Artemisinin-Based Combination Therapy Versus Quinine or Other Combinations for Treatment of Uncomplicated Plasmodium falciparum Malaria in the Second and Third Trimester of Pregnancy: A Systematic Review and Meta-Analysis

Abstract

The World Health Organization recommends artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated falciparum malaria in the second and third trimesters of pregnancy. We conducted a meta-analysis to compare efficacy, safety and tolerability of ACTs versus quinine and other non-ACT antimalarials. The median PCR-adjusted failure rate by days 28 to 63 in the non-ACT group was 6 (range 0-37) per 100 women, lower in the ACT group overall (pooled risk ratio [PRR] random effects, 0.41; 95% confidence interval [CI], 0.16-1.05; 6 trials), and significantly lower compared with oral quinine (PRR, 0.20; 95% CI, 0.08-0.49; 4 trials). There were no differences in fetal deaths and congenital abnormalities. Compared with quinine, artemisinin-based combinations therapies were associated with less tinnitus (PRR, 0.19; 95% CI, 0.03-1.11; 4 studies), dizziness (PRR, 0.64; 95% CI, 0.44-0.93; 3 trials), and vomiting (PRR, 0.33; 95% CI, 0.15-0.73; 3 trials). Artemisinin-based combination therapies are better than quinine in the second and third trimesters; their use should be encouraged among health workers.

Keywords: artemisinins; malaria; pregnancy; quinine; treatment.

Figure 1.

PRISMA flow diagram. Abbreviation: ACTs, artemisinin-based combination therapies.

Figure 2.

(A) Meta-analysis of PCR-adjusted parasitological treatment failure risk comparing artemisinin-based combination therapies (ACTs) vs. non-ACTs, stratified by comparator drug. (B) Meta-analysis of PCR-adjusted parasitological treatment failure risk comparing ACTs versus non-ACTs, stratified by geographical region. (Note: Because statistical programs cannot handle 0% treatment failure for both arms in meta-analysis, information from Bounyasong [10] was entered as 1/28 for each arm, to attain a balanced risk ratio (RR) of 1 [26].) The shaded areas around the estimates are proportional to the weight of each study in the analysis. Abbreviations: AM, artemether; AQ, amodiaquine; AS, artesunate; ATP, atovaquone-proguanil; AZ, azithromycin; CD, chlorproguanil-dapsone; CI, confidence interval; L, lumefantrine; MQ, mefloquine; Q, quinine; SP, sulfadoxine-pyrimethamine.

Figure 3.

Polymerase chain reaction (PCR)-adjusted cure rates (proportions) after treatment with artemisinin-based combination therapies (ACTs) and non-ACTs for uncomplicated malaria in pregnancy. The number after the drug indicates the number of days the drug was given. The red dashed vertical bar indicates the 0.95 proportion mark, which is the cut-off recommended by the World Health Organization (WHO) as the minimum efficacy for antimalarial medicines to be adopted as part of national malaria programs [27]. Abbreviations: AM, artemether; AQ, amodiaquine; AS, artesunate; ATP, atovaquone-proguanil; AZ, azithromycin; CI, confidence interval; L, lumefantrine; MQ, mefloquine; Q, quinine; SP, sulfadoxine-pyrimethamine.

Figure 4.

Mean birth weight (grams) of newborns born to artemisinin-based combination therapy (ACT) and non-ACT recipients. (Note: All participants in the study by Kalilani et al [11] received the same treatment again at least 4 weeks after the first treatment, regardless of whether they were parasitemic at that subsequent visit.) The shaded areas around the estimates are proportional to the weight of each study in the analysis. Abbreviations: AM, artemether; AQ, amodiaquine; AS, artesunate; ATP, atovaquone-proguanil; AZ, azithromycin; CD, chlorproguanil-dapsone; CI, confidence interval; L, lumefantrine; MQ, mefloquine; N, sample size; Q, quinine; SD, standard deviation; SP, sulfadoxine-pyrimethamine.

Figure 5.

Other efficacy, safety, and tolerability outcomes and subgroup analyses by control drug. The Assumed control-group risk (ACR) represents the observed median risk (expressed per 100 women) and range for each subgroup in the control-drug arm. The range for the ACR is only provided to illustrate high‐ and low‐risk populations, whereas the median risk is illustrative of a population with a moderate risk. The Corresponding intervention-group risk ([CIR] 95% confidence interval [CI]) is the corresponding risk in the ACT group computed as the ACR × risk ratio ([RR] 95% CI) [28]. Heterogeneity relating to the extent that the RRs vary between subgroups are shown as the I² statistic, which depicts the percentage of the between‐study or between subgroup heterogeneity that is attributable to variability in the effect, rather than sampling variation. The corresponding P value is based on the χ² statistic. *The number in brackets depicts the number of studies that were excluded in the analysis because of 0 events in both arms. †Heterogeneity between subgroups (quinine vs other non-ACT as control drug): low birth weight I² 0%, P = .89; miscarriage or stillbirth I² 0%, P = .39; congenital abnormalities I² 0%, P = .48.