Efficacy and tolerability of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: a systematic review and individual patient data meta-analysis

Abstract

Summary Background Malaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women. Methods We did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov ) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013. Findings Of the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57–14·54, p<0·0001) but lower for artesunate-amodiaquine (n=840, 0·27, 95% 0·14–0·52, p<0·0001), artesunate-mefloquine (n=1028, 0·56, 95% 0·34–0·94, p=0·03), and dihydroartemisinin-piperaquine (n=872, 0·35, 95% CI 0·18–0·68, p=0·002) than artemether-lumefantrine (n=1278) after adjustment for baseline asexual parasitaemia and parity. The risk of gametocyte carriage on day 7 was higher after quinine-based therapy than artemisinin-based treatment (adjusted odds ratio [OR] 7·38, 95% CI 2·29–23·82). Interpretation Efficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation. Funding The Bill & Melinda Gates Foundation, ExxonMobil Foundation, and the University of Oxford Clarendon Fund.

Pregnancy outcomes and risk of placental malaria after artemisinin-based and quinine-based treatment for uncomplicated falciparum malaria in pregnancy: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis

“…Artemisinin-based combination therapies (ACTs) are highly effective with expected ≥ 95% treatment success (clearance of peripheral parasitaemia) in pregnancy [23,24]. However, few studies have been powered to specifically explore the impact of different treatments on adverse pregnancy outcomes and placental malaria.…”

Drug treatment and prevention of malaria in pregnancy: a critical review of the guidelines

“…Treatment regimen complexity, including the duration, frequency of dosing, number of pills prescribed (Table 3), and poor tolerability by pregnant women with uncomplicated malaria who may require full supervision, are more likely barriers to universal endorsement of quinine plus clindamycin regimen. This controversy can be resolved by revising WHO Guidelines to include ACT as a firstline treatment option for uncomplicated malaria in first trimester as recommended by the WHO Malaria Policy Advisory Committee [31] based on growing evidence on artemisinin safety [32][33][34][35]. US-CDC updated recommendation in 2018 states that during first trimester of pregnancy falciparum malaria should be treated with the currently available options of either mefloquine or quinine plus clindamycin.…”

“…In 2015, WHO recommended the use of ACT, including DHA-PPQ, as first-line treatment in second and third trimesters [1]. More recent data from SSA and many GMS countries confirm that exposure to ACT (AL or artemisinin derivatives) were not associated with adverse pregnancy outcomes during first trimester [32][33][34][35][36]38] as well as in second and third trimesters [25,32,36,[38][39][40][41]. Adverse effects of AL, such as asthenia, poor appetite, dizziness, nausea, and vomiting, occur significantly less often with AL compared to other ACT [42].…”

Efficacy and Safety of Artemisinin-Piperaquine for the Treatment of Uncomplicated Malaria: A Systematic Review

“…During the treatment of ACTs, most adverse reactions are considered to be caused by partner drugs, and AL and DP are well-tolerated drug regimens. The risk of anorexia, nausea, vomiting, and dizziness in ASAQ and ASAM is higher than that of AL or DP (Saito et al, 2020). Artemisinin is currently the only antimalarial drug that has not caused clinical resistance, and it is still effective against multidrug-resistant falciparum malaria.…”