Improving treatment for malaria in pregnancy

Malaria in pregnancy can have devastating consequences for the mother and the unborn child. To reduce the risk in sub-Saharan Africa, where 32 million pregnancies occur annually, the World Health Organization (WHO) recommends the use of intermittent preventive treatment in pregnancy (IPTp). The strategy has proven to be very effective in reducing maternal anaemia, low birth weight and neonatal deaths.

Sulfadoxine-pyrimethamine (SP) is currently the only antimalarial medicine recommended for IPTp, however, high levels of parasite resistance to this drug in some parts of Africa now threaten the efficacy of this treatment.

In Africa, 37 countries currently implement the IPTp policy using SP;the rise in SP resistance has subsequently led to increased pressure from malaria-endemic countries for further guidance from the WHO on the effectiveness of IPTp-SP in areas where resistance occurs.

To support the WHO with the design of a molecular policy decision tool for IPTp, partners from the Malaria in Pregnancy (MiP) Consortium* and WWARN worked together to assess the impact of SP resistance on the effectiveness of IPTp in reducing the risk of low birth weight.

Data from 42,000 births recorded from observational studies, randomized trials and household surveys were combined with data on molecular markers of SP resistance from WWARN’s first molecular surveyor database. In addition, prospective molecular data were added from the lab of Prof Steve Meshnick from the University of North Carolina.**

The meta-analysis showed a clear and significant trend towards lower effectiveness of IPTp with increasing SP resistance. The effectiveness varied from a 30% reduction in the risk of low birth weight in West African regions with low resistance to an 8% reduction in areas with high resistance. The 8% reduction occurred in areas of east and southern Africa where there is a high prevalence of the Pfdhps-K540E (a proxy for the quintuple pfdhps/dhfr haplotype), suggesting some beneficial impact remains, albeit modest and clearly much less than in the low resistance areas in West Africa.

However, further analysis showed that the beneficial effect of SP was no longer evident in ‘super resistant’ areas*** where the prevalence of parasites with an additional mutation (Pfdhps-A581G a proxy for the ‘sextuple’ haplotype) exceeded 10% prevalence. In these areas the risk of low birth weight was the same in women who received SP versus those that did not.

These collaborative analyses concluded that IPTp-SP remains associated with a reduction in low birth weight up to very high levels of parasite resistance, but that the effectiveness is compromised once the prevalence of the super resistant sextuple haplotype exceeds 10%. The study also showed that the use of molecular policy decision tools, when combined with clinical data, are potentially useful to guide IPTp-SP treatment implementation.

Prof Feiko ter Kuile from the Liverpool School of Tropical Medicine and lead author comments on the studies, “These new insights are very helpful. Although it was of course anticipated that SP resistance would decrease the effect of IPTp, it was not clear what the actual impact was and at what levels the effectiveness would be compromised to a degree that countries should consider switching to alternative medicines. Fortunately super resistant parasites remain relatively rare, for now, providing countries with some time to prepare for a switch to alternative treatment approaches.”

But what alternative strategies are available? Fortunately trials conducted by the MiP Consortium are exploring several alternative approaches for IPTp. ‘Intermittent Screen and treat (IST)’ trials are nearing completion and the final results will be available and shared with the WHO and malaria community in mid-2015.

To date, WWARN has not yet systematically collected or collated data on the treatment and prevention of malaria drugs in pregnancy. WWARN hopes to work closely with partners from the MiP Consortium to develop a malaria in pregnancy module. These collaborations could work to ensure that the infrastructure, databases and expertise relevant to resistance - including the efficacy, safety, tolerability and pharmacokinetic properties of antimalarials in pregnancy - can also integrate with efforts by the WWARN network to continue to provide valuable evidence to inform malaria treatment policies and programmes.

*The Liverpool School of Tropical Medicine (LSTM) is the coordinating centre of the global Malaria in Pregnancy Consortium, comprising 47 partner institutions in 31 countries around the world undertaking a joint programme of research to improve the control of malaria in pregnancy.

** The Molecular resistance assays were run in the laboratory of Prof Steve Meshnick as part of the MiP Consortium’s ‘IPTp Monitoring study’ lead by Dr Meghna Desai from CDC-Kenya and Prof Feiko ter Kuile from LSTM.

***Super resistant was first defined by Cally Roper, Senior Lecturer at London School of Hygiene & Tropical Medicine and co-contributor to the development of the dhps 540E Molecular Surveyor.