Low-level Plasmodium vivax exposure, maternal antibodies, and anemia in early childhood: Population-based birth cohort study in Amazonian Brazil

Abstract

Background: Malaria causes significant morbidity and mortality in children under 5 years of age in sub-Saharan Africa and the Asia-Pacific region. Neonates and young infants remain relatively protected from clinical disease and the transplacental transfer of maternal antibodies is hypothesized as one of the protective factors. The adverse health effects of Plasmodium vivax malaria in early childhood-traditionally viewed as a benign infection-remain largely neglected in relatively low-endemicity settings across the Amazon.

Methodology/principal findings: Overall, 1,539 children participating in a birth cohort study in the main transmission hotspot of Amazonian Brazil had a questionnaire administered, and blood sampled at the two-year follow-up visit. Only 7.1% of them experienced malaria confirmed by microscopy during their first 2 years of life- 89.1% of the infections were caused by P. vivax. Young infants appear to be little exposed to, or largely protected from infection, but children >12 months of age become as vulnerable to vivax malaria as their mothers. Few (1.4%) children experienced ≥4 infections during the 2-year follow-up, accounting for 43.4% of the overall malaria burden among study participants. Antenatal malaria diagnosed by microscopy during pregnancy or by PCR at delivery emerged as a significant correlate of subsequent risk of P. vivax infection in the offspring (incidence rate ratio, 2.58; P = 0.002), after adjusting for local transmission intensity. Anti-P. vivax antibodies measured at delivery do not protect mothers from subsequent malaria; whether maternal antibodies transferred to the fetus reduce early malaria risk in children remains undetermined. Finally, recent and repeated vivax malaria episodes in early childhood are associated with increased risk of anemia at the age of 2 years in this relatively low-endemicity setting.

Conclusions/significance: Antenatal infection increases the risk of vivax malaria in the offspring and repeated childhood P. vivax infections are associated with anemia at the age of 2 years.

Fig 1. Study site.

The map shows Brazil and Peru in South America (panel A) and the location of the municipality of Cruzeiro do Sul (dark green) in the Upper Juruá Valley region, Acre State (light green), northwestern Brazil (panel B). The urban area of Cruzeiro do Sul is shown in greater detail in panel C. Other cities and towns in the region (Mâncio Lima, Guajará, and Rodrigues Alves) are also indicated by triangles. Roads and streets are represented in light gray. Rivers are represented in blue. Figure created with QGIS software version 3.14, an open source Geographic Information System (GIS) licensed under the GNU General Public License (https://bit.ly/2BSPB2F). Publicly available shape files were obtained from the Brazilian Institute of Geography and Statistics (IBGE) website (https://bit.ly/34gMq0S). Roads, streets, and rivers were obtained from the Open Street Map Foundation website (https://bit.ly/3pzh4xp). All utilized geographical data are under the Creative Commons Attribution License (CC BY 4.0).

Fig 2. Study flowchart.

Between July 2015 and June 2016, pregnant women attending antenatal clinics or admitted for delivery to the maternity ward of the Women and Children’s Hospital of Juruá Valley in Cruzeiro do Sul, Brazil, were invited to participate. Reasons for exclusion and the final number of subjects analyzed for each study outcome are indicated.

Fig 3. Monthly malaria incidence in mothers and their children.

Panel A shows the incidence of laboratory-diagnosed P. vivax malaria and their respective 95% confidence intervals among mothers (n = 1,533) and their children (n = 1,539) participating in the MINA-Brazil study. Panel B shows the incidence of laboratory-diagnosed P. falciparum or mixed-species malaria in mothers and children. Each study participant contributed 2 person-years (24 person-months) of follow-up.

Fig 4. Spatial distribution of malaria incidence among MINA-Brazil study children.

The map shows the upper Juruá Valley and the localities of residence of study children (circles) within and surrounding the municipality of Cruzeiro do Sul (A). The inset (B) shows the localities within and next to the urban area. Circle sizes are directly proportional to the number of study participants in each locality and their color (from blue to red) indicates the overall malaria incidence among study participants living in each locality (highest incidence in red). Roads and streets are represented in light gray. Rivers are represented in blue. Figure created with QGIS software version 3.14, an open source Geographic Information System (GIS) licensed under the GNU General Public License (https://bit.ly/2BSPB2F). Publicly available shape files were obtained from the Brazilian Institute of Geography and Statistics (IBGE) website (https://bit.ly/34gMq0S). Roads, streets, and rivers were obtained from the Open Street Map Foundation website (https://bit.ly/3pzh4xp). All utilized geographical data are under the Creative Commons Attribution License (CC BY 4.0).

Fig 5. Age-related prevalence of maternal IgG antibodies to the blood-stage P. vivax antigens PvAMA1, PvDBP, and PvMSP1₁₉ in MINA-Brazil study participants.

Numbers of tested samples per age group were: <16 years, n = 47; 16–20 years, n = 312; 21–25 years, n = 274; 26–30 years, n = 226; 31–35 years, n = 163; and 36+ years, n = 73. Age-related differences in antibody prevalence were significant only for PvAMA-1 (Mantel-Haenszel χ² test for linear trend, P = 0.015).

Fig 6. Maternal antibodies and risk of Plasmodium vivax malaria.

Cumulative proportions of mothers (A) and their children (B) participating in the MINA-Brazil study who had vivax malaria over 2 years of follow-up are shown according to levels of antibodies to the blood-stage P. vivax antigens PvAMA-1, PvDBP, and PvMSP1₁₉ measured at delivery and stratified in quintiles (1 = lowest antibody levels). Children and mothers were censored at the time they had falciparum malaria.

Fig 7. Impact of the frequency and timing of malaria episodes, as well as the infecting malaria parasite species, on the risk of anemia.

Odds ratios (OR) indicate the magnitude of association between anemia at the age of 2 years and malaria type (any species or vivax), frequency (1 or 2+), or timing (since birth or within the last 12 months) in MINA-Brazil study participants (n = 860), compared with no malaria, while controlling for the potential confounders listed in Table 3. OR estimates and their respective 95% confidence intervals (95% CIs) and P value were derived from separate multiple logistic regression models in which exposure to malaria was introduced in different ways.