Malaria in pregnancy studies address knowledge gaps in efficacy, safety

4 January 2018

A systematic review of research on treatments for malaria in pregnancy has suggested new approaches to analysing available efficacy data and to assessing and reporting safety in studies, two articles published recently in Malaria Journal report.

The articles reviewed 48 published efficacy studies of uncomplicated falciparum malaria in pregnancy treated with either artemisinin- or quinine-based treatments. The first article identifies research challenges, including gaps in available evidence on treatment efficacy, and describes how individual patient data meta-analyses (IPDs) can expand the field of analysis; the second article proposes a standard list of minimum parameters necessary to assess and report the pregnancy outcomes in efficacy studies.

Researchers value efficacy studies as a way to test how patients respond to treatment, and for the safety information about therapies that such studies provide – prospective clinical information researchers often lack in drug exposure studies.

“These studies are an important step that will advance work on treatment efficacy and improve the methodology for reporting safety in efficacy studies in the future,” said Dr Makoto Saito, the lead author of the studies and a researcher at the WorldWide Antimalarial Resistance Network (WWARN).

Standards for assessing the efficacy of antimalarial treatments exist but not for addressing the specific responses observed in pregnant women.

The first article presents available evidence from observational and interventional cohort studies on a population of pregnant women, and summarises the assessment and reporting employed. Researchers systematically reviewed the efficacy assessment methodologies for artemisinin- and quinine-based treatments using seven literature databases and two clinical trial registries.

The article showed that efficacy studies in pregnancy are not only limited in number but they use varied assessment methodologies. In five randomised control trials (RCTs) with comparable methodologies that rely on aggregated data, artemisinin-based treatments resulted in higher efficacy than quinine-based treatments in the second and third trimester of pregnancy.

However, aggregated data analysis does not allow comparison between artemisinin-based treatments or further exploration of the risk factors of treatment failure in this vulnerable population.

The paper shows that conducting an individual patient data (IPD) analysis is a desirable approach to summarising the available evidence because it can include data from a wider range of sources, such as non-RCTs, cohort studies, pharmacokinetic analyses and single arm studies. It also provides a list of suggested information to be assessed in antimalarial efficacy studies in pregnancy beyond the current WHO guideline for non-pregnant populations.

“These findings reflect the limited evidence available for measuring antimalarial efficacy and safety during pregnancy and highlight the scientific questions which could be addressed by conducting IPD meta-analyses,” said Prof Philippe Guerin, a co-author of the efficacy paper and WWARN’s Director. “They have the potential to increase our understanding of optimal study designs, which could lead to optimising treatment.”

The second article describes the methods used to assess the safety of artemisinin- and quinine-based treatments applied in efficacy studies.

Although recently there is growing evidence on the safety of antimalarial drugs, efficacy studies provide one of the few sources of clinical safety data, particularly regarding the prospective nature of the data and the detailed clinical and pathological information provided in addition to the drug exposure information.

Due to the incomplete reporting of – and the varying methodologies for assessing – pregnancy outcomes, researchers say it is difficult to compare studies. Therefore, the article proposes a standard list of minimum parameters necessary to assess and report safety in efficacy studies, including details about participants’ backgrounds; haematology; fetal loss; preterm birth; anthropometric assessment of infants; congenital abnormality; growth and development; and, mortality.

Authors said the paper would help close the gap in safety reporting and assessment.

“Defining this list of minimum parameters will help ensure that researchers produce efficacy studies with valuable safety content,” said Dr Saito.

Prof Rose McGready, a researcher at the Shoklo Malaria Research Unit (SMRU) in Thailand and a co-author of the safety paper, agreed.

“Given the paucity of safety studies of new treatments of antimalarials and other drugs in pregnant women, it is essential that drug efficacy work in resource-constrained settings reflects this important topic where possible,” said Professor McGready, who is based in Mae Sot, near the Burmese border. “We believe these papers together will help facilitate this provision, with some aspects applicable to other tropical infectious diseases.”

Publication details:

Saito M, Gilder ME, Nosten F, McGready R, Guérin PJ (2017), ‘Systematic literature review and meta-analysis of the efficacy of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: methodological challenges,’ Malaria Journal, doi: 10.1186/s12936-017-2135-y

Saito M, Gilder ME, Nosten F, Guérin PJ, McGready R, (2017), ‘Methodology of assessment and reporting of safety in anti-malarial treatment efficacy studies of uncomplicated falciparum malaria in pregnancy; a systematic literature review,’ Malaria Journal, doi: 10.1186/s12936-017-2136-x