A large LSTM-led trial confirms that a new antimalarial, dihydroartemisinin-piperaquine, is more effective in Prevent malaria of current treatment recommended by the World Health Organization but does not improve adverse outcomes of childbirth.
A large multi-country trial of 4,680 women in sub-Saharan Africa, looking at a new antimalarial treatment for pregnant women in Africa, led by Professor Vico Ter Coel, Professor of Tropical Epidemiology, Liverpool School of Tropical Medicine, publishes results in The Lancet this week.
The trial, known as the IMPROVE trial, was jointly funded by the EDCTP-2 program (supported by the European Union) and the UK’s Joint Global Health Trials. It confirms that the new antimalarial, dihydroartemisinin-piperaquine, is better tolerated, safer and prevents malaria more effectively than the treatment currently recommended by the World Health Organization but does not improve birth outcomes.
Malaria during pregnancy can have severe consequences for the mother and the developing fetus, resulting in severe anemia in the mother, death of the mother, the mother losing the pregnancy or the baby being born too early or too small. These premature, low-birth-weight babies have four times the risk of dying within their first year.
The World Health Organization currently recommends using a form of malaria prevention called intermittent preventive therapy in pregnancy, or IPTp for short. IPTp is used in 35 countries in sub-Saharan Africa, but the malaria parasite is becoming increasingly resistant to the only drug currently recommended by the World Health Organization for IPTp: sulfadoxine-pyrimethamine (SP), which threatens it. effectiveness in eastern and southern Africa.
In 2003, researchers began a global series of clinical trials to find other antimalarials as suitable alternatives to SP. Of the five candidates evaluated, the antimalarial dihydroartemisinin-piperquine (DP) was the only candidate that was tolerated well enough to be considered for further trials. By 2015, DM was shown to be more effective than SP in killing malaria parasites or preventing new infections and reducing severe anemia in the mother. However, these earlier trials were not large enough to determine whether this also reduces the risk of babies being born too early or too small. WHO recommended that more research is needed to evaluate the effect of IPTp in combination with dihydroartemisinin-piperquine on adverse pregnancy outcomes.
In response, the LSTM IMPROVE study was conducted in 12 hospitals in high-malarial areas of western Kenya, northern Tanzania, and southern Malawi, in a multi-country collaboration.
The trial confirmed that the new antimalarial DP was well tolerated, safe and more effective than SP. However, the results on birth outcomes were surprising. Despite the apparent superior effect of DP on malaria infection, the risk of an adverse pregnancy outcome was lower, not higher, in the SP arm, the arm with the most malaria during pregnancy. Consecutive ultrasound scans showed that the babies showed better fetal development during pregnancy. The chance of being born with a low birth weight was 30% lower in the SP arm. There were no differences in the number of children born very early, pregnancy loss or early infant mortality. The study also revealed that mothers in the SP arm had better weight gain during pregnancy and better nutritional status at birth. Results were seen in all three countries, including northern Tanzania, which has the highest rates of SP resistance in sub-Saharan Africa.
The third arm, which involved adding a single dose of the broad-spectrum antibiotic azithromycin at enrollment in the monthly IPTp with DP, did not produce better pregnancy outcomes but increased the incidence of nausea in the mother.
Another surprising finding was that monthly SP was better at reducing the risk of contracting chlamydia, one of the sexually transmitted diseases we looked at, when compared to azithromycin, which is the WHO-recommended standard of care.”
Dr Matthew Chico, associate professor at the London School of Hygiene and Tropical Medicine, and co-author
Dr Mwayiwawo Madanitsa, Senior Lecturer and Chair, Department of Clinical Sciences, Academy of Medical Sciences, University of Malawi of Science and Technology, and first author, said: “These findings suggest that despite the waning antimalarial activity of SP, IPTp-SP continues to offer some benefits.” , even in areas with very high SP resistance. Our study also shows the importance of well-conducted trials before making policy recommendations.”
Vico Ter Coel, lead researcher, said: “These results were unexpected because they showed that the new antimalarial was more effective in treating and preventing malaria infection during pregnancy. However, children in standard care with SP did this much better in terms of birth weight, although newborns in this arm were born to mothers with twice the incidence of malaria during pregnancy than those in that arm.
“This is surprising because malaria is one of the most important causes of low birth weight. We now assume that SP has strong non-malarial effects on fetal development. This is not to say that MS does not have a beneficial effect on birth outcomes, but it does have a beneficial effect.” on birth outcomes.The malaria effects of SP on birth weight may outweigh any improvements in birth weight associated with better malaria prevention in the DP arm, masking the beneficial effects of DP.We do not yet fully understand how SP promotes increased gestational weight and fetal growth, regardless of its effects antimalarial. More research is needed to explore the mechanism.”
It remains to be seen whether WHO and countries in eastern and southern Africa have updated their recommendation for malaria prevention during pregnancy, in line with the findings. Feiko ter Kuile continues: “DP is clearly the most effective drug in reducing malaria during pregnancy. Therefore, if the main goal is to prevent severe malaria and malaria-related deaths in the mother, DP is the best option. However, there is another option.” Currently it is being explored combining the potent non-malarial effects of SP on fetal development with the superior antimalarial effects of DP, rather than replacing SP with DP in areas of high SP resistance.”
An accompanying commentary in The Lancet indicates that studies combining DP and SP are underway in Uganda and Papua New Guinea, and the first results may be available by 2025.
