Is artesunate (antimalarial medication) safe to use during the first trimester of pregnancy?

Artesunate Safety in First Trimester of Pregnancy

Artesunate can be used in the first trimester of pregnancy when treating malaria, though mefloquine or quinine plus clindamycin remain the preferred first-line options; however, when these are unavailable, artesunate-containing regimens (such as artemether-lumefantrine) should be used without hesitation, as untreated malaria poses far greater risks to both mother and fetus than the theoretical concerns about artesunate. 1, 2

Current Guideline Recommendations

The CDC explicitly states that women with uncomplicated malaria during the first trimester should be treated with either mefloquine or quinine plus clindamycin as first-line options. 1, 2 However, when neither of these options is available, artemether-lumefantrine (which contains artesunate's derivative artemether) should be considered for treatment. 1, 2

This recommendation reflects a pragmatic approach: the guidelines acknowledge that artemisinin-based combination therapies (ACTs) including artesunate are acceptable alternatives when preferred options are unavailable. 1

Safety Evidence from Human Studies

The safety profile of artesunate in first trimester is reassuring based on multiple lines of evidence:

No Increased Risk of Miscarriage or Congenital Malformations

• A large observational study on the Thai-Myanmar border following 25,485 pregnancies found no difference in miscarriage rates between artemisinin treatment (n=183) versus quinine (n=842) in first trimester (HR 0.78,95% CI 0.45-1.34). 3

• The same study found no increased risk of major congenital malformations with artemisinin exposure: 2% (2/109) with artemisinins versus 1% (8/641) with quinine. 3

• A meta-analysis including data from six sub-Saharan African countries and Thailand showed that artemisinin regimens compared to quinine had an adjusted hazard ratio of 0.73 (95% CI 0.44-1.21) for miscarriage and 0.29 (95% CI 0.08-1.02) for stillbirth. 1

• A Tanzanian cohort study found artemether-lumefantrine exposure in first trimester had an adjusted odds ratio of 1.4 (95% CI 0.8-2.5) for miscarriage/stillbirth, which was not statistically significant. 4

Quinine May Actually Be More Harmful

Importantly, the evidence suggests quinine—the traditional "safe" option—may carry greater risks:

• Quinine exposure in first trimester was associated with significantly increased risk of miscarriage/stillbirth (OR 2.5,95% CI 1.3-5.1) and premature birth (OR 2.6,95% CI 1.3-5.3) compared to artemether-lumefantrine. 4

• Quinine causes substantially more maternal adverse effects including tinnitus (44.9% vs 8.9% with artesunate), dizziness, and vomiting. 1, 5

The Animal Study Concern vs. Human Reality

The historical hesitation about artesunate in first trimester stems from animal studies showing embryotoxicity and depletion of primitive erythroblasts. 6 However, this toxicity has not been demonstrated in humans despite extensive observational data. 6

The mechanism of embryotoxicity in animals relates to species-specific differences in the timing of erythroblast development, and the presence of malaria infection itself may reduce drug distribution to the fetus. 6 These factors make direct extrapolation from animal studies to human pregnancy inappropriate.

Clinical Decision Algorithm

For first trimester uncomplicated malaria:

1. First choice: Mefloquine OR quinine plus clindamycin 1, 2

2. When first-line options unavailable: Use artemether-lumefantrine (or other artesunate-containing ACT) immediately 1, 2

3. Never delay treatment waiting for preferred medications—untreated malaria causes far greater harm 1

For first trimester severe malaria:

• Use intravenous artesunate without hesitation—it is superior to quinine for severe malaria and should be the preferred treatment in all trimesters. 7

Critical Pitfalls to Avoid

• Do not withhold artesunate-based treatment in first trimester when other options are unavailable—the risks of untreated malaria (maternal death, miscarriage, stillbirth) far exceed any theoretical artemisinin risks. 1, 3

• Do not assume quinine is "safer" than artesunate—human data suggests quinine may actually carry higher risks of adverse pregnancy outcomes. 4

• Do not delay treatment for severe malaria in any trimester—intravenous artesunate should be used immediately as it reduces mortality compared to quinine. 7

• First-trimester falciparum malaria itself increases miscarriage risk 1.61-fold for initial episodes and 3.24-fold for recurrences—emphasizing that the disease, not the treatment, is the primary threat. 3