Prophylactic use of antimalarials during pregnancy

Abstract

Question Some of my pregnant patients wish to travel to malaria-endemic regions. Are there medications that can be used safely during pregnancy for malaria prophylaxis?

Answer Pregnant women should avoid travel to malaria-endemic areas if possible. However, if travel cannot be avoided, measures to prevent mosquito bites, along with an effective chemoprophylaxis regimen, should be implemented. Chloroquine or hydroxychloroquine are considered safe to use in all trimesters of pregnancy. Mefloquine is the agent of choice for chloroquine-resistant areas, and evidence suggests it is not associated with an increased risk to the fetus. Although the atovaquone-proguanil drug combination is not currently recommended for use during pregnancy, limited data suggest that it is not harmful to the fetus. Doxycycline and primaquine are not recommended during pregnancy.

Malaria is caused by Plasmodium parasites. Of the various species, Plasmodium falciparum and Plasmodium vivax are the most common.¹ Malaria is transmitted to humans by the bite of Anopheles mosquitoes, and during pregnancy it can be congenitally transmitted from mother to fetus.² Pregnant women are twice as likely to be bitten by mosquitoes.³ Malaria-endemic areas include Central and South America, parts of the Caribbean, Africa, Asia, Eastern Europe, and the South Pacific,² although most malaria cases occur in sub-Saharan Africa.¹ Malaria presents with fever and influenza-like symptoms such as chills, headache, and myalgia, and can progress to a more severe presentation involving multiple organ systems, sometimes leading to death. Severe illness is most commonly caused by P falciparum.^1,2 In nonimmune pregnant women, malaria carries an additional risk of miscarriage (up to 60% in P falciparum infection),¹ neonatal death,³ stillbirth,³ low birth weight,⁴ and high maternal death rates (10% to 50%).¹ For these reasons, and because no prophylactic regimen provides complete protection, it is recommended that pregnant women avoid traveling to malaria-endemic areas.² However, it might not always be possible for pregnant women to avoid travel, and thus an effective chemoprophylaxis regimen should be selected and appropriate mosquito-avoidance measures should be encouraged (Box 1^2,3). The chemoprophylactic regimen that is selected will depend on many factors, including the travel itinerary and antimalarial drug resistance reported in that location. The available evidence for the safety of each antimalarial drug during pregnancy is summarized below. Table 1^2–4 summarizes Motherisk recommendations for malaria chemoprophylaxis during pregnancy.

Box 1. Mosquito-avoidance measures Mosquito-avoidance measures include the following:

Remain in well-screened areas, especially between dusk and dawn Use mosquito bed nets (preferably insecticide-treated nets) Use a pyrethroid-containing flying-insect spray in living and sleeping areas during evening and nighttime hours Consider wearing clothing that is impregnated with insecticide (permethrin) Wear clothes that cover most of the body; also, tuck shirts into pants, and tuck pants into socks or footwear Dress in light-coloured clothing Use an effective mosquito repellent that contains DEET (diethyltoluamide) in concentrations of 30% or less; apply to clothing and the exposed parts of the skin

Data from the Centers for Disease Control and Prevention² and the Committee to Advise on Tropical Medicine and Travel.³

Table 1.

Summary of Motherisk recommendations for malaria chemoprophylaxis during pregnancy

ANTIMALARIAL DRUG	EVIDENCE OF TERATOGENICITY	TIMING OF EXPOSURE	LEVEL OF EXPERIENCE	RECOMMENDATIONS FOR USE DURING PREGNANCY
Chloroquine or hydroxychloroquine	No	All trimesters	Substantial data available	Drug of choice in chloroquine-sensitive areas3
Doxycycline	No	First 4 mo of pregnancy	Limited data available	Not recommended owing to adverse effects on the fetus with the use of tetracyclines when used after the fourth month of pregnancy, including discoloration and dysplasia of the teeth, and inhibition of bone growth3,4
Atovaquone-proguanil combination	No	All trimesters	Limited data available	Might be considered after careful discussion of the benefits and risks in women who cannot avoid travel to mefloquine-resistant areas
Mefloquine	No	All trimesters	Substantial data available	Recommended for use anytime during pregnancy in chloroquine-resistant areas
Primaquine	No data available	No data available	No data available	Not recommended, as the G6PD status of the fetus cannot be established and the drug can be passed transplacentally2

G6PD—glucose-6-phosphate dehydrogenase.

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.

Motherisk

Motherisk questions are prepared by the Motherisk Team at the Hospital for Sick Children in Toronto, Ont. Ms Irvine is a doctoral candidate in the Faculty of Pharmacy at the University of Toronto. Ms Einarson is a consultant for the Motherisk Program. Ms Bozzo is Assistant Director of the Motherisk Program.

Do you have questions about the effects of drugs, chemicals, radiation, or infections in women who are pregnant or breastfeeding? We invite you to submit them to the Motherisk Program by fax at 416 813-7562; they will be addressed in future Motherisk Updates. Published Motherisk Updates are available on the Canadian Family Physician website (www.cfp.ca) and also on the Motherisk website (www.motherisk.org).