Editorial: Maternal malaria: time for action

Among human parasitic diseases, malaria remains the world's most important cause of morbidity and mortality. The impact of malaria on health and on development is huge and, because of the spread of drug resistance in P. falciparum, it is worsening. In all endemic regions, children and pregnant women are the two groups mostly at risk of severe disease and death. The true magnitude of the burden of maternal malaria is unknown, but recent reports indicate that it may be much higher than previously thought. For example recently, falciparum malaria was identified as the leading cause of maternal death in a hospital study in Mozambique (Granja et al. 2001) and in a population in Zimbabwe (Rutgers 2001). Falciparum malaria is particularly lethal in pregnant women during epidemics. Through the adverse effects of malaria on birthweight and prematurity, maternal infection also results in excess infant mortality (Luxemburger et al. 2001; Steketee et al. 2001). In areas of high stable transmission, the most visible impact of malaria on maternal health is severe anaemia, an important contributor to maternal mortality (Brabin et al. 2001). Prevention strategies include vector control (impregnated bed nets) and chemoprophylaxis (where still effective) or intermittent preventive treatment (IPT). In areas of low or unstable transmission, severe disease is more common and early detection and prompt treatment are essential to reduce mortality. In all situations antimalarial drugs play the central role. It is recommended that pregnant women living in malaria-endemic areas receive antimalarial chemoprophyl-axis – but with what drug? Chloroquine, still the most widely recommended and used antimalarial for pregnant women in Africa, has become ineffective against P. falciparum in most endemic countries. There is no universally effective drug, with a similarly good safety profile in pregnancy, to replace it. This is partly the result of the systematic exclusion of pregnant women from any drug development programme, because of the fear of potential adverse effects on the unborn child. In a world increasingly driven by economic forces, the spectre of liability looms over the pharmaceutical industry and also over international institutions. The debate on antimalarials for pregnant women has shifted from 'Which drug has the most favourable risk-benefit ratio for the mother?' to 'Who is responsible if an unwanted side effect of the drug on the foetus is discovered?' In endemic areas of Africa, most of the pregnant women remain unprotected against malaria. Those who are treated, often receive ineffective drugs. These are difficult times for public health authorities in many malaria-affected countries, as they come under increasing pressure to change antimalarial drug policies. In this issue of TMIH, Newman and colleagues present a comprehensive analysis of available antimalarials, with the aim of helping maternal malaria prevention programmes in sub-Saharan Africa. Importantly, the authors take into account not only the efficacy of various drug regimens (using the data on children as a proxy of the efficacy in pregnancy, because there are usually no data for pregnant women) but also their 'effectiveness': a combination of efficacy with availability, acceptability, affordability, and deliverability. It was concluded that, the best possible option to date is to use intermittent presumptive therapy (IPT) with sulfadoxine-pyrimethamine (SP). Five studies have been conducted, all in high transmission settings in East Africa (two in Malawi and three in Kenya). These have shown that two treatment doses of SP given to HIV-negative mothers during pregnancy, can reduce maternal anaemia (significant in three of the four studies in which this was evaluated) and low birth weight (two of four studies) (Schultz et al. 1994; Parise et al. 1998; Verhoeff et al. 1998; Shulman et al. 1999). Three doses are needed for HIV-positive mothers. On the basis of these results, IPT is now recommended for pregnant women by WHO (2000) and more recently, has been proposed for infants and children (Pasha et al. 2003). But resistance to SP has taken hold in East Africa, where 28-day failure rates range between 30 and 60% and it is spreading rapidly across the continent; for example SP failed to cure more than 50% of the treated children in a recent study from Liberia (Checchi et al. 2002). Newman et al. describe the therapeutic efficacy of SP as being 'fair to good' in most of Africa, but this may be over-optimistic. Since the four pivotal studies on the use of SP-based IPT were conducted in Kenya and Malawi 5 years ago, resistance to SP has worsened significantly in East Africa. Although, therapeutic responses in mothers may be better than in children, because of their greater immunity, SP resistance is likely to have compromised the undoubted benefits seen in these trials already. Mutations conferring resistance to sulfadoxine and pyrimethamine are spreading fast, encouraged by the increased gametocyte production