Prophylactic use of antimalarials during pregnancy

Chloroquine or hydroxychloroquine

No harmful effects on the fetus have been observed when chloroquine or hydroxychloroquine are used in the recommended doses for malaria prophylaxis.² Observational data^5,6 (amounting to more than 1000 exposures) and 1 double-blind randomized-controlled trial⁷ (N = 951) have evaluated the use of chloroquine at various stages of pregnancy for the prevention of malaria and have not identified any teratogenicity or other adverse events. As a result, this agent is considered safe for use in all trimesters of pregnancy.

Doxycycline

There is no evidence for human teratogenicity with doxycycline use during pregnancy.⁸ Despite this, the main concern with doxycycline, like tetracycline, is the risk to the fetus of inhibition of bone growth and discoloration and dysplasia of the teeth,³ which can occur during the period of calcification beyond the fourth month of gestational age.⁴ Because of the potential harm, doxycycline is not recommended during pregnancy. However, keeping in mind that treatment is continued for 4 weeks after leaving the malaria-endemic area,⁹ doxycycline can be considered as long as treatment is completed by the fourth month of pregnancy.

Atovaquone-proguanil

Proguanil has been used as a malarial prophylactic agent for decades, with no known toxic effects on the fetus.¹⁰ Four small 3-day treatment studies with the atovaquone-proguanil combination in the second and third trimesters of pregnancy did not identify any adverse effects in the fetuses or newborns.^11–14 In a recent retrospective cohort study of the Danish Medical Birth Register, based on a limited number of exposed pregnancies (N = 149), there was no significant association between atovaquone-proguanil use during the first trimester and major birth defects. Most of the exposed mothers were likely travelers receiving atovaquone-proguanil for prophylaxis, as mothers diagnosed with malaria were excluded from the cohort to avoid potential confounding from other therapies.¹⁵

Although the available data are reassuring, the evidence for its use during pregnancy remains limited, and thus it is not currently recommended for the prevention of malaria in pregnant women.² However, it might be considered if the expected benefit for the mother outweighs any potential risk to the fetus.

Mefloquine

Observational data⁶ and a placebo-controlled trial¹⁶ evaluating mefloquine use in the second half of pregnancy have found no effect on the rate of stillbirths, birth defects, or other adverse fetal or pregnancy outcomes. Mefloquine registries and surveillance data have recorded thousands of exposures mainly in the first trimester of pregnancy with no increased rate of malformations or spontaneous abortions.^17,18 Based on the available evidence, malaria prophylaxis with mefloquine does not appear to be associated with risks to the fetus, even when used in the first trimester.

Primaquine

There are no data on the use of primaquine during pregnancy. Primaquine causes acute hemolysis in those with a glucose-6-phosphate dehydrogenase deficiency.¹⁹ Therefore, because the glucose-6-phosphate dehydrogenase status of the fetus cannot be established, primaquine is not recommended for use during pregnancy.²

Conclusion

Current data suggest that chloroquine, hydroxychloroquine, mefloquine, and the proguanil-atovaquone combination do not pose any safety concerns for pregnant women. However, experience with the proguanilatovaquone combination in the first trimester is limited. Primaquine and doxycycline are not recommended during pregnancy, although, theoretically, doxycycline could be considered for use in the first trimester of pregnancy.