Malaria in pregnancy: research must be stepped up

3 Nov 2009

Tatum Anderson

Source: TropIKA.net

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Professor Rose Gana Fomban Leke.

Not enough research is being done on malaria and pregnancy. That’s the message from Rose Gana Fomban Leke, Professor of Immunology and Parasitology at the University of Yaoundé in Cameroon, who has spent the best part of her career looking at how malaria affects women.

Fifty million pregnant women contract malaria around the world every year. The disease can have dramatic and tragic consequences, resulting in pregnancy loss, maternal death, severe maternal anaemia and low infant birth-weight, which greatly increases the risk of death.

Indeed, malaria in pregnancy is estimated to claim the lives of 100,000 children every year and, in sub-Saharan Africa, it is responsible for 25,000 maternal deaths, according to the Malaria in Pregnancy Consortium (MiP), a collection of research groups led by the Liverpool School of Tropical Medicine.

But although many groups look at malaria in pregnancy, Professor Leke comments that few laboratories have committed to basic research in this area, particularly at the level of the placenta.

“We are one of the few labs that have developed expertise in the area of malaria in pregnancy and have looked more into the placenta, how it affects mother and baby,” she says. “Even today you don’t find too many labs involved in doing the longitudinal studies that we are doing. There are only a few in the world.”

Drumming up interest

Leke has taken to hosting workshops to drum up interest from other laboratories. In 2004, the University of Yaoundé hosted an NIH-funded workshop on placental malaria. And more recently, her team hosted another conference for MiP.

Focus on the area has certainly improved since Leke wrote her first grant proposal – to study malaria in pregnancy more closely – in the early nineties. Then, there was little interest or understanding of how the disease affected women, she says.

She established that pregnant women, who had been infected with malaria, sometimes showed no evidence of parasites in their blood using microscopy smear tests, the traditional way to determine whether a patient has been infected with malaria.

“We started out with diagnosis, because we realised sometimes women have malaria but when you take a smear you don’t see the parasites,” she says.

Her team looked at the placentas and cord blood of a thousand women and found that a fifth contained parasites in the placenta, but not in the blood. A link has subsequently been made between parasites in the placenta and premature deliveries and low birthweight babies.

This work is part of a long-term collaboration with Professor Diane Taylor of Georgetown University in the US (who has now moved to the University of Hawaii). The two have collaborated since 1990, first on Malaria during Pregnancy, then on further studies, including one looking at the acquisition of immunity to malaria in Cameroon, from 1999 to 2004. As well as collaborations with US researchers, Leke has also helped to build a Cameroon-based multi-disciplinary team with her husband, Robert Leke, now retired, but currently chair of Cameroon’s obstetrician and gynaecologist association.

“We work together – the paediatricians, clinicians, gynaecologists, and researchers – on the projects,” she says.

Leke and Taylor’s work on malaria in pregnancy came just before ground-breaking research carried out at NIH by Michal Fried and Patrick Duffy. These researchers, in the mid-nineties, established the exact mechanism used by a malaria parasite to hide in the placenta. They showed that parasites in pregnant women use a unique surface antigen, a protein coded VAR2CSA, to bind to the placenta by latching on to a substance called chondroitin sulphate A (CSA) in the placenta tissue (1). Researchers reckon that this sort of information can be used to design a vaccine for pregnant women (2).

“We had worked out the parasite is not in the blood. It was in the placenta we knew,” says Leke. “They showed that there is a binding of the parasite to the placenta.”

New interventions

Today, Leke’s work focuses on the effect of new interventions on the placenta. Pregnant women start to generate antibodies against CSA-binding parasite forms, from around the twentieth week of pregnancy. The more pregnancies a woman has, the more of these antibodies exist and protect against malaria. (That is why contracting malaria in the first pregnancy is usually far more dangerous than in subsequent pregnancies).

Leke is now studying intermittent preventive treatment (IPT), a two or three-dose course of malaria tablets taken during pregnancy to prevent disease, and how it affects the build up of those antibodies. IPT is standard practice in Cameroon, where sulphadoxine-pyrimethamine is given to women free. It is an important study, because it will establish the benefits of IPT.

In clearing parasites from the blood, IPT might also reduce the ability for women to generate their own antibodies and build up immunity to malaria in subsequent pregnancies. The outcome of the research, says Leke, will be to establish once and for all that, even if IPT reduces the ability for women to generate antibodies, it still protects them against disease.

“We are encouraging women to use IPT, and we know that the parasite is being cleared,” she says. “Scientifically we have to show IPT is doing what it’s supposed to. We are trying to say even if she is making less antibodies, a pregnant woman is still protected by IPT.”

This work builds upon another study that has kept Leke and Taylor busy for five years. They have tracked a group of women through pregnancy as well as their babies for about a year after birth. The plan is to establish the types of antibody responses babies and children at different ages have to various antigens.

