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

Saito, Makoto; Mansoor, Rashid; Kennon, Kalynn; Anvikar, Anupkumar R.; Ashley, Elizabeth A.; Chandramohan, Daniel; Cohee, Lauren M.; D’Alessandro, Umberto; Genton, Blaise; Gilder, Mary Ellen; Juma, Elizabeth; Kalilani-Phiri, Linda; Kuepfer, Irene; Laufer, Miriam K.; Lwin, Khin Maung; Meshnick, Steven R.; Mosha, Dominic; Muehlenbachs, Atis; Mwapasa, Victor; Mwebaza, Norah; Nambozi, Michael; Ndiaye, Jean-Louis; Nosten, François; Nyunt, Myaing M.; Ogutu, Bernhards; Parikh, Sunil; Paw, Moo Kho; Phyo, Aung Pyae; Pimanpanarak, Mupawjay; Piola, Patrice; Rijken, Marcus J.; Sriprawat, Kanlaya; Tagbor, Harry; Tärning, Joel; Tinto, Halidou; Valéa, Innocent; Valecha, Neena; White, Nicholas J.; Wiladphaingern, Jacher; Stepniewska, Kasia; McGready, Rose; Guérin, Philippe J

doi:10.1186/s12916-020-01592-z

Cited by 16 publications

(19 citation statements)

References 65 publications

(93 reference statements)

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“…The prevalence of SGA (26.3%) was slightly higher than the regional estimate (21.6%, 14.2 to 37.7) [ 37 ], but similar to that among women who had malaria in pregnancy in this area reported previously (27%) [ 38 ]. The positive association between the increased number of malaria episodes in pregnancy and SGA is consistent with previous reports [ 9 , 38 ]. This emphasizes the importance of prevention of malaria in pregnancy.…”

Section: Discussionsupporting

confidence: 92%

“…Artemisinin-based combination therapy (ACT) is recommended as the first-line treatment for both falciparum and non-falciparum malaria [ 3 ]. In pregnancy, ACTs have superior efficacy, effectiveness and tolerability compared with quinine in the treatment of falciparum malaria [ 4 ] and are considered safe during pregnancy, including in the first trimester; previous meta-analyses of clinical studies showed that artemisinin in the first trimester was not associated with increased risks of miscarriage, stillbirth or congenital abnormality compared with quinine [ 5 – 9 ].…”

Section: Introductionmentioning

confidence: 99%

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A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border

Saito

Carrara

Gilder

et al. 2021

BMC Med

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Background Artemisinin and artemisinin-based combination therapy (ACT) partner drug resistance in Plasmodium falciparum have spread across the Greater Mekong Subregion compromising antimalarial treatment. The current 3-day artemether-lumefantrine regimen has been associated with high treatment failure rates in pregnant women. Although ACTs are recommended for treating Plasmodium vivax malaria, no clinical trials in pregnancy have been reported. Methods Pregnant women with uncomplicated malaria on the Thailand-Myanmar border participated in an open-label randomized controlled trial comparing dihydroartemisinin-piperaquine (DP), artesunate-mefloquine (ASMQ) and a 4-day artemether-lumefantrine regimen (AL+). The primary endpoint for P. falciparum infections was the PCR-corrected cure rate and for P. vivax infections was recurrent parasitaemia, before delivery or day 63, whichever was longer, assessed by Kaplan-Meier estimate. Results Between February 2010 and August 2016, 511 pregnant women with malaria (353 P. vivax, 142 P. falciparum, 15 co-infections, 1 Plasmodium malariae) were randomized to either DP (n=170), ASMQ (n=169) or AL+ (n=172) treatments. Successful malaria elimination efforts in the region resulted in premature termination of the trial. The majority of women had recurrent malaria (mainly P. vivax relapses, which are not prevented by these treatments). Recurrence-free proportions (95% confidence interval [95% CI]) for vivax malaria were 20.6% (5.1–43.4) for DP (n=125), 46.0% (30.9–60.0) for ASMQ (n=117) and 28.7% (10.0–50.8) for AL+ (n=126). DP and ASMQ provided longer recurrence-free intervals. PCR-corrected cure rates (95% CI) for falciparum malaria were 93.7% (81.6–97.9) for DP (n=49), 79.6% (66.1–88.1) for AMSQ (n=55) and 87.5% (74.3–94.2) for AL+ (n=50). Overall 65% (85/130) of P. falciparum infections had Pfkelch13 propeller mutations which increased over time and recrudescence occurred almost exclusively in them; risk ratio 9.42 (95% CI 1.30–68.29). Among the women with falciparum malaria, 24.0% (95% CI 16.8–33.6) had P. vivax parasitaemia within 4 months. Nausea, vomiting, dizziness and sleep disturbance were more frequent with ASMQ. Miscarriage, small-for-gestational-age and preterm birth did not differ significantly among the treatment groups, including first trimester exposures (n=46). Conclusions DP was well tolerated and safe, and was the only drug providing satisfactory efficacy for P. falciparum-infected pregnant woman in this area of widespread artemisinin resistance. Vivax malaria recurrences are very common and warrant chloroquine prophylaxis after antimalarial treatment in this area. Trial registration ClinicalTrials.gov identifier NCT01054248, registered on 22 January 2010.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border

