Tropical Health Matters

At our panel on malaria in pregnancy during the Women Deliver conference, a participant asked about the importance of cerebral malaria (CM) in pregnancy. Below is a brief review of recent available literature, which does indeed highlight CM as an important danger to pregnant women in certain settings.

For the most part the literature mentions the problem of CM in the form of review without presenting original data. For example, malaria is cited as one of the most frequent parasitic diseases in pregnancy in tropical countries, with CM as an important complication. [1] Such reviews distinguish that CM is more common and dangerous in low or seasonal transmission areas where the population has not built some natural immunity. CM has a wide geographic scope according to Karnad and Guntupalli who said that, “Infections such as cerebral malaria and acute viral hepatitis with fulminant hepatic failure are common causes of coma and seizures during pregnancy in tropical regions of Asia, Africa, and Latin America. [2]

As noted by Duffy and Fried, “In low transmission areas, women of all parities are at risk for severe syndromes like cerebral malaria, and maternal and fetal mortality are high. In high transmission areas, where women are most susceptible during their first pregnancies, severe syndromes like cerebral malaria are uncommon.” [3] Likewise, “Acute and severe consequences of pregnancy-associated malaria (PAM), such as materno-fetal death or cerebral malaria, seem limited to unstable malaria areas.” [4]

An example of a specific study came from Ethiopia where Mengistu et al., observed that, “Out of 204 reproductive age women admitted with severe malaria 57.8% were pregnant. Signs of severity occurred more frequently in the pregnant women and rural dwellers. The several neurological manifestations were most common complications for more than 70.0% of the pregnant women and in 60.0% of the non-pregnant women, namely cerebral malaria, convulsions, altered mental state and prostration. The case fatality rate 33.1% among the pregnant women was found to he significantly higher than the non pregnant (p = 0.03, OR 2.2. 95% confidence interval 1.1-4.2).” [5] Much of malaria in Ethiopia is of the highland and seasonal variety.

In addition a 10-year review of malaria in pregnancy cases in Karnataka, India, which had risen to an incidence1.3% in 1998, found that, “Complications noted in our study were haemolysis, renal failure, hepatopathy and cerebral malaria.” [6] In the Arusha highlands a study of maternal death documented, “cerebral malaria [as a cause] of indirect death, accounting for 20 cases, with most of them occurring during an epidemic season.” [7]

Although at present the biggest attention to malaria in pregnancy is focused on stable transmission areas of the African region, this brief review suggests that vigilance to protect pregnant women from CM in all malaria zones is required. Not only are preventive interventions needed early in antenatal care, but staff involved in emergency obstetric care need to be trained to manage CM.

References.

1. Bourée P, Bisaro F. Parasitic diseases and pregnancy [Article in French] Rev Prat. 2007; 57(2):137-47

2. Karnad DR, Guntupalli KK.Neurologic disorders in pregnancy. Crit Care Med. 2005 Oct;33(10 Suppl):S362-71.

3. Duffy PE, Fried M. Malaria in the pregnant woman. Curr Top Microbiol Immunol. 2005; 295:169-200.

4. Cot M, Deloron P.Malaria prevention strategies. Br Med Bull. 2003;67:137-48.

5. Mengistu G, Diro E, Kassu A. Outcomes of pregnancy in severe malaria with emphasis on neurological manifestations in Gondar Hospital northwest Ethiopia. Ethiop Med J. 2006; 44(4):321-30.

6. Sitalakshmi S, Srikrishna A, Devi S, Damodar P, Mathew T, Varghese J. Changing trends in malaria–a decade’s experience at a referral hospital. Indian J Pathol Microbiol. 2003 Jul;46(3):399-401.

7. Olsen BE, Hinderaker SG, Bergsjø P, Lie RT, Olsen OH, Gasheka P, Kvåle G.Causes and characteristics of maternal deaths in rural northern Tanzania. Acta Obstet Gynecol Scand. 2002; 81(12): 1101-9.

