LRBA (from Lipopolysaccharide-responsive and beige-like anchor protein) result in a primary immunodeficiency with clinical features ranging from hypogammaglobulinemia and lymphoproliferative syndrome to inflammatory bowel disease and heterogeneous autoimmune manifestations. LRBA deficiency has been shown to affect vesicular trafficking, autophagy and apoptosis, which may lead to alterations of several molecules and processes that play key roles for immunity.Bi-allelic mutations in In this review, we will discuss the relationship of LRBA with the endovesicular system in the context of receptor trafficking, autophagy and apoptosis. Since these mechanisms of homeostasis are inherent to all living cells and not only limited to the immune system and also, because they are involved in physiological as well as pathological processes such as embryogenesis or tumoral transformation, we envisage advancing in the identification of potential pharmacological agents to manipulate these processes. Among them is included LRBA (Lipopolysaccharide-responsive and beige-like anchor protein); either homozygous or compound heterozygous mutations in this gene cause loss of LRBA protein expression, which is associated with a broad spectrum of clinical and immunological manifestations . Subsequently, several reports of individuals with LRBA deficiency have been published, who suffer from a wider spectrum of clinical manifestations including: increased susceptibility to infections, polyautoimmunity, lymphoproliferation and gastropathy, all associated or not with hypogamaglobulinemia -More than 400 genes have been reported to affect the immune system either quantitative and/or qualitatively and also, in a symptomatic manner in vitro production of antibodies was observed, together with an increase in apoptosis and a defect in the starvation-induced autophagy With regard to the immunological findings, T lymphocytes from patients with the LRBA deficiency presented with an increase in either starvation- or staurosporine-induced and controversially, a decrease in Fas-induced apoptosis (Staurosporine is a potent inhibitor of protein kinases and activator of caspases) LRBA is located on chromosome 4q31.3 and comprises 750,839 bp along 58 exons. The protein contains 2,863 amino acids and has a molecular mass of  is the most characterized. This domain, with  In addition to these domains, LRBA seems to contain a VHS domain (VPS (vacuolar protein sorting)-27, Hrs (hepatocyte growth factor-regulated tyrosine kinase sustrate) STAM  domain) The possible functions of all these domains are explained in With respect to tissue-specific expression, transcripts of this protein have been observed mainly bone marrow, lymph nodes, spleen, fetal liver, placenta, kidney and pancreas by RT-PCR (Reverse transcription polymerase chain reaction) and qPCR (quantitative polymerase chain reaction) ,CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) is a protein receptor located in the plasmatic membrane of activated T cells. It functions to regulate homeostasis and peripheral immunological tolerance through the inhibition of T cell activation, competing with the costimulatory molecule CD28 for the specific ligation of CD80 and CD86, which are expressed on the surface of antigen-presenting cells LRBA mutants decreases the expression and phosphorylation of EGFR ,.Other study that demonstrates the LRBA role in vesicular trafficking is related to the epidermal growth factor receptor (EGFR). Dominant-negative Finally, LRBA deficient patients exhibited a decrease in apoptosis mediated by the death receptor Fas, as compared to healthy donors These evidences suggest that LRBA might be involved in the vesicular trafficking of other receptors in lymphocytes. In LRBA deficient mice, defects have been reported in the phosphorylation of ERK1/2  and AKT in natural killer (NK) cells stimulated with anti-NKG2D or anti-NKp46 antibodies, with a significant decrease in the production of IFN-gamma by these cells after stimulation Drosophila suggests a possible functional interaction between bchs (blue cheese), a member of the BEACH family, and Rab11 Despite these studies on the LRBA-mediated modulation of some cellular receptors, little is known about the intracellular pathways that this molecule employ to perform this function. This transport seems to be carried out by the recruitment of proteins in clathrin-coated vesicles, on which the receptors are removed to early endosomes and subsequently degraded by lysosomal enzymes or recycled to the cell surface Therefore, studies quantifying the expression of the mentioned receptors in LRBA deficient cells (either by silencing or from patients) are needed. It would also be useful to use advanced microscopy techniques to investigate the location of LRBA in other organelles involved in this type of trafficking. In addition, studies of co-immunoprecipitation between LRBA and vesicular trafficking proteins, the use of drugs that block this trafficking or the implementation of negative dominant ARFs, phospholipase D or Rab, could expand our knowledge about the interaction of LRBA with other vesicular trafficking molecules and thus determine its relationship with the membrane expression of receptors such as EGFR, Fas or the activating receptors of NK cells, B cells or others in immune cells. ,Autophagy is a mechanism of lysosomal degradation by which the cell destroys damaged organelles and microorganisms and helps to recycle macromolecules. In this process, a double membrane of isolation or phagophore is formed near to the target, which is then elongated, surrounding it, to later mature with the assimilation of a cytosolic charge forming the autophagosome. For the maturation to be effective, the autophagosome must be fused with early or late endosomes forming a structure called amphisome ,,,mauve (mv) in Drosophila, which is ortholog of LYST, affect the autophagosome function Several of the genes homologous to LRBA are involved in autophagy. WDFY3 (WD and FYVE zinc finger domain containing protein 3) encodes a protein that colocalizes with autophagosome markers -in silico tools have predicted that LRBA interacts with LC3 In immortalized B cells from patients with LRBA deficiency, a significant reduction in the autophagy influx in response to starvation, together with an increase in the Golgi apparatus area, accumulation of autophagosomes and the presence of centrioles is observed, in comparison with those cells from healthy individual -). An increase in the production of IL-1β in the interstitial mucosa has been implicated with uncontrolled inflammation in the course of this disease ATG16L1 (autophagy-related 16-like 1)-knockout mice present with a defect in autophagy and exhibit a high production of IL-1β after LPS stimulation ATG16L1 increased the production of IL-1β in peripheral blood mononuclear cells isolated from patients with IBD ,,In an attempt to associate the defects in autophagy with the clinical characteristics found in LRBA deficiency individuals, it is important to bear in mind that one of the most common clinical manifestations among these individuals is the gastropathy, phenotypically expressed in many cases as Inflammatory Disease Intestinal (IBD) or IBD-like disease, a condition characterized by recurrent destructive inflammation in the intestinal tract Microscopy studies with LRBA deficient cells are required to study the intracellular distribution of molecules such as Rab7 and LC3 after the autophagic influx. It would also be interesting to investigate if LRBA interacts physically with any of the Rab molecules involved in the different types of autophagy, by means of co-immunoprecipitation assays. The role of LRBA in inflamosome activity could be addressed by measuring the production of IL-1β in LRBA deficient phagocytic or intestinal epithelial cells or by determining the activity of active auto-inflammosome by means of redistribution of ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), which is a protein that recruits the necessary caspases for the activation of the inflammosome. LRBA-knockdown HeLa cells exposed to ultraviolet light or staurosporine, a greater cleavage of PARP (Poly (ADP-ribose) polymerase) and caspase 3 are observed, events that are necessary to initiate the cascade of signaling that eventually leads to apoptosis In LRBA deficient patients’ immortalized B cells subjected to starvation, a significant increase in apoptosis is observed ,Apoptosis is a type of programmed cell death to control development and growth. For long time, caspases have been considered as the proteases involved in the execution of the apoptosis program, and nowadays it is known that the partial destabilization of the lysosomal membrane, with the consequent release of hydrolytic enzymes, can initiate and execute apoptosis, byactivating caspases . However, in other conditions, autophagy may culminate in cell death, dependently or independently of apoptosis However, a complex crosstalk between autophagy and apoptosis exists, that is critical for cell fate. Under certain cellular conditions, autophagy can promote cell survival and prevent apoptosis Therefore, it is necessary to evaluate the quantity and integrity of the lysosomes in LRBA deficient immune cells. In addition, the kinetics of lysosomal destabilization could be estimated in relation to the kinetics of other apoptotic parameters such as mitochondrial instability, caspase-3 activation and DNA cleavage.Drosophila leads to Rab11-dependent vesicular trafficking. This raises the possibility that LRBA modulates several immune receptors by vesicle trafficking and, therefore, it is determinant in the normal development of the immune response.In the last