Travel to an area with multidrug-resistant falciparum malaria by pregnant women should be avoided if possible. If travel is unavoidable or if a woman plans to conceive while on an extended stay in a malaria endemic area, the woman should be advised of the risks involved, with emphasis on the importance of preventative measures, and educated about the symptoms of malaria and the need to treat promptly.
The choice of regimen will need to balance the efficacy with the most current knowledge of safety during pregnancy.
Mefloquine. The CDC, WHO and other national expert groups have expanded their indications for mefloquine to include pregnant women in their second and third trimesters (Phillips-Howard et al, 1998; Schlagenhauf, 1999). Mefloquine is not recommended during the first trimester, nor is conception recommended for 2 months after the last dose unless there is high-risk exposure. There have been numerous reported cases of inadvertent use in pregnancy in which there was no increase in congenital malformations. In fact, mefloquine use at any stage of pregnancy is not an indication for an abortion. Large scales studies need to be performed.
Melfloquine use is being monitored by a registry at the CDC. A few studies have suggested a slight increase in the number of stillbirths in the mefloquine group (Nosten et al., 1999b). Another study on the use of mefloquine by the armed forces in Somalia also indicated an increase in spontaneous abortion (Smoak et al., 1997). These studies are small and it is difficult to eliminate other variables, such as nutrition and extreme stress, that may be related to the slight increase in stillbirths. There are also studies demonstrating that pregnant women given mefloquine in their first trimester, followed by weekly prophylaxis, did not experience any significant untoward effects (Na Bangchang et al, 1994; Phillips-Howard et al, 1998).
A more rapid clearance of mefloquine late in pregnancy may necessitate an increase in the dose when the drug is used for prophylaxis. More studies need to be carried out to confirm this effect and to assess whether there would be a toxicity associated with a higher dose.
There are limited data to suggest that late pregnancy is associated with accelerated clearance of mefloquine when the drug is used prophylactically, necessitating an increase in the dose (Nosten et al., 1990) described above. Lactation is not an absolute contraindication to mef-loquine use, although low concentrations (3-4%) are excreted in breast milk with a 250 mg dose. Breast milk should not, however, be construed as having enough concentration of mefloquine to protect a newborn.
Other issues with mefloquine relate to its long half-life.
For women of reproductive age it is recommended that they do not become pregnant while taking the drug and for 3 months afterwards.
Atovaquone with proguanil (Malarone). Malarone has been available in Europe and Canada. It was approved in the USA in 2000. It is listed as FDA pregnancy category C. Data from research trials suggest that atovaquone was not teratogenic and did not cause reproductive toxicity in rats at maternal plasma concentrations up to 5-6.5 times the estimated human exposure during treatment of malaria. The combination of atovaquone and proguanil hy-drochloride was not teratogenic in rats at plasma concentrations up to 1.7 times for atovaquone and 0.10 times for proguanil, the estimated human exposure during treatment of malaria. In rabbits, the combination of atovaquone and proguanil hydrochloride was not teratogenic or embryotoxic to rabbit fetuses at plasma concentrations up to 0.34 and 0.82 times, respectively, the estimated human exposure during treatment of malaria.
While there are no adequate and well-controlled studies of atovaquone and/or proguanil hydrochloride in pregnant women, Malarone may be used if the potential benefit justifies the potential risk to the fetus. The proguanil component of malarone acts by inhibiting the parasitic dihydrofolate reductase. To date there are no clinical data indicating that folate supplementation diminishes drug efficacy. Women of childbearing age receiving folate supplements to prevent neural tube birth defects may continue to take these supplements while taking Malarone. In clinical trials, there was only one subject who became pregnant while taking Malarone. She delivered a healthy term infant.
WHO is sponsoring two safety, efficacy and phar-macokinetic studies of Malarone in the treatment of women with symptomatic malaria in the third trimester of pregnancy. One study will be in Thailand, the other in Zambia. These studies will provide important data on which to base further recommendations.
Chloroquine with proguanil. Another option in some areas of the world is a combination of weekly choloquine and the biguanine proguanil daily. Proguanil appears to be safe in pregnancy, however studies are limited. The main concern is that resistance to biguanides and cholor-quine is increasing in Southeast Asia, Thailand, Papua New Guinea, parts of Africa, and South America. The other concern is that this combination is less effective than mefloquine: it is estimated to be only 80-85% as effective.
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