Pharmacological activation of peroxisome proliferator-activated receptor γ (PPAR-γ) protects against hypoxia-associated fetal growth restriction.

The hypoxia of high-altitude (HA) residence increases the risk of intrauterine growth restriction (IUGR) and preeclampsia 3-fold, augmenting perinatal morbidity and mortality and the risk for childhood and adult disease. Currently, no effective therapies exist to prevent these vascular disorders of pregnancy. The peroxisome proliferator-activated receptor γ (PPAR-γ) is an important regulator of uteroplacental vascular development and function and has been implicated in the pathogenesis of IUGR and preeclampsia. Here, we used a model of HA pregnancy in mice to determine whether hypoxia-induced fetal growth restriction reduces placental PPAR-γ protein expression and placental vascularization and, if so, to evaluate the effectiveness of the selective PPAR-γ agonist pioglitazone (PIO) for preventing hypoxia-induced IUGR. Hypoxia resulted in asymmetric IUGR, placental insufficiency, and reduced placental PPAR-γ expression; PIO prevented approximately half of the fetal growth restriction and attenuated placental insufficiency. PIO did not affect fetal growth under normoxia. Although PIO was beneficial for fetal growth, PIO treatment reduced placental vascular density of the labrynthine zone in normoxic and hypoxic (Hx) conditions, and mean vascular area was reduced in the Hx group. Our results suggest that pharmacological PPAR-γ activation is a potential strategy for preventing IUGR in pregnancies complicated by hypoxia, although further studies are needed to identify its likely metabolic or vascular mechanisms.-Lane, S. L., Dodson, R. B., Doyle, A. S., Park, H., Rathi, H., Matarrazo, C. J., Moore, L. G., Lorca, R. A., Wolfson, G. H., Julian, C. G. Pharmacological activation of peroxisome proliferator-activated receptor γ (PPAR-γ) protects against hypoxia-associated fetal growth restriction.

Aspirin use during pregnancy and hypoxia-related placental pathology.

OBJECTIVE: Aspirin has been shown to prevent preeclampsia. But the mechanisms remain unclear despite that improved placental circulation is considered as an underlying contributor. Our aim was to examine the hypoxia-related morphological and histopathological placental measures in relation to aspirin use during pregnancy. STUDY DESIGN: We used the Collaborative Perinatal Project (CPP) data, which is a cohort study conducted in the U.S. from 1959 to 1976. A total of 23, 604 women who had information on placental pathology and aspirin intake during pregnancy were included in the analysis. Among them, 1474 women had a history of hypertension or preeclampsia/eclampsia and were classified as a high-risk population; the rest were considered as a low-risk population. 47 placenta measures considered to be relevant to hypoxia were selected to build a composite hypoxia- related placenta index. The generalized linear mixed model was used to fit the relationship between aspirin and placental pathology. MAIN OUTCOME MEASURES: Hypoxia-related placental pathology. RESULTS: Aspirin use during pregnancy was associated with a reduced risk of hypoxia-related placental pathology in the high-risk population [the adjusted odds ratio and 95% confidence interval in the 1st, 2nd, and 3rd trimesters: 0.55 (0.31, 1.00), 0.76 (0.49, 1.17), and 0.53 (0.29, 0.94), respectively]. Longer duration of aspirin use in pregnancy tended to have a lower risk of hypoxia-related placental pathologies in the high-risk population. CONCLUSIONS: Aspirin use during pregnancy reduced risks of hypoxia-related placental pathologies in the high-risk women for preeclampsia. The duration of aspirin use determined its effects.

Study protocol for a randomised controlled trial: treatment of early intrauterine growth restriction with low molecular weight heparin (TRACIP).

