Opinion: Malaria clinical research must include pregnant women

Malaria is a dangerous disease. One that, according to the World Health Organization, resulted in 249 million cases and 608,000 deaths in 2022 worldwide. For pregnant women, particularly those in their first trimester, it can cause serious complications, a concern for over 120 million women of childbearing age living in malaria-endemic areas. Malaria in pregnancy can result in maternal and neonatal mortality, miscarriage, low birth weight, and stillbirth.

United Nations member states adopted the Sustainable Development Goals in 2015, which include Goal 3 of ensuring healthy lives and promoting well-being for all at all ages, and Goal 5 of achieving gender equality and empowering all women and girls by 2030. The SDGs include specific targets for ending malaria, ending all forms of discrimination against women and girls, and achieving universal health coverage. However, medicines can take 20 years to be approved for use in pregnant women; time that the global health community does not have if it is to meet the 2030 deadline to achieve these goals.  

Few medicines for malaria in the first trimester

In 2014, researchers Bich-Tram Huynh, Gilles Cottrell, Michel Cot, and Valérie Briand asked if the burden of malaria in early pregnancy was a neglected problem. A decade later, there have been few victories, but progress is (slowly) being made: At the end of 2022, WHO updated its guidelines for malaria to include a strong recommendation for the first artemisinin-based combination therapy, or ACT, artemether-lumefantrine to treat malaria during the first trimester of pregnancy. Artemether-lumefantrine was registered in 1998 and has become the most commonly used ACT in children and adults infected with malaria parasites.

In 35 countries in sub-Saharan Africa, intermittent preventive treatment of malaria in pregnancy, or IPTp, is a monthly intervention, typically administered by community health workers, to prevent malaria infection in pregnant women. However, there is only one drug, sulfadoxine-pyrimethamine, recommended for IPTp by WHO. This drug is contraindicated for use in the first trimester, as well as by pregnant women with HIV who take preventive treatment to guard against opportunistic infections. Yet research shows that over 60% of malaria in pregnancy cases take place in the first trimester, making it an urgent issue.

Pregnant women have been excluded from clinical trials for fear of causing harm to both the mother and her baby. This leads to pregnant patients routinely receiving therapies that have not been adequately studied in pregnancy. Dr. Catriona Waitt from the University of Liverpool argued that it is misguided to exclude pregnant women from clinical trials to minimize risk.

“Worldwide, at least a third of pregnancies are unplanned, and in many regions of the world, late presentation to antenatal care is common … If a drug is prescribed to those with childbearing potential in a population, pregnancy exposures will occur, but outside a trial context these will not be carefully scrutinized and there may be a delay in recognizing any adverse effects.”

In other words, excluding pregnant women from clinical research puts them at greater risk of adverse effects in the real world due to the lack of evidence on how they can safely use medicines.

Medicines for all pregnant women

Universal health coverage means that all people have access to the full range of quality health services they need, when and where they need them, without financial hardship. Without rapid action from relevant partner groups, it will be impossible to achieve health coverage for pregnant women and other at-risk groups.

Their needs should be considered from drug discovery through development and post approval. New drugs should be assessed for potential toxicity, appropriate dosage, and administration to pregnant women. National ethics committees and regulators must be sensitized to the importance of enrolling pregnant women in clinical trials, especially in their first trimester.

As with all clinical trials, culturally appropriate informational materials that enable study participants to understand the purpose, risks, and benefits of their participation, and informed consent forms should be provided. In the preclinical phase of drug development, using in vitro assays — experiments conducted outside of a living organism — enables researchers to prioritize lead compounds that are nontoxic to fetal development. Once they are selected, compounds should go through the required regulatory developmental and reproductive toxicity studies to test the potential effects on embryos.

Once a drug reaches the clinical research phase, mathematical models can help researchers adjust drug doses appropriate for pregnant women prior to their participation in a study and possible exposure of the baby to the drug. In phase I clinical studies, a compound is typically tested for the first time in healthy people, while in phase II, it is tested in patients to assess safety and tolerability, efficacy, and dosing. When phase III — large-scale pivotal — studies start for the general patient population, researchers can begin phase I studies in pregnant patients in parallel and continue to phase II-III development if the risk-benefit is deemed appropriate. Such a staggered approach could ensure that the gap in the availability of new medicines is minimized, and access is more equitable.

A malaria-free future for pregnant women

Achieving a malaria-free future requires a shift in the way partners think about clinical research. Rather than “protecting” groups at risk for malaria from clinical research, partners must recognize that it is better to include their needs in drug discovery and development. While scaling up measures like IPTp with SP for eligible pregnant women, the global health community must also prioritize finding new tools to protect and treat pregnant women at risk of malaria.