Prevalence and risk factors of sub-microscopic malaria infections in pregnancy: aggregated and individual participant data meta-analyses

Background: Malaria infections during pregnancy can cause adverse birth outcomes, yet many infections are undetected by microscopy. We describe the epidemiology of submicroscopic malaria infections in pregnancy using aggregated and individual participant data (IPD). Methods: For this systematic review, studies (January 1997-November 2021) with information on both microscopic and submicroscopic infections during pregnancy, identified in the Malaria-in-Pregnancy Library were eligible. IPD and aggregated data were obtained, and estimates of malaria transmission intensity and sulfadoxine-pyrimethamine resistance added, matched by study location and year, using publicly available data. One-stage multivariable logit and multinomial models with random intercepts for study site were used in meta-analysis to assess prevalence of and risk factors for submicroscopic infections during pregnancy and at delivery. Findings: Of 87 eligible studies, IPD were available from 45 (48,869 participants) and aggregated data from 23 (14,665 participants). During pregnancy, median prevalence estimates were 13·5% (range 0·0-55·9%, n=66) for submicroscopic and 8·0% (0·0-50·6%) for microscopic malaria. Among nucleic acid amplification test (NAAT) Plasmodium-positive women, the median proportion of submicroscopic infections was 58.7% (range 0-100%); this was highest in the Americas (73.3%), followed by Asia (67.2%) and Africa (56.5%). In Africa, this submicroscopic proportion decreased with increasing malaria transmission. Compared to uninfected women, those with submicroscopic infections were more likely to present with fever (adjusted odds ratio [aOR]=1·32, 95%CI 1·02-1·72) in Africa but not in other regions. Among NAAT-positive women in Asia, P. vivax infections were more likely to be submicroscopic than P. falciparum infections (aOR=4·45, 2·83-6·99). Risk factors for submicroscopic infections among NAAT-positive women in Africa included older age, multigravidity, and no HIV-infection. Interpretation: During pregnancy, submicroscopic infections are more common than microscopic infections and are associated with fever in Africa. Malaria control in pregnancy should target both microscopic and submicroscopic infections.