Atovaquone-proguanil chemoprophylaxis during pregnancy: a case series and a systematic review and meta-analysis

BACKGROUND: Pregnant women travelling to malaria endemic areas require effective chemoprophylaxis, with limited options including atovaquone-proguanil (AP) for which safety data remain limited. Our objective was to describe the prevalences of pregnancy outcomes and major congenital anomaly (MCA) following AP chemoprophylaxis during pregnancy. METHODS: We combined a case series from the French national Teratology Information Service (CRAT) and a systematic review and meta-analysis (SRMA), including prospective pregnancies exposed to AP for chemoprophylaxis. Outcomes were prevalence of pregnancy outcomes and MCA. The case series included all pregnancies referred to the CRAT with an expected date of delivery between 2009-2025, and known outcome. The SRMA searched Medline, Embase, Cochrane databases and grey literature up to 16/09/2025. Study selection and data extraction were performed using an independent dual review process. Risk of bias was assessed with ROBINS-I. Pooled prevalences were estimated using random-effects models. GRADE was used to assess certainty of evidence. RESULTS: Our case series included 191 AP-exposed pregnancies (133 during first-trimester (T1) and 75 during second/third trimester) resulting in 85.9% livebirths (n=164), 10.0% miscarriages (n=19), 1.0% medical abortions (n=2), 1.0% stillbirth (n=2) and 2.1% elective termination (n=4). The prevalence of MCA among T1-exposed pregnancies with documented MCA status (n=110) was 3.6% (95%CI[1.0;9.0]). The SRMA included four studies, which when combined with our case series (555 AP-exposed pregnancies, 457 during T1) produced a pooled prevalence of livebirths of 80.3% (95%CI[72.3;87.2], I2=67.2%, Phet=0,047), 14.6% miscarriages (95%CI[7.3;23.9], I2=73.2%, Phet=0,024) and 2.7% for MCA (95%CI[1.2;4.8], I2=0.0%, Phet=0,45). Level of evidence was low. CONCLUSIONS: Our findings suggest that pregnancy outcomes and MCA following AP chemoprophylaxis exposure are similar to the general population prevalences, with a low level of evidence. These data strengthen the evidence supporting a reassuring safety profile, and AP may represent a reasonable option for pregnant women requiring malaria chemoprophylaxis after risk-benefit assessment.