decade, a great amount of new information has been generated about the association of LRBA with the immune system, its cellular localization and function. This has improve our understanding about their role in processes such as vesicular trafficking, autophagy and apoptosis. However, many questions remain to be answered. First, is LRBA located in the endomembrane system? Does LRBA form protein complexes with either Rab or Arf? Does LRBA modulate the traffic of receptors such as Fas, NKG2D or NKp46? There is evidence that LRBA prevents the degradation of CTLA-4 by competing AP-1 in human regulatory T lymphocytes, a protein that interacts with Arf1 and Arf6. In addition, the Bchs ortholog gene in Secondly, although defects in LRBA lead to poor autophagy, what are the functions of this protein in these cell mechanism? What is its localization in autophagosome, amphisomes and autophagolysomomes? Does LRBA interact physically with autophagy-related molecules such as LC3, ATG or Rab7?, By studying vesicular trafficking and autophagy, we found a possible connection mediated by Rab7, which is needed for the fusion between late endosomes and the autophagolysosome, which might suggest that LRBA is required for the fusion between these two organelles.Third, can LRBA deficiency affect lysosomal stability and thereby trigger apoptosis? The interaction of LRBA with lysosomes has been described, however, the mechanism underlying its function in lysosomes have not yet been fully elucidated.Finally, the association between endosomal trafficking, autophagy, apoptosis in the context of the LRBA function have not yet been addressed. We propose a model for the function of LRBA in the CTLA-4 trafficking . A complNew technologies of advanced microscopy, genetic editing such as CRISPR / Cas9 system or next-generation genomics tools, in the context of transcriptomes, proteomes, metabolomes and epigenomes would help to solve many of these questions to clarify the role of this protein and raise strategies for its regulation. LRBA ; las mutaciones homocigotas o heterocigotas compuestas en este gen, causan pérdida de la expresión de la proteína LRBA, lo que se asocia a un amplio espectro de manifestaciones clínicas e inmunológicas -Se han reportado más de 400 genes que afectan cuantitativa y/o cualitativamente y de manera sintomática el sistema inmune Cytotoxic T-Lymphocyte Antigen 4), tanto en la membrana como a nivel intracelular in vitro, un incremento en la apoptosis y un defecto en la autofagia tras la inanición Con relación a los hallazgos inmunológicos, se observó que los linfocitos T de pacientes con deficiencia de LRBA presentaron un aumento en la apoptosis inducida por inanición o estaurosporina (un potente inhibidor de las proteinas-cinasas y activador de las caspasas) y controversialmente, una disminución en la apoptosis inducida por Fas LRBA está localizado en el cromosoma 4q31.3, posee un tamaño de 750,839 pb y está organizado en 58 exones. La proteína posee 2,863 aminoácidos con un peso aproximado de ~319 KDa (LRBA se incrementó entre dos y cuatro veces luego de la estimulación con lipopolisacárido (LPS) en líneas celulares ~319 KDa . En el rbeige and Chediak-Higashi). Este dominio, de aproximadamente ~280 aminoácidos, se conserva en varias proteínas agrupadas como familia BDCP  , PH  y WD40  es compartido solo por LRBA y su parálogo Neurobeachin, lo cual podría indicar una función específica de estas dos proteínas no compartida por otros miembros de las BDCP.Esta proteína posee diferentes dominios, entre ellos el más caracterizado es el dominio BEACH -27, Hrs (hepatocyte growth factor-regulated tyrosine kinase sustrate) STAM   y qPCR  Con respecto a la expresión específica de tejido, se han observado transcriptos de esta proteína principalmente en células de médula ósea, nódulo linfático, bazo, hígado fetal, placenta, riñón y páncreas por medio de RT-PCR  es un receptor proteico situado en la membrana celular de los linfocitos T activados. Su función es regular la homeostasis y la tolerancia inmunológica periférica inhibiendo la activación de los linfocitos T, por competición con la molécula coestimuladora CD28, mediante la unión a los ligandos CD80 y CD86, los cuales se expresan en la superficie de las células presentadoras de antígeno T cell receptor) promueve el tráfico de CTLA-4 desde los compartimentos vesiculares hacia la membrana celular, sin embargo, en la membrana, este receptor es continuamente endocitado dentro de las vesículas cubiertas de clatrina. Una vez endocitadas, algunas moléculas de CTLA-4 son recicladas a la membrana celular, mientras que otras son rápidamente degradadas en los compartimentos lisosomales ,201VKM y Y218FIP. Diversas proteínas intracelulares se unen al motivo Y201VKM, incluyendo AP-1 y AP-2 (del inglés clathrin-associated adaptor). AP-2 media la internalización de CTLA-4 desde la superficie celular a los endosomas y los compartimentos lisosomales, mientras que AP-1 regula en el tráfico de CTLA-4 desde el aparato de Golgi a los compartimentos endosomales y lisosomas para su degradación like y el dominio PH-BEACH con la cola citoplasmática de CTLA-4, específicamente con el motivo Y201VKM. Finalmente, el silenciamiento de AP-1, pero no AP-2 puede rescatar parcialmente la pérdida CTLA-4 en las células deficientes de LRBA. Estos resultados sugieren que LRBA bloquea el tráfico de CTLA-4 a los lisosomas, compitiendo con AP-1 por la unión a este motivo CTLA-4 . Mutantes dominantes negativas para LRBA disminuyeron la expresión y fosforilación de EGFR Transforming growth factor-, y otros ligandos. Esto induce la dimerización y trans-auto-fosforilación del receptor, reclutando proteínas que activan las vías de señalización necesarias para la proliferación, la diferenciación, el crecimiento, la migración e la inhibición de la apoptosis ,Otro estudio que ilustró el papel de LRBA en el tráfico vesicular fue realizado con el receptor del factor de crecimiento epidermal  y AKT en células NK  estimuladas con anticuerpos anti-NKG2D o anti-NKp46, con una disminución significativa en la producción de IFN-gamma después de estos estímulos Estas evidencias nos llevan también a preguntarnos si LRBA estaría implicado en el tráfico vesicular de otros receptores en linfocitos?. En ratones deficientes para LRBA se ha reportaron defectos en la fosforilación de ERK1/2 -1 y específicamente en endosomas de reciclaje, a Arf-6, entre otros complejos proteicos Drosophila, sugiere una posible interacción funcional entre bchs (del inglés blue cheese), un miembro de la familia BEACH, y Rab11 A pesar de los estudios sobre la modulación de algunos receptores celulares mediada por LRBA, es poco lo que se conoce sobre las vías de tráfico intracelular utilizadas por esta molécula para realizar dicha función. Se ha descrito que dicho transporte se realiza mediante el reclutamiento de proteínas en vesículas recubiertas por clatrina, en el cual el receptor es removido a endosomas tempranos y posteriormente degradado por enzimas lisosomales o reciclado a la superficie celular Por lo tanto, son necesarios estudios que cuantifiquen la expresión de los receptores mencionados en células deficientes de LRBA (silenciadas o provenientes de pacientes). También sería útil el uso de técnicas avanzadas de microscopía, con lo cual se pudiera demostrar la localización de LRBA en otras organelas involucradas en este tipo de tráfico. Además, estudios de co-inmunoprecipitación entre LRBA y las proteínas de tráfico vesicular, el uso de drogas que bloqueen este tráfico o la implementación de dominantes negativos de ARFs, fosfolipasa D o las Rab, podrían ampliar nuestro conocimiento sobre la interacción de LRBA con otras moléculas de tráfico vesicular y así determinar su relación con la expresión en membrana de receptores como EGFR, Fas o los receptores activadores de las células NK, linfocitos B u otros en células inmunes.,La autofagia es un mecanismo de degradación lisosomal por el cual la célula destruye organelas dañadas y microorganismos y ayuda a reciclar macromoléculas. En este proceso se forma una doble membrana de aislamiento o fagóforo cerca al blanco, que luego se elonga, rodeándolo, para posteriormente madurar con la asimilación de una carga citosólica formando el autofagosoma. Para que la maduración sea efectiva, el autofagosoma se debe fusionar con los endosomas tempranos o tardíos formando una estructura llamada anfisoma LRBA, encontramos que varios de ellos están implicados en la autofagia. WDFY3 (del inglés - WD and FYVE zinc finger domain containing protein 3), codifica una proteína que colocaliza con marcadores de autofagosomas ,microtubule-associated protein 1A/1B-light chain 3) como con proteínas ubiquitinadas ,,LYST, mauve (mv) en Drosophila, afecta la función de autofagosomas Cuando estudiamos los genes homólogos de ,in silico han predicho que LRBA interactúa con LC3 En células B inmortalizadas provenientes de pacientes con deficiencia de LRBA se observó una reducción significativa en el proceso de autofagia en respuesta a la inanición, además hubo un incremento en el área del aparato de Golgi, una acumulación de los autofagosomas y la presencia de centriolos, al compararse con las células provenientes de un individuo sano -ATG16L1 , los cuales presentan un defecto en la autofagia, muestran una elevada producción de IL-1β después de la estimulación con LPS ATG16L1 incrementó la producción de IL-1β en células mononucleares de sangre periférica aisladas de pacientes con EII reactive oxygen species) y liberando ADN mitocondrial al citoplasma, eventos que activan el inflamosoma, aumentando la producción de IL-1β ,,En un intento por asociar los defectos en la autofagia con las características clínicas encontradas en