INTRODUCTION: The incidence of intrauterine growth restriction (IUGR) is estimated at about 3% of pregnancies, and it is associated with 30% of all perinatal mortality and severe morbidity with adverse neurodevelopmental and cardiovascular health consequences in adult life. Early onset IUGR represents 20%-30% of all cases and is highly associated with severe placental insufficiency. The existing evidence suggests that low molecular weight heparin (LMWH) has effects beyond its antithrombotic action, improving placental microvessel structure and function of pregnant women with vascular obstetric complications by normalising proangiogenic and antiapoptotic protein levels, cytokines and inflammatory factors. The objective of our study is to demonstrate the effectiveness of LMWH in prolonging gestation in pregnancies with early-onset IUGR. METHODS AND ANALYSIS: This is a multicentre, triple-blind, parallel-arm randomised clinical trial. Singleton pregnancies qualifying for early (20-32 weeks at diagnosis) placental IUGR (according to Delphi criteria) will be randomised to subcutaneous treatment with bemiparin 3500 IU/0.2 mL/day or placebo from inclusion at diagnosis to the time of delivery. Analyses will be based on originally assigned groups (intention-to-treat). The primary objective will be analysed by comparing gestational age and prolongation of pregnancy (days) in each group with Student's t-tests for independent samples and by comparing Kaplan-Maier survival curves (from inclusion to delivery, log-rank test). A linear regression model for gestational age at birth will consider the following covariates: gestational age at inclusion (continuous) and pre-eclampsia (binary). ETHICS AND DISSEMINATION: The study will be conducted in accordance with the principles of Good Clinical Practice. This study was approved by the Clinical Research Ethics Committee (CEIC) of Sant Joan de Déu Hospital, on 13 July 2017. The trial is registered in the public registry www.clinicaltrial.gov. according to Science Law 14/2011, and the results will be published in an open access journal. TRIAL REGISTRATION NUMBER: NCT03324139; Pre-results.

Update on the diagnosis and prognosis of pre-eclampsia in singleton pregnancies based on the sFlt-1/PlGF ratio / Actualización del diagnóstico y el pronóstico de la preeclampsia en embarazos únicos con la ayuda del cociente sFlt-1/PlGF

Pre-eclampsia belongs to a group of obstetric complications that are closely related through placental insufficiency, which also includes intrauterine growth restriction and placental abruption. Timely and accurate detection and treatment of pre-eclampsia is usually difficult, since diagnostic criteria are still based on nonspecific signs and symptoms and there is no clear association between the usual criteria for severity and unfavorable outcomes for mother and fetus. The discovery of the role of angiogenic factors (sFlt-1 y PlGF) in the pathophysiology of placental insufficiency is a key step toward improving early diagnosis and establishing a prognosis in cases occurring before week 34 of pregnancy. At present, ≤ 38 is widely accepted to be threshold value of the sFlt-1/PlGF ratio that rules out suspected pre-eclampsia. The use of the ratio is considered cost-effective. However, current data on the treatment and prognosis of women with an abnormally high sFlt1/PlGF ratio are more limited. The present article summarizes current knowledge on the clinical application of the sFlt-1/PlGF for the diagnosis and prognosis of pre-eclampsia and highlights those areas that should be addressed with respect to biomarkers, for example, their role as targets in the development and follow-up of new treatments

La preeclampsia pertenece a un grupo de complicaciones obstétricas estrechamente relacionadas entre ellas por la existencia de una insuficiencia placentaria, que incluye también la restricción del crecimiento intrauterino y el desprendimiento placentario. El reconocimiento y tratamiento oportuno y preciso de la preeclampsia suele ser difícil, ya que los criterios diagnósticos aún se basan en signos y síntomas inespecíficos y no existe una relación clara entre los criterios habituales de gravedad y los resultados desfavorables para la madre o el feto. El descubrimiento del papel que juegan los factores relacionados con la angiogénesis (sFlt-1 y PlGF) en la fisiopatología subyacente de la insuficiencia placentaria ha constituido un paso importante a la hora de mejorar el diagnóstico precoz y establecer un pronóstico en los casos que se presentan antes de la semana 34 de gestación. En la actualidad está ampliamente aceptado que el valor límite del cociente sFlt-1/PlGF que permite excluir la existencia de preeclampsia en pacientes en las que se sospecha esta enfermedad es de 38 o menos, y que el uso de este cociente resulta costo-eficiente. Sin embargo, los datos disponibles relativos al tratamiento y al pronóstico de las mujeres con niveles anormalmente altos del cociente sFlt1/PlGF son más limitados. Este artículo resume los conocimientos actuales relativos a la aplicación clínica del cociente sFlt-1/PlGF para diagnosticar y pronosticar el curso de la preeclampsia, y señala las próximas tareas que serán necesarias abordar en relación con estos biomarcadores, como por ejemplo el papel que pueden jugar como dianas para el desarrollo y el seguimiento de nuevos tratamientos

Evidence-based national guidelines for the management of suspected fetal growth restriction: comparison, consensus, and controversy.

