By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
SYNOPSIS: History, data, and international consensus lead to the same conclusion: Artemether-lumefantrine is the first choice for treatment of uncomplicated falciparum malaria in everyone, even pregnant women.
SOURCE: Castro L, Ridpath A, Mace K, Gutman JR. Have you heard the news? Artemether-lumefantrine is now recommended for ALL uncomplicated malaria in the United States, including in pregnancy. Clin Infect Dis 2023; Oct 17:ciad638. doi: 10.1093/cid/ciad638. [Online ahead of print].
In an invited commentary from the Centers for Disease Control and Prevention (CDC), Castro and colleagues provided a review of history, data, and international consensus regarding the treatment of uncomplicated malaria. Helpfully, they make it clear that treatment of uncomplicated malaria can be, well, uncomplicated.
Malaria still is a major problem for pregnant women and young children in many parts of the world. Each year, approximately 13 million pregnancies are affected by malaria, and half a million children are born at low birthweight because of malaria. Pregnant women suffer from malaria-induced anemia. In addition to small size, newborns whose mothers had malaria during pregnancy can have still birth, prematurity, and congenital malaria. Travelers and migrants account for one to two dozen cases of gestational malaria in the United States each year.
For more than a decade, artemether-lumefantrine has been used in non-pregnant individuals with uncomplicated malaria in the United States, and it has been authorized for use during the second and third trimesters of pregnancy by the World Health Organization (WHO) since 2006 and by the CDC since 2018. Since November 2022, the WHO recommends the use of artemisinin combination therapies (such as artemether-lumefantrine) for all individuals with uncomplicated Plasmodium falciparum malaria, regardless of pregnancy, breastfeeding, and age considerations.
What do the data show? The authors discussed a systematic review of papers dealing with artemisinin use during pregnancy. A total of 10 papers included 34,178 pregnancies during which 737 included first-trimester treatment with artemisinin combination therapy and 1,076 included first-trimester treatment with a different antimalarial regimen. There was less miscarriage, still birth, and congenital anomaly noted in those treated with artemisinins than in those treated with other medications. Specifically, adverse pregnancy outcomes were seen in only about half as many women treated with artemether-lumefantrine (4.8%) as in those treated with quinine (9.2%). (Malaria without treatment during the first trimester of pregnancy carries a much higher risk of fetal loss.)
Based on these data, the CDC has revised its recommendations in alignment with the WHO, suggesting artemether-lumefantrine as first-line treatment of uncomplicated falciparum malaria during all stages of pregnancy. (Quinine along with clindamycin is another option, as is mefloquine — although quinine carries more risk and mefloquine is contraindicated in individuals with seizures or significant mental health issues.)
Most P. falciparum malaria is resistant to chloroquine, and P. vivax malaria can be resistant to chloroquine in Papua New Guinea and Indonesia; in these situations, artemether-lumefantrine is the first-line treatment for uncomplicated malaria. For malaria due to P. vivax in other parts of the world and for malaria due to P. ovale, P. malariae, and P. knowlesi, chloroquine or hydroxychloroquine could be used.
The CDC provides more detailed information about treatment of malaria in pregnancy at https://www.cdc.gov/malaria/diagnosis_treatment/clinicians1.html#pregnant.html#pregnant.
COMMENTARY
Castro and colleagues provide a helpful review and reminder about treatment of uncomplicated falciparum malaria during pregnancy. Specifically, artmether-lumefantrine is the primary treatment option. This is helpful, practical information. Unfortunately, the title of the paper (at least in its current online version) is a bit misleading in claiming that “artemether-lumefantrine is now recommended for ALL uncomplicated malaria in the United States.” In fact, chloroquine or hydroxychloroquine still would be first-line treatment for most non-falciparum malaria.
The systematic review discussed by Castro and colleagues included patients in Africa and Asia.1 There is no clear reason to suspect that patients in the United States would fare differently with artemether-lumefantrine during the first trimester of pregnancy than did patients elsewhere.
Women residing in malaria-endemic areas benefit from intermittent preventive malaria medications during pregnancy.2 Typically, a monthly combination treatment including sulfadoxine-pyrimethamine has been used.2 However, there is increasing evidence of resistance by malaria parasites to these medications.2 A new (last month) meta-analysis involving six randomized controlled trials in Africa with 7,969 pregnant women suggests that artemisinin combination treatment with dihydroartemisinin piperaquine is effective as a preventive regimen.2 Women receiving dihydroartemisinin piperaquine had slightly prolonged QT intervals (without evidence of significant cardiotoxicity) and more post-administration vomiting.2 These data imply that there will be growing use of artemisinin-related medications throughout pregnancy.
As mentioned by Castro and colleagues, congenital malaria is possible in babies born to mothers who were infected by malaria parasites during pregnancy. Congenital malaria can present with fever and sepsis-like symptoms during the first week of life or later.3 It behooves physicians caring for sick newborns to consider the possibility of congenital malaria when the mother had spent part of the pregnancy in a malaria-endemic area.3
REFERENCES
- Saito M, McGready R, Tinto H, et al. Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: A systematic review and individual patient data meta-analysis. Lancet 2023;401:118-130.
- Muthoka EN, Usmael K, Embaye SM, et al. Safety and tolerability of repeated doses of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnancy: A systematic review and an aggregated data meta-analysis of randomized controlled trials. Malar J 2023;22:320.
- Mohan K, Omar BJ, Chacham S. Malaria in newborn: A missed entity for primary care physician. J Family Med Prim Care 2023;12:1511-1515.