los individuos con deficiencia de LRBA, es importante tener en cuenta que una de las manifestaciones clínicas más comunes entre estos individuos es la gastropatía, en muchos casos expresada como Enfermedad Inflamatoria Intestinal (EII) o enfermedad similar a EII, una condición que se caracteriza por una inflamación recurrente destructiva en el tracto intestinal apoptosis-associated speck-like protein containing a caspase-recruitment domain), la cual es una proteína que recluta las caspasas necesarias en para la activación del inflamosoma. Se requieren estudios de microscopia con células deficientes de LRBA que estudien la distribución intracelular de moléculas como Rab7 y LC3 tras el flujo autofágico. Sería interesante también investigar si LRBA interactúa físicamente con alguna de las moléculas Rab involucradas en los diferentes tipos de autofagia, por medio de ensayos de co-inmunoprecipitación. El papel de LRBA en la actividad del inflamosoma pudiera abordarse mediante la medición de la producción de IL-1β en células fagocíticas o del epitelio intestinal deficientes de LRBA o determinando la actividad del auto-inflamosoma activo por medio de redistribución de ASC  polymerase) y de la caspasa 3, eventos necesarios para iniciar la cascada de señalización que finalmente lleva a la apoptosis En linfocitos B inmortalizados sometidos a inanición provenientes de pacientes deficientes de LRBA, se observó un incremento significativo de la apoptosis ,LRBA es regulado negativamente por p53 P53 es un gen supresor de tumores que codifica un factor de transcripción nuclear cuya expresión se incrementa en respuesta al daño, deteniendo el ciclo celular y facilitando la reparación del ADN o induciendo apoptosis LRBA, p53 induce desestabilización lisosomal y como consecuencia la apoptosis en linfocitos. Sin embargo, hasta el momento no se conoce el mecanismo por el cual p53 induce la desestabilización lisosomal ni como LRBA protege las células de la apoptosis. La apoptosis es un tipo de muerte celular programada por la misma célula con el fin de controlar su desarrollo y crecimiento. Por mucho tiempo se ha considerado a las caspasas como las proteasas involucradas en la ejecución del programa de apoptosis, y hoy en día se conoce que la desestabilización parcial de la membrana lisosomal, con la consecuente liberación de enzimas hidrolíticas, puede iniciar y ejecutar el programa de apoptosis, activando las caspasas No obstante, parece existir una conexión entre los mecanismos de autofagia y la apoptosis. Aunque la diafonía entre los procesos de autofagia y la apoptosis es compleja también es crítica para el destino celular. Bajo ciertas condiciones celulares, la autofagia puede promover la supervivencia celular y evitar la apoptosis Por lo tanto, es necesario evaluar la cantidad y la integridad de los lisosomas en las células inmunes deficientes de LRBA. Además, se pudiera estimar la cinética de desestabilización lisosomal en relación con la cinética de otros parámetros apoptóticos como, inestabilidad mitocondrial, activación de caspasa-3 y escisión de ADN.Bchs en Drosophila modela el tráfico dependiente de Rab11. Esto plantea la posibilidad de que LRBA module varios receptores inmunes mediante el tráfico de vesículas y, por lo tanto, sea determinante en el desarrollo normal de la respuesta inmune. En la última década se ha generado una gran cantidad de nueva información sobre la asociación de LRBA con el sistema inmune, su localización celular y su función. Esto ha impulsado nuestra comprensión de su papel en los procesos como el tráfico vesicular, la autofagia y la apoptosis. Sin embargo, muchas preguntas quedan por responder. Primero, ¿Está LRBA localizado en el sistema de endomembranas? ¿Forma LRBA complejos proteicos con otras proteínas como las Rab o las Arf? ¿modula LRBA el tráfico de receptores como Fas, NKG2D o NKp46? Hay evidencia de que LRBA evita la degradación de CTLA-4 por competición de AP-1 en linfocitos T reguladores humanos, una proteína que interactúa con Arf1 y Arf6. Además, el gen ortólogo En segundo lugar, aunque se ha determinado que los defectos en LRBA conlleva a una autofagia deficiente, ¿cuáles son las funciones de esta proteína en estos procesos?, ¿Cuál es su localización en autofagosoma, anfisomas, autofagolisomas?, ¿interactua LRBA físicamente con moléculas implicadas en la autofagia como LC3, ATG o Rab7?, Al estudiar el tráfico vesicular y la autofagia encontramos una conexión medida por Rab7, el cual se necesita para la fusión entre los endosomas tardíos y el autofagolisosoma, por lo que es posible pensar que LRBA puede ser requerido para la fusión entre estas dos organelas. En tercer lugar, ¿puede la deficiencia de LRBA afectar la estabilidad lisosomal y de este modo desencadenar la apoptosis? Se sabe de la interacción de LRBA con estas vesículas, sin embargo, los mecanismos que subyacen a su función en este contexto, aún no se han dilucidado por completo. Finalmente, la asociación entre el tráfico endosomal, la autofagia, la apoptosis y la proteína LRBA aún no se han abordado. Sin embargo, con base a lo expuesto en esta revisión nosotros proponemos un modelo de LRBA en el tráfico de CTLA-4 . Una comSe espera que las nuevas tecnologías de microscopia avanzada, de edición genética como CRISPR/Cas9 o la genómica, y los nuevos conceptos como transcriptoma, proteoma, metaboloma, epigenoma, ayuden a resolver muchas de estas preguntas para delucidar el papel de esta proteína y plantear estrategias para su regulación.


Venous thromboembolism (VTE) is a common disease with high rates of morbidity and mortality and is considered the number one cause of avoidable mortality among hospitalized patients. Although VTE incidence is extremely high in all countries and there is ample evidence that thromboprophylaxis inexpensively reduces the rate of thromboembolic complications in both clinical and surgical patients, a great deal of doubt remains with respect to patient safety with this type of intervention and in relation to the ideal thromboprophylaxis methods. Countless studies and evidence-based recommendations confirm the efficacy of prophylaxis for prevention of VTE and/or patient deaths, but it remains underutilized to this day. This article presents a wide-ranging review of existing prophylaxis methods up to the present, from guidelines and national and international studies of thromboprophylaxis.  It is now clear that clinical patients are as much at risk of VTE as surgical patients. Patients who undergo orthopedic surgery or general surgery and those with acute myocardial infarction are at high risk of VTE, and the proportions are almost equal among surgical and clinical patients (22 and 24% respectively). , Immobilization caused by lower limb paralysis or confinement for more than 3 days, severe trauma, and spinal cord trauma can increase the risk of thrombosis by as much as ten times, and the effect is cumulative over time.  The frequency of thromboembolic complications among hospitalized patients, the adverse consequences of these events, and their economic impact justify prioritizing thromboprophylaxis for the safety of these patients, since it is a significant factor in reducing short and long term morbidity and mortality. However, despite the extremely high incidence of VTE recorded and published in many different studies and the evidence that thromboprophylaxis reduces thromboembolic complications among clinical and surgical patients at low cost, there is still a great deal of doubt with relation to the safety of this type of intervention and to the ideal prophylaxis methods. This situation remains despite more than five decades having passed since the first published study demonstrating that the rate of fatal and symptomatic VTE can be reduced by prophylaxis and almost 30 years since the first evidence-based guideline recommending prophylaxis for the majority of hospitalized patients.  This article presents a wide-ranging review of the literature on thromboprophylaxis, based on a systematic analysis of bibliographic references from the PubMed, SciELO, MEDLINE, and LILACS databases for the period 1990-2017 and of selected articles from the CAPES periodicals portal.  The objective of this article is to raise awareness of the need for thromboprophylaxis and of strategies for increasing compliance, since, in spite of all efforts, rates are still unsatisfactory all over the world. , There are now many thromboprophylaxis methods available. Non-pharmacological methods, including elastic graduated compression stockings (EGCS), intermittent pneumatic compression (IPC), and venous pumps for feet, have proven effective for reduction of DVT in several patient groups. - Many effective prophylaxis strategies, such as combinations of IPC, EGCS, or pharmacological prophylaxis  in high-risk patients, are not included in the guidelines because there are few randomized clinical trials, when compared to any of the options that are recommended, and also because these combinations may not be effective, but are more complex and expensive than simple options.  The International Multicenter Trial on PE prevention described by Kakkar is the point of reference for the start of pharmacological prophylaxis and demonstrated that 5,000 international units (IU) of unfractionated heparin (UFH) subcutaneously three times a day reduced the rate of DVT by 25%, while in the group control this reduction was 8%. Fatal PE was eight times less frequent in patients undergoing major surgery. , Low molecular weight heparin (LMWH) is a more effective prophylaxis option for a large number of patients and tends to be used as a substitute for UFH. ,, Oral vitamin K antagonists (VKA), such as warfarin, have been used for prophylaxis in major orthopedic surgery for several decades and, when used correctly, are effective for reducing VTE rates, but they have certain disadvantages: slow onset of action, large variations in dosage from patient to patient, and higher rates of bleeding when prophylaxis is of long duration. , A synthetic indirect factor Xa inhibitor (fondaparinux) demonstrated greater efficacy than LMWH in more than 7,000 orthopedic surgery patients in a meta-analysis of four randomized studies.  