Pregnancy reduces blood levels of the antimalarial drug sulfadoxine-pyrimethamine (SP) in Kenyan HIV-positive and HIV-negative pregnant women, according to the findings of a prospective study published in the November 1st issue of the Journal of Infectious Diseases.
Malaria in pregnancy is a major cause of maternal, fetal, and neonatal disease and deaths with the greatest incidence being reported in sub–Saharan Africa where over 30 million women become pregnant annually in malaria-endemic areas. The Roll Back Malaria Strategy recommends case management, treatment for anaemia, use of insecticide treated nets (ITNs), and intermittent preventive treatment (IPTp) with SP for controlling malaria in pregnancy.
IPTp with SP is now being implemented in malaria-prone African countries. The benefits of IPTp may be through the clearance of parasites from the placenta (treatment effect) or the prevention of new infections (prophylactic effect). The duration of the prophylactic effect is compromised in regions with high SP resistance.
Malaria and HIV co-infections are of significant public health importance in many sub-Saharan countries with an escalating HIV/AIDS problem. In such countries, the World Health Organization (WHO) recommends that all pregnant women must receive at least two doses of SP given one month apart. However, HIV-positive women require more frequent doses of IPTp with SP than do HIV-negative women.
Placental malaria during pregnancy increases the risk of mother to child transmission, but monthly treatment during pregnancy with SP significantly reduces the risk of placental malaria in HIV-positive women when compared with the standard IPTp regimen.
The poor efficacy of IPTp in HIV-positive women might be due to either an impaired immunity which results in poor parasite clearance in HIV-positive women, or physiological changes during pregnancy which results in altered SP levels and half-lives in both HIV-positive and HIV-negative women. There are currently no research data which support the latter notion, largely because the pharmacokinetics of SP are unknown in pregnancy.
An international team of US, Dutch, UK, and Kenyan researchers investigated whether the poor efficacy of IPTp in HIV-positive women was due to impaired immunity or altered pharmacokinetics in Kenyan women. The study took place at New Nyanza Provincial Hospital in Kisumu from 1999 to early 2000.
Study subjects were HIV+ and HIV- pregnant women with uncomplicated singleton (non-twin) pregnancies of 16-28 weeks gestation, an hemoglobin level of > 8 g/dL, and who satisfied strict exclusion criteria. Blood samples were obtained at pre-determined intervals for malaria microscopy and high performance liquid chromatographic analysis of whole blood for SP levels. Antiretroviral drugs or cotrimoxazole were not available in Kenya at the time.
Out of 95 pregnant women screened, SP blood levels were obtained for 33 subjects (17 pregnant HIV-negative women and 16 pregnant HIV-positive women) who received a dose of 1500mg of sulfadoxine and 75mg of pyrimethamine. The same women served as non-pregnant controls by returning two to three months after delivery (postpartum) for another SP dose. In all, five HIV-negative and six HIV-positive postpartum women received SP. The pharmacokinetics of sulfadoxine and pyrimethamine were compared between these groups.
HIV status did not affect the total exposure (AUC) or the half-lives of sulfadoxine or pyrimethamine in prepartum or postpartum women. However, pregnancy had a significant effect on sulfadoxine but not pyrimethamine pharmacokinetics. Among prepartum women, the median half-life for sulfadoxine was significantly shorter than that in postpartum women (148 versus 256 h; P
Both sulfadoxine and pyrimethamine are required for the action of SP on malaria parasites. The finding that pregnancy significantly modifies the disposition of SP and other antimalarial drugs including artemisinin and lumefantrine has important policy implications for the future implementation of IPTp in sub-Saharan Africa.
Dose-optimisation studies of SP during IPTp are urgently needed in those countries where SP resistance has not yet reached alarming levels, say the authors of the study. Current clinical trials in Africa of artemisinin-based combination therapies (ACTs) during malaria in pregnancy must pay particular attention on the effect of pregnancy on the pharmacokinetics of ACTs.
Cotrimoxazole in combination with ITNs significantly reduces the incidence of malaria in HIV-positive subjects. Clinical trials of this drug in HIV+ pregnant women must be an urgent imperative in sub-Saharan Africa.
Green MD et al. Pharmacokinetics of sulfadoxine-pyrimethamine in HIV-Infected and uninfected pregnant women in Western Kenya. J Infect Dis 196: 1403-1408, 2007.