Prevalence of and risk factors for microscopic and submicroscopic malaria infections in pregnancy: a systematic review and meta-analysis

Abstract

Background: Malaria infections during pregnancy can cause adverse birth outcomes, yet many infections are undetected by microscopy. We aimed to describe the epidemiology of submicroscopic malaria infections in pregnant women in Asia, the Americas, and Africa using aggregated and individual participant data (IPD).

Methods: For this systematic review and meta-analysis, studies (published Jan 1, 1997 to Nov 10, 2021) with information on both microscopic and submicroscopic infections during pregnancy from Asia, the Americas, or Africa, identified in the Malaria-in-Pregnancy Library, were eligible. Studies (or subgroups or study groups) that selected participants on the basis of the presence of fever or a positive blood smear were excluded to avoid selection bias. We obtained IPD (when available) and aggregated data. Estimates of malaria transmission intensity and sulfadoxine-pyrimethamine resistance, matched by study location and year, were obtained 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. This study is registered with PROSPERO, number CRD42015027342.

Findings: The search identified 87 eligible studies, 68 (78%) of which contributed to the analyses. Of these 68 studies, 45 (66%) studies contributed IPD (48 869 participants) and 23 (34%) studies contributed aggregated data (11 863 participants). During pregnancy, median prevalence estimates were 13·5% (range 0·0-55·9, 66 substudies) for submicroscopic and 8·0% (0·0-50·6, 66 substudies) for microscopic malaria. Among women with positive Plasmodium nucleic acid amplification tests (NAATs), the median proportion of submicroscopic infections was 58·7% (range 0·0-100); this proportion was highest in the Americas (73·3%, 0·0-100), followed by Asia (67·2%, 36·4-100) and Africa (56·5%, 20·5-97·7). In individual patient data analysis, compared with women with no malaria infections, those with submicroscopic infections were more likely to present with fever in Africa (adjusted odds ratio 1·32, 95% CI 1·02-1·72; p=0·038) but not in other regions. Among women with NAAT-positive infections in Asia and the Americas, Plasmodium vivax infections were more likely to be submicroscopic than Plasmodium falciparum infections (3·69, 2·45-5·54; p<0·0001). Risk factors for submicroscopic infections among women with NAAT-positive infections in Africa included older age (age ≥30 years), 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.

Funding: Bill & Melinda Gates Foundation through the Worldwide Antimalarial Resistance Network.

Figure 1:. PRISMA flow diagram showing study selection process

IPD=individual participant data. *Items refer to articles, abstracts, reports, or theses. Items could publish from the same study. From the 200 items, 87 studies were identified that were eligible for IPD. †Reasons for non-availability of submicroscopic infections at the individual scale (excluded participants): nucleic acid amplification tests not conducted or not available or blood smear not available; submicroscopic information not available at all available timepoints (cohort studies); or only submicroscopic information for a random sample of participants but not for the full set. ‡One study had two publications which covered different time periods from the same study. §Studies from which data could be extracted.

Figure 2:. Prevalence of submicroscopic malaria in pregnancy, by study, 1998–2019

The pooled estimate was obtained using metaprop combining individual patient data and aggregated data, using information during pregnancy. Studies in Asia and the Pacific were included under Asia and studies in central or South America were included under the Americas. G1=primigravidae. G2=secundigravidae. G3+=multigravidae. PfPR_2–10=Plasmodium falciparum prevalence among children aged 2–10 years at the year of study visit, as estimated by the Malaria Atlas Project. *Enrolment criteria could have affected parasite prevalence (appendix p 28).

Figure 3:. Proportion of submicroscopic malaria among women with NAAT-positive test results by malaria transmission rate

Studies in Asia and the Pacific were combined under Asia; studies in central or South America were combined under the Americas. The relationship and 95% CI were estimated for Africa only using fractional polynomials logistic regression with robust variance (p<0·0001 for comparison with linear and non-covariate model); for modelling the graphs at delivery, one outlier at PfPR_2–10 of 81% was omitted (for the plot for first antenatal clinic visit and by gravidity, see appendix pp 59–60). NAAT=nucleic acid amplification test (PCR or loop-mediated isothermal amplification). PfPR_2–10=Plasmodium falciparum prevalence among children aged 2–10 years at the year of study visit, as estimated by the Malaria Atlas Project.