For a considerable length of time, the anticoagulants available did not meet criteria for a theoretically ideal anticoagulant, which stimulated researchers to investigate new molecules, with more predictable pharmacokinetics and pharmacodynamics and which would more closely approach the ideal profile of efficacy, safety, and posological comfort. The direct oral anticoagulants  The RECORD1 study compared the efficacy of rivaroxaban with enoxaparin during the postoperative period for 5 weeks in THA patients and found a 70% reduction in the relative risk of the primary efficacy outcome when rivaroxaban was used.  RECORD3 was the first study to show a significant reduction in symptomatic VTE among TKA patients, showing the superior efficacy of a 10 mg daily oral dose of rivaroxaban over enoxaparin for 10 to 14 days. , Apixaban is easily absorbed orally and clearance is renal 25-30%) and hepatic (65%). -30% and , The ADVANCE2 study, with TKA patients, confirmed that apixaban, at a dosage of 2.5 mg twice a day for 10 to 14 days, was more effective than enoxaparin (40 mg/day), with similar safety.  A phase III trial compared edoxaban at a dosage of 30 mg once a day with 20 mg enoxaparin every 12 hours for TKA prophylaxis. The efficacy results for edoxaban were superior to those for enoxaparin at this dosage, and safety (bleeding) was similar. ,- Dabigatran was used for DVT prophylaxis in TKA and THA surgery in three phase III trials , which demonstrated it was not inferior to LMWH. Dabigatran was tested at doses of 150 or 220 mg/day during the postoperative period after THA vs. 40 mg/day enoxaparin (RE-NOVATE) and vs. 30 mg enoxaparin twice a day (RE-MOBILIZE). The primary outcome used for analysis was the rate of DVT, VTE and/or death from all causes.  It is currently recommended that pharmaceutical prophylaxis should be extended up to 35 days in certain situations, such as orthopedic surgery , because the majority of symptomatic thromboembolic events are diagnosed after discharge and an increased risk of VTE remains for more than 3 months after THA and for more than 1 month after TKA.  A meta-analysis of nine randomized studies with a total of 4,000 major orthopedic surgery patients found a 51% reduction in risk of DVT and 61% for symptomatic VTE with extended prophylaxis, without increased bleeding.  Extended use of fondaparinux for 7 days in patients with hip fractures eliminated asymptomatic DVT and symptomatic VTE. , In 1959, publication of a controlled trial of thromboprophylaxis demonstrated that use of an oral anticoagulant in patients undergoing surgical treatment for hip fractures reduced symptomatic VTE and deaths, without increasing clinically significant bleeding. Recommendation grades:Grade 1: the benefits outweigh harms, burden, and costs;Grade 2: individual patient characteristics may lead to different choices.Evidence level: A : results are from well-planned and conducted RCTs, with parallel groups and adequate controls, appropriate data analysis, and consistent findings;  B (moderate): from RCTs with small confidence intervals, or cohort, case-control, or observational studies;  C (low): results from cohort and case-control studies of low quality with a high likelihood of bias.  Recommendation options in favor of or against thromboprophylaxis are described for each group of patients and it is recommended that every hospital should develop its own formal strategy for VTE prevention (Grade 1A) and that thromboprophylaxis should be provided for many hospitalized patients. Use of AAS in isolation was not recommended for any patient group (Grade 1A) and mechanical methods are primarily recommended for patients with a high risk of bleeding (Grade 1A) or as an adjuvant to pharmacological prophylaxis (Grade 2A).  In the ninth edition (AT9), from 2012, many recommendations with lower impact substituted the higher impact recommendations in the AT8, because of a more critical evaluation of the inferences underlying evidence and exclusion of specialists with conflicts of interests from the final recommendation process.  The Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) trial was the first multicenter randomized study to evaluate efficacy and safety of pharmacological prophylaxis in patients with acute clinical diseases and demonstrate the risk of VTE among these patients.  Patients over the age of 40 years admitted with CHF or acute respiratory failure without a need for ventilatory support, or patients with other clinical conditions and at least one risk factor for VTE  were randomized to receive placebo or enoxaparin, daily, at doses of 20 and 40 mg, over periods ranging from 6 to 14 days. The incidence of VTE in the 1,102 patients was significantly lower among those given 40 mg of enoxaparin (5.5%) than in groups given placebo (14.9%) or 20 mg of enoxaparin (15%). The observed benefit of 40 mg of enoxaparin was maintained for 3 months. The incidence of adverse effects did not differ significantly between the placebo group and the enoxaparin group.  In the multicenter, randomized PREVENT  The ARTEMIS study  The PREVAIL study,  The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) was an observational study that evaluated practices for VTE prevention in 15,156 hospitalized clinical patients in twelve countries over 4 years, finding that 50% of the patients received pharmaceutical or mechanical thromboprophylaxis. In the United States, 52% of the patients should have been given thromboprophylaxis, but only 60% of patients with risk factors for VTE actually were given it. In the United States, UFH was the most frequently used drug (20%), whereas LMWH was used most often in the other countries studied (40%).  The EXCLAIM  A large, observational, multicenter study assessed the prevalence of VTE in hospitalized clinical patients over the age of 40 years, or over the age of 18 years admitted for surgical treatment or because of traumas, and also studied the proportion of at-risk patients given the appropriate prophylaxis . The study reviewed 37,356 (55%) medical records for clinical patients and 30,827 (45%) for surgical patients against the seventh edition of the ACCP guidelines. The proportion of patients considered at risk of VTE ranged from 36 to 73%.  After publication of the MEDENOX study, prophylaxis with enoxaparin was once more evaluated in a double-blind, placebo-controlled, randomized study entitled Low-Molecular-Weight Heparin and Mortality in Acutely Ill Medical Patients (LIFENOX), with the objective of evaluating 30-day all-causes mortality after use of 40 mg of subcutaneous enoxaparin for 10±4 days, compared to placebo.  At 30 days, no significant difference was observed between the enoxaparin and placebo groups in terms of the primary outcome, which was all-causes mortality . The study confirmed the need for continued use of pharmacological prophylaxis to prevent VTE and its nonfatal complications in clinically ill hospitalized patients. However, this study suffered from several limitations: 1) the rate of events in the placebo group was lower (4.8%) than expected (7%), and the rate of fatal PE in the placebo group was less than 0.1% at 30 days; 2) patients were younger, with less overweight and had had fewer prior thromboembolic events; and 3) mobility, a major determinant of risk of VTE, was also not assessed, which could have lead to selection of patients with lower rates of events.  The MAGELLAN  The multinational Assessment for VTE management in hospital-Middle East (AVAIL ME)  The AVAIL ME Extension Project was published in 2011. Among patients eligible for VTE prophylaxis, 77% were given some type of pharmaceutical prophylaxis, and there was 38% compliance with the AT8 guidelines.  An observational cohort study in the United States enrolled 294,896 critically ill patients admitted to intensive care units (ICU) and treated with pharmacological thromboprophylaxis, with mechanical methods, with both, or not given prophylaxis. The main finding of this study is that adult ICU patients on prophylaxis with anticoagulants had a lower risk of mortality than those using mechanical methods or not given any type of prophylaxis. These findings confirm the recommendation of pharmaceutical prophylaxis rather than mechanical prophylaxis for critical patients who do not have any contraindications to anticoagulation. , In Brazil, the guidelines for VTE risk factors and risk stratification and thromboembolic recommendations are certified by the Brazilian Medical Association (Associação Médica Brasileira).  A study conducted from 1995 to 1999 at the Hospital Naval Marcílio Dias (Rio de Janeiro) analyzed 18,690 patients using Caprini risk stratification, classifying 5% of them as at high risk, 43% as intermediate, and 52% as low risk. The authors observed that the recommended prophylaxis was adopted in 47% of high risk patients, that 33% of moderate risk patients were not given prophylaxis, and that 4.6% of low risk patients were given pharmaceutical prophylaxis, despite not having indications.  A new multicenter study was conducted investigating the incidence and distribution of risk factors for VTE in clinical, surgical, and obstetric-gynecological patients in hospital and use of prophylaxis in Brazil.  