Updated CDC Recommendations for Using Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria in Pregnant Women in the United States

Malaria infection during pregnancy is associated with an increased risk for maternal and fetal complications. In the United States, treatment options for uncomplicated, chloroquine-resistant Plasmodium falciparum and P. vivax malaria in pregnant women are limited to mefloquine or quinine plus clindamycin (1). However, limited availability of quinine and increasing resistance to mefloquine restrict these options. Strong evidence now demonstrates that artemether-lumefantrine (AL) (Coartem) is effective and safe in the treatment of malaria in pregnancy. The World Health Organization (WHO) has endorsed artemisinin-based combination therapies (ACTs), such as AL, for treatment of uncomplicated malaria during the second and third trimesters of pregnancy and is currently considering whether to add ACTs, including AL, as an option for malaria treatment during the first trimester (2,3). This policy note reviews the evidence and updates CDC recommendations to include AL as a treatment option for uncomplicated malaria during the second and third trimesters of pregnancy and during the first trimester of pregnancy when other treatment options are unavailable. These updated recommendations reflect current evidence and are consistent with WHO treatment guidelines.


Updated CDC Recommendations for Using Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria in Pregnant Women in the United States
Sarah-Blythe Ballard, MD, PhD 1,2 ; Allison Salinger, MPHc 2,3 ; Paul M. Arguin, MD 2 ; Meghna Desai, PhD 2 ; Kathrine R. Tan, MD 2 Malaria infection during pregnancy is associated with an increased risk for maternal and fetal complications. In the United States, treatment options for uncomplicated, chloroquine-resistant Plasmodium falciparum and P. vivax malaria in pregnant women are limited to mefloquine or quinine plus clindamycin (1). However, limited availability of quinine and increasing resistance to mefloquine restrict these options. Strong evidence now demonstrates that artemetherlumefantrine (AL) (Coartem) is effective and safe in the treatment of malaria in pregnancy. The World Health Organization (WHO) has endorsed artemisinin-based combination therapies (ACTs), such as AL, for treatment of uncomplicated malaria during the second and third trimesters of pregnancy and is currently considering whether to add ACTs, including AL, as an option for malaria treatment during the first trimester (2, 3). This policy note reviews the evidence and updates CDC recommendations to include AL as a treatment option for uncomplicated malaria during the second and third trimesters of pregnancy and during the first trimester of pregnancy when other treatment options are unavailable. These updated recommendations reflect current evidence and are consistent with WHO treatment guidelines.

Background
Each year, approximately 1,700 cases of imported malaria occur in the United States; approximately 630 (37%) of these cases occur in women, including 5%-6% who are pregnant at the time they are infected (4). Treatment options for uncomplicated, chloroquine-resistant P. falciparum and P. vivax malaria infections in pregnant women in the United States are threatened by the spread of mefloquine resistance in Southeast Asia. Having only one quinine and mefloquine manufacturer in the United States can adversely affect access. In 2009, the Food and Drug Administration (FDA) approved AL for the treatment of uncomplicated malaria. At that time, this combination was not approved for use in pregnancy because animal research data indicated a potential association with poor pregnancy outcomes, and insufficient human data were available. Since then, global experience has contributed substantial evidence of the safety and efficacy of AL throughout pregnancy. Given the need for an additional option to treat uncomplicated malaria in pregnant women in the United States, a systematic review of the literature was performed to evaluate the safety and efficacy of AL use during pregnancy, and findings were used to update CDC recommendations.