Small for gestational age is usually defined as an infant with a birthweight <10th centile for a population or customized standard. Fetal growth restriction refers to a fetus that has failed to reach its biological growth potential because of placental dysfunction. Small-for-gestational-age babies make up 28-45% of nonanomalous stillbirths, and have a higher chance of neurodevelopmental delay, childhood and adult obesity, and metabolic disease. The majority of small-for-gestational-age babies are not recognized before birth. Improved identification, accompanied by surveillance and timely delivery, is associated with reduction in small-for-gestational-age stillbirths. Internationally and regionally, detection of small for gestational age and management of fetal growth problems vary considerably. The aim of this review is to: summarize areas of consensus and controversy between recently published national guidelines on small for gestational age or fetal growth restriction; highlight any recent evidence that should be incorporated into existing guidelines; and identify future research priorities in this field. A search of MEDLINE, Google, and the International Guideline Library identified 6 national guidelines on management of pregnancies complicated by fetal growth restriction/small for gestational age published from 2010 onwards. There is general consensus between guidelines (at least 4 of 6 guidelines in agreement) in early pregnancy risk selection, and use of low-dose aspirin for women with major risk factors for placental insufficiency. All highlight the importance of smoking cessation to prevent small for gestational age. While there is consensus in recommending fundal height measurement in the third trimester, 3 specify the use of a customized growth chart, while 2 recommend McDonald rule. Routine third-trimester scanning is not recommended for small-for-gestational-age screening, while women with major risk factors should have serial scanning in the third trimester. Umbilical artery Doppler studies in suspected small-for-gestational-age pregnancies are universally advised, however there is inconsistency in the recommended frequency for growth scans after diagnosis of small for gestational age/fetal growth restriction (2-4 weekly). In late-onset fetal growth restriction (≥32 weeks) general consensus is to use cerebral Doppler studies to influence surveillance and/or delivery timing. Fetal surveillance methods (most recommend cardiotocography) and recommended timing of delivery vary. There is universal agreement on the use of corticosteroids before birth at <34 weeks, and general consensus on the use of magnesium sulfate for neuroprotection in early-onset fetal growth restriction (<32 weeks). Most guidelines advise using cardiotocography surveillance to plan delivery in fetal growth restriction <32 weeks. The recommended gestation at delivery for fetal growth restriction with absent and reversed end-diastolic velocity varies from 32 to ≥34 weeks and 30 to ≥34 weeks, respectively. Overall, where there is high-quality evidence from randomized controlled trials and meta-analyses, eg, use of umbilical artery Doppler and corticosteroids for delivery <34 weeks, there is a high degree of consistency between national small-for-gestational-age guidelines. This review discusses areas where there is potential for convergence between small-for-gestational-age guidelines based on existing randomized controlled trials of management of small-for-gestational-age pregnancies, and areas of controversy. Research priorities include assessing the utility of late third-trimester scanning to prevent major morbidity and mortality and to investigate the optimum timing of delivery in fetuses with late-onset fetal growth restriction and abnormal Doppler parameters. Prospective studies are needed to compare new international population ultrasound standards with those in current use.

Monitoring of Hemostasis and Management of Anticoagulant Thromboprophylaxis in Pregnant Women with Increased Risk of Fetal Loss.

Physiological prothrombotic changes during pregnancy and the postpartum period, along with other preexisting maternal risk factors, increase the risk of both venous thromboembolism (VTE) and adverse pregnancy outcomes. Pregnancy complications that develop due to placental insufficiency as a result of inappropriate activation of coagulation are present in more than 5% of pregnancies and can contribute to significant maternal morbidity and mortality. Therefore, anticoagulant prophylaxis in women with congenital and acquired thrombophilic conditions should be actively considered. According to the Guidelines of American College of Chest Physicians, the use of low-molecular-weight heparin is suggested for prophylaxis of VTE and pregnancy complications in high-risk pregnant women. However, personalized refinements of such thromboprophylaxis remains unspecified, despite the necessity of better targeted recommendations for life-threatening conditions. We, therefore, review the possibilities of longitudinal monitoring and comprehensive assessment of changes in hemostasis in the group of high-risk pregnant women, which can then be used for early prediction and individualization of the optimal anticoagulant thromboprophylaxis of pregnancy complications. Simultaneously, we present our single-center experience with such monitoring and our first series of results.

