New drugs, based on artemisinin combination therapies, have recently revolutionized malaria treatment, but so far they have not normally been available to women in the early stages of pregnancy because of fears they could damage the embryo. Now a large-scale study, carried out in northern Thailand and published in the London-based medical journal, the Lancet, has provided some reassurance that any risk of harm is outweighed by the benefits they provide.
Malaria is a major hazard for all pregnant women exposed to the parasite. Being pregnant makes them more vulnerable to infection, and far more likely to develop full malaria symptoms even if they would normally have a good level of resistance to the disease. It is estimated that malaria causes at least 10,000 maternal deaths a year in sub-Saharan Africa. It also causes miscarriages, and leads to maternal anaemia and low birthweight babies.
Prompt and effective treatment is clearly important, but has been tricky, especially for women in the first three months of pregnancy. Artemisinin combination therapy (ACT), normally the World Health Organization (WHO) drug of choice, has been found to cause miscarriage, abnormalities or foetal resorbtion in some animal studies, and so is not recommended in early pregnancy. Doctors have to fall back on older drugs - chloroquine, to which there is now widespread resistance, or quinine, which is unpleasant to take and has side-effects.
Daniel Chandramohan, a specialist in malaria in pregnancy at the London School of Hygiene and Tropical Medicine, says a newly pregnant patient presenting with malaria is something which all physicians dread. “At the moment,” he told IRIN, “we are treating with quinine, but adherence to that for seven days is not good. And the complications of malaria can be serious, for the woman herself, not just for the foetus.
“Pregnant women are usually excluded from new drug trials, and all the drug company pamphlets say ‘not recommended during pregnancy’. But at the same time you have a patient, and what do you do? The responsibility falls on the physician because the drug companies don’t want to incur liability.”
Clearly there is a pressing need to know if ACT is safe in early pregnancy, but it’s not an easy thing to establish. You cannot do a drug trial for fear of causing harm to the subjects, and trying to find a large enough sample of women who have already taken it is difficult, largely because women in the areas most at risk - the rural tropics - rarely come to ante-natal clinics until later in their pregnancies, if indeed they come at all.
Rare opportunity
But the Shoklo Malaria Research Unit, on the Thai-Burma border, provided a rare opportunity. It ran clinics for refugees and migrants in the border area and encouraged pregnant women to come for early treatment. And because this was one of the first areas to show resistance to other drugs, it was also one of the first to use ATC on a large scale, making it inevitable that some pregnant women would inadvertently be exposed to the drug before they were known to be pregnant. ATC was also given to some women in early pregnancy if their malaria was very severe or did not respond to other treatments.
A trawl through the medical records of over 48,000 women treated over a period of more than 20 years came up with 908 who had had malaria in the first three months of pregnancy; 770 had been treated with either chloroquine, quinine or atresunate. It is not a huge sample, but much the largest studied up until now.
First of all, the study - carried out by a team at the Shoklo Malaria Research Unit - showed how much of a threat malaria is to a pregnancy; 34 percent of them miscarried, around three times as many as among uninfected women. They were more likely to miscarry even if the malaria was asymptomatic, but the worse the symptoms, the higher the risk.
But crucially this risk did not appear to be increased by the drugs used to treat them. Miscarriage rates were 26 percent for those treated with chloroquine, 27 percent for quinine, and 31 percent for artesunate, despite the fact that the latter included high risk groups, and those for whom other treatments had failed. Women who had inadvertently received ACT had only a 24 percent miscarriage rate. There was no sign that any of the groups had a higher than usual rate of birth defects.
The team at the Shoklo Malaria Research Unit do not pretend that their findings conclusively prove that ACT is safe, but they say: “Overall these results suggest that the adverse effects of malaria in the first trimester substantially outweigh any adverse effects of its treatment.” Calling for a proper randomized trial, they say “the time has come to re-assess the treatment of malaria in early pregnancy.”
Reactions to the findings
The findings of the group were welcomed by Meghna Desai of Centers for Disease Control and Prevention (CDC) who works at Kenya’s Medical Research Institute in Kisumu, as filling in some important current gaps in medical knowledge. “Although the number of well-documented early exposures to artemisinins was relatively small,” she said, “the study was adequately powered to rule out a doubling of the risk of late miscarriage associated with artemisinin exposure during the embryo-sensitive period.” She added that “the study provides a level of reassurance regarding the potential risk associated with artemisinin exposure in early pregnancy, compared with the established risk of malaria.”
Chandramohan said the study also highlighted the dangers of even asymptomatic malaria during pregnancy. He told IRIN: “For the first time this shows very clearly that asymptomatic malaria is associated with a high risk of foetal loss, and puts pressure on public health authorities in developing countries to encourage women to come to clinics much earlier in their pregnancies.” He adds his voice to those calling for full clinical trials. Even though the numbers in the study were small, he said, its findings will probably tilt the balance towards getting such a trial approved in the near future.
