Widely used malaria treatment to prevent malaria in pregnant women at risk of failing in areas where drug resistance is rising

IDDO's Malaria in Pregnancy Scientific Group (MiP) as part of its malaria platform WWARN, has recently published in the Lancet Infectious Diseases the results of a systematic review and meta-analysis of the drug-based strategy used to prevent malaria infections in pregnant women, led by Feiko ter Kuile at the Liverpool School of Tropical Medicine (LSTM). 

The WHO recommends intermittent preventive treatment (IPTp) in malaria endemic areas. The only antimalarial currently recommended for IPTp is Sulphadoxine-Pyrimethamine (SP); to date IPTp with SP has effectively resulted in reductions in maternal anaemia, low birth weight and neonatal mortality. However, with the growing threat of high-grade resistance of the malaria parasite to SP in Sub-Saharan Africa, this protection is now at risk.

The MiP Group worked with a multi-disciplinary team* to complete the most comprehensive study to date of the impact of SP drug resistance on the effectiveness of IPTp.

The results demonstrate that the effectiveness of SP in protection of pregnant women against malaria is compromised in certain areas. The team calls for further urgent investigation into alternative strategies or drugs to prepare for further growing resistance to this mainstay of preventive therapy.

It is estimated that without protection during pregnancy, 45% of 32 million pregnancies in malaria endemic Sub-Saharan Africa are exposed to Plasmodium falciparum malaria, leading to 900,000 malaria-associated low birthweight deliveries. Low birth weight, anaemia and other serious adverse birth outcomes result in numerous longer-term health issues for infants.

Prof ter Kuile from LSTM comments, “We reviewed more than 100,000 birth outcomes across Sub-Saharan Africa, and our results suggest that the widely used antimalarial SP for preventive therapy remains very effective in many parts of Africa, but that there is a clear trend toward reduced effectiveness with increasing levels of resistance of the malaria parasite to SP. In areas with the highest grade of resistance, where more than 37% of parasites carry six mutations in the so-called pfdhfr and pfdhps genes, the effectiveness of SP appears to be fully compromised. It is clear that in these high resistance settings alternative drugs or approaches for the prevention of malaria in pregnancy are urgently needed to achieve better birth outcomes for pregnant women.”

Carol Sibley, WWARN’s Senior Scientific Advisor, adds, “This large-scale analysis has given us a powerful message: the increasing prevalence of molecular markers of SP is correlated with a decrease in effectiveness of SP to reduce malaria infections in pregnant women and low birth weight in their babies. Since resistance evolves by an accumulation of specific mutations in the parasite, we also have a clear recommendation that molecular monitoring of levels of resistance of these parasites is a valuable tool for policy makers to monitor the spread of antimalarial resistance. This can support policy makers and health professionals to make important decisions about the need for alternative prevention options and therefore help to improve the lives of newborns in low income settings across Africa.”

Anna Maria van Eijk, first author concludes, “We are also calling for further analysis into the potential additional benefits that SP may continue to have on birth outcomes even in areas where it is no longer able to kill malaria parasites. For example, SP could also have anti-microbial effects, and anti-inflammatory and immune modulating effects, which could be similar to those discovered for the widely used antibiotic, cotrimoxazole. This is important as SP may not work as well as other antimalarials in high SP resistance areas, but it may still be able to help reduce poor birth outcomes, such as low birth weight, through these other mechanisms.

We hope that by examining the risks, outcomes and alternative strategies available we will ensure that vulnerable babies born in low resource settings are given the best possible chance of good health, by receiving the most effective antimalarial prevention approaches and medicines available to us today, and in the future.”

Discover our latest Malaria in Pregnancy research Study Groups:

• Screening strategies to prevent malaria in pregnancy Study Group led by Julie Gutman at CDC and Feiko ter Kuile.
• Subpatent Malaria and Pregnancy Outcome Study Group led by Annemieke van Eijk (Anna.vanEijk@lstmed.ac.uk), together with Jenny Hill Coordinating.
• Malaria in Pregnancy Treatment Efficacy Study Group led by Philippe Guérin and coordinated by Makoto Saito and Jenny Hill.

Study Groups to start soon:

• The effect of malaria in pregnancy on infant malaria, anaemia and growth, led by Annemieke van Eijk (Contact: Anna.vanEijk@lstmed.ac.uk)
• IPTp with dihydroartemisinin-piperaquine as alternative to IPTp with SP: IPD analysis. Led by Julie Gutman at CDC (Contact: fff2@cdc.gov) and Feiko ter Kuile (feiko.terkuile@LSTMed.ac.uk).

Read the paper: Anna Maria van Eijk et al. Effect of Plasmodium falciparum sulfadoxine-pyrimethamine resistance on the effectiveness of intermittent preventive therapy for malaria in pregnancy in Africa: a systematic review and meta-analysis. Lancet Infectious Diseases. Online March 25, 2019.

*Research partners for the Lancet ID paper included Syracuse University, University of Sciences, Techniques, and Technologies of Bamako, Mali, London School of Hygiene & Tropical Medicine, Imperial College, UK; the Centers for Disease Control & Prevention, University of Washington, University of North Carolina, and Duke University in the USA and the University of Melbourne, Australia. See the paper for a full list of co-authors.