Maternal fructose drives placental uric acid production leading to adverse fetal outcomes.

Maternal metabolic diseases increase offspring risk for low birth weight and cardiometabolic diseases in adulthood. Excess fructose consumption may confer metabolic risks for both women and their offspring. However, the direct consequences of fructose intake per se are unknown. We assessed the impact of a maternal high-fructose diet on the fetal-placental unit in mice in the absence of metabolic syndrome and determined the association between maternal serum fructose and placental uric acid levels in humans. In mice, maternal fructose consumption led to placental inefficiency, fetal growth restriction, elevated fetal serum glucose and triglyceride levels. In the placenta, fructose induced de novo uric acid synthesis by activating the activities of the enzymes AMP deaminase and xanthine oxidase. Moreover, the placentas had increased lipids and altered expression of genes that control oxidative stress. Treatment of mothers with the xanthine oxidase inhibitor allopurinol reduced placental uric acid levels, prevented placental inefficiency, and improved fetal weights and serum triglycerides. Finally, in 18 women delivering at term, maternal serum fructose levels significantly correlated with placental uric acid levels. These findings suggest that in mice, excess maternal fructose consumption impairs placental function via a xanthine oxidase/uric acid-dependent mechanism, and similar effects may occur in humans.

Does low-molecular-weight heparin influence fetal growth or uterine and umbilical arterial Doppler in women with a history of early-onset uteroplacental insufficiency and an inheritable thrombophilia? Secondary randomised controlled trial results.

OBJECTIVE: Does low-molecular-weight heparin (LMWH) added to low-dose aspirin influence fetal growth and flow velocity in uterine and umbilical arteries in women with an inheritable thrombophilia and previous early-onset uteroplacental insufficiency? DESIGN: Secondary outcomes of the FRUIT-RCT. SETTING: Multicentre, international. POPULATION: The FRUIT-RCT included 139 women with inheritable thrombophilia before 12 weeks of gestation. Inclusion criteria were previous delivery before 34 weeks of gestation with a hypertensive disorder of pregnancy and/or small-for-gestational-age infant and an inheritable thrombophilia. METHODS: After randomisation to either daily LMWH with aspirin, or aspirin only, ultrasound measurements were performed at 22-24, 28-30 and 34-36 weeks of gestation. Development during gestation of growth, birthweight and flow velocity of the umbilical artery was examined using the linear mixed model. Uterine artery flow velocity at a single time-point (22-24 weeks) was examined using a chi-square test. MAIN OUTCOME MEASURES: Fetal growth over time including birthweight, using Scandinavian, Dutch and customised growth curves; and flow velocity within the uterine and umbilical arteries. RESULTS: No difference of fetal growth over time could be demonstrated between the study arms, regardless of which reference criteria were used. The flow velocity within the uterine artery and umbilical artery did not differ between study arms. CONCLUSION: The addition of LMWH to aspirin did not influence fetal growth or umbilical artery flow velocity over time; nor did it influence uterine artery flow velocity. TWEETABLE ABSTRACT: LMWH does not influence fetal growth or uterine or umbilical flow velocities.

Prevention of Defective Placentation and Pregnancy Loss by Blocking Innate Immune Pathways in a Syngeneic Model of Placental Insufficiency.

Defective placentation and subsequent placental insufficiency lead to maternal and fetal adverse pregnancy outcome, but their pathologic mechanisms are unclear, and treatment remains elusive. The mildly hypertensive BPH/5 mouse recapitulates many features of human adverse pregnancy outcome, with pregnancies characterized by fetal loss, growth restriction, abnormal placental development, and defects in maternal decidual arteries. Using this model, we show that recruitment of neutrophils triggered by complement activation at the maternal/fetal interface leads to elevation in local TNF-α levels, reduction of the essential angiogenic factor vascular endothelial growth factor, and, ultimately, abnormal placentation and fetal death. Blockade of complement with inhibitors specifically targeted to sites of complement activation, depletion of neutrophils, or blockade of TNF-α improves spiral artery remodeling and rescues pregnancies. These data underscore the importance of innate immune system activation in the pathogenesis of placental insufficiency and identify novel methods for treatment of pregnancy loss mediated by abnormal placentation.

Risk factors and consequences of maternal anaemia and elevated haemoglobin levels during pregnancy: a population-based prospective cohort study.

