Pathogenic mechanisms in pre-eclampsia and eclampsia at Muhimbili National hospital Dar es Salaam Tanzania

Abstract

Pre-eclampsia (PE) is a disorder that occurs in pregnancy and affects about 7-10% of all pregnancies. It is characterized by hypertension and proteinuria, and there may be involvement ofthe central nervous system and the blood or disseminated intravascular coagulation (DIC). The aim of the study were to determine expression of Platelet Cell Adhesion Molecule-l (PECAM-l) and E-selectin, Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR-l), endothelial Nitric Oxide Synthase (eNOS) and Plasminogen Activator Inhibitor 1 (PAl-I) to determine their role in pathogenesis of PE and eclampsia. The secondary aim was to determine the risk factors for PE and eclampsia and relate placental histopathological lesions to clinical findings and neonatal outcome. Other aims included determining changes in haematological and coagulation indices in PE/eclampsia and evaluate if early involvement of platelets could be used as a suitable marker for early detection of PE. METHODOLOGY: Included in the study were 114 pregnant women delivering in Muhimbili National Hospital between January and December 2001 with a diagnosis of pre-eclampsia or eclampsia and healthy pregnant women (controls). Placenta, cord, extraplacental membranes and serum for coagulation indices determination were collected from these women of which 43 were pre-eclamptic, 31 eclamptic and 40 were healthy pregnant women (controls) Standardized questionaire designed for this study was used to record maternal and infant clinical characteristics and placental parameters. Placenta, cord and membranes which were collected immediately after delivery, fixed in formalin and paraffin embedded. The sections were stained by Hand E and examined by light microscopy.Placenta and membrane sections were stained by immunohistochemistry. RESULTS: Pre-eclamptics/eclamptis were mostly primigravida and had significantly lower gestational age and birth weight of infants. Multigravida women with PE/Eclampsia were more likely to have positive family history or have changed husbands from the previous pregnancy. Presence of extensive infarction was significantly associated with low birth weight of the neonate (P< 0.001, OR; 24.22 (95 % Cl: 7.0-83.3). Immunohistochemical findings: There were no statistical significant differences in placental expression of PE CAM-l and E-selectin in placenta from PE/eclamptic patients compared to controls. Significantly strong staining intensity ofVEGF and VEGFR-l (Flt-l ), e-NOS3 and PAl-l expression in villous syncytiotrophoblasts was seen in the placenta from pre-eclamptic and eclamptic patients compared to controls. DISCUSSION: The present study has shown similar risk factors for PE as is reported in other studies. High expression ofVEGF and VEGFR-l found in patients with PE/eclampsia implies that blocking ofVEGFR and its receptor can be exploited to plan for new therapeutic protocols in these conditions. Anti- VEGF are now currently being used for the treatment of various cancers. The findings in this study can therefore be used to extend this management to pre-eclamptic/eclamptic patients. However, this needs pre-clinical and clinical trials to determine efficacy and safety levels.The increase in VEGFR and its receptor in placenta from pre-eclamptic and eclamptic patients and colocalization found in this study implies that the association may have pathogenetic role. Since PAI-l is involved in fibrin deposition and placental occlusive lesions, its increased expression observed in PE/eclamptic patients in this study supports a thrombotic role. CONCLUSIONS: Pre-eclampsia and eclampsia in Muhimbili National Hospital is associated with multiple risk factors. Over expression ofVEGF and its receptor, eNOS and PAI-l suggests that these molecules may play a significant role in the pathogenesis of PE and eclampsia in our patients. These findings may be important in the formulation of new therapeutic approaches to treatment of PE and eclampsia. Health education to all women to avoid change of husbands may help in the prevention of pre-eclampsia. Strategies which target VEGF/ VEGFR-l pathway may halt progression of PE/eclampsia. RECOMMENDATIONS: Administration of anti-thrombotic agents such as low molecular weight heparin or low dose aspirin to at risk patients for PE/eclampsia may improve pregnancy outcome in these patients. The use of vasodilators to improve the vascular tone in patients with PE/eclampsia should be explored. Further pre-clinical and clinical studies are needed to further elucidate the pathogenesis of preeclampsia and eclampsia and the usefulness of targeting VEGFNEGFR-l pathway in the management.