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Title: Synthesizing the quality of study methodology and evidence to support guidelines for optimal treatment of falciparum malaria in pregnancy
Author: Saito, Makoto
ISNI:       0000 0004 8503 4014
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Pregnant women are particularly susceptible to malaria, which is the leading cause of mortality and morbidity of the mother and fetus in the tropics. The current World Health Organization (WHO) recommended study design for assessing antimalarial efficacy excludes pregnant women, which has resulted in fewer studies on treatment efficacy and greater variability of study designs in pregnant women. Based on limited evidence, WHO has recommended quinine (with clindamycin, if available) for first-trimester and artemisinin-based combination therapy (ACT) for second- and third-trimester women since 2015. The data on the safety of artemisinin-derivatives in the first trimester have been collected, mostly from inadvertent treatments, over two decades, and form reassuring evidence of safety, strikingly different to animal-based reproductive health studies. This thesis aims to summarize the evidence on the efficacy of antimalarials for uncomplicated falciparum malaria in pregnancy and to improve future research in tropical infectious diseases in pregnancy. Secondary data from prospective studies that assessed antimalarial efficacy by polymerase chain reaction were sought. Individual patient data of 4968 pregnant women (92% of all published work) from 19 studies in ten countries were pooled in a standardized format and analysed. These confirmed that quinine is less effective and less tolerable than ACTs. Quinine is also less suitable for elimination because of a higher risk of gametocyte development. Among ACTs, artemether-lumefantrine (AL) showed a slightly lower efficacy. In the second and third trimesters, the risks of congenital abnormality, miscarriage, stillbirth, preterm birth and small-for-gestational-age were similar among the four major ACTs (namely, AL, artesunate-amodiaquine, artesunate-mefloquine and dihydroartemisinin-piperaquine). Study designs need to be tailored for pregnant women. It is probably necessary to follow up pregnant women for longer to assess efficacy accurately, but proof can only be obtained by including them alongside non-pregnant reproductive-age women. To assess pregnancy outcomes, precise and reliable estimates of gestational age and longitudinal recording of repetitive malaria episodes through to delivery are essential. Quinine monotherapy should be replaced with ACTs for treating uncomplicated Plasmodium falciparum malaria in pregnant women. For AL, the most commonly used compound, dose optimization studies are needed. Investigations to find safe and effective drugs for pregnant women should be continued as every effort to prevent and reduce recurrence contributes to health of the mother and fetus.
Supervisor: Guérin, Philippe ; McGready, Rose Sponsor: Clarendon Fund
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pregnancy ; Infectious Diseases ; Malaria