BACKGROUND: To determine sociodemographic and life style-related risk factors and trimester specific maternal, placental, and fetal consequences of maternal anaemia and elevated haemoglobin levels in pregnancy. METHODS: In a population-based prospective cohort study of 7317 mothers, we measured haemoglobin levels in early pregnancy [gestational age median 14.4 weeks (inter-quartile-range 12.5-17.5)]. Anaemia (haemoglobin ≤11 g/dl) and elevated haemoglobin levels (haemoglobin ≥13.2 g/dl) were defined according to the WHO criteria. Maternal blood pressure, placental function and fetal growth were measured in each trimester. Data on gestational hypertensive disorders and birth outcomes was collected from hospitals. RESULTS: Older maternal age, higher body mass index, primiparity and European descent were associated with higher haemoglobin levels (P < 0.05). Elevated haemoglobin levels were associated with increased systolic and diastolic blood pressure throughout pregnancy (mean differences 5.1 mmHg, 95% confidence interval [CI] 3.8, 6.5 and 4.1 mmHg, 95% CI 3.0, 5.2, respectively) and with a higher risk of third trimester uterine artery notching (RR 1.3, 95% CI 1.0, 1.7). As compared with maternal normal haemoglobin levels, not anaemia, but elevated haemoglobin levels were associated with fetal head circumference, length, and weight growth restriction from third trimester onwards (P < 0.05). Elevated haemoglobin levels were associated with increased risks of gestational hypertensive disorders (RR 1.4, 95% CI 1.1, 1.8) and adverse birth outcomes (RR 1.4, 95% CI 1.1, 1.7). CONCLUSIONS: In a low-risk population, various sociodemographic and life style factors affect haemoglobin levels during pregnancy. Elevated haemoglobin levels are associated with increased risks of maternal, placental, and fetal complications.

Maternal floor infarction: management of an underrecognized pathology.

Maternal floor infarction is a relatively rare condition characterized clinically by severe early onset fetal growth restriction with features of uteroplacental insufficiency. It has a very high recurrence rate and carries a significant risk or fetal demise. Pathological characteristics include massive and diffuse fibrin deposition along the decidua basalis and the perivillous space of the basal plate. We present a case of recurrent maternal floor infarction and propose diagnostic clues as well as potential therapeutic options.

[Selective intrauterine growth restriction in monochorionic twin pregnancies]. / Selektywne wewnatrzmaciczne ograniczenie wzrastania w ciazach blizniaczych jednokosmówkowych.

Selective intrauterine growth restriction (sIUGR) is a major complication of monochorionic pregnancies, with potentially high risk of intrauterine fetal death or neurological dysfunction in both fetuses. Diagnostic ultrasound has contributed to the understanding of the pathophysiology of sIUGR and allowed to propose a classification. That, in turn, allows to interpret a wide clinical variety of sIUGR and, depending on the type, to propose a specific clinical management. The introduction of diagnosis based on Doppler studies enables the correct diagnosis of the disorders, fetal monitoring, to determine the prognosis and optimal strategies, and to propose the best therapeutic intervention.

[Peculiarities of metabolic rearrangement of gas-transporting function of the blood in the pregnant women under the influence of medical ozone applied in obstetrical practice].

This clinical and laboratory study was designed to evaluate the influence of an ozone-oxygen mixture on the characteristics of blood oxygen supply in pregnant women presenting with chronic placental insufficiency. The study has demonstrate that dosed ozone application modulates the oxygen-transporting function of the blood and promotes adaptive capacities of the organism by activation of aerobic metabolism and stabilization of cellular membranes. It is concluded that the proposed method can be recommended for the treatment of women with the complicated course of pregnancy in order to improve their endurance of and resistibility to the action of hypoxemia.

[Placental insufficiency in pregnancy with gestosis: pathogenesis, diagnosis, evaluation, and obstetric care strategy].

Pathogenesis of placental insufficiency during pregnancy with gestosis was investigated by high-tech methods including ultrasonography, dopplerometry, echocardiography, and measurement of placental and endothelial growth factors. Their utility for the evaluation of the severity of placental insufficiency was demonstrated. Diagnostic criteria for compensated and uncompensated placental insufficiency were proposed along with an algorithm for the examination of pregnant women with gestosis and obstetric strategies at different severity of this disorder. Also, criteria for prolongation of pregnancy with uncompensated placental insufficiency, indications for planned and emergency delivery by cesarean section were developed. The importance of differential approach to the choice of obstetric strategy to reduce perinatal and maternal morbidity and mortality in case of gestosis and placental insufficiency is emphasized.

