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Title: The potential of intermittent screening and treatment with dihydroartemisinin-piperaquine for the control of malaria in pregnancy in areas with high sulphadoxine-pyrimethamine resistance
Author: Madanitsa, Mwayiwawo
ISNI:       0000 0004 6057 8488
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2015
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Importance: In Africa most P. falciparum malaria infections during pregnancy remain asymptomatic yet are associated with maternal anaemia and low birthweight. WHO recommends intermittent preventive therapy in pregnancy during the second and third trimester with Sulphadoxine-Pyrimethamine (IPTp-SP). However, SP efficacy is threatened by high-level parasite resistance. Thesis objectives: The objectives of this thesis were three fold: Efficacy and safety of ISTp-DP To evaluate the efficacy and safety of scheduled intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with Dihydroartemisinin-piperaquine (ISTp-DP) as an alternative strategy to IPTp-SP in an area of high malaria transmission and SP resistance. Effect of asymptomatic malaria infections To investigate the effect of asymptomatic malaria infections, specifically evaluating the role of asymptomatic infections missed by a malaria rapid diagnostic test (mRDT) on pregnancy and birth outcomes. Diagnostic sensitivity of HRP2/pLDH RDT for active placental malaria To determine the sensitivity of an mRDT to detect active malaria infection sequestered in the placenta. Design, setting, and participants: This was an open-label two-arm individually randomised superiority trial in 3 sites with high SP resistance in Malawi. Between July 2011 and March 2013, 1873 HIV-seronegative women at 16-28 weeks of gestation were recruited (1155 primigravidae and secundigravidae [paucigravidae], 718 multigravidae). Interventions: IST and IPTp-SP were administered at 3 or 4 scheduled visits in the 2nd and 3rd trimester, 4 to 6 weeks apart. The IPTp-SP arm received SP at each visit. The ISTp-DP arm were screened for malaria at every visit and treated with DP if RDT-positive. Main outcomes and measures: Efficacy and safety The primary outcomes of interest to evaluate the efficacy and safety of ISTp-DP were gravidity dependent. Amongst paucigravidae these were any adverse live birth outcome (composite of small-for-gestation age, low birthweight or preterm birth) whilst amongst multigravidae, any P. falciparum infection at delivery was of primary interest. Analysis was by modified intention to treat. Effect of asymptomatic malaria infections Outcomes of interest in this analysis were composite adverse live birth outcome, individual adverse live birth outcomes (small for gestational age, preterm birth and low birthweight) and maternal anaemia. Analysis was restricted to only women in the IST arm fulfilling the modified intention to treat criteria. Diagnostic sensitivity of HRP2/pLDH RDT for active placental malaria The diagnostic sensitivity of mRDT on peripheral maternal venous blood at delivery for active placental malaria against placental histology as the gold standard was the primary outcome of interest. Analysis included women from both trial arms at delivery. Results: Efficacy and safety The prevalence of adverse birth outcome was similar in both arms: ISTp-DP=29.9%, IPTp-SP=28.8%, Risk-Difference: 1.08%, 95% confidence interval (CI): -3.25 to 5.41; Relative Risk (RR) =1.04 (0.90-1.20), p=0.625, (paucigravidae: RR=1.10 [0.92-1.31], p=0.282; multi-gravidae RR=0.92 [0.71-1.20], p=0.543). The prevalence of malaria at delivery was higher in the ISTp-DP arm (48.7% vs 40.8%): Risk-Difference=7.85 (3.07-12.63); RR=1.19 (1.07-1.33), p=0.007 (paucigravidae: RR=1.16 [1.04-1.31], p=0.011; multi-gravidae: RR=1.29 [1.02-1.63], p=0.037). Foetal loss was more common with ISTp-DP (2.6% vs 1.3%; RR=2.06 [1.01-4.21], p=0.046) and highest among non DP-recipients (3.1%) in the ISTp-DP arm. Effect of asymptomatic malaria infections by RDT 46.2% of women had malaria infection by either RDT or PCR at their first antenatal visit. The prevalence of sub-RDT infection was consistently higher in multigravidae than paucigravidae throughout pregnancy. The risk for any placental malaria was higher with asymptomatic missed RDT parasitaemia than never having had any detected parasitaemia at study visits: 38.8% vs 20.4%; RR= 1.90; 95% CI 1.28, 2.82; p=0.002. This was consistent when stratified by gravidity. Missed infections were also associated with higher risk for composite any adverse live birth outcome (26.5% vs 12.8%; RR=2.06; 95%CI 1.23, 3.42; p=0.005) which was driven by the strong association with preterm birth: 19.1% vs 4.1%; RR=4.7; 95% CI 2, 11.1; p<0.001. Asymptomatic patent RDT infections were associated with increased risk for maternal anaemia, placental malaria, composite adverse live birth outcome, preterm birth and low birth weight. Diagnostic sensitivity of HRP2/pLDH RDT for active placental malaria Peripheral blood RDTs at delivery were 48% sensitive (95% C.I 39.6, 56.4%) to diagnose active placental malaria infection. This was lower than PCR (64% vs 48%; difference=16.4%; 95% CI 8.4, 24.5%; p < 0.001) but higher than LM (48% vs 16%; difference=31.5%; 95% CI 22.4, 40.6%; p < 0.001). The sensitivity of RDTs on placental blood to diagnose active placental infection was lower than in peripheral blood: 34% vs 48%; difference=-13.7%; 95% CI -21.1, -6.3%, p < 0.001. Peripheral blood RDT had a low diagnostic sensitivity at 70% (95% CI 47.1, 86.8%) in detecting an active placental infection density of above 100 parasites/500 RBCs, associated with an increased risk of low birth weight. Conclusion and relevance: Scheduled screening for malaria parasites with RDTs provided 3 to 4 times during pregnancy as part of focused antenatal care was not superior to IPTp-SP in a setting of high SP resistance, being associated with higher foetal loss and more malaria at delivery. This may be attributable to the effect of asymptomatic parasitaemia that are left to persists in the peripheral blood without treatment due to low rate of detection of infection by RDTs through subsequent antenatal visits, and/or the low sensitivity to detect active infection sequestered in the placenta. As such, in areas with high SP resistance, ISTp-DP is not a viable option. There remains an urgent need to identify alternative drugs that can replace SP for antenatal malaria prevention.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral