Effects of metronidazole plus intermittent preventive treatment of malaria in pregnancy on birth outcomes: a randomised controlled trial in Zambia

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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.