Pharmacology and toxicology
Mefloquine is a very effective antimalarial drug. It is a potent, long-acting blood schizonticide that destroys the erythrocytic forms of all Plasmodium species. It is still effective against most chloro-quine-resistant pathogens, except for clearly defined regions of multidrug resistance.
As yet, experience with first-trim ester use of mefloquine for prophylaxis in several hundred pregnancies gives no indication for a teratogenic potential in humans (Schlagenhauf 1999, Philips-Howard 1998, unpublished experience by the European Network of Teratology Information Services, ENTIS). More extensive experience with mefloquine prophylaxis in the second and third trimesters of pregnancy gave no clear indication for mefloquine-associatcd adverse effects (Schlagenhauf 1999, Philips-Howard 1996).
Cumulative evidence is reassuring, and has led the WHO and the US CDC&P to sanction the use of mefloquine in the second and third trimesters of pregnancy both for prophylaxis and treatment (Schlagenhauf 1999, WHO 1996A). However, one group of investigators reported that their data provided evidence that mefloquine treatment during pregnancy may be associated with stillbirth: women who were treated with mefloquine in pregnancy had a significant greater risk of stillbirth than did women treated with quinine alone (Nosten 1999).
Recommendation. Mefloquine can be used for prophylaxis or treatment of malaria in cases with chloroquine/proguanil-resistant P. falciparum. It is important to keep informed of current recommendations for the region in question. Exposure to mefloquine in the first trimester does not require termination of pregnancy or invasive diagnostic procedures.
2,6,28 Pyrimethamine, sulfadoxine and dapsone
2.6.28 Pyrimethamine, sulfadoxine and dapsone
Pyrimethamine is an inhibitor of folic-acid synthesis and a well-tried malaria prophylactic agent in pregnancy. However, nowadays it is only used in combination with sulfonamides and sulfones such as sulfadoxine, sulfalene, and dapsone: these agents are also inhibitors of folic-acid synthesis.
Severe cutaneous reactions like erythema exsudativum multiforme and Stevens-Johnson syndrome were reported as unwanted side effects of the combination sulfadoxin/pyrimethamine. Therefore, use of the combination for malariaprophylaxis is not recommended, but the combination is used for treatment of acute chloroquine-resistant falciparum malaria and as intermittent preventive treatment (IPT) for prevention of malaria-associated adverse effects during pregnancy in women living in malaria-endemic areas. Pregnant women suffering from resistant malaria forms were successfully treated with the combination sulfadoxine/pyrimethamine (Philips-Howard 1996). Intermittent preventive treatment (ITP) with sulfadoxin/ pyrimethamine seems to be the most effective in preventing the adverse outcomes associated with malaria in pregnancy in countries where Plasmodium falciparum is sensitive, although the spread of resistance is affecting its efficacy (Newman 2003).
The combination dapson/pyrimethamine is used for prophylaxis of chloroquine-resistant malaria. Significant side effects like agranulocytosis have restricted its use (for dapsone, see also tuberculostatics). Data on pregnancy outcome after the use of this combination during pregnancy for malaria prophylaxis and treatment are limited and insufficient for a well-grounded risk assessment (review by Brabin 2004).
Pyrimethamine, in combination with a long-acting sulfonamide, is also used therapeutically for toxoplasmosis infection of the fetus, in particular after the first trimester, The effectiveness of the various schedules for prevention and treatment of toxoplasmosis is an ongoing topic of discussion (Wallon 1999).
Because of embryotoxic effects in animal experiments, there were initial objections against use of these folic acid antagonists in early pregnancy (see also trimethoprim). Currently, there is an ongoing discussion concerning the association between the use of folic-acid antagonists and an increased risk of congenital malformations (Shepard 2002, Hernandez-Diaz 2001. 2000).
Recommendation. If indicated, the combination sulfadoxine/pyrimethamine can be used during pregnancy for the treatment of acute chloroquine-resistant malaria tropica; the combination can also be used in intermittent preventive treatment (IPT) in the second and third trimesters although it is not recommended for prophylaxis, Significant side effects have restricted the use of dap-sone/pyrimethamine for prophylaxis of chloroquine-resistant malaria tropica. "Hiis combination should be considered as second choice in pregnancy, It is important to keep informed of current recommendations for the region in question. Pyrimethamine, in combination with a long-acting sulfonamide, can be used for the prevention/treatment of toxoplasmosis infection of the fetus.
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