observed in patients treated with SP. There is no doubt we are losing SP; the only question is 'How fast?' If adopted widely, the recommendation of Newman et al. to use SP may soon have to be changed because of resistance. But implementing changes in drug policies is a lengthy and painful process, and it is notoriously difficult to achieve. The deployment of SP across Africa is part of a wider debate, on the use of antimalarials. The main WHO–RBM contributors (USAID and DFID) have been encouraging the use of SP across Africa for all cases of malaria (not just in pregnancy) as a temporary response to the final demise of chloroquine and the resulting serious increase in morbidity and mortality. This approach is based – as in the paper of Newman et al. – on the claim that SP has the best 'efficacy-effectiveness' score. There are serious objections to this, notably from the African malaria control programmes themselves and from WHO and malaria researchers (McNeil 2002). As emphasized rightly by Newman and colleagues, the 'practice' of treating patients with ineffective drugs must be abandoned. Efficacy is essential for effectiveness. Combination therapies containing artemisinin derivatives are the most efficacious antimalarial treatments (WHO 2001). In all trials in Africa, adding artesunate to SP has resulted in consistently faster clinical recovery and higher parasitological cure rates. But pregnant women have been excluded from systematic studies because of concerns over the safety of artemisinin derivatives in pregnancy. The paradox is that SP is not free of toxicity to pregnant animals (Phillips-Howard & Wood 1996; Uche-Nwachi 1998) and fewer than 2000 exposed pregnancies have been documented properly, although SP is certainly widely used and is generally regarded as safe. On the other hand, the artemisinin derivatives are being denied to pregnant women, in programmatic terms, despite no evidence of adverse effects in more than 600 well-documented exposures (McGready et al. 2001). The artemisinin derivatives have been known for many years to induce foetal resorption in early animal pregnancy, and so does SP. A recent WHO consensus meeting concluded after detailed review of all available evidence that artemisinins could be used in the second and third trimesters but, pending further information, should not be used in the first trimester (WHO 2002). Malaria control programmes urgently need to know if artemisinin combinations (ACT) can replace the failing SP for IPT in pregnancy. We strongly support the plea of Newman and colleagues for urgent evaluation of ACTs in pregnancy. If we are to achieve the Abuja declaration objectives of providing pregnant women with effective malaria prevention and treatment by the year 2005, action is needed. New strategies of prevention and treatment (and the means to support them) must be developed and must be adapted to the various epidemiological situations within and outside Africa. Further data on the safety and efficacy of ACT treatment must be obtained urgently in pregnant women. Large community studies of their use in IPT should start in high transmission areas where SP resistance is established. Large-scale deployment of ACTs should be accompanied by a surveillance system, to monitor their positive and any negative impact in pregnancy. There is a pressing need to evaluate the true burden of maternal malaria: to improve detection, prevention and treatment in high transmission settings, to revisit the dogma that pregnant women in hyperendemic malarious areas remain asymptomatic, and to try and measure the malaria attributable direct and indirect maternal mortality. ACTs require administration over 3 days for the treatment of malaria. Efforts will be needed to improve prescribing practices and packaging to improve adherence, particularly if 3-day regimines are used as IPTs in otherwise healthy women. More information is needed on the relationship between levels of resistance, and effects of IPT on maternal anaemia and birth weight, and also the relative effectiveness of insecticide-impregnated bed nets and IPT, and the interaction between the two, at differing levels of transmission intensity. Only then can a risk-benefit analysis for the mother be performed, based on evidence. This will be achievable if the 'partnership' between the governments, the pharmaceutical industry, international institutions and the research community is more than a trendy, but often empty word. In sub-Saharan Africa and elsewhere, maternal malaria is a potentially life-threatening disease. Pregnant women and their babies need protection by truly effective antimalarial drugs. It is certainly time for action, and time is running out. Authors Dr François Nosten (corresponding author) and Dr Rose McGready Shoklo Malaria Research Unit, P.O. Box 46, 63110 Mae Sot, Thailand. E-mail: shoklo@cscoms.comProf. Sornchai Looareesuwan and Prof. Nicholas J. White Faculty of Tropical Medicine, Mahidol University, 121–126 Rajvithi Road, 10400 Bangkok, Thailand E-mail: fnnjw@diamond.mahidol.ac.th