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Review
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Systematic Review and Meta-Analysis: Rapid Diagnostic Tests Versus Placental Histology, Microscopy and PCR for Malaria in Pregnant Women

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Review

Systematic Review and Meta-Analysis: Rapid Diagnostic Tests Versus Placental Histology, Microscopy and PCR for Malaria in Pregnant Women

Johanna H Kattenberg et al. Malar J.

Abstract

Background: During pregnancy, malaria infection with Plasmodium falciparum or Plasmodium vivax is related to adverse maternal health and poor birth outcomes. Diagnosis of malaria, during pregnancy, is complicated by the absence or low parasite densities in peripheral blood. Diagnostic methods, other than microscopy, are needed for detection of placental malaria. Therefore, the diagnostic accuracy of rapid diagnostic tests (RDTs), detecting antigen, and molecular techniques (PCR), detecting DNA, for the diagnosis of Plasmodium infections in pregnancy was systematically reviewed.

Methods: MEDLINE, EMBASE and Web of Science were searched for studies assessing the diagnostic accuracy of RDTs, PCR, microscopy of peripheral and placental blood and placental histology for the detection of malaria infection (all species) in pregnant women.

Results: The results of 49 studies were analysed in metandi (Stata), of which the majority described P. falciparum infections. Although both placental and peripheral blood microscopy cannot reliably replace histology as a reference standard for placental P. falciparum infection, many studies compared RDTs and PCR to these tests. The proportion of microscopy positives in placental blood (sensitivity) detected by peripheral blood microscopy, RDTs and PCR are respectively 72% [95% CI 62-80], 81% [95% CI 55-93] and 94% [95% CI 86-98]. The proportion of placental blood microscopy negative women that were negative in peripheral blood microscopy, RDTs and PCR (specificity) are 98% [95% CI 95-99], 94% [95% CI 76-99] and 77% [95% CI 71-82]. Based on the current data, it was not possible to determine if the false positives in RDTs and PCR are caused by sequestered parasites in the placenta that are not detected by placental microscopy.

Conclusion: The findings suggest that RDTs and PCR may have good performance characteristics to serve as alternatives for the diagnosis of malaria in pregnancy, besides any other limitations and practical considerations concerning the use of these tests. Nevertheless, more studies with placental histology as reference test are urgently required to reliably determine the accuracy of RDTs and PCR for the diagnosis of placental malaria. P. vivax-infections have been neglected in diagnostic test accuracy studies of malaria in pregnancy.

Figures

Figure 1
Figure 1
Flow diagram of selection procedure.
Figure 2
Figure 2
Methodological quality assessment of all 61 included studies. Top: general QUADAS items, scored for each study; Bottom: Items assessed separately for each index and comparator tests (n = 108) within the studies. Data presented as stacked bars representing the percentage of studies scored as 'yes' (green), 'unclear' (yellow) or 'no' (red) by the authors on each particular quality item.
Figure 3
Figure 3
Forest plots of sensitivity and specificity of microscopy of peripheral and placental blood with placental histology as reference test. The squares represent the calculated specificity and sensitivity of one test within a study; the black line is the 95% confidence interval. Tests with a * in front were excluded from the meta-analysis, because of high risk of bias or complete data was not available.
Figure 4
Figure 4
Forest plots of sensitivity and specificity of peripheral blood microscopy with placental blood microscopy as reference test. The squares represent the calculated specificity and sensitivity of one test within a study; the black line is the 95% confidence interval. Tests with a * in front were excluded from the meta-analysis, because of high risk of bias or complete data was not available.
Figure 5
Figure 5
Forest plots of sensitivity and specificity of RDTs with microscopy of placental blood as reference test. The squares represent the calculated specificity and sensitivity of one test within a study; the black line is the 95% confidence interval. Tests with a * in front were excluded from the meta-analysis, because of high risk of bias or complete data was not available; with ** means that a pLDH-based RDT has been used; *** means that a HRP2-Aldolase-based RDT has been used.
Figure 6
Figure 6
Forest plots of sensitivity and specificity of PCR with microscopy of placental blood as reference test. The squares represent the calculated specificity and sensitivity of one test within a study; the black line is the 95% confidence interval. Tests with a * in front were excluded from the meta-analysis, because of high risk of bias or complete data was not available.
Figure 7
Figure 7
Forest plots of sensitivity and specificity of RDTs and PCR with microscopy of peripheral blood as reference test. The squares represent the calculated specificity and sensitivity of one test within a study; the black line is the 95% confidence interval. Tests with a * in front were excluded from the meta-analysis, because of high risk of bias or complete data was not available; with ** means that a pLDH-based RDT has been used; *** means that a HRP2-Aldolase-based RDT has been used.
Figure 8
Figure 8
Summary ROC plot of sensitivity and specificity of peripheral and placental blood microscopy with placental histology as a reference test. The sensitivity of a test is plotted against 1-specificity, allowing comparison of both parameters at the same time for multiple tests. The rectangles and diamonds represent individual studies and size of the rectangles/diamonds is proportional to the number of patients included in the study. The thick round spots are the summary estimates of sensitivity and specificity and the dotted ellipses around the spots represent the 95% confidence intervals around the summary estimates. Black: peripheral blood microscopy; Red: placental blood microscopy. The reference test used to determine the plotted accuracies in this figure is placental histology.
Figure 9
Figure 9
Summary ROC plot of sensitivity and specificity of RDT and PCR of peripheral and placental blood and microscopy of peripheral blood with placental blood microscopy as reference test. The sensitivity of a certain test is plotted against 1-specificity, allowing comparison of both parameters at the same time for multiple tests. The squares, diamonds and open circles represent individual studies and size of the rectangles/diamonds/circles is proportional to the number of patients included in the study. The thick round spots are the summary estimates of sensitivity and specificity and the dotted ellipses around the spots represent the 95% confidence intervals around the summary estimates. Black (squares): RDTs (detecting HRP2 or pLDH or HRP2-Aldolase). Red (diamonds): peripheral blood microscopy. Green (circles): PCR; The reference test used to determine the plotted accuracies in this figure is placental blood microscopy.
Figure 10
Figure 10
Summary ROC plot of sensitivity and specificity of RDT and PCR with peripheral blood with peripheral blood microscopy as reference test. The sensitivity of a certain test is plotted against 1-specificity, allowing comparison of both parameters at the same time for multiple tests. The rectangles, diamonds and circles represent individual studies and size of the rectangles/diamonds/circles is proportional to the number of patients included in the study. The thick round spots are the summary estimates of sensitivity and specificity for the different test types and the dotted ellipses around the spots represent the 95% confidence intervals around the summary estimates. Black (rectangles): PCR studies; Red (diamonds): studies with HRP2 based RDTs only; Green (circles): studies with RDTs, including both HRP2, pLDH and HRP2-Aldolase detecting tests. The reference test used to determine the plotted accuracies in this figure is placental histology. The inclusion of the pLDH and Aldolase-HRP2 based RDTs dramatically changes the summary estimate and confidence interval (green) compared to HRP2 tests alone (red), the sensitivity is much lower with the pLDH tests.

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