Optimization of intermittent preventive therapy for malaria during pregnancy : effectiveness of dihydroartemisinin-piperaquine versus sulfadoxine-pyrimethamine

Abstract: Malaria is a Tropical disease caused by different parasites species of genius Plasmodium. Because of pregnancy associated lowered immunity, women who are pregnant are at higher risk to malaria infection than non-pregnant women. Malaria infection in pregnancy is public health problem particularly in sub-Saharan Africa causing anemia to mothers, premature-birth, stillbirth and low birth weights (LBW) . To minimize the risk of malaria and its associated poor outcomes, the World Health Organization (WHO) endorsed preventive policy for all pregnant women residing in endemic areas. The policy include receiving intermittent preventive treatment in pregnancy (IPTp) with a drug sulfadoxine-pyrimethemine (SP) each month commencing from early second trimester, owning and using insecticide treated bed nets (ITNs) and timely symptomatic malaria case treatment. The rapidly growing resistance of malaria-causing organisms (P. falciparum) to SP rises questions on the potency of IPTp with SP (IPTp-SP). This activated the exploration of an alternative drug for IPTp. In endemic areas with high malaria transmission intensity, IPTp with dihydroartemisin-piperaquine (IPTp-DHP) given early during the second trimester (≤20 weeks) was reported to be superior to the standard IPTp-SP for protection against parasitemia and placental malaria but not negative birth outcomes. However, variability in malaria transmission intensity is a crucial factor which could possibly impact the outcomes of an intervention. In addition, the association between piperaquine pharmacogenetics and pharmacokinetics with IPTp-DHP outcomes were lacking in the literature. This thesis investigated the effectiveness of the standard monthly IPTp-SP versus IPTp-DHP for protection of malaria and negative birth outcomes from a setting with moderate malaria transmission intensity. We recruited women on their really timing to the first ANC, thus pregnant women both on their second and third trimesters were included. Firstly, we explored the burden of asymptomatic parasitemia, anemia and associated factors among pregnant women attending their first antenatal care (ANC) (Paper I). We found that, 36.4% of women had asymptomatic parasitemia associated with anemia at their initial ANC. Women who are pregnant for the first time and adolescent were found to have higher risk of asymptomatic parasitemia and anemia compared to women who are pregnant for more than once and adult, respectively. In paper II, we prospectively evaluated the safety and effectiveness of the standard IPTp-SP for preventing malaria in pregnant women and negative birth outcomes . We observed that, one sixth (16%), one fifth (20.9%), and one fourth (26.5%) of women receiving the standard monthly IPTp-SP had parasitemia during pregnancy, any parasitemia at delivery and any adverse birth outcomes, respectively. We also found 9.4% of women had histopathological placental malaria associated with negative birth outcomes. In addition, significant association between three and above doses of monthly IPTp-SP with improved birth weight was found as compared to less than three IPTp-SP doses. In paper III, the effectiveness of the standard monthly IPTp-SP for prevention of malaria and associated negative birth outcomes was compared with monthly IPTp-DHP in a randomized controlled trial. From a moderate P. falciparum transmission area, IPTp-DHP was found to be superior to IPTp-SP for prevention of symptomatic malaria and parasitemia during pregnancy, parasitemia and placental malaria at delivery. In addition, this thesis observed the superior impact of IPTp-DHP on birth weight as compared to the standard IPTp-SP for the first time. Finally, we assessed piperaquine pharmacogenetics and day-7 pharmacokinetics with their relevance on IPTp-DHP outcomes (Paper IV). We found Day-7 piperaquine concentration increasing significantly after each monthly IPTp-DHP. Women with day-7 piperaquine concentrations <30ng/mL were found to have significantly higher risk of having parasitemia during pregnancy as compared to those with higher concentration (≥30ng/mL). Also, carriers of defective CYP2C8 allele were found to have significantly lower day 7 piperaquine concentration overtime as compared to wild type. In conclusion, Asymptomatic malaria and associated anemia at first ANC visit is common in sub-Sahara Africa particularly among primigravida and adolescent pregnant women. In addition, we reported considerable burden of parasitemia, placental malaria and associated negative birth outcomes among women receiving the standard IPTp-SP. This thesis also reaffirmed the role higher doses of IPTp-SP in improving birth weight from areas with high P. falciparum resistance to SP. Notably, we reported for the first time the superior effect of IPTp-DHP for prevention of malaria in pregnancy and improving birth weight as compared to IPTp-SP from a setting with moderate malaria transmission intensity. We also reported significant association between lower day-7 piperaquine concentrations with the risk of malaria during pregnancy. Lastly, we found significant association between CYP2C8 genotypes with day-7 piperaquine pharmacokinetics.