Efforts to reduce the global burden of small vulnerable newborns (SVNs) by scaling up existing preventive interventions must be complemented with new preventive approaches to achieve global targets. Intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) was originally designed to protect pregnant women from malaria infection, but appears to retain efficacy against low birthweight even when Plasmodium infection is absent or the parasite is highly resistant to sulphadoxine-pyrimethamine. This specific effect might occur through the antimicrobial activity of sulphadoxine-pyrimethamine against maternal genitourinary tract infections and pathogenic gut bacteria, direct effects on maternal gut physiology that might reverse environmental enteric dysfunction, or anti-inflammatory actions. Refining our understanding of the pathways underlying the protective efficacy of sulphadoxine-pyrimethamine will require mechanistic studies and placebo-controlled randomised trials of IPTp-SP in non-malarious settings. These studies will be crucial to confirm whether sulphadoxine-pyrimethamine could be considered for reducing the risk of SVNs in settings with high prevalence of SVNs and little or no malaria transmission.