 mg/day) or folinic acid (leucovorin; 5 mg/day) supplementation is recommended, especially during the 1st trimester, to prevent folate deficiency (4,5,6,7 and 8,13,24,29).
Breast Feeding Summary
Pyrimethamine is excreted into breast milk (31,32). Mothers treated with 2575 mg orally produced peak concentrations of 3.13.3 g/mL at 6 hours (31). The drug was detectable up to 48 hours after a dose. Malaria parasites were completely eliminated in infants up to 6 months of age who were entirely breast-fed. In a 1986 study, three women were treated with a combination tablet containing 100 mg of dapsone and 12.5 mg of pyrimethamine at 25 days postpartum (32). Blood and milk samples were collected up to 227 hours after the dose. The milk:plasma area under the concentration-time curve ratios ranged from 0.46 to 0.66. Based on an estimated ingestion of 1000 mL of milk/day, the infants would have consumed between 16.8% and 45.6% of the maternal doses during a 9-day period. The American Academy of Pediatrics considers pyrimethamine to be compatible with breast feeding (33).
- Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:3623.
- Kudo G, Tsunematsu K, Shimoda M, Kokue E. Effects of folic acid on pyrimethamine teratogenesis in rats. Adv Exp Med Biol 1993;338:46972.
- Product information. Daraprim. Glaxo Wellcome, 2000.
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- Anonymous. Pyrimethamine combinations in pregnancy. Lancet 1983;2:10057.
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- Nahlen BL, Akintunde A, Alakija T, Nguyen-Dinh P, Ogunbode O, Edungbola LD, Adetoro O, Breman JG. Lack of efficacy of pyrimethamine prophylaxis in pregnant Nigerian women. Lancet 1989;2:8304.
- Keuter M, van Eijk A, Hoogstrate M, Raasveld M, van de Ree M, Ngwawe WA, Watkins WM, Were JBO, Brandling-Bennett AD. Comparison of chloroquine, pyrimethamine and sulfadoxine, and chlorproguanil and dapsone as treatment for falciparum malaria in pregnant and non-pregnant women, Kakamega district, Kenya. Br Med J 1990;301:46670.
- Greenwood AM, Armstrong JRM, Byass P, Snow RW, Greenwood BM. Malaria chemoprophylaxis, birth weight and child survival. Trans Roy Soc Trop Med Hyg 1992;86:4835.
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- Greenwood AM, Menendez C, Todd J, Greenwood BM. The distribution of birth weights in Gambian women who received malaria chemoprophylaxis during their first pregnancy and in control women. Trans Roy Soc Trop Med Hyg 1994;88:3112.
- Schultz LJ, Steketee RW, Macheso A, Kazembe P, Chitsulo L, Wirima JJ. The efficacy of antimalarial regimens containing sulfadoxine-pyrimethamine and/or chloroquine in preventing peripheral and placental Plasmodium falciparum infection among pregnant women in Malawi. Am J Trop Med Hyg 1994;51:51522.
- Menendez C, Todd J, Alonso PL, Lulat S, Francis N, Greenwood BM. Malaria chemoprophylaxis, infection of the placenta and birth weight in Gambian primigravidae. J Trop Med Hyg 1994;97:2448.
- Sowunmi A, Akindele JA, Omitowoju GO, Omigbodun AO, Oduola AMJ, Salako LA. Intramuscular sulfadoxine-pyrimethamine in uncomplicated chloroquine-resistant falciparum malaria during pregnancy. Trans Roy Soc Trop Med Hyg 1993;87:472.
- Wong S-Y, Remington JS. Toxoplasmosis in pregnancy. Clin Infect Dis 1994;18:85362.
- Matsui D. Prevention, diagnosis, and treatment of fetal toxoplasmosis. Clin Perinatol 1994;21:67588.
- Clyde DF, Shute GT, Press J. Transfer of pyrimethamine in human milk. J Trop Med Hyg 1956;59:27784.
- Edstein MD. Veerendaal JR, Newman K, Hyslop R. Excretion of chloroquine, dapsone and pyrimethamine in human milk. Br J Clin Pharmacol 1986;22:7335.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.