La insuficiencia venosa crónica en el periodo gestacional

Abstract

La enfermedad venosa crónica es una condición persistente, progresiva y frecuentemente subestimada; ampliamente representada en la población general, que tiene un enorme impacto socioeconómico, físico y psicológico asociado. Las mujeres tienen un mayor riesgo de aparición de insuficiencia venosa debido a diferentes factores hormonales y fisiológicos, especialmente durante el período gestacional. El objetivo de la tesis es evaluar el impacto de la insuficiencia venosa crónica en mueres durante la gestación. Para ello, se han realizado diferentes trabajos, presentándose esta tesis por compendio de artículos. El artículo I es una revisión bibliográfica actualizada de la Enfermedad Venosa Crónica, incluyendo su epidemiología, etiología y factores de riesgo, la fisiopatología y semiología de estos pacientes, incluidas las manifestaciones clínicas, el diagnóstico y los tratamientos¿encontrándose que prácticamente no existen estudios del efecto de la aparición de enfermedad venosa en las mujeres durante la gestación. El artículo II, es un estudio transversal en el que se analiza y demuestra la asociación entre la aparición de varices infradiafragmáticas durante la gestación y alteraciones fetoplacentarias observadas por los clínicos y reflejadas en sus informes de alta, secundarias a hipoxia por compromiso fetal intraparto. El artículo III es un estudio longitudinal en el que se hace analiza si existe alteración en la estructura y función celular de la placenta que sea el sustrato de los resultados gestacionales. En concreto, la implicación de la ILK y un conjunto de cadherinas (e-adherina, cadherina-6, y cadherina 7) en la placenta de mujeres con enfermedad venosa.

