Pharmacovigilance

Project Coordinator:    Prof Andy Stergachis (University of Washington, USA)

Prof Esperanca Sevene (Eduardo Mondlane University, Mozambique), Dr Stephanie Dellicour (LSTM, Kenya), Prof Halidou Tinto (Research Institute of Health Sciences (IRSS), Burkina Faso)

There were two primary objectives for this area of work. The first was to set up Centralised Safety Database (CSD) to record drug safety information in relation to all of the drugs used in the MiP Consortium clinical trials. The second was the to look at safety of all antimalarials used during pregnancy in the Assessment of the Safety of Antimalarial Drug Use During Early Pregnancy (ASAP) study with a cohort of over 2,800 pregnant women.

Centralised Safety Database: All serious adverse events from the MiP Consortium trials was collated and analysed at LSTM. Newborn training materials were developed and provided to all the MiP trials for standardised assessment in each site.

Observational cohort study (ASAP): A cohort study of over 2,8000 pregnant women in Burkina Faso, Kenya and Mozambique was undertaken with the aim of developing field-test active surveillance tools to assess pregnancy outcomes related to malaria. The primary analysis compared artemisinin vs quinine exposures during the first trimester of pregnancy, while secondary analysis examined artemisinin as well as quinine exposures vs those unexposed in the first trimester of pregnancy.

Overall, no safety concerns were identified from the aggregated data from across the MiPc trials.

An individual patient level data meta-analysis of data from the ASAP sites and data from additional studies conducted in Zambia, Rwanda, and Tanzania, showed there was no increased risk of miscarriage, stillbirth or congenital anomalies following artemisinin treatment for uncomplicated malaria in either the first trimester of pregnancy or during the embryo-sensitive period, compared to oral quinine. In a subsequent meta-analysis of safety data from 717 artemisinin and 947 quinine documented exposures in the first trimester from Asia and Africa, results showed that, contrary to data from animal models, ACT exposure in the first trimester of pregnancy does not increase the risk of miscarriage, stillbirths or major congenital anomalies compared to quinine (Dellicour et al, 2018).

The results were presented and reviewed by WHO-ERG and MPAC in 2015 which recommended the review of the WHO Guidelines for the treatment of malaria to consider the timely inclusion of ACT as a first-line therapeutic option for (first trimester) uncomplicated falciparum malaria (see WHO Malaria Policy Advisory Committee (2016). "Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of eighth biannual meeting (September 2015)." Malar J 15(1): 117.). This recommendation was subsequently endorsed by WHO’s Technical Expert Group on Malaria Chemotherapy in December 2017 (World Health Organization. Intermittent screening and treatment in pregnancy and the safety of ACTs in the first trimester, November 2015, recommendations (WHO/HTM/GMP/2015.9). 2015.). The update of these guidelines by WHO is anticipated to enable national programmes to markedly improve the standard and quality of case management in the first trimester, compared to current practice which is based on 7 days of quinine which has to be taken 3 times daily and is badly tolerated resulting in low adherence and frequent treatment failure and adverse consequences to pregnancy outcomes.