Bill and Melinda Gates held an important malaria summit this week, where Melinda Gates stressed , “A goal of anything short of eradication would be unethical and a bad business decision, despite unsuccessful efforts to stamp out the disease in the 1950s and 1960s.” She stressed that scientific advances since those early eradication days make it worthwhile to revisit the idea of eradication. Truly there are vaccines on the horizon, new malaria treatments, long lasting insecticide nets, a variety of insecticides for IRS and strategies like IPTp to prevent malaria in pregnancy that did not exist before.

Bill Gates also pointed to the relatively large infusion of funding into malaria control: “The new initiatives have committed 3.6 billion dollars to control malaria.” Though of course this is still below amounts needed for control, let along eradication. This raises the issue of national and health systems support, not only in terms of financially matching donor funds but also in guaranteeing a system that is capable of long term sustainability of gains and concerted prompt effort to really achieve eradication.

A veteran in the efforts to eradicate smallpox and guinea worm, Donald Hopkins of the Carter Center, did raise a note of caution. “We have a very complicated disease with a history of failure in eradication,” he said. Simply striving to control the disease is a difficult enough task, he pointed out.” Experience has shown that eradication needs to rally strong human, organizational, financial and technical resources in a relatively short period of time. The lack of the organizational resources was a stumbling block of first effort to eradicate malaria, and one needs to be sure that health systems are up to the task this time. GFATM and World Bank do give resources for health systems strengthening, but other malaria programs do not.

Donors and people lose interest if eradication is promised but not fulfilled. “Bill Gates also called on US politicians running in the 2008 presidential campaign to keep Bush’s 1.2 billion-dollar malaria initiative alive,” according to the Seattle Times, so the advocacy process for eradication has started. Let’s take this as a sign of hope, but remain realistic of the hard work needed by all partners to make eradication happen.

Over 2500 people have gathered in London to observe the 20^th anniversary of the launching of the Safe Motherhood Initiative at the Women Deliver Conference. While progress has been reported over half a million women still die annually of pregnancy and child birth related causes. In fact there has been little progress in sub-Saharan Africa since 1995 where the maternal mortality rate (MMR) still hovers around 900/100,000. Not coincidentally, this is the region where the threat of malaria in pregnancy (MIP) is highest.

Big disparities and inequities were reported not only between developed and developing countries (the former having a MMR of only 9/100,000), but even between rich and poor women within developing countries. A major concern is the lack of access to quality antenatal and obstetric care. In fact it is challenges in the health care system that make it deliver malaria in pregnancy control services effectively through ANC.

In recognition of the role of malaria in maternal health, the Women Deliver Conference is holding a panel on Malaria in Pregnancy, organized by JHPIEGO. I am moderating the panel and have able input from four colleagues.

• Scott Filler from the US Centers from Disease Control is talking about the importance and efficacy of sulfadoxine-pyrimethamine as the foundation of Intermittent Preventive Treatment
• Kaende Munguti of JHPIEGO’s Kenya office is sharing success stories from Kenya, Tanzania, Burkina Faso and Madagascar in improving the quality of ANC and IPTp coverage
• Lori Jackson of ExxonMobil is discussing the corporate role in promoting women’s health and sharing experiences from the ExxonMobil supported MIP projects of JHPIEGO in Nigeria and Kenya
• Juliana Yartey of WHO is stressing the importance of integrating MIP control into maternal and reproductive health services as the way to sustain MIP services
• Scott Filler again is explaining the role of the US President’s Malaria Initiative in providing IPTp, ITNs and malaria medicines to support MIP activities in its 15 countries.

Join us on the Women Deliver website to learn how to ensure that safe motherhood will become the reality promised in the Millennium Development Goals before 2015.

A recent WHO publication, Preventing Disease through Health Environments, addresses environmental factors responsible for malaria spread and control. Malaria contributed 10% to the environmental burden of disease for children aged 0-14 years worldwide. Specifically, “An estimated 42% of the global malaria burden, or half a million deaths annually, could be prevented by environmental management.” According to the document, There are three main approaches to the environmental management of malaria:

• Modify the environment. This approach aims to permanently change land, water or vegetation conditions, so as to reduce vector habitats.
• Manipulate the environment. This approach temporarily produces unfavourable conditions for vector propagation and therefore needs to be repeated.
• Modify or manipulate human habitation or behaviour. This approach aims to reduce contact between humans and vectors

Although some elements of individual and household behavior are involved in environmental control, it would be be an exercise in victim blaming to assume that individuals and households can take the main responsibility for taking environment measures. Water supply, drainage, road construction, river and stream control and other environmental measures are the responsibility of institutions and governments. Unfortunately such infrastructural improvements are costly, and one does not see them addressed in major malaria control programs like GFATM and PMI.