Pereira et al. conducted a prospective study with 850 patients admitted to the Hospital de Roraima to investigate whether DVT prophylaxis was being used correctly, according to the Caprini model. ,, Rocha et al.  Okuhara et al.  Finally, the most recent cross-sectional study involving analysis of medical records in the city of Curitiba (published in 2017) compared use or not of prophylaxis within surgical and clinical specialties according to their VTE risk factors and showed that just 66% of the patients were given prophylaxis. In this study, 93% of clinical patients were given prophylaxis compared with 44% in the surgical group. Clinical patients at moderate and high risk were given more prophylaxis than surgical patients.  Several different studies have reported evidence that alerting health professionals to patients at risk of VTE increases the probability that prophylaxis will be used. , There are many different approaches and strategies. Simple didactic education and passive distribution of guidelines based on evidence alone are ineffective. , In the United Kingdom, a computerized Clinical Decision Support (CDS) system was used to instruct and guide professionals to prescribe prophylaxis appropriately. The increases in compliance in response to reminders on computers are still modest,  A cross-sectional study conducted in two phases (before and after implementation of a new VTE prophylaxis protocol) was conducted in a hospital in Porto Alegre (Brazil) to evaluate the impact on prophylaxis of a computerized CDS system combined with instructional seminars. Adequacy of prophylaxis increased from 46.2% to 57.9% in the before and after comparison between the two periods, and the increases were greatest among patients with cancer (18.1% to 44.1%) and those with three or more risk factors (25% to 42.9%). , Despite the many initiatives and the increased use of VTE risk assessment, prophylaxis is still being underutilized today and there is also evidence of low compliance with published guidelines.  Lau & Haut conducted a MEDLINE search to identify studies published from 2001 to 2012 that evaluated the different types of interventions designed to improve use of VTE prophylaxis in hospitalized patients, classified according to the following parameters: exclusively educational, paper-based, computerized, real time auditing, or a combination of interventions.  There is robust evidence from many different high quality studies demonstrating the effectiveness of VTE prophylaxis in specific populations; however, risk stratification is needed to ensure that prophylaxis is targeted to the appropriate patients and, even then, prophylaxis rates remain sub-optimal and VTE continues to be a problem for patient safety. Furthermore, there is a lack of evidence to show which specific interventions are effective for increasing these prophylaxis rates. Education of professionals with no other interventions is not the best mechanism for increasing prophylaxis utilization.  Although derived from non-randomized studies without control patients and, therefore, considered of low quality, there is evidence to suggest that education combined with other strategies for quality improvement and technological initiatives, such as reminders and obligatory computerized CDS systems, is probably the best strategy to promote the practice of prophylaxis use, thereby avoiding harm to patients caused by VTE.  , A trombose venosa profunda (TVP) e a embolia pulmonar (EP) constituem graves problemas de saúde pública nacional e internacional, devido aos altos custos associados a episódios agudos de tromboembolismo venoso (TEV) e a complicações a longo prazo  É evidente nos dias de hoje que pacientes clínicos são de risco para TEV tanto quanto pacientes cirúrgicos. Pacientes submetidos a cirurgia ortopédica, a cirurgia geral e com infarto agudo do miocárdio apresentam alto risco de TEV, e a proporção é quase igual nos pacientes cirúrgicos e clínicos (22% e 24% respectivamente) , A imobilização devido à paralisia de membros inferiores ou repouso por mais de 3 dias, assim como trauma grave e trauma raquimedular, aumenta o risco de trombose em até dez vezes, com efeito cumulativo com o tempo  A frequência de complicações tromboembólicas em pacientes hospitalizados, as consequências adversas desses eventos e seu impacto econômico justificam a prioridade da tromboprofilaxia para segurança desses pacientes e constitui fator significativo para reduzir a morbidade a curto e longo prazo e a mortalidade. Entretanto, apesar da incidência altíssima de TEV registrada e publicada em vários estudos e das evidências de que a tromboprofilaxia reduz complicações tromboembólicas em pacientes clínicos e cirúrgicos a custo baixo, persistem grandes dúvidas quanto à segurança desse tipo de intervenção e quanto à forma ideal de profilaxia. Isso ocorre mesmo após mais de cinco décadas desde o primeiro estudo publicado demonstrando que o TEV sintomático e fatal poderia ser reduzido com a profilaxia, e quase 30 anos após a primeira diretriz baseada em evidências recomendando profilaxia na maioria dos pacientes hospitalizados.  Neste artigo, os autores fazem ampla revisão da literatura sobre tromboprofilaxia, com análise sistemática das referências bibliográficas nas bases de dados PubMed, SciELO, MEDLINE e LILACS no período de 1990-2017 e de artigos selecionados dos periódicos CAPES.  O objetivo deste artigo consiste em alertar sobre a necessidade da tromboprofilaxia e as estratégias para aumentar sua adesão pois, apesar de todos os esforços, esta ainda permanece insatisfatória no mundo todo. , Muitas opções de tromboprofilaxia estão atualmente disponíveis. Métodos não farmacológicos, incluindo meias elásticas de compressão graduada (MECG), compressão pneumática intermitente (CPI) e bombas venosas para pés, têm-se mostrado eficientes na redução de TVP em vários grupos de pacientes - Várias estratégias de profilaxia efetivas, como a combinação de CPI, MECG ou farmacoprofilaxia [ácido acetilsalicílico (AAS) ou anticoagulantes] em pacientes de alto risco, não estão incluídas nas diretrizes, porque existem poucos ensaios clínicos randomizados, quando comparados a qualquer das opções recomendadas, e também porque essas combinações podem não ser mais efetivas, além de serem mais complexas e caras que as opções simples International Multicenter Trial, conduzido por Kakkar, foi o ponto de referência para o início da farmacoprofilaxia, demonstrando que heparina não fracionada (HNF) 5.000 unidades internacionais (UI) subcutânea três vezes ao dia reduziu a TVP em 25%, enquanto que no grupo controle essa redução foi de 8%. A EP fatal diminuiu oito vezes em pacientes submetidos a cirurgias maiores  O , A heparina de baixo peso molecular (HBPM) é uma opção mais eficiente de profilaxia para um grande número de pacientes, tendendo a substituir a HNF ,, Os antagonistas da vitamina K (AVK) orais, como a varfarina, têm sido usados na profilaxia de cirurgias ortopédicas maiores por várias décadas e, quando utilizados de forma correta, são eficazes na redução do TEV, porém com algumas desvantagens: início de ação prolongada, variação grande na dose entre os pacientes e taxas maiores de sangramento na profilaxia estendida , O inibidor indireto sintético do fator Xa (fondaparinux) mostrou maior eficácia que a HBPM em mais de 7.000 pacientes submetidos a cirurgia ortopédica em uma metanálise que incluiu quatro estudos randomizados Regulation of Coagulation in Major Orthopaedic surgery Reducing Risk of Deep Venous Thrombosis and Pulmonary Embolism (RECORD), incluíram mais de 12.500 pacientes submetidos a cirurgia eletiva de ATQ e ATJ e demonstraram a superioridade da rivaroxabana, na dose de 10 mg diária, com redução superior a 50% de risco nas taxas de TEV sintomática e de morte, quando comparada à enoxaparina 40 mg/dia  Por muito tempo, os anticoagulantes disponíveis não preencheram os critérios de um anticoagulante teoricamente ideal, o que motivou pesquisas de novas moléculas, com farmacocinética e farmacodinâmica mais previsível e que se aproximassem desse perfil de eficácia, segurança e conforto posológico. Entre os anticoagulantes orais diretos  O estudo RECORD1 comparou a eficácia da rivaroxabana com a da enoxaparina no pós-operatório durante 5 semanas em pacientes submetidos a ATQ e evidenciou redução de 70% do risco relativo no desfecho primário de eficácia com rivaroxabana  O RECORD3 foi o primeiro estudo que mostrou a diminuição significativa do TEV sintomático em pacientes submetidos a ATJ, evidenciando a eficácia superior de uma posologia oral diária de 10 mg de rivaroxabana comparada à enoxaparina durante 10 a 14 dias , A apixabana tem fácil absorção oral e apresenta eliminação renal 25-30%) e hepática (65%) -30% e he, O estudo ADVANCE2, com pacientes submetidos a ATJ, comprovou que a apixabana, na dose de 2,5 mg duas vezes ao dia por 10 a 14 dias, foi mais eficaz que a enoxaparina (40 mg/dia), com segurança semelhante  A edoxabana na dose de 30 mg uma vez ao dia foi comparada à enoxaparina 20 mg de 12 em 12 horas em um estudo fase III de profilaxia em ATJ. Os resultados de eficácia da edoxabana foram superiores aos da enoxaparina nessa dosagem, e os de segurança (sangramentos) foram similares versus enoxaparina 40 mg/dia (RE-NOVATE) e versus enoxaparina 30 mg duas vezes ao dia (RE-MOBILIZE). A análise do desfecho primário foi a taxa de TVP, TEV e/ou morte por todas as causas ,- A dabigatrana foi usada para profilaxia de TVP em ATJ e ATQ em três estudos fase III , que demonstraram a não inferioridade em comparação à HBPM. A dabigatrana foi testada nas doses de 150 ou 220 mg/dia no pós-operatório de ATQ  Atualmente, sugere-se a extensão da profilaxia medicamentosa por