A Origem fetal das doenças dos adultos (a hipótese de Barker) / Fetal origin of adults' diseases (Barker's hypothesis)

Os Trabalhos do epidemiologista inglês David Barker, iniciados na década de 80 levaram ao desenvolvimento de uma nova teoria para a origem de algumas doenças crônico-degenerativas da vida adulta, como hipertensão arterial, diabetes e coronariopatias. Segundo Barker, o feto seria programado intra-útero, principalmente por fatores nutricionais, que influenciariam o metabolismo e a fisiologia desse indivíduo por toda a vida. O texto a seguir apresenta uma síntese dos dados acumulados na literatura mundial nos últimos 17 anos (o primeiro artigo de Barker foi publicado em 1986), iniciando com dados históricos, passando pelas correlações epidemiológicas e teorias que ligam a programação intra-útero às doenças do adulto e finalizando com algumas perspectivas para a aplicação prática desses novos conhecimentos

Antiphospholipid syndrome in obstetrics.

Antiphospholipid syndrome (APLS) in pregnancy is characterized by the presence of autoantibodies in association with recurrent fetal loss and severe complications such as preeclampsia, fetal growth retardation, or placental insufficiency. The most clinically important serologic markers are lupus anticoagulant, anticardiolipin antibodies, and recently anti-beta-2-glycoprotein 1 antibodies. At present, standardization does not exist and a definitive association between specific clinical manifestation and antibody level is not yet known. Experimental data gave evidence that passive transfer of antiphospholipid antibodies result in clinical manifestation of APLS, that is, fetal loss and thrombocytopenia. Treatment with heparin, aspirin, or intravenous immunoglobulins decreased the fetal loss rate. Treatment regimens in human are very difficult to interpret. Evidence from two prospective studies supported treatment with heparin and aspirin to improve pregnancy outcome. The risk of preeclampsia and placental insufficiency was substantial and occurred in 50% of patients. The general failure rate of heparin/aspirin treatment is approximately 30%. In such cases intravenous immunoglobulin in combination with heparin and aspirin has been used to treat APLS.

[Prognosis, prophylaxis, and early therapy of fetoplacental insufficiency]. / Prohnozuvannia, profilaktyka ta rannia terapiia fetoplatsentarnoï nedostatnosti.

Parameters characterizing the bloodflow, system of hemostasis, were determined together with the level of the key hormones (estriol and placental lactogen) in 70 pregnant women running a risk for development of placental insufficiency as well as in those pregnant women presenting with clinical manifestations of placental insufficiency at week 6 to 40. The parameters have been noted to get worse during the period of placentation. Augmentation of resistance of the uterine arteries and umbilical artery, ultrasonic signs, decline in the hormonal activity of the placental complex, changes in the hemostasiogram--all these events come to be seen before the appearance of the first clinical signs of placental insufficiency. The studied parameters have been shown to get improved by early complex treatments of administration.

La microscopia electrónica de barrido del infarto placentario / Scanning electron microscopy of placental infartion

Muestras de regiones de infartación placentaria se tomaron de una paciente con preeclampsia y se procesaron con las técnicas convencionales de la Microscopía Electrónica de Barrido. Los resultados revelan aglomeración de vellosidades con disminución del espacio intervelloso, dilatación de capilares e hipertrofía de la vellosidad. Se notaron en las observaciones necrosis del trofoblasto y deposición de fibrina en la periferia de las vellosidades simultáneamente con fibrosis del estroma y necrosis de los vasos a medida que envejece el infarto. En algunos casos el borde periférico vellositario se rodea de fibrinoide, con células trofoblásticas proliferativas en él incluidas que posteriormente sufren necrosis. Los infartos más viejos contienen depósitos de fibrinoide que envuelven a vellosidades fantasmales que contienen gran cantidad de fibras colágenas. Estos resultados indican cambios isquémicos agudos y crónicos, mostrando una visión de conjunto tridimensional que expresan mejor las lesiones con una mayor profundidad de campo y superficie de análisis. Este nuevo aspecto morfológico detalla y extiende previas investigaciones revelando cambios degenerativos desde la fase hemorrágica hasta la colagenosis del estroma velloso