Methods
A systematic review of English-language research articles listed in PubMed was conducted using the keywords "artemether," "lumefantrine," "Coartem," and "malaria in pregnancy." Clinical trials, observational studies, meta-analyses, and case reports of uncomplicated malaria treatment during pregnancy were included. Studies that did not include treatment or pregnancy outcomes were excluded, as were studies that did not identify the trimester of treatment. Review article and metaanalysis references were examined for additional primary source articles for inclusion. Online search results were compiled and deduplicated. Two independent reviewers determined the relevance of each article to the research objective based first on title, then abstract, then full text. If reviewers had discordant findings from title or abstract review, the article was included in the next review phase. The following data were abstracted and reviewed: participant age; geographic location; parity; reason for drug treatment (uncomplicated versus severe malaria); trimesters during which treatment occurred; medication dose administered; treatment duration; treatment outcomes; and pregnancy outcomes, which included miscarriage (pregnancy loss at <28 weeks' gestation), stillbirth (pregnancy loss at ≥28 weeks' gestation), preterm birth (<37 weeks' gestation), low birth weight (<2,500 g), congenital abnormalities, and any maternal adverse events reported.
women taking ACTs versus non-ACTs to treat uncomplicated malaria in the second and third trimesters of pregnancy (pooled risk ratio random effects = 0.41; 95% confidence interval (CI) = 0.16-1.06; six trials) (5). With respect to AL efficacy during the second and third trimesters of pregnancy, a concern existed that a reduction in relative bioavailability of lumefantrine in pregnant women might affect treatment success later in pregnancy (11)(12)(13)(14)(15). However, the evidence presented indicates that treatment in pregnancy is efficacious at the doses currently recommended for nonpregnant women.
Second and third trimester safety. Data evaluating pregnancy outcomes in women taking ACTs during the second or third trimesters of pregnancy were available from 16 studies (Table 2). No differences in pregnancy outcomes were identified in four trials comparing ACTs with quinine-based regimens in Uganda and Thailand (6,7,9,10), one of which used AL (9), and in four other trials comparing AL with other ACTs in Nigeria (two studies), Thailand, and multiple sites in Africa (16)(17)(18)(19). A Zambian cohort study comparing treatment of uncomplicated malaria using AL with treatment using sulfadoxine-pyrimethamine found similar pregnancy outcomes between groups (20). In addition, two meta-analyses of women with malaria in the second and third trimester of pregnancy found no association between ACT treatment and congenital malformations or miscarriage (5,21). Overall, fewer maternal adverse events occurred among women taking ACTs than among those taking non-ACTs (Table 2). One trial in Thailand found a relatively higher proportion of day 7 anemia among those treated with mefloquine-artesunate (67%) than among those treated with a quinine-based regimen (42%) (6). Four trials and one meta-analysis comparing ACTs with quinine-based regimens found that pregnant women taking quinine had higher rates of tinnitus, dizziness, and vomiting than did pregnant women taking ACTs (5-9). The three trials comparing AL with other ACTs found no differences in rates of serious adverse maternal effects between groups (9,16,18).
First trimester safety. No randomized trials evaluating AL use during the first trimester of pregnancy were found (Table 3). However, a meta-analysis of observational and other studies from six sub-Saharan African countries and the Thai-Burmese border included data from a total of 717 women taking ACTs during the first trimester of pregnancy (22). Comparisons of pregnancy outcomes between women taking ACTs and those receiving a quinine-based regimen   Miscarriage, 0 (0) Any defect, 0 (0) Not assessed Stillbirth, 0 (0) Premature, 0 (0)

TABLE 2. (Continued) Summary of studies using artemisinin-based treatment for malaria in second and third trimesters of pregnancy and safety outcomes
anytime during the first trimester and treatment with ACTs versus quinine-based regimen during 6-12 weeks' gestational age demonstrated no differences in miscarriage, stillbirth, or pregnancy loss (miscarriage and still birth combined) for women treated with ACTs versus quinine-based regimens during either period. Although limited by sample size, the pooled prevalences of congenital anomalies in infants born to mothers taking ACTs versus quinine-based regimens in the first trimester were similar (1.5%, 95% CI = 0.6-3.5 versus 1.2%, 95% CI = 0.6-2.4, respectively) (22).

Recommendation
Malaria infection during pregnancy can result in serious maternal and fetal complications. On the basis of the strength and quality of this evidence, CDC recommends AL as an additional option for treatment of uncomplicated malaria in pregnant women in the United States during the second and third trimesters of pregnancy at the same doses recommended for nonpregnant women. Women in the United States with uncomplicated malaria during the first trimester of pregnancy should be treated with the currently recommended options of either mefloquine or quinine plus clindamycin. However, when neither of these options is available, AL should be considered for treatment.

Discussion
This update of CDC recommendations based on accumulated evidence of the safety of AL in pregnancy is in line with the malaria treatment guidelines of other countries without endemic malaria and WHO (3,23,24). On the basis of the current strength and quality of the first trimester safety and efficacy evidence, the addition of ACTs, including AL, as a first-line treatment option for uncomplicated malaria during the first trimester of pregnancy is being considered by WHO after the Malaria Policy Advisory Committee's review (2,3). Women seeking care in the United States will now have a third treatment option for uncomplicated malaria during the second and third trimesters of pregnancy, and during the first trimester of pregnancy when other treatment options are unavailable, that is safe and effective for treating P. falciparum infections acquired in regions with chloroquine resistance. To assess the implementation and impact of these updated recommendations in the United States, data from the National Malaria Surveillance System will be used to examine how antimalarials   are used to treat uncomplicated malaria in pregnant women, as well as population-specific disease burden; in addition, the FDA Adverse Event Reporting System maintains adverse event and medication error data, which can be used to monitor adverse events associated with AL use during pregnancy.