até 35 dias em algumas situações, como cirurgias ortopédicas , pois a maioria dos eventos tromboembólicos sintomáticos é diagnosticada após a alta e o risco aumentado de TEV continua por mais de 3 meses após ATQ e por mais de 1 mês após ATJ  Uma metanálise com nove estudos randomizados, abrangendo 4.000 pacientes submetidos a cirurgia ortopédica maior, evidenciou redução de risco de 51% para TVP e de 61% para TEV sintomático com profilaxia estendida, sem aumento no sangramento  O uso estendido de fondaparinux por 7 dias em pacientes com fratura de quadril eliminou a TVP assintomática e o TEV sintomático ,American College of Chest Physicians (ACCP) tem publicado diretrizes para tratamento e prevenção do TEV  Em 1959, a publicação de ensaio controlado de tromboprofilaxia demonstrou que o uso de anticoagulante oral em pacientes submetidos a tratamento cirúrgico de fraturas de quadril reduziu TEV sintomático e morte, sem aumento de sangramento clinicamente significativo Grau de recomendação:Grau 1: os benefícios superam os riscos, encargos e custos; Grau 2: características individuais do paciente podem levar a diferentes escolhas. Nível de evidência: A : resultados são provenientes de ECR bem planejados e conduzidos, com grupos paralelos e controles adequados, análise de dados adequada e achados consistentes;  B (moderada): provenientes de ECR com intervalo de confiança pequeno, estudos de coorte, caso-controle ou observacionais;  C (baixa): resultado de estudos de coortes e caso-controle com baixa qualidade e alta probabilidade de viés.  Opções de recomendações a favor ou contra tromboprofilaxia foram descritas para cada grupo de pacientes, sendo recomendado que cada hospital desenvolvesse uma estratégia formal própria para prevenção de TEV (Grau 1A) e que a tromboprofilaxia deveria ser realizada em muitos pacientes hospitalizados. Não foi recomendado uso de AAS isolado para qualquer grupo de paciente (Grau 1A), e recomendou-se o uso de métodos mecânicos, principalmente para pacientes com alto risco de sangramento (Grau 1A) ou como adjuvante à farmacoprofilaxia (Grau 2A).  Na nona edição (AT9), de 2012, muitas recomendações de impacto menor substituíram as de maior impacto da AT8, devido à avaliação mais crítica de inferências que resultam em evidências e exclusão de especialistas com conflito de interesses no processo final das recomendações Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) foi o primeiro estudo multicêntrico randomizado que avaliou a eficácia e a segurança da farmacoprofilaxia em pacientes com doença clínica aguda e demonstrou o risco de TEV nesses pacientes.  O  Pacientes com mais de 40 anos admitidos com ICC, insuficiência respiratória aguda sem necessidade de suporte ventilatório, ou pacientes com outras condições clínicas e ao menos um fator de risco para TEV  foram randomizados para receberem placebo ou enoxaparina, diariamente, nas doses de 20 e 40 mg, durante um período de 6 a 14 dias. A incidência de TEV nos 1.102 pacientes foi significativamente menor no grupo que recebeu 40 mg de enoxaparina  do que nos grupos que receberam placebo  e enoxaparina 20 mg (15%). O benefício observado com 40 mg de enoxaparina foi mantido por 3 meses. A incidência de efeitos adversos não diferiu significativamente entre o grupo placebo e o grupo enoxaparina  No estudo multicêntrico e randomizado PREVENT  O estudo ARTEMIS  O estudo PREVAIL International Medical Prevention Registry on Venous Thromboembolism (IMPROVE), um estudo observacional que avaliou práticas de prevenção de TEV em 15.156 pacientes clínicos hospitalizados em doze países por 4 anos, verificou que 50% dos pacientes receberam tromboprofilaxia medicamentosa ou mecânica. Nos EUA, 52% dos pacientes deveriam ter recebido tromboprofilaxia, mas somente 60% dos pacientes com fatores de risco para TEV a receberam. A HNF foi a mais usada nos EUA (20%), enquanto HBPM foi mais utilizada em outros países (40%)  O  O estudo randomizado EXCLAIM Epidemiologic International Day for the Evaluation of Patients at Risk of Venous Thrombosis in the Acute Hospital Care Setting, ENDORSE). Foram revisados 37.356 (55%) prontuários de pacientes clínicos e 30.827 (45%) de pacientes cirúrgicos, e foi usada a sétima edição das diretrizes do ACCP. Os pacientes considerados de risco para TEV variavam entre 36 e 73%  Um grande estudo multicêntrico observacional avaliou a prevalência de TEV em pacientes hospitalizados clínicos com mais de 40 anos, ou maiores de 18 anos admitidos para tratamento cirúrgico ou devido a traumas, e a proporção de pacientes de risco que recebiam profilaxia apropriada , com o objetivo de verificar a mortalidade em 30 dias devido a qualquer causa após o uso de enoxaparina 40 mg subcutânea durante 10±4 dias, comparada ao placebo  Desde a publicação do estudo MEDENOX, a profilaxia com enoxaparina foi novamente avaliada em um estudo randomizado, duplo-cego, placebo controlado denominado versus 4,8%, respectivamente). O estudo confirmou a necessidade do uso continuado de farmacoprofilaxia para prevenir TEV e suas complicações não fatais em pacientes hospitalizados clinicamente doentes. Todavia, esse estudo apresentou várias limitações: 1) a taxa de eventos no grupo placebo foi menor  que a esperada (7%), e a taxa de EP fatal no grupo placebo foi menor que 0,1% em 30 dias; 2) os pacientes eram mais jovens, com menos sobrepeso e tinham menos eventos tromboembólicos prévios; 3) a mobilidade, um risco determinante maior para TEV, também não foi avaliada, o que pode ter levado à seleção de pacientes com taxas de eventos menores.  Em 30 dias, nenhuma diferença significativa foi observada entre os grupos enoxaparina e placebo no resultado primário de mortalidade por todas as causas  pode não sugerir seu uso. Sangramento clinicamente relevante em 35 dias também foi observado em 4,1% dos pacientes no grupo rivaroxabana e em 1,7% no grupo controle.  O estudo MAGELLAN Assessment for VTE management in hospital Middle East (AVAIL ME)  O estudo multinacional  O AVAIL ME Extension Project foi publicado em 2011. Dos pacientes elegíveis para receber profilaxia de TEV, 77% receberam alguma profilaxia medicamentosa, com 38% de adesão às diretrizes da AT8  Um estudo de coorte observacional nos EUA incluiu 294.896 pacientes criticamente doentes internados em unidade de terapia intensiva (UTI) e tratados com tromboprofilaxia farmacológica, com métodos mecânicos, com ambos, ou que não receberam profilaxia. O principal achado desse estudo é que pacientes adultos em UTI em uso de profilaxia com anticoagulantes apresentavam menor risco de mortalidade do que os que usavam métodos mecânicos ou que não utilizaram profilaxia alguma. Esses achados confirmam a recomendação da profilaxia medicamentosa em vez de profilaxia mecânica para pacientes críticos que não possuem contraindicação à anticoagulação , No Brasil, as diretrizes que abordam os fatores e a estratificação de risco de TEV e as recomendações tromboembólicas são apoiadas pela Associação Médica Brasileira  Estudo desenvolvido entre 1995 e 1999 no Hospital Naval Marcílio Dias (Rio de Janeiro) analisou 18.690 pacientes utilizando a estratificação de risco de Caprini, sendo 5% deles classificados como de alto risco, 43% como intermediário, e 52% como de baixo risco. Os autores observaram que a profilaxia recomendada foi adotada em 47% dos pacientes de alto risco, que 33% dos pacientes de risco moderado não receberam profilaxia, e que 4,6% dos pacientes de baixo risco receberam profilaxia medicamentosa, embora não houvesse indicação  Um novo registro multicêntrico foi realizado para investigar a incidência e a distribuição de fatores de risco para TEV em pacientes clínicos, cirúrgicos e obstétrico-ginecológicos internados e o uso de profilaxia no Brasil  Pereira et al. realizaram estudo prospectivo com 850 pacientes internados em um Hospital de Roraima para constatar se a profilaxia para TVP era utilizada de forma adequada, segundo o modelo de Caprini ,, Rocha et al.  Okuhara et al.  Por fim, o mais recente estudo transversal com análise de prontuários realizado em Curitiba e publicado em 2017 comparou o uso ou não da profilaxia nas especialidades clínicas e cirúrgicas de acordo com seu fator de risco para TEV e mostrou que apenas 66% dos pacientes receberam profilaxia. Dentre os pacientes clínicos, 93% receberam contra 44% do grupo cirúrgico. Pacientes clínicos de moderado a alto risco receberam mais profilaxia que os cirúrgicos  Vários estudos evidenciam que o alerta aos profissionais da saúde sobre os pacientes com risco de TEV aumenta a probabilidade do uso de profilaxia. , Muitas abordagens e estratégias existem. Educação didática simples ou disseminação passiva de diretrizes baseadas apenas em evidências não são efetivas Clinical Decision Support (CDS), um sistema baseado em computador, tem sido uma forma de solicitar e orientar profissionais para prescrever profilaxia apropriadamente. Modificações na adesão deles com lembretes nos computadores ainda são modestas , No Reino Unido, o  Estudo transversal em duas fases (antes e após implantação de um novo protocolo de profilaxia para TEV) foi realizado em hospital de Porto Alegre para avaliar o impacto da implantação na profilaxia de um sistema informatizado de suporte à decisão clínica combinado a seminários de orientação. A adequação da profilaxia aumentou de 46,2% para 57,9% quando foram comparados os dois períodos, principalmente em pacientes com câncer  e naqueles com três ou mais fatores de risco  , Apesar de muitas tentativas e do aumento nas avaliações de risco de TEV, a profilaxia é subutilizada até hoje, e existem algumas evidências da pequena aderência às diretrizes publicadas  Lau & Haut conduziram uma pesquisa MEDLINE para identificar estudos publicados entre 2001 e 2012 que avaliavam os diversos tipos de intervenções para melhorar o uso de profilaxia de TEV em pacientes hospitalizados, de acordo com os seguintes parâmetros: educação somente, baseada em papéis, computadorizada, auditoria em tempo real, ou combinação de intervenções  Fortes evidências de vários estudos de alta qualidade demonstram a efetividade da profilaxia do TEV para populações especificas; entretanto, é preciso estratificação de risco para assegurar que a profilaxia seja direcionada a pacientes apropriados e, mesmo assim, as taxas de profilaxia permanecem sub-ótimas e o TEV continua a ser um problema na segurança dos pacientes. Além disso, existem poucas evidências de quais intervenções específicas são efetivas para aumentar essas taxas de profilaxia. Educação apenas dos profissionais não é o melhor mecanismo para aumentar o uso da profilaxia.  Evidências, embora baseadas em estudos não randomizados sem pacientes controles e, portanto, considerados de baixa qualidade, apoiam que educação combinada com outras estratégias de melhoria de qualidade e abordagens tecnológicas, como alertas e apoio à decisão clínica informatizada obrigatória, provavelmente promova mais a prática do uso da profilaxia, evitando danos aos pacientes com TEV.


