Invitations to contributors for the meta-analysis were sent out in Q3 2015. Data analysis has been completed and the publication is planned for Q3 2016. 

Malaria infection during pregnancy is a major public health problem, with the potential to cause severe maternal and fetal morbidity and mortality.¹ The World Health Organization (WHO) recommends a three pronged approach to control malaria in pregnancy including the provision of intermittent preventive treatment in pregnancy (IPTp) using sulphadoxine-pyrimethamine (SP), the use of insecticide-treated nets (ITNs), and appropriate case management through prompt and effective treatment of malaria in pregnant women.²

Effective case management of first trimester malaria infections is particularly important as women do not usually benefit from preventive interventions until later in the pregnancy. This is because women usually initiate antenatal care, where they receive MiP prevention, in their second trimester, and IPTp with SP is contra-indicated in the first trimester due to fear of potential neural tube defects associated with folate antagonists such as sulphadoxine.

Artemisinin-based combination therapy (ACT) is the first line treatment for uncomplicated malaria in the second and third trimesters recommended by the WHO. ACTs are not currently recommended for treatment of pregnant women in their first trimester unless it is the only treatment available, or if treatment with quinine plus clindamycin fails or uncertainty of compliance with a 7-day treatment exists.  This restriction is based on embryo-toxicity identified in animal studies and the limited information on human exposures.

Animal reprotoxicology studies showed that artemisinin derivatives have embryotoxic effects in all species studied (i.e. rat, rabbit and monkey) at low dose ranges. The embryotoxic effects were observed with all artemisinin derivatives (including artesunate, artemether, dihydroartemisinin, arteether, artemisone and artelinic acid), indicating a general class effect. Pre-clinical studies showed that the mechanism of embryotoxicity was through insult to immature red blood cells (primitive erythroblasts) causing severe anaemia in the embryo and leading to either embryolethality or malformations, skeletal (shortened or bent long bones and scapulae, misshapen ribs, cleft sternebrae and incompletely ossified pelvic bones) and cardiovascular (ventricular septal and vessel defects). Embryolethality was observed in monkeys but only after prolonged 12 days of treatment. No malformations was observed in exposed monkeys.

Recent observational studies have revealed that in actual practice, women in their first trimester were more likely to be treated with an ACT than with quinine in sub-Saharan Africa.^{3, 4, 5, 6} This is because women may not know or declare they are pregnant at the time of seeking care, because quinine is unavailable, less well tolerated and/or or because healthcare providers and drug dispensers may not know that ACTs are not currently recommended in the first trimester.

Clinical trials that assess the safety and efficacy of new drugs, including antimalarials, typically exclude pregnant women due to fear of harm to the mother and her fetus. Evidence for treating pregnant women in early pregnancy is scarce and is based on observational rather than interventional studies.⁷  Moreover, many adverse pregnancy outcome events, such as specific congenital anomalies, are rare and large sample sizes from well-designed studies are needed.  This can be pooled data from multiple studies.

The First Trimester Safety of ACTs Study Group’s aim is to establish the evidence-base and safety profile to inform decision-making on the use of artemisinin combination therapies in the first trimester of pregnancy. To achieve these important goals, we aim to pool individual patient data from all available observational studies to better define the safety of ACTs in the first trimester to inform WHO policy and clinical practice.

The specific objectives are:

1. Conduct a IPD meta-analysis to assess whether use of artemisinin derivatives in the first trimester increase the risk of adverse pregnancy outcomes relative to quinine or no antimalarial treatment in prospectively followed pregnancies.
2. Promote optimal data collection in any future observational studies of antimalarials in first trimester pregnancy through, for example, scientific support, sharing tools, and providing advice. 

• Prospective observational studies in first trimester pregnant women

• Baseline data on patient demographics
• Drug regimen
• Follow-up of pregnant women to delivery or termination of pregnancy

• Information on dosing (mg/kg)
• Safety data to include information on pregnancy outcomes, including those defined as serious adverse events during follow-up

Once uploaded into the WWARN Data Repository, prospective datasets will be standardised according to the WWARN Clinical (and, if applicable, Pharmacology) Data Management and Statistical Analysis Plan. Data sets will be pooled into a single database of quality-assured individual patient data. A full Statistical Analysis Plan will be developed collaboratively and approved by the Study Group prior to the analysis. 

The Study Group comprises investigators who contribute relevant data sets to the pooled analysis and invited technical experts. Data sets remain the property of the investigator. More details about sharing data with WWARN and how WWARN will use data are available on the WWARN website.

The Study Group collectively makes decisions with respect to including additional studies, data analysis and plans for publication, in line with the WWARN Publication Policy. Prof Andy Stergachisand and Dr Esperanca Sevene lead the Study Group, and Dr Stephanie Dellicour is the Scientific Coordinator for the Study Group.

For further information, email Dr Stephanie Dellicour: stephanie.dellicour@LSTMed.ac.uk or clinical@wwarn.org.