The World Bank has noted that, “Malaria affects millions in the East Asia and Pacific (EAP) region and impedes economic development, particularly affecting the rural poor. In the early 1900s malaria was controlled in many parts of the region using environmental management (EM) for vector control. EM is where the environment is modified or manipulated to reduce malaria transmission by attacking local vector mosquitoes and requires an understanding of the ecology of these species. Today malaria control is based on drugs and insecticides…” Because of questions of sustainability and resistance, the possibility of a return to environmental management is raised.

The World Bank’s Malaria Booster Program document does consider some elements of environmental management, but many of these fall more in line with integrated vector control measures in country examples like IRS, larviciding, and larvivorous fish. Some mention is made of filling spots of standing water. The larger infrastructural issues are not addressed. This is not to say that wider World Bank projects don’t address such issues, but what is needed is a more integrated approach that the malaria control potential of infrastructural projects is assessed and planned. Other development partners need to join in this effort.

For the past several years a consortium has been investigating whether intermittent preventive treatment with sulfadoxine-pyrimethamine (SP) for infants (IPTi) could be as effective a malaria control tool as its counterpart for pregnant women (IPTp). According to Ghanaweb.com on Friday, “Professor John Gyapong, Director of the Health Research Unit of the GHS (Ghana Health Service, noted that IPTi with SP had been found to be very efficacious, safe and cost effective.” Reductions in malaria and related factors found in the Ghana research are seen in the attached graph.
Although Prof. Gyapong appeared to advocate for quick adoption of IPTi in Ghana, he also did note that WHO has yet to endorse the practice. In fact some would say that a verdict on IPTi is overdue considering the volume of research generated so far and available for review on the IPTi Consortium website. This delay may not be surprising based on the reluctance of WHO’s Global Malaria Program to embrace IPTp even though evidence of its effectiveness persists.

Of course, there are some legitimate concerns about expanding IPT, which need to be addressed, even based on the data generated in Ghana. Among these issues are the following:

• resistance of parasites to SP
• appropriateness of EPI as a delivery mechanism for IPTi
• equity of access to IPTi
• timing of IPTi dosages
• concerns about seasonality of transmission

These issues are explored in detail in the various journal articles available for free download at the IPTi website. Fortunately, Dr. Andrea Egan from IPTi Consortium has assured that, “a comprehensive research and implementation agenda had been developed to resolve any outstanding scientific questions on whether IPTi was safe and effective to use as a malaria control intervention and move the intervention into policy and practice.”

Clearly IPTi would not be implemented as a stand alone intervention, but would and should be integrated with other control measures including ITNs and prompt case management with ACTs. There is always benefit to having another strategy to add to a comprehensive malaria program in order to outwit mosquitoes and parasites.

Malaria and HIV overlap in much of Africa. In 2004 WHO held discussions about potential interactions between HIV and malaria. At that time the technical group found there was need for more research to determine if there were any interactions of any magnitude between HIV drugs and artemether, lumefantrine or quinine.

Two recent reports address HIV and Malaria drug interactions. German et al. published a brief correspondence entitled, “Hepatotoxicity Due to a Drug Interaction between Amodiaquine (AQ) plus Artesunate and Efavirenz.” Parikh et al. have also suggested potential problems. “Considering drugs likely to be coadministered with AQ, the antiretroviral drugs efavirenz, saquinavir, lopinavir, and tipranavir (could inhibit AQ metabolism and) may have important clinical implications for the efficacy and toxicity of AQ.” Meanwhile, Kokwaro and colleagues indicate that the jury is still out on interactions between artemether-lumefantrine and antiretrovirals.

