Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: a systematic review

Abstract

Background: In endemic areas, pregnant women are highly susceptible to Plasmodium falciparum malaria characterized by the accumulation of parasitized red blood cells (pRBC) in the placenta. In subsequent pregnancies, women develop protective immunity to pregnancy-associated malaria and this has been hypothesized to be due to the acquisition of antibodies to the parasite variant surface antigen VAR2CSA. In this systematic review we provide the first synthesis of the association between antibodies to pregnancy-specific P. falciparum antigens and pregnancy and birth outcomes.

Methods: We conducted a systematic review and meta-analysis of population-based studies (published up to 07 June 2019) of pregnant women living in P. falciparum endemic areas that examined antibody responses to pregnancy-specific P. falciparum antigens and outcomes including placental malaria, low birthweight, preterm birth, peripheral parasitaemia, maternal anaemia, and severe malaria.

Results: We searched 6 databases and identified 33 studies (30 from Africa) that met predetermined inclusion and quality criteria: 16 studies contributed estimates in a format enabling inclusion in meta-analysis and 17 were included in narrative form only. Estimates were mostly from cross-sectional data (10 studies) and were heterogeneous in terms of magnitude and direction of effect. Included studies varied in terms of antigens tested, methodology used to measure antibody responses, and epidemiological setting. Antibody responses to pregnancy-specific pRBC and VAR2CSA antigens, measured at delivery, were associated with placental malaria (9 studies) and may therefore represent markers of infection, rather than correlates of protection. Antibody responses to pregnancy-specific pRBC, but not recombinant VAR2CSA antigens, were associated with trends towards protection from low birthweight (5 studies).

Conclusions: Whilst antibody responses to several antigens were positively associated with the presence of placental and peripheral infections, this review did not identify evidence that any specific antibody response is associated with protection from pregnancy-associated malaria across multiple populations. Further prospective cohort studies using standardized laboratory methods to examine responses to a broad range of antigens in different epidemiological settings and throughout the gestational period, will be necessary to identify and prioritize pregnancy-specific P. falciparum antigens to advance the development of vaccines and serosurveillance tools targeting pregnant women.

Keywords: Antibodies; Epidemiology; Immunity; Malaria; Meta-analysis; Plasmodium falciparum; Pregnancy; Systematic review.

Fig. 1

Flow chart of study identification. ^aExcluded studies are annotated in Additional file 5. ^bCharacteristics of included studies that provided estimates are presented in Table 1. ^cCharacteristics of studies included in narrative terms are presented in Table 2

Fig. 2

Forest plot of the association between antibodies to pregnancy-associated P. falciparum antigens and placental malaria. a Estimates represent the odds of placental malaria in Ab responders compared with Ab non-responders, where antibodies were measured at delivery (cross-sectional studies). b Estimates represent the relative risk of placental malaria in Ab responders compared to Ab non-responders, where antibodies were measured at various times during pregnancy, as indicated (prospective studies). Estimates are for all gravidities included in original studies. Staalsoe et al. (Yaounde site) included secundigravidae and multigravidae only; Babakhanyan et al. [52] included multigravidae only; and Cox et al. [55] included primigravidae only. Estimate for McLean et al. [63] represents IgG3 responders only as total IgG was not available. Meta-analysis was only performed on estimates where VAR2CSA antigen or functional assay (where applicable) and timing of antibody determination were the same. Meta-analysis of Ab responses to FV2 and odds of PM showed a high degree of heterogeneity (I² = 93.1%, P < 0.001) so results were not pooled. ^aEstimate calculated by current authors from data in original publication; ^bData supplied by original authors and estimate calculated by current authors. CC, case-control; CS, cross-sectional; CSA adhes. inhib., CSA adhesion inhibition assay; flow cyto., flow cytometry; n, number of participants included in estimate; OR, odds ratio; plac. isolate, placental isolate; pRBC, parasitized red blood cells; RCT, randomized controlled trial; RR, risk ratio

Fig. 3

Forest plot of the association between antibodies to pregnancy-associated P. falciparum antigens and peripheral parasitaemia. a Estimates represent the odds of peripheral P. falciparum parasitaemia in Ab responders compared to Ab non-responders, where antibodies were measured at the same time point as parasitaemia (cross-sectional studies). b Estimates of peripheral P. falciparum parasitaemia in Ab responders compared to Ab non-responders, where antibodies were measured at time points prior to parasitaemia determination. Estimates are risk ratios for RCT and cohort studies and odds ratio for the nested case-control study. Estimates are for women of all gravidities included in original studies: Cox et al. [55] included primigravidae only. The timing of antibody and parasitaemia determination is indicated. Estimate for McLean et al. [63] represents IgG3 responders only as total IgG was not available. DBL5 estimates were only combined when study design was the same. Estimates for FCR3 responses at T2/T3 were not combined because I² = 82.9%. ^aData supplied by original authors and estimate calculated by current authors; ^bEstimate calculated by current authors from data in original publication. CC, case control; CS, cross-sectional; ES, estimate; n, number of participants included in estimate; Flow cyto., flow cytometry; nCC, nested case-control; OR, odds ratio; PI time, timing of determination of parasitaemia; pRBC, parasitized red blood cells; RCT, randomized controlled trial; T1, first trimester; T2, second trimester; T3, third trimester

Fig. 4

Forest plot of the association between antibodies to pregnancy-associated P. falciparum antigens and low birthweight. a Estimates represent the odds of low birthweight birth in Ab responders compared with Ab non-responders, where antibodies were measured at delivery (cross-sectional studies). b Estimates represent the risk of low birthweight in Ab responders compared with Ab non-responders, where antibodies were measured at time points prior to delivery, as indicated (prospective studies). Estimates are for women of all gravidities included in the original studies. Teo et al. included secundigravidae and multigravidae only. ^aData supplied by original authors and estimate calculated by current authors; ^bEstimate provided by original author; ^cEstimate calculated by current authors from data in original publication. CC, case-control; CS, cross-sectional; n, number of participants included in estimate; OR, odds ratio; pRBC, parasitized red blood cells; RCT, randomized controlled trial; RR, risk ratio; T1, first trimester; T2, second trimester; T3, third trimester