Saito

Carrara

Gilder

et al. 2021

BMC Med

Self Cite

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“…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].…”

Section: Uncomplicated and Complicated Malaria In Second And Third Trmentioning

confidence: 99%

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

Khaja

Sequeira

2021

Malar J

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Background Malaria caused by Plasmodium falciparum in pregnancy can result in adverse maternal and fetal sequelae. This review evaluated the adherence of the national guidelines drawn from World Health Organization (WHO) regions, Africa, Eastern Mediterranean, Southeast Asia, and Western Pacific, to the WHO recommendations on drug treatment and prevention of chloroquine-resistant falciparum malaria in pregnant women. Methods Thirty-five updated national guidelines and the President’s Malaria Initiative (PMI), available in English language, were reviewed. The primary outcome measures were the first-line anti-malarial treatment protocols adopted by national guidelines for uncomplicated and complicated falciparum malaria infections in early (first) and late (second and third) trimesters of pregnancy. The strategy of intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) was also addressed. Results This review evaluated the treatment and prevention of falciparum malaria in pregnancy in 35 national guidelines/PMI-Malaria Operational Plans (MOP) reports out of 95 malaria-endemic countries. Of the 35 national guidelines, 10 (28.6%) recommend oral quinine plus clindamycin as first-line treatment for uncomplicated malaria in the first trimester. As the first-line option, artemether–lumefantrine, an artemisinin-based combination therapy, is adopted by 26 (74.3%) of the guidelines for treating uncomplicated or complicated malaria in the second and third trimesters. Intravenous artesunate is approved by 18 (51.4%) and 31 (88.6%) guidelines for treating complicated malaria during early and late pregnancy, respectively. Of the 23 national guidelines that recommend IPTp-SP strategy, 8 (34.8%) are not explicit about directly observed therapy requirements, and three-quarters, 17 (73.9%), do not specify contra-indication of SP in human immunodeficiency virus (HIV)-infected pregnant women receiving cotrimoxazole prophylaxis. Most of the guidelines (18/23; 78.3%) state the recommended folic acid dose. Conclusion Several national guidelines and PMI reports require update revisions to harmonize with international guidelines and emergent trends in managing falciparum malaria in pregnancy. National guidelines and those of donor agencies should comply with those of WHO guideline recommendations although local conditions and delayed guideline updates may call for deviations from WHO evidence-based guidelines.

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“… c Statistical analyses compared the PCR‐corrected failure rates to that for AL (artemether–lumefantrine); data from Saito, Mansoor, Kennon, Anvikar, et al, 2020. …”

Section: Clinical Studies Of Oral Artemisinins Acts and Quinine In Tmentioning

confidence: 99%

“…In an analysis of 2,987 pregnant women with malaria (primarily in the second or third trimester) from four studies that assessed placental histopathology at term, the risk of malaria pigment deposition in the placenta (indicating past or chronic placental infection) did not differ significantly among five artesunate/ACT treatments (67–87% with pigment deposition) and quinine (68% with pigment deposition) when compared to artemether–lumefantrine (83% with pigment deposition (Saito, Mansoor, & Kennon, 2020).…”

Section: Clinical Studies Of Oral Artemisinins Acts and Quinine In Tmentioning

confidence: 99%

Teratogen update: Malaria in pregnancy and the use of antimalarial drugs in the first trimester

Clark

2020

Birth Defects Research

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Malaria is a particular problem in pregnancy because of enhanced sensitivity, the possibility of placental malaria, and adverse effects on pregnancy outcome. Artemisinin-containing combination therapies (ACTs) are the most effective antimalarials known. WHO recommends 7-day quinine therapy for uncomplicated Plasmodium falciparum malaria in the first trimester despite the superior tolerability and efficacy of 3-day ACT regimens because artemisinins caused embryolethality and/or cardiovascular malformations at relatively low doses in rats, rabbits, and monkeys. The developmental toxicity of artesunate, artemether, and DHA were similar in rats but artesunate was embryotoxic at lower doses in rabbits (5 mg/kg/day) than artemether (no effect level = 25 mg/kg/day). In clinical studies in Africa, treatment with artemether-lumefantrine in the first trimester was observed to be highly efficacious and the miscarriage rate (≤3.1%) was similar to no antimalarial treatment (2.6%). When data from the first-trimester use of largely artesunate-based therapies in Thailand were pooled together, there was no difference in miscarriage rate compared to quinine. However, individually, artesunate-mefloquine was associated with a higher miscarriage rate (15/ 71 = 21%) compared to other artemisinin-based therapies including 7-day artesunate + clindamycin (2/50 = 4%) and quinine (92/842 = 11%). Thus, appropriate statistical comparisons of individual ACT groups are needed prior to assuming that they all have the same risk for developmental toxicity. Current limitations in the assessment of the safety of ACTs in the first trimester are a lack of exposures early in gestation (gestational weeks 6-7), limited postnatal evaluation for cardiovascular malformations, and the pooling of all ACTs for the assessment of risk.

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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

Cited by 16 publications

References 65 publications

A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border

A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border

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

Teratogen update: Malaria in pregnancy and the use of antimalarial drugs in the first trimester

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