Author Affiliations: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Malaria infection in pregnancy is associated with increased risk of complications for the mother and fetus,1 particularly in individuals not previously exposed to malaria, eg, travelers. Pregnant women are advised to avoid travel to countries where there is elevated risk of contracting malaria.2,3 For pregnant individuals who still choose to or must travel to malaria-endemic areas where there is chloroquine resistance, currently none of the available prophylactic drugs are recommended in early pregnancy. This is either owing to adverse fetal effects (doxycycline), paucity of safety data (mefloquine), or absence of such (atovaquone-proguanil).2- 4
We conducted a registry-based cohort study to investigate whether exposure to atovaquone-proguanil in early pregnancy was associated with increased risk of any major birth defect.
On the basis of the Danish Medical Birth Register, which registers all deliveries by women living in the country, we established a cohort of all live-born infants (birth date, January 2000–September 2008). Individual-level data were linked between nationwide registries to ascertain information on dispensed atovaquone-proguanil prescriptions to cohort mothers (Prescription Drug Register), birth defect diagnoses among infants (National Patient Register), and potential confounders. We evaluated the association between exposure to atovaquone-proguanil in the period of maximal susceptibility to teratogenic agents (weeks 3 through 8 after conception) and the risk of major birth defects diagnosed within the first year of life. Any filling of an atovaquone-proguanil prescription was considered as exposure and timing of exposure was defined by the date of filling the prescription. All methods used in this study have been described in detail previously.5 The study was approved by the Danish Data Protection Agency.
The majority of exposed mothers were likely travelers receiving atovaquone-proguanil on prophylactic indications. Because mothers diagnosed as having malaria may have received other treatment, potentially confounding the studied association, they were excluded from the cohort (n = 10).
Logistic regression was used to estimate prevalence odds ratios with 95% confidence intervals comparing prevalence odds of any major birth defect in infants from pregnancies exposed to atovaquone-proguanil and in infants from unexposed pregnancies. Multivariate models included those potential confounders that were significant (P < .05) risk factors for birth defects in univariate analyses. Multiple imputation was used for variables with missing values.
Among 570 877 live births included in the cohort, 13 995 (2.5%) were diagnosed as having a major birth defect within the first year of life. Atovaquone-proguanil exposure at any time in weeks 3 through 8 after conception was not significantly associated with increased risk of any major birth defect (Table). A sensitivity analysis that tested the robustness of the exposure definition by including pregnancies exposed at any time in the first trimester produced similar estimates (Table).
This study of a large nationwide cohort study found no significant association between exposure to atovaquone-proguanil in early pregnancy and the risk of any major birth defect. To our knowledge, these are the first safety data ever reported on early pregnancy exposure to atovaquone-proguanil.
Although based on a limited number of exposed pregnancies and cases, the findings provide some reassurance that atovaquone-proguanil is not a major teratogen. However, the analysis could only exclude more than a 3-times higher risk of birth defects associated with atovaquone-proguanil exposure.
Main strengths of this study include its registry-based design, providing the opportunity to investigate an uncommon drug exposure in pregnancy among women living in an industrialized country and allowing independent ascertainment of dispensed prescriptions and birth defect diagnoses. However, a main limitation is that after filling prescriptions for atovaquone-proguanil, some participants may have found out that they were pregnant. Therefore, some of them may have cancelled their trip and never taken the drug. Any noncompliance to the dispensed drugs would bias estimates toward the null.
Correspondence: Dr Pasternak, Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark (email@example.com).
Author Contributions: Both authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Pasternak and Hviid. Acquisition of data: Hviid. Analysis and interpretation of data: Pasternak and Hviid. Drafting of the manuscript: Pasternak. Critical revision of the manuscript for important intellectual content: Pasternak and Hviid. Statistical analysis: Hviid. Obtained funding: Hviid. Study supervision: Hviid.
Financial Disclosure: None reported.
Funding/Support: This study was funded by research grants from the Danish Medical Research Council and the Lundbeck Foundation.
Role of the Sponsors: The funding agencies had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, and approval of the manuscript.
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