To evaluate the clinical factors, as well as weight gain, in a group of pregnant women, associating them with fetal macrosomia in a public institution in Antioquia, Colombia, from 2010-2017. A case-control study, using secondary information registries. Cases were defined using newborn weight of ≥ 4000g, while controls were defined as newborn weight between 3000–3999g. A proportion ratio (PR) was established to evaluate factors associated with macrosomia, and a generalized linear model (GLM) of Poisson regression with robust variance was used to evaluate the aspects that best explained macrosomia in the neonate. 122 pregnant women participated in the study, of which 611 were cases and 61 were controls. Of the participants, 44.3% had pre-pregnancy overweight and 48.4% had excess gestational weight gain. Statistically significant differences were found between the groups in the following variables: pre-pregnancy BMI (p = 0.004), gestational weight gain (p = 0.000), gestational diabetes (p = 0.000), and type of delivery (p = 0.004). According to the regression model, a macrosomic newborn is 3.5 times more likely in women with excessive gestational weight gain (95%CI 1.78-7.18) and twice more likely in women who have gestational diabetes (95%CI 1.51-2.76). Of women with pre-pregnancy excess weight, 63% had excess gestational weight gain. Within this cohort, pre-pregnancy BMI, excess weight gain in pregnancy, and the presence of gestational diabetes were associated with an increased risk of neonatal macrosomia. pre-pregnancy BMI and weight gain in pregnancy are modifiable risk factors that are responsive to nutrition interventions, which can minimize adverse perinatal outcomes. A report prepared in 2015 by the United Nations states that one in four women in adulthood is obese2 . The situation is no different in Colombia: the prevalence of overweight and obesity in the adult population is 55.2% in women compared with 45.6% in men3 .The figures of excess weight have had an increase in the world population in recent decades. Report of the Panorama of Food and Nutrition Security in Latin America and the Caribbean has shown that overweight and obesity, in more than 20 countries on the continent, was 10 percentage points higher in women than in men in 20163 . Other observational studies in representative samples of pregnant women in countries such as Peru4 , Brazil5 , and Uruguay6 show overweight prevalence of 63.8%, 47.5% and 32.6%, respectively.More and more women begin pregnancy in excess weight. The 2015 National Survey of Nutrition Situation in Colombia indicates that 39.9% of pregnant women of all age groups were overweight (24.7% overweight and 15.2% obese) in the country7 . In Colombia, an investigation was conducted based on the Live Birth Registry of the Administrative Department of Vital Statistics from 2002 to 2011, among which about 6,000,000 births were registered. Low birth weight amounted to 3.8%, while macrosomia reached 4.5% in full-term newborns (NB)8 .This scenario directly affects birth weight. A study in 23 countries showed a prevalence of macrosomia of 4.5% and 5.4% in Latin America. In developed countries, it ranged between 5% and 20%, and a 15-25% increase has been reported in the last three decades9 ; in addition to greater admission to the neonatal intensive care unit, respiratory disturbances and neonatal death10 .The excess weight-gestation binomial can mark the origin of a range of diseases. Various mechanisms seem to come together in the metabolic programming and generational transfer of obesity and its associated comorbidities: inflammation, oxidative stress, neurohormonal disorders, epigenetic modifications, quality of the maternal microbiota, macrosomia and greater fetal adiposity10 . An analytical study conducted with more than 3,000 mothers in Buga, Colombia, between 2005 and 2015, showed correlations between maternal obesity, preeclampsia, eclampsia and gestational diabetes. Children of mothers with gestational diabetes and obesity were significantly heavier at birth11 .Risks of excess weight in the mother include preeclampsia, venous thromboembolism, hypertension, gestational diabetes, postpartum hemorrhage and a greater chance of assisted vaginal delivery or caesarean section12 . However, the increased numbers of female obesity and macrosomia support the need for this to be considered an important indicator in prenatal care and surveillance due to its deleterious effects in the short, medium, and long term in the health of the newborn.There are few studies focused on macrosomia at the national level. Scientific evidence has focused on obstetric complications and the study of maternal-fetal metabolic disorders. In addition, the risk analysis of public health events in NBs has focused on low birthweightThe purpose of this research was to analyze clinical factors and weight gain in pregnant women and their association with fetal macrosomia.Analytical case-control study, nested in a defined cohort of NB in a second level institution responsible for the health care of the southwestern department of Antioquia between 2010–2017, and their mothers, who performed prenatal control in the same institution or in others from nearby municipalities. Information sources were the birth record, the Latin American Center for Perinatology (CLAP) record, and the maternal medical history.case group. The same inclusion criteria were applied for the control group, except for birth weight, which was defined as a weight between 3,000 and 3,999 g, considered adequate.Selection criteria were: mothers between 15 and 45 years old; prenatal control carried out in the institution or institutions of nearby municipalities; minimum 90% of the data in the CLAP file or clinical history; data on pre-pregnancy weight, or measured before week 14, one ≥ at week 36, and anthropometric data of the newborn. Mothers with multiple pregnancies, pre-pregnancy diabetes and NB with congenital diseases were excluded. Macrosomic NBs weighing ≥ 4,000 g were identified, as specific inclusion criteria for the study From the census population of NB in the institution, 300 macrosomic infants were obtained, of which 61 met the selection criteria. Pairing of cases and controls 1:1 was performed   . The foAspects such as pre-pregnancy body mass index (BMI), weight gain and pathologies during pregnancy were studied. In the neonate, data on sex, weight, length, head circumference and gestational age at birth were collected, which were classified according to data reported in the medical history, date of the last menstruation or first trimester ultrasound.13 . pre-pregnancy BMI in pregnant women under the age of 19 was performed using the BMI indicator for age; for those over 19 years old, classification was made according to the BMI indicator for gestational age, based on the standard proposed by Atalah et al.14 : underweight below 20 kg/m2, normal 20–24.9 kg/m2, overweight 25–29.9 kg/m2, and obesity ≥ 30 kg/m2. Both standards are accepted by the national standard.For the analysis plan, the classification of the pregnant women nutritional status according to age was considered, according to 2016 Resolution no. 2465 by the Ministry of Health and Social Protection of the Republic of Colombia2. Weight gain in adults was classified as follows: underweight 12-18 kg, adequate weight 10–13 kg, overweight 7–10 kg, and obesity 6–7 kg15 . In adolescents, it was classified as: underweight between 12–20 kg, adequate weight between 12.5–17 kg, overweight between 7.5–12.5 kg and, in obese women, less than 7kg16 . Inadequate gain due to deficit was defined as lower than the recommended weight ranges; excessive weight gain was related to that which exceeded the recommendation, and adequate gain remained within the specified ranges.The weight gain goal was calculated according to the healthy pre-pregnancy weight, equivalent to a BMI of 22.5 kg/m17 .For the classification of total weight gain, the difference between the last pre-delivery weight recorded in week 36 or later weeks and the pre-pregnancy weight recorded at week 14 or less was calculated. If the birth occurred after the week in which the last weight of the mother was recorded, weight gain was projected according to the percentile of gain of each pregnant woman. Maternal height greater than 1.55 m was considered as a cut-off point for the risk of macrosomia at birth, according to previous studiesA systematized instrument