Bretlinger et al. express concern that “Standard clinical guidelines do not reflect the full complexity of the interactions and overlaps between the 2 infections” because of their “vertical” nature. Now that more is becoming known about HIV-Malaria interactions generally and drug interactions specifically, the time for integrated disease management guidelines is upon us. WHO and partners like GFATM, US Government (PMI, PEPFAR) and World Bank, among others need to come together and develop an integrated approach to researching, funding and fighting these two diseases.

In its most recent newsletter “Malaria Bytes” Care Net Nigeria raises an important health and development question – can Local African pharmaceutical manufacturers play a bigger role in production of needed drugs to treat malaria. Although this issue is not yet posted to the website, the two previous offerings are available for download. In West Africa several drug exporters (e.g. IPCA) and manufacturers (e.g. SWIPHA) have stepped in with branded artesunate-amodiaquine (AS-AQ) products in both adult and child packets. There are many other AS-AQ producers and suppliers. As we know, Coartem, the artemether- lumefantrine (AS-AL) ACT is only produced by Novartis to date. This ‘monopoly’ is supported by WHO’s prequalification processes, although one AS-AQ manufacturer has been added. Mepha also markets its artesunate + mefloquine product in Africa.

Even with these pharmaceutical participants, there are still challenges. For example, when Ghana introduced AS-AQ as a first line ACT, there were problems with formulation and strong side effects. Quality control is needed. In 2005 Ghanaian health authorities had to withdraw the drug for more safety testing.

Recent discussions with representatives of the private sector in Kenya aired concerns that technical assistance is needed to help the African based pharmaceutical manufacturers improve their quality and capacity. In parallel there was also a call for technical assistance to help national Food and Drug Agencies/Authorities improve their capacity for testing and monitoring. Care Net Nigeria echoes this view: “Rather than continue with the monopoly already created by the Global Fund and WHO, manufacturers in developing countries should be assisted to catch up with the quality standards through this financial boom.” Such assistance is needed if the growing gap in malaria treatment needs is to be closed.

The Future Health Systems (FHS) Research Programme Consortium aims to find ways to translate political and financial commitments to meet the health needs of the poor. The consortium addresses fundamental questions about the design of future health systems, and work closely with actors who are leading the transformation of health systems in their new realities. This consortium addresses fundamental questions about the design of future health systems, and works closely with people who are leading the transformation of health systems in their own countries. FHS research themes are:

• Protecting the poor against the impact of health-related shocks
• Developing innovations in health provision
• Understanding health policy processes and the role of research

Eight partners in eight different countries are exploring various ways to make health systems work for the poor. The team based at the University of Ibadan, Nigeria, has been exploring the role of Patent Medicine Vendors (PMVs) in providing quality, appropriate malaria treatment in the poor communities where they are based. A recent workshop analyzed and wrote a working paper based on the first-year scoping study.

Several key aspects of PMV behavior and knowledge were identified. “This study has documented the problems that people have in getting access to appropriate treatment for malaria. They have little knowledge of the changing patterns of drug resistance and the consequent changes in the drugs that are effective. They must rely either on traditional practices or on the advice of the people who provide the drugs. Since patent medicine vendors provide anti-malarial treatment in a substantial proportion of cases, their knowledge and practice strongly influence people’s wellbeing. This study made two major findings about this knowledge and practice. First, patent medicine vendors have little knowledge about new guidelines for drug use and they still recommend that people use drugs whose efficacy is doubtful. Second, there is a lot of concern about the quality of the drugs they supply. Action is needed to address these problems.”

Watch here as well as the FHS website for further updates on this important research that documents the challenges of a major informal provider, the patent medicine vendor, who has been ignored in formulating malaria access policy. In fact the 2003 Nigeria Demographic and Health Survey found that only about 25% of parents sought malaria treatment for their children in the formal sector. The few efforts to train and upgrade PMVs has been documented by BASICS, but more needs to be done if malaria drugs are going to reach all.

