Pregnant women in Zambia are being given a common antibiotic alongside malaria treatment to see if it prevents stillbirths, low birth weight, and preterm delivery. In East and Southern Africa, roughly one-third of pregnant women carry malaria parasites, half have bacterial vaginosis, and a quarter have trichomonas—all of which harm birth outcomes. The standard malaria preventive drug, sulphadoxine-pyrimethamine (SP), is losing effectiveness due to resistance, and its replacement, dihydroartemisinin-piperaquine (DP), may not protect against these co-infections. This three-arm trial compares SP alone, SP plus the antibiotic metronidazole, and DP plus metronidazole in a high-transmission area of northeast Zambia. If adding metronidazole to either malaria drug improves birth outcomes, it could offer a low-cost, safe intervention that is already approved for use in the second and third trimesters. The trial also includes an economic evaluation to determine cost-effectiveness, and will analyse vaginal and stool samples to understand how treatments affect the microbiome and identify inflammatory triggers of preterm birth. The results could directly change antenatal care protocols across malaria-endemic regions.
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In areas of East and Southern Africa, malaria infection during pregnancy and curable sexually transmitted and reproductive tract infections (STIs/RTIs) are very common. About one-third of women in the sub-region are infected with malaria parasites during pregnancy, one-half of them have bacterial vaginosis (BV) and one-quarter are infected with trichomonas vaginalis (TV). All of these cause adverse birth outcomes. Malaria parasites sequester in the placenta and, therefore, taking conventional blood test may not detect the infection. Thus, the World Health Organization recommends that women who live in malaria-endemic areas receive intermittent preventive treatment (IPTp) using sulphadoxine-pyrimethamine (SP) during their second and third trimesters of pregnancy. However, malaria parasites have developed resistance against SP. An alternative to SP, dihydroartemisinin-piperaquine (DP), has been shown to clear malaria parasites from pregnant women better than SP. However, SP appears also to confer some protection against non-malaria causes of adverse birth outcomes including curable STIs/RTIs. So a switch from SP to DP might not be best. It is possible that SP or DP - if combined with treatment against BV and TV metronidazole (MTZ), a medicine that is also safe to administer in the second and third trimesters of pregnancy - may be better than providing SP, the current standard of care. To examine this, we are proposing a three-arm trial, partially placebo-controlled, that will compare SP plus MTZ placebo versus SP plus MTZ versus DP plus MTZ in a geographic area of north-east Zambia where malaria transmission is high, malaria parasite-resistance to SP is high, and the prevalence of BV and TV in pregnant women is also high. As part of the main trial, we will also conduct a full economic evaluation of trial interventions establish costs, the incremental cost-effectiveness, and acceptability of the three study treatments using discrete choice experiments. We will ask prospective participants if they will provide vaginal swabs and stool samples which we will use to characterise the effect of treatment across trial arms on the vaginal and intestinal microbiota communities, vaginal and intestinal bacterial loads and identify potential triggers of preterm birth that are related to inflammation. Finally, we will also measure the drug sensitivity of several pathogens implicated with vaginal discharge, lower abdominal pain, or genital ulcers.
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