Research in context
anaemia, small-for-gestational-age, malaria, malaria infections, weight gain, peripheral malaria infection, infection, malaria infection
ANAEMIA, PRETERM BIRTH, SEXUALLY TRANSMITTED INFECTIONS, MALARIA, INFECTIONS, INFECTION, BACTERIAL VAGINOSIS, MALARIA

A 2018 meta-analysis of two trials (one from western Kenya and one from Uganda) of intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin–piperaquine versus standard of care of IPTp with sulfadoxine–pyrimethamine concluded that in areas of high resistance to sulfadoxine–pyrimethamine, the fixed-dose combination of dihydroartemisinin–piperaquine is a promising candidate to replace sulfadoxine–pyrimethamine as IPTp. Dihydroartemisinin–piperaquine was well tolerated and associated with greater reductions in the incidence of moderate-to-severe maternal anaemia, clinical malaria, and the prevalence of maternal peripheral malaria infection at delivery, and placental malaria infections than sulfadoxine–pyrimethamine. In addition, the risk of fetal loss was lower in the IPTp in the dihydroartemisinin–piperaquine group. However, no difference was reported in adverse morbidity outcomes among livebirths (low birthweight, preterm birth, or small for gestational age). WHO recommended that more research was needed to evaluate the effect of IPTp with dihydroartemisinin–piperaquine on adverse pregnancy outcomes. Before the final design of this trial, we did an initial electronic literature search for trials comparing IPTp with sulfadoxine–pyrimethamine with IPTp with dihydroartemisinin–piperaquine using the search terms (“intermittent” OR “IPT”) AND (“sulfadoxine–pyrimethamine” OR “sulphadoxine–pyrimethamine”) AND “dihydroartemisinin–piperaquine” AND (“malaria” OR “Plasmodium”) AND (“pregnan*” OR “antenatal”) AND “trial”. We searched MEDLINE and the Malaria in Pregnancy Library, which consists of references from Web of Knowledge, Scopus, CINAHL, Bioline, the Cochrane Library databases, and WHO Global Health Library, from inception of the database to Dec 1, 2016. The Malaria in Pregnancy Library also contains grey literature and conference abstracts. No language restrictions were used. No new trials were identified. We updated our literature search on June 20, 2022, and identified two additional trials, one from Uganda (n=782) and one from southern Tanzania (n=956). In both trials, monthly IPTp with dihydroartemisinin–piperaquine was superior to sulfadoxine–pyrimethamine for reducing the risk of malaria infections during pregnancy. In the trial in Tanzania, dihydroartemisinin–piperaquine was also superior with regards to mean birthweight and low birthweight, but this was not observed in the Ugandan trial. No trials were identified that combined azithromycin with IPTp with dihydroartemisinin–piperaquine.
None of the four previous trials were powered to assess the effect of dihydroartemisinin–piperaquine on adverse pregnancy outcomes, and the results were conflicting. Our trial in 4680 women was designed to address the recommendation by WHO for larger definitive trials to investigate the effect of monthly IPTp with dihydroartemisinin–piperaquine compared with IPTp with sulfadoxine–pyrimethamine on adverse pregnancy outcomes. We found that the standard of care of monthly IPTp with sulfadoxine–pyrimethamine was associated with fewer adverse pregnancy outcomes (primary composite endpoint) than monthly dihydroartemisinin–piperaquine, and that this difference was driven by better maternal gestational weight gain and fewer low-birthweight and small-for-gestational-age births. However, compared with monthly IPTp with sulfadoxine–pyrimethamine, monthly IPTp with dihydroartemisinin–piperaquine was associated with reductions in clinical malaria, malaria infection detected by microscopy during pregnancy, and placental malaria at delivery. To our knowledge, this is the first trial to assess the effect of IPTp with dihydroartemisinin–piperaquine and azithromycin on sexually transmitted infections and bacterial vaginosis. We showed that adding a single 2 g dose of azithromycin at the initial antenatal visit between 16 weeks and 28 weeks gestation did not enhance the effect of monthly dihydroartemisinin–piperaquine on adverse pregnancy outcomes (primary composite endpoint). IPTp with sulfadoxine–pyrimethamine was associated with a lower prevalence of 
Replacing IPTp with sulfadoxine–pyrimethamine with dihydroartemisinin–piperaquine will probably result in marked and clinically relevant reductions in clinical malaria and maternal malaria infection during pregnancy in areas with high sulfadoxine–pyrimethamine resistance. However, countries that choose to do so need to be aware that replacing sulfadoxine–pyrimethamine with dihydroartemisinin–piperaquine may increase the absolute number of adverse pregnancy outcomes compared with IPTp with sulfadoxine–pyrimethamine, even in areas with very high sulfadoxine–pyrimethamine resistance. We hypothesise that sulfadoxine–pyrimethamine has potent non-malarial effects on fetal growth that outweigh any improvements in birthweight associated with better prevention from malaria by dihydroartemisinin–piperaquine. IPTp with dihydroartemisinin–piperaquine combined with sulfadoxine–pyrimethamine warrants investigation to evaluate the potential benefits of combining the non-malarial effects of sulfadoxine–pyrimethamine on fetal growth with the superior antimalarial effects of dihydroartemisinin–piperaquine. Moreover, additional studies of the mechanisms by which sulfadoxine–pyrimethamine promotes maternal gestational weight gain and fetal growth, independent of its antimalarial effects, are also warranted.