was developed in the Epi Info program, version 7.2.1.0, for the collection of information. Collection was carried out by previously trained and standardized personnel. Descriptive analysis included absolute and relative distributions, as well as summary indicators such as arithmetic mean, standard deviation, quartiles and interquartile range. The normality criterion for some sociodemographic and clinical variables was established by the Shapiro Wilk test. U-Mann Whitney test or Student t-test for independent samples were used to determine the relationship between macrosomia and some quantifiable sociodemographic and clinical aspects. The relationship between sociodemographic aspects and clinical history with macrosomia was defined by Pearson’s chi-square test or Fisher’s exact test. Strength of association was evaluated by proportion ratio (PR), with its respective 95% confidence intervals (95%CI) (p < 0.05).A parsimonious model was applied, which selected the variables that best explained the effect of macrosomia by a generalized linear model (GML) of Poisson regression with robust variance. Statistical data processing was performed in SPSS Software, version 23.The research was approved by the ethics committee of the Faculty of Nursing of the University of Antioquia. Institutions in which the data collection process was carried out gave their endorsement and authorization for the review of data sources. The study was considered an “investigation with minimal risk”, with strict custody and confidentiality of information, in accordance with Statutory Law 1581, of 2012, and Resolution number 1995, of 1999.In both groups, the median age was 24 years old and 75.4% of the participants were between 19 and 34 years old; the predominant educational level (81.1%) was secondary-university; 74.6% had low socioeconomic status; 82% were affiliated with the subsidized health regime, and 68% had the presence of a partner (married or in free union).Of the mothers, 59.8% were multiparous, 18.0% had previous abortions, and 78.7% performed six or more prenatal controls. They presented a family history of 50% arterial hypertension, and 26.2% of diabetes mellitus. Prior preeclampsia was 6.2% and, during pregnancy, 2.5%. The threat of preterm birth reached 27.8% and premature rupture of membranes, 5.7%.The average gestational age at birth of the NB was 39 weeks in both groups, with an average birth weight in the case group of 4120 grams, and of 3334 grams in the control group. Mean length at birth was 52.3 cm and 50 cm in the case and control groups, respectively. The mean head circumference in the cases was 36 and, in the controls, 34.5 cm. The predominant sex in the NB was male, with 60.7%, compared with 39.3% of females, with a similar distribution among the groups. Regarding the type of delivery, 63% of macrosomic NBs were born by caesarean section.The median pre-pregnancy weight of pregnant women was 60.7 Kg; 65.1 kg in the case group and 57.8 kg in control. The average height was 1.57 m. The median pre-pregnancy BMI in the studied sample was 26.6 kg/m2, and 23.2 kg/m2 in the control group. Average weight at the end of pregnancy 78.5 kg and 68.8 kg in the case and control groups, respectively. Half of the mothers started gestation with adequate weight; 28.7% overweight, 15.6% with obesity, and 5.7% underweight. The average weight gain was 12.2 kg.Of the pregnant women who presented excess pre-pregnancy BMI, 64.8% had macrosomic children, while in pregnant women with adequate BMI the percentage was 38.2%. Macrosomia was 1.6 times more likely in pregnant women with excess pre-pregnancy BMI compared with those who did not . 63.9% were > 1.55 m tall; however, no statistical differences were found between the groups regarding this variable (p = 0.131)   .In pregnant women with excessive weight gain, 71.2% presented macrosomic NB. The risk of macrosomia increased 3.6 times in pregnant women who had excessive weight gain, compared with those who had adequate or poor gain    .Of women with excess pre-pregnancy weight, 63% had excessive weight gain and 24.1% had adequate weight gain; statistically significant differences were found between pre-pregnancy BMI and weight gain classification   .Of the pregnant women with gestational diabetes, 88.9% had macrosomic children. Macrosomia was 43.3% in those who did not have diabetes. The risk of macrosomia was twice as high in pregnant women with gestational diabetes, compared with those who did not present it Of the participants with excess pre-pregnancy weight (n = 54), 31.5% had diabetes; of those who did not present pre-pregnancy excess weight (n = 68), 1.5% presented it; statistically significant differences were found between pre-pregnancy BMI and the presence of diabetes in the mother (p <0.00001). Weight gain showed no association with gestational diabetes   .The variables that best explained macrosomia were gestational weight gain and gestational diabetes in the final multiple regression model. The probability of being macrosomic increased 3.5 times in pregnant women with excessive weight gain (95%CI 1.78–7.18) compared with pregnant women with adequate or insufficient weight gain. Likewise, pregnant women with gestational diabetes (95%CI 1.51–2.76) were twice as likely to have a macrosomic child, compared with those who did not develop this disease   .Maternal factors such as excess pre-pregnancy weight, excessive weight gain, and diabetes during pregnancy increase the likelihood of macrosomia in the newborn. Overweight and obesity at the start of pregnancy were risk factors for excessive weight gain and the onset of gestational diabetes.3 , which found that 39.9% of them presented excess weight.Excess weight changes the intrauterine environment and leads to a higher risk of obstetric and neonatal complications. In this study, almost half of the pregnant women were overweight or obesity before pregnancy. This is in line with results of the 2015 National Survey of Nutrition Situation in Colombia7 . Other studies conducted in countries such as Cameroon18 , the USA19 , Lebanon20 , Uruguay6 , Peru17 , Argentina21 and Paraguay22 showed an association between excess pre-pregnancy weight and macrosomia, similarly to this study. Excess pre-pregnancy weight has contributed to the increased prevalence of macrosomia in different countries, in some cases, regardless of weight gain in pregnancy7 . The evidence of a relationship between BMI and effects on birthweight is overwhelming23 .The relationship between excess pre-pregnancy weight and newborn macrosomia has been evidenced, which are conditions associated with an increased risk of perinatal mortality and neonatal morbidity. In an investigation conducted by Koyanagi et al. in 23 countries, he concluded that excess pre-pregnancy BMI is associated with a birth weight > 4000 g24 .Pregnant women with excess pre-pregnancy weight exceeded the gain recommendations in this study. Multiple investigations in different countries coincide with these findings and state that pre-pregnancy overweight or obesity imply a greater possibility of exceeding the recommended weight gains, which aggravates the prospect for this group of pregnant women26 . This can generate a fetus of greater birthweight, even in women without pre-pregnancy excess weight22 . An expert review published in 2016 shows that women were more likely to have macrosomia when they had excessive BMI variations. This shows the need to carry out a strict monitoring of weight gain, especially in those women with pre-pregnancy excess. They require a differentiated attention that contributes to achieving a gain adjusted to their pre-pregnancy weight27 .Excessive gestational weight gain was the variable with the greatest effect on the probability of a newborn with macrosomia, according to the findings of this investigation. Other authors have reported similar results and state that obese and overweight women had higher proportions of total weight gain28 . Additionally, the prevalence of diabetes is higher in pregnant women with excess weight, compared with pregnant women with normal BMI, and grows as the BMI increases. Women with BMI > 25 are up to six times more likely to develop it and have a higher risk of simultaneous diagnoses of gestational hypertension and post-gestational diabetes11 .Another aspect associated with the appearance of macrosomia was gestational diabetes mellitus. Hyperglycemia states are linearly associated with the increase in newborn weight30 . This study indicates that pre-pregnancy excess weight and excessive weight gain have a marked effect on the onset of macrosomia, which is independent of other variables.Macrosomia occurred in a greater proportion in infants of young mothers, with a secondary or university education level, with one or without previous pregnancies, and with a low proportion of gestational diabetes. The maternal variables associated with newborn macrosomia are age > 35 years old, low educational level, greater number of children, few prenatal controls, and pre-pregnancy diabetes or that develops during pregnancyTo restrain the spread of epidemic excess weight, women must receive a comprehensive intervention before, during, and after pregnancy. Within the strategies to improve sexual and reproductive health in Colombia, establishing a guide or protocol containing guidelines addressed to decision-makers, public health policymakers, health care institutions, and interprofessional groups at all levels of attention is a priority. These guidelines should be geared towards the prevention and timely intervention of excess weight in women, as well as the prevention of excessive gestational weight gain in pregnant women, regardless of their pre-pