Circulating Endothelial Progenitor Cells And Preeclampsia In Women With Placental Malaria

ABSTRACT

Background

Placental malaria and preeclampsia are major complications of pregnancy associated with high

incidence of maternal/foetal morbidity and mortality particularly in sub-Saharan Africa.

Similarities in pathophysiology such as systemic inflammation and generalized endothelial

activation/dysfunction exist and are exacerbated in concurrent situations. The combined

pathologic and immunologic effects of these pregnancy disorders, prevalent in malaria endemic

regions, have not been tested. This study evaluated the pathologic risk associated with

Plasmodium falciparum infection in the placenta and the outcome of preeclampsia. Immune

mediators associated with placental malaria and the risk of preeclampsia were evaluated. In

addition, the relationship between endothelial cell phenotypes implicated in vascular

activation/injury/damage/repair and the factors that mediate their release were assessed.

Methods

A total of 140 pregnant women (18 - 42 years) diagnosed with and without preeclampsia were

recruited into the study in Accra, Ghana. Peripheral blood samples were collected at delivery while

cord blood, placental intervillous blood and placental biopsies were collected after delivery.

Circulating endothelial cells (cECs) and circulating endothelial progenitor cell phenotypes (cEPCs,

mEPCs and iEPCs) were quantified by flow cytometry. Immunological (inflammatory and

angiogenic) factors were tested by multiplex ELISA using plasma separated from whole blood.

Placental biopsies were histologically evaluated for unique placental lesions and placental malaria

(classified as active and past infections).

Results

Of 133 placentas scored for placental malaria, women diagnosed with preeclampsia had 39

(29.3%) and 15 (11.3%) active and past infections respectively while the non-preeclamptic

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women had 25 (18.8%) active infections and 6 (4.5%) past infections. Both active (adjusted

odds ratio (AOR) 6.7, 95% CI 2.3 – 18.9; P < 0.0001) and past infections (AOR 11.6, 95% CI

3.0 – 45.8; P < 0.0001) increased the risk of preeclampsia. This association was enhanced in

primigravidae (AOR 6.6, 95% CI 2.4 – 18.2; P < 0.0001) and in women with pathological

alterations in the placenta (AOR 3.0, 95% CI 1.2 – 7.5; P < 0.019). The preeclamptic

pregnancies with active placental parasites showed higher levels of proinflammatory and antiangiogenic

markers. In multivariate analysis, active parasite infection (AOR = 7.14, 95% CI =

1.1 – 44.7; P = 0.04), past infection (AOR = 12.9, 95% CI = 1.1 – 155.5; P = 0.04),

primigravidity (AOR = 7.2, 95% CI = 1.1 – 48.0; P = 0.04) and increased levels of the

plasminogen activator inhibitor (PAI)-1 molecule (AOR = 7.1, 95% CI = 1.3 – 38.3; P = 0.02)

were all associated with placental malaria.

Furthermore, proportions of endothelial cell phenotypes were higher in the placenta and cord

compared to peripheral blood. Alterations in their levels correlated strongly with angiogenic

factors that stimulate their release mostly in non-preeclamptic compared to preeclamptic

pregnancies.

Conclusion

Findings from this study have demonstrated that the pathophysiology of preeclampsia is

pathologically and immunologically exacerbated in women exposed to placental malaria. In

addition, endothelial cell phenotypes that contribute to vascular homeostasis and the factors

that mediate their release into circulation are altered. Altogether, this study provides a new

paradigm in assessing preeclampsia in malaria endemic regions.