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As a note of interest, the previous entry here on Kenya’s looming drug shortage was filed from one of only two cyber cafes in the town of Igbo-Ora in southwest Nigeria pictured here. The town has 60,000 residents, but electricity is erratic to rare. It took several visits to find that the cafe’s generator was working strongly enough to access this site and make a posting. That is life on the edge of the digital divide. This current posting is being made at the airport lounge in Lagos on wireless connection – shows how the average person in Africa has little access to the internet to gather malaria information and engage in malaria advocacy.

Not long ago, Kenya was sharing its malaria achievements with the Director of WHO’s Global Malaria Program. According to a government brochure to mark the occasion, “12 million treatment doses of the new first line treatment, artemether-lumefantrine, have been procured and distributed.” In addition after the new drug treatment policy was rolled out in 2006, “numbers of children accessing free treatment in government health facilities (increased) from 50% to 63%.” In this column we also made note of the importance of Kenya’s national policy of universal coverage rather than targeting only vulnerable groups. It would seem that these achievements are at risk.

The East African Standard quoted the advocacy group Kenya NGO Alliance Against Malaria (KeNAAM) on 28th September 2007 that, “Failure on the part of the Government to budget for this vital drug and to adequately account for Global Funds resources now puts the lives of thousands of Kenyans at risk”.

Although we found stocks of artemether- lumefantrine in clinics in the Kisumu area in late August 2008, apparently there are stock-outs now that threaten the life saving achievements to date. KeNAAM therefore, calls on other donors to step in and fill the void.

A closer look into the funding situation sheds some light on the current problem. Kenya has two grants from the Global Fund to fight AIDS, TB and Malaria (Rounds 2 and 4) as can be found on the GFATM website. Round 2 includes drugs for integrated management of child illness (IMCI) along with ITNs and IPT. The Round 4 Grant addresses prompt reatment, epidemic control and ITNs. According to the Grant Score Card for Phase 1 of the Round 2 Grant, only half of the funds planned were disbursed due to slow implementation and late reporting.

The Round 2 Grant was given a ‘conditional go’ requiring additional clarification from Kenya’s Central Coordinating Mechanism before additional funds could be released. Additional report cards on the GFATM website show that disbursements have been held up due to procurement problems as well as lack of forecasting based on workplans.

Although disbursements for Round 4 are more closely in line with expectations, the grant report card still expresses concerns about procurement, transparency and also linkages with Round 2 activities.

Like KeNAAM we stress the need for all donors to help in the short term. In the long term though there is need for
better management of GFATM resources. The competition for these resources is high, and malaria proposals have not fared as well as those for TB and HIV, in part due to management problems and bottlenecks in national malaria programs. Kenya would do well by its people by paying more heed to the accountability and performance standards required from the Global Fund.

Population Action International made an important point that the Global Fund to Fight AIDS, TB and Malaria could save even more lives it it addressed reproductive health issues. In particular PAI explains that, “After just a few short years, the Global Fund has saved over 1.8 million lives worldwide. Just think what can be accomplished—how many more lives saved—if the Global Fund partnered with the life-saving work of sexual and reproductive health providers.”

In the area of Malaria control, GFATM funds to contribute toward improving reproductive health through a variety of malaria in pregnancy (MIP) interventions including 1) Intermittent Preventive Treatment (IPTp) with sulfadoxine-pyrimethamine (SP), 2) long lasting insecticide-treated bednets (LLINs) and prompt and appropriate case management with artemisinin-based combination therapy (ACTs)

Of course the potential for including MIP in GF proposals and the actual emphasis on MIP in reality are sometimes different. Since SP is so cheap, its procurement is often overlooked. A recent visit to rural Kenyan clinics found plenty of ACT stocks, but stockouts of SP. ACTs are procured with GAFTM funds through international contracts, while SP is often purchased locally when funds are available in national health budgets.  LLINs are often distributed widely to children under five years of age through well publicized campaigns, while it is difficult to get a bednet as part of regular antenatal care in come countries.  Often GFATM projects are implemented through the vertical disease units in health agencies, leaving little opportunity for reproductive health, or even integrated management of childhood illness units to become involved.
So in short, while we might point out that reproductive health issues can already be part of GFATM activities in principle, we agree with Population Action International that active involvement of reproductive health services, particularly in our area of malaria control, is urgently needed.