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Malaria is a major hazard for all pregnant women exposed to the parasite. Being pregnant makes them more vulnerable to infection, and far more likely to develop full malaria symptoms even if they would normally have a good level of resistance to the disease. It is estimated that malaria causes at least 10,000 maternal deaths a year in sub-Saharan Africa. It also causes miscarriages, and leads to maternal anaemia and low birthweight babies.
Prompt and effective treatment is clearly important, but has been tricky, especially for women in the first three months of pregnancy. Artemisinin combination therapy (ACT), normally the World Health Organization (WHO) drug of choice, has been found to cause miscarriage, abnormalities or foetal resorbtion in some animal studies, and so is not recommended in early pregnancy. Doctors have to fall back on older drugs - chloroquine, to which there is now widespread resistance, or quinine, which is unpleasant to take and has side-effects.
Daniel Chandramohan, a specialist in malaria in pregnancy at the London School of Hygiene and Tropical Medicine, says a newly pregnant patient presenting with malaria is something which all physicians dread. “At the moment,” he told IRIN, “we are treating with quinine, but adherence to that for seven days is not good. And the complications of malaria can be serious, for the woman herself, not just for the foetus.
“Pregnant women are usually excluded from new drug trials, and all the drug company pamphlets say ‘not recommended during pregnancy’. But at the same time you have a patient, and what do you do? The responsibility falls on the physician because the drug companies don’t want to incur liability.”
Clearly there is a pressing need to know if ACT is safe in early pregnancy, but it’s not an easy thing to establish. You cannot do a drug trial for fear of causing harm to the subjects, and trying to find a large enough sample of women who have already taken it is difficult, largely because women in the areas most at risk - the rural tropics - rarely come to ante-natal clinics until later in their pregnancies, if indeed they come at all.
Rare opportunity
But the Shoklo Malaria Research Unit, on the Thai-Burma border, provided a rare opportunity. It ran clinics for refugees and migrants in the border area and encouraged pregnant women to come for early treatment. And because this was one of the first areas to show resistance to other drugs, it was also one of the first to use ATC on a large scale, making it inevitable that some pregnant women would inadvertently be exposed to the drug before they were known to be pregnant. ATC was also given to some women in early pregnancy if their malaria was very severe or did not respond to other treatments.
 The study provides a level of reassurance regarding the potential risk associated with artemisinin exposure in early pregnancy, compared with the established risk of malaria |
First of all, the study - carried out by a team at the Shoklo Malaria Research Unit - showed how much of a threat malaria is to a pregnancy; 34 percent of them miscarried, around three times as many as among uninfected women. They were more likely to miscarry even if the malaria was asymptomatic, but the worse the symptoms, the higher the risk.
But crucially this risk did not appear to be increased by the drugs used to treat them. Miscarriage rates were 26 percent for those treated with chloroquine, 27 percent for quinine, and 31 percent for artesunate, despite the fact that the latter included high risk groups, and those for whom other treatments had failed. Women who had inadvertently received ACT had only a 24 percent miscarriage rate. There was no sign that any of the groups had a higher than usual rate of birth defects.
The team at the Shoklo Malaria Research Unit do not pretend that their findings conclusively prove that ACT is safe, but they say: “Overall these results suggest that the adverse effects of malaria in the first trimester substantially outweigh any adverse effects of its treatment.” Calling for a proper randomized trial, they say “the time has come to re-assess the treatment of malaria in early pregnancy.”
Reactions to the findings
The findings of the group were welcomed by Meghna Desai of Centers for Disease Control and Prevention (CDC) who works at Kenya’s Medical Research Institute in Kisumu, as filling in some important current gaps in medical knowledge. “Although the number of well-documented early exposures to artemisinins was relatively small,” she said, “the study was adequately powered to rule out a doubling of the risk of late miscarriage associated with artemisinin exposure during the embryo-sensitive period.” She added that “the study provides a level of reassurance regarding the potential risk associated with artemisinin exposure in early pregnancy, compared with the established risk of malaria.”
Chandramohan said the study also highlighted the dangers of even asymptomatic malaria during pregnancy. He told IRIN: “For the first time this shows very clearly that asymptomatic malaria is associated with a high risk of foetal loss, and puts pressure on public health authorities in developing countries to encourage women to come to clinics much earlier in their pregnancies.” He adds his voice to those calling for full clinical trials. Even though the numbers in the study were small, he said, its findings will probably tilt the balance towards getting such a trial approved in the near future.
eb/cb
This article was produced by IRIN News while it was part of the United Nations Office for the Coordination of Humanitarian Affairs. Please send queries on copyright or liability to the UN. For more information: https://shop.un.org/rights-permissions
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