May 24, 2017

Team finds no adverse risk to use of common antimalarials in first trimester

Women and their children await medical care at a clinic.

Women and their children await medical care at a clinic.Photo courtesty of Malaria in Pregnancy Consortium

UW and international researchers publish the most comprehensive international analysis on artemisinin combination antimalarials safety in pregnancy

Malaria is more common and severe in pregnant women, increasing their risk of miscarriage and other adverse outcomes. The adverse consequences of malaria in pregnancy require prompt, safe, and effective treatment. However, limited data on the safety of the most efficacious and widely used antimalarial medications, artemisinin combination therapies (ACTs), has prevented ACTs from being recommended in the first trimester except in life-saving circumstances. The World Health Organization currently recommends the use of ACTs in pregnant women in the 2nd or 3rd trimester.

An international collaboration led by first authors Stephanie Dellicour of the Liverpool School of Tropical Medicine, UK, and Esperança Sevene of the Manhiça Health Research Centre/Eduardo Mondlane University, Maputo, Mozambique, and senior author Andy Stergachis of University of Washington School of Pharmacy and School of Public Health released the largest meta-analysis of all observational studies-to-date showing there was no difference in the risk of miscarriage, still births or major birth defects associated with the use of artemisinins anytime during the first trimester, compared with quinine. The study, “First- trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies,” was published in PLoS Medicine and coordinated through the Malaria in Pregnancy Consortium, established in 2007 at the Liverpool School of Tropical Medicine to improve the control and prevention of malaria in pregnancy.

“This study is clearly significant and reflects many years of work in Thailand and Africa by a large group of scientists,” said Liverpool’s Professor Feiko ter Kuile, head of the Malaria in Pregnancy consortium. “We have been able to show that artemisinins, which we know to improve outcomes in malaria, are as safe to use in the first trimester as quinine, which is currently recommended in the first trimester, but needs to be taken 3 times per day for 7 days. Quinine is associated with transient side effects such a ringing in the ears and dizziness, leading women not to complete their treatment course and risking inadequately treating their malaria. The artemisinin-based combinations are more efficacious, much better tolerated and can be taken over three days.”

The team analyzed data from five studies involving 30,618 pregnancies: four studies from Zambia, Tanzania, Rwanda, Kenya, Mozambique, Burkina Faso, and one large study from the Thailand based Shoklo Malaria Research Unit. They examined the records of women who had taken artemisinins for malaria, including during the first trimester of pregnancy. In malaria endemic countries, many early pregnancies are advertently or inadvertently exposed to artemisinins because women are not aware they are pregnant or do not report an early pregnancy.

The team summarized all available safety data on the effect of artemisinin exposure in the first trimester and compared the risk of miscarriage, stillbirth, and major congenital anomaly for pregnancies treated with artemisinin, quinine, or no antimalarials in the first trimester.

Through their meta-analysis, they determined the risk of miscarriages, stillbirths, and major anomalies associated with first-trimester artemisinin treatment versus quinine. The results were then combined with summary effect estimates from the Shoklo Malaria Research Unit on the Thailand–Myanmar border.

They found no increase in the risk of miscarriage, stillbirth, or major birth defects associated with the use of artemisinins anytime during the first trimester compared with the use of quinine during the same gestational period. These findings suggest that the artemisinin class of antimalarials should be considered for treatment of malaria in the first trimester of pregnancy. The limited data on the risk of birth defects require further observational studies.

Limited safety data on the use of artemisinins in human pregnancies have historically prevented health authorities from recommending these therapies for malaria treatment in the first trimester, except in life-saving circumstances. It is possible that this study may result in a major change to recommended guidelines for the administration of artemisinins in the first trimester of pregnancy.

“Our results show that artemisinins can now be formally considered for first trimester treatment,” said Andy Stergachis, Professor of Pharmacy and Global Health, University of Washington. While there is more work to be done in terms of monitoring birth defects, the available evidence suggests that the benefits of using this class of antimalarial are likely to outweigh any adverse outcomes and could help save the lives and maintain the pregnancies of women when they are most vulnerable to malaria.”

This project was supported by the Malaria in Pregnancy (MiP) Consortium, which is funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine. The Malaria in Pregnancy Consortium consists of over 40 partner institutions in 29 countries around the world, joined in the fight against malaria in pregnancy and committed to improving its control and treatment in Africa, Asia and Latin America. The Shoklo Malaria Research Unit is part of the Mahidol Oxford University Research Unit, supported by the Wellcome Trust of Great Britain.

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About Liverpool School of Tropical Medicine

The Liverpool School of Tropical Medicine (LSTM) is the world’s oldest centre of excellence in tropical medicine and international public health. It has been engaged in the fight against infectious, debilitating and disabling diseases since 1898 and continues that tradition today with a research portfolio in excess of well over £210 million and a teaching programme attracting students from over 65 countries. LSTM has been the international coordinating centre for the Malaria in Pregnancy (MiP) Consortium (http://www.mip-consortium.org/) with over 40 research partners world-wide, established with a $30 million grant from the Bill and Melinda Gates Foundation and subsequent grants from European & Developing Countries Clinical Trials Partnership (EDCTP) and European Union. For more information please visit www.lstmed.ac.uk

About University of Washington School of Pharmacy

The UW School of Pharmacy is a global leader in pharmacy education, research and service, committed to providing a transformative learning experience in a collaborative and diverse environment focused on improving the health and well-being of the communities we serve. The UW School of Pharmacy is comprised of three departments: Medicinal Chemistry, Pharmaceutics, and Pharmacy, offering Ph.D., M.S., and PharmD degrees, post docs and certificate programs. The Department of Pharmacy leads in pharmacy education, research, professional and outreach initiatives, including the Pharmaceutical Outcomes Research & Policy Program (PORPP), which conducts research in pharmaceutical economics, drug safety and pharmaceutical policy.

About University of Washington School of Public Health

The UW School of Public Health, established in 1970, enrolls 1,500 students and has 270 primary and joint faculty members. Its mission is to create a world of healthy people in sustainable communities – locally, nationally and globally. Through its five departments, five interdisciplinary programs and more than 50 research centers, it carries out projects with partners in more than 130 countries.

About Shoklo Malaria Research Unit

The Shoklo Malaria Research Unit (SMRU) is a field station of the faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, and is part of the Mahidol-Oxford Research Unit supported by the Wellcome Trust, United Kingdom. The main objective of SMRU is to provide quality health care to the marginalized populations living on both sides of the Thai-Myanmar border in the Mae Sot area, Tak Province through the dual activities of research and humanitarian services, with an emphasis on maternal-child health and infectious diseases.