Vascular Biomarkers Predictive of the Progression from Gestational Hypertension to Preeclampsia in Pregnant Women

Hypertension during pregnancy remains a leading cause of maternal and foetal morbidity and mortality. The frequency (5 to 10% of pregnancies) and potential severity of these diseases, both for the mother and the child, are reasons for standardizing and optimizing medical practices.

The cause of hypertension during pregnancy and in particular the pathophysiology of preeclampsia remains poorly understood. Guidelines distinguish these two entities by the existence of proteinuria from and after the 20th week of amenorrhea and by maternal-foetal complications, more serious in pre-eclampsia than in gestational hypertension.

During gestational hypertension and preeclampsia acute placental vasculature and blood flow abnormalities were observed, maybe due to generalized vascular endothelial activation and vasospasm resulting in systemic hypertension and organ hypoperfusion. Endothelial dysfunction and abnormal expression of several specific blood biomarkers are now well accepted as characteristics of preeclampsia.

However, the progression of gestational hypertension to preeclampsia is difficult to predict; between 15 and 40 % of gestational hypertension cases progress to preeclampsia, suggesting that it is the same worsening disease.

Endothelial dysfunction could be at the origin of gestational hypertension, and subsequent development of preeclampsia through an imbalance between pro- and anti-angiogenic factors.

The main objective of this research is to assess whether the alteration of endothelium-dependent vasodilatation in pregnant women with stable hypertension is correlated with the occurrence of preeclampsia later during pregnancy.

Hypertension in pregnancy is defined by PAS ≥140 mmHg and/or PAD ≥ 90 mmHg, mild to moderate hypertension by PAS = 140-159 mmHg and/or PAD = 90-109 mmHg and severe hypertension by PAS ≥ 160 mmHg and/or PAD ≥ 110 mmHg.

During gestational hypertension (GE) there is no pathologic elevation of proteinuria (after 20 weeks of amenorrhea). Preeclampsia (PE) is defined as high blood pressure (controlled or uncontrolled) associated with proteinuria discovered after the 20th week of amenorrhea.

The cause of hypertension and pathophysiology during pregnancy and in particular of preeclampsia remains poorly understood. Endothelial dysfunction and abnormal blood levels of several biomarkers are associated with PE, such as: soluble Fms-like- tyrosine kinase 1 (sFlt-1), Placental Growth Factor (PIGF) and Vascular Endothelial Growth Factor (VEGF). VEGF is of particular importance due to its direct vasodilating effect at systemic level through its interaction with nitric oxide (NO). There is a bi-directional regulation between VEGF and NO, which has direct implications for endothelium, capillary permeability and angiogenesis. sFlt-1 (circulating form of VEGF receptor) has the property of neutraliting the growth factors VEGF and PIGF. Inhibition of VEGF has a known biological effect on endothelial function in adults and is believed to be a key factor in explaining elevated blood pressure. This has been demonstrated in patients undergoing anti-angiogenic therapy in combination with chemotherapy. Other biomarkers of preeclampsia are less known and could be involved in pathophysiological mechanisms; mainly hypervolemia, renal dysfunction and activation of inflammation. The progression of gestational hypertension to preeclampsia is difficult to predict; between 15 and 40 % of gestational hypertension cases progress to preeclampsia, suggesting that it is a single worsening disease. Preeclampsia is known to be one of the few diseases in which acute placental abnormalities manifest at the mother's vascular and renal system levels. These abnormalities are attributable to generalized vascular endothelial activation and vasospasm, resulting in hypertension and hypoperfusion of organs.

Endothelial dysfunction could be at the origin of gestational hypertension, and subsequently itself contribute to the subsequent development of preeclampsia through an imbalance between pro- and anti-angiogenic factors likely in relation with increased oxidative stress.

It is now accepted that angiogenic biomarkers (such as soluble fms-like tyrosine kinase 1, Placenta growth factor and soluble endoglin) contribute to endothelial dysfunction through VEGF antagonizing among others. The dosage of these angiogenic biomarkers in the maternal bloodstream is highly predictive and significantly abnormal from the 23th week of amenorrhea on average, and with a maximum peak between the 32th and 36th week of amenorrhea.

Endothelial microparticles (EMPs) are involved in intracellular communication and produced in normal pregnancy and in PE. The renal damage associated with PE and the potential role of extracellular vesicles are in the main adverse mechanisms that distinguish the different types of hypertension in pregnancy.

Adequate levels of circulating endothelial microparticles (CEMP), circulating endothelial cells (CECs), and endothelial progenitor cells most likely play an important role in the development and regulation of the vasculature during pregnancy, but the exact role in the pathogenesis of PE is unknown.

These endothelial microparticles (EMPs) reflects systemic endothelial damage and can also be measured in urine by flow cytometry. In general, in hypertensive patients, there is peritubular capillary loss (PCL) and it can be measured by these EMPs. Urinary (not blood) MP levels correlate directly with renal hypoxia and fibrosis and inversely with cortical perfusion. Therefore, the level of EMPs could be useful as "new biomarkers" of intrarenal capillary loss. However, only a few in-depth studies in the field of hypertension in pregnancy have focused on this issue.

The main objective is to assess whether the presence of urinary endothelial microparticles (UEMP) in the pregnant woman in a stable condition with discovery of gestational hypertension is a marker of the occurrence of preeclampsia later during pregnancy.

The investigators further explore a possible correlation of alteration of UEMP to other biomarkers of pre-eclampsia endothelial dysfunction and vascular involvement in pregnancy hypertension.

Eligibility Criteria:
Inclusion Criteria:

* Patients with gestational hypertension and/or preeclampsia from the 20th amenorrhea week until the 26th ± 2 amenorrhea week.
* Age between 18 and 40 years old.
* Having given written consent
* Patients affiliated to a social security scheme

Exclusion Criteria:

* Presence of pathologies interfering in a major way with vascular parameters: known multicomplicated diabetes treated before pregnancy, hypercholesterolemia known (or LDL\>130 mg/dl), connectivitis, proven cardiovascular disease (ischemic heart disease, stroke, arteriopathy of the lower limbs, heart failure), pre-existing known renal failure (MDRD \<60 ml/min) and/or pre-existing proteinuria ≥ 300 mg/24h).
* Cardiac arrhythmia.
* Hepatitis C, HIV infection (assay performed within 6 months prior to diagnosis of pre- eclampsia)
* Recent history of venous (pulmonary embolism, phlebitis) or arterial (myocardial infarction, unstable angina, stroke, transient ischemic attack), thrombotic event ≤ 3 months.
* Patient already engaged in a therapeutic protocol
* Patients under legal protective measures
* Patients receiving State Medical Assistance