Aims: Chronic venous disease is a persistent, progressive and frequently underestimated condition, despite being widely represented in the general population in the World. It has been demonstrated that women has a higher risk of suffer venous insufficiency problems due to the different hormonal and physiological factors they present during the perinatal period. The general objective of this dissertation is to evaluate the specific impact of venous insufficiency in perinatal women. Methods: To achieve the objective stated above, we conducted 3 specific scientific studies. In the study I，we carried out a cross-sectional descriptive bibliographic review of all the research published on chronic venous disease since 1988. From this review, we compiled the most relevant evidence published on the topic of chronic venous disease, with special emphasis on the pathophysiology and medical cognition of disease. Secondly, the article II includes a cross-sectional study, in which we use accurate and updated data from the administrative medical records (CMBD) corresponding to the care registered in 2015, both in the public and private health systems of the different Autonomous Communities of Spain. We used these data to study the association between the prevalence of LEPVI and different risk factors, such as smoking, obesity, asthma, hypothyroidism, and intrapartum fetal distress. We performed a conditional logistic regression to estimate the adjusted odds ratios and the 95% Confidence Intervalto assess the associations between LEPVI and the risk factors, as well as their relationship with intrapartum fetal distress. Finally, in Article III we developed an observational, analytical and prospective study which included a sample of 114 women in the third trimester of pregnancy. A cohort study was conducted by gathering information from a database from the Carlos III Health Institute in 2017. Of these, 62 women were diagnosed with CVD according to the CEAP classification. The rest of women (n= 52) did not presented CVD diseases in their Electronic Health Record, and were included in the control group. Those women IX with CVD during pregnancy were identified to investigate its relationship with ILK expression in placental villi associated with E-cadherin. The relationship between the expression level of Cadherin 17 and Cadherin 6 with CVD was also explored. For this purpose, we conducted a conditional logistic regression model to obtain 95% confidence intervals (95% CI) during pregnancy. Results：Each study included in this dissertation provided several results which jointly contributed to achieving the objective of this thesis. In article I, we find that CVD is a progressive and disabling condition widely represented in the world population. We compiled some of the most relevant data on such a complex topic, with special emphasis on the pathophysiological and medical perceptions of the disease. In particular for the most vulnerable groups, such as the elderly people, individuals with additional comorbidities and pregnant women. In article II, we observed that, women with LEPVI were older and presented higher prevalence of smoking, obesity, asthma, and hypothyroidism, in comparision with those without LEPVI in the group control. In addition, women with LEPVI were more likely to have conditions associated with intrapartum fetal distress (9.35%) than women without this disease (7.41%). Women with LEPVI are 30% (OR = 1.30, 99.5% CI: 1.08-1.54) more likely to have an IFC outcome during the pregnancy, and to have placental dysfunction (OR = 1.74, 99.5% CI: 1.00-3-05), as well. After adjusting for age, smoking, obesity, asthma, hypothyroidism, coagulopathy disorders, and anemia, this association remained significant but slightly attenuated for IFC (OR=1.25, 99.5% CI, 1.05-1 .50) and placental dysfunction (OR = 1.23, 99.5% CI: 1.01-1.49). However, there was no association between LEPVI and fetal distress (OR = 1.01, 99.5% CI: 0.46- 2.21). In article III, women with CVeD during pregnancy show an increase in ILK expression in the placental villi associated with a decrease in E-cadherin. Histological analysis of protein expression by immunohistochemical techniques showed a significant increase X in ILK expression in placental villi of women with CVD during pregnancy compared to HC, ***p < 0.001 [CVeD = 2.379 ± 0.084 vs HC = 0.976 ± 0.082]. In contrast, we observed a significant decrease in E-Cad gene expression in the placental villi of women with CVeD during pregnancy compared to HC, **p = 0.0084 [CVeD = 10.726 ± 0.359 vs HC = 11.893 ± 0.461]. In addition, protein expression showed a significant decrease in E-Cad expression in the placental villi of women with CVeD during pregnancy compared to HC, ***p = 0.002 [CVeD = 0.903 ± 0.062 vs HC = 1.240 ± 0.058]. The expression level of Cadherin 17 and Cadherin 6 increases in the placental villi of women with CVD during pregnancy. Cad-17 gene expression showed a significant increase in placental villi of women with CVD during pregnancy compared to HC, *p = 0.0228 [CVeD = 7.804 ± 0.325 vs HC = 6.780 ± 0.263]. In this sense, protein expression showed a significant elevation by immunohistochemical techniques in the placental villi of women with CVD during pregnancy compared to HC, ** p = 0.0026 [CVeD = 1.403 ± 0.067 vs HC = 1.159 ± 0.085 ]. Similarly, our results have shown an increase in Cad-6 gene expression in the placental villi of women with CVD during pregnancy compared to HC, ** p = 0.0016 [CVeD = 7.083 ± 0.251 vs HC = 5.807 ± 0.247]. Furthermore, protein expression showed a significant increase in the placental villi of women with CVeD during pregnancy compared to HC, **p = 0.0033 [CVeD = 1.202 ± 0.065 vs HC = 0.923 ± 0.066]. Conclusions: CVD is a progressive and disabling disease with high impact in the world population health. Therefore, the management of pathophysiology and therapeutics is fundamental and was one of the objectives of our study. An increasing number of studies, focused on CVD, show the relevance of this vascular pathology, especially in the most advanced stages (CVI). In this dissertation, we collect some of the most relevant data on this important topic, with a special emphasis on pathophysiological and medical insights into the disease. An integrative perspective of this condition would bring immediate benefits for the clinical management of these patients, particularly for the most vulnerable groups, such as the elderly people, individuals with additional comorbidities and pregnant women. XI The second study aimed to determine the association between varicose veins in pregnancy and placental insufficiency. This study represented a nationwide crosssectional analysis in Spain to explore the association between the presence of varicose veins and the existence of alterations in the ischemic placental function. An extensive database gathered from hospital administrations was used for that purpose. In the third study, the relationship between chronic venous disease in pregnant women was observed, causing an increase in ILK in the placental villi associated with a decrease in E-Cadherin, demonstrating a significant increase in the expression of ILK proteins and genes, cadherin-6 and cadherin-17 and a reduction in e-cadherin, associated with the development of CVD during pregnancy.