Hypertension and maternal-fetal conflict during placental malaria

Abstract

Background: Malaria and hypertension are major causes of maternal mortality in tropical countries, especially during first pregnancies, but evidence for a relationship between these syndromes is contradictory.

Methods and findings: In a cross-sectional survey of Tanzanian parturients, the rate of hypertension was similar in placental malaria (PM)-positive (11/85 = 13%) and PM-negative (73/602 = 12%) individuals. However, we found that PM was associated with hypertension in first-time mothers aged 18-20 y but not other mothers. Hypertension was also associated with histologic features of chronic malaria, which is common in first-time mothers. Levels of soluble vascular endothelial growth factor receptor 1 (sVEGFR1), a preeclampsia biomarker, were elevated in first-time mothers with either PM, hypertension, or both, but levels were not elevated in other mothers with these conditions. In first-time mothers with PM, the inflammatory mediator vascular endothelial growth factor (VEGF) was localized to maternal macrophages in the placenta, while sVEGFR1, its soluble inhibitor, was localized to the fetal trophoblast.

Conclusions: The data suggest that maternal-fetal conflict involving the VEGF pathway occurs during PM, and that sVEGFR1 may be involved in the relationship between chronic PM and hypertension in first-time mothers. Because placental inflammation causes poor fetal outcomes, we hypothesize that fetal mechanisms that promote sVEGFR1 expression may be under selective pressure during first pregnancies in malaria-endemic areas.

Figure 1. Line Graph Illustrating the Prevalence of Hypertension in PM-Positive and PM-Negative Women in Different Age Strata

Figure 2. sVEGFR1 Expression Levels in PM-Positive and PM-Negative Women

(A) Peripheral plasma sVEGFR1 levels (median [IQR]). Levels are indicated for mothers stratified by parity, PM, and hypertension (HT). (B and C) Placental sVEGFR1 mRNA abundance (median [IQR]) in first-time mothers. Levels indicate fold-increase over trophoblast-specific cytokeratin 7 (KRT7) mRNA. Women were stratified (B) by PM and hypertension or (C) by PM and intervillous inflammation.

Figure 3. Immunofluorescence of Placental Cryosections from First-Time Mothers Showing VEGFR1 Extracellular Domain (Green), Trophoblast (Red), and Nuclear DNA (Blue)

All fields are 200X magnification. Cryosections from (A) PM-negative normotensive pregnancy; (B) PM-positive normotensive pregnancy with intervillous inflammation; (C) PM-positive hypertensive pregnancy.

Figure 4. Placental VEGF Expression and Localization in First-Time Mothers

(A) Placental VEGF mRNA abundance (median [IQR]) in first-time mothers. Levels indicate fold-increase over trophoblast-specific cytokeratin 7 (KRT7) mRNA. (B and C) Visualization of VEGF in placental cryosections from first-time mothers with intervillous inflammation (B) by immunofluorescence with VEGF (green), trophoblast (red), and nuclear DNA (blue) labeling, 320X magnification, and (C) by immunohistochemistry using DAB and counterstained with Giemsa, 400X magnification.