Using a technique to extract tiny amounts of blood, and a so-called multiplex assay, the babies’ blood is tested against a range of vaccine candidates with different antigens, such as AMA, MSP-1 or RESA. The aim of the research is to determine any trends in the way these babies respond to the antigens. The results are being analysed currently.

Coinfections

But plenty more research needs to be done, says Leke. The link between malaria and helminth filarial or schistosome infections is not well understood, for instance, even though women with malaria often suffer from these other infections too. “We tend to just go in and look at malaria. More and more we should maybe be looking at the co-infections,” she says. “There is a need to look at the kinds of interactions between these different parasites and the immune system so that we can better understand the immune interactions.”

Existing malaria co-infection studies have already revealed a host of interesting discoveries. HIV impairs immunity to malaria in pregnant women for instance and thus increases the chances of contracting malaria, developing anaemia or giving birth to low-birth-weight babies. There is also a higher chance of mother-to-child HIV transmission too – malaria has been shown to increase the viral load. Indeed studies in Kenya show that co-infection increases the incidence of AIDS by 8% and in Malaria 13% (3,4,5).

Other areas related to pregnant women require focus, she says. The effect of insecticide-treated bed-nets on pregnant women needs more research, especially from social scientists. An increased focus on rapid diagnostic tests to pinpoint serious infection early is also vital.

Today, Leke is working on the expansion of malaria home management in Cameroon. The country’s malaria control commission has already recruited residents in villages who will stock a home-management malaria kit to diagnose and treat their neighbours in order to increase access to life-saving medicines.

Leke and a number of other scientists have been recruited to work out exactly which rapid diagnosis tests should be included in the kit, in different parts of the country, from a shortlist of around twenty candidate tests. Although there has been widespread research on the types of tests that exist, it is up to individual countries to work out exactly which tests are appropriate for different environments.

“Countries are still trying to find ways of deciding which ones to use,” she says. “We can look at the settings where these kits would be best. In the northern part of Cameroon one may be best but in the South, something else may be best.”

Reaching every child

Two years away from retirement from the university, Leke is looking forward to spending time with her grandchildren. She is currently winding down commitments both at a national and international level. And there are plenty of them. She is the Vice-Chair of the Technical Evaluation Reference group (TERG) of the Global Fund to fight HIV/AIDS, TB and Malaria and part of the team managing the five-year assessment of the Global Fund’s activities. That post will end next month, in November for instance.

But before she sits back to relax, Leke must complete a couple of tasks. One is to create a research team with returning Cameroon scientists who have been trained in Georgetown University, USA, to continue research into malaria and pregnancy.

The second is another mission – work on polio. Because of her background in microbiology, Leke has worked as chair of the African Regional Commission for the Certification of the Eradication of Poliomyelitis (ARCC) and a member of the Global Certification Commission (GCC) for some time. It is her team which designates countries in Africa as free from polio. (They must show evidence of no polio from three years.)

Of course, it has been a long hard slog, because just as the world was on the verge of eradicating this ancient disease, wild polioviruses began to spread again. The reason – unfortunately – was that vaccinations stopped in northern Nigeria. “It was very, very disappointing to all of us,” she says.

But Leke remains optimistic, however, about continued immunisation efforts and hopes eradication is imminent. “Eradication is so possible if you reach every child with the polio vaccine,” she says. “But reaching every child is difficult.”

References

1. Fried M, Duffy PE (1996). Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science; 272:1502-1504. Available from http://www.ncbi.nlm.nih.gov/pubmed/8633247

2. Targett GA, Greenwood BM (2008). Malaria vaccines and their potential role in the elimination of malaria. Malar J; 11:7 Suppl 1:S10. Available from http://www.ncbi.nlm.nih.gov/pubmed/19091034

3. Ayisi JG, van Eijk AM, ter Kuile FO, Kolczak MS, Otieno JA, Misore AO, Kager PA, Steketee RW, Nahlen BL (2003). The effect of dual infection with HIV and malaria on pregnancy outcome in western Kenya. AIDS; 17:585-594. Available from http://www.ncbi.nlm.nih.gov/pubmed/12598779

4. Brahmbhatt H, Kigozi G, Wabwire-Mangen F, Serwadda D, Sewankambo N, Lutalo T, Wawer MJ, Abramowsky C, Sullivan D, Gray R (2003). The effects of placental malaria on mother-to-child HIV transmission in Rakai, Uganda. AIDS; 17:2540-2541. Available from http://www.ncbi.nlm.nih.gov/pubmed/14600529

5. Ticconi C, Mapfumo M, Dorrucci M, Naha N, Tarira E, Pietropolli A, Rezza G (2003). Effect of maternal HIV and malaria infection on pregnancy and perinatal outcome in Zimbabwe. Effect of maternal HIV and malaria infection on pregnancy and perinatal outcome in Zimbabwe. J Acquir Immune Defic Syndr; 34:289-294. Available from http://www.ncbi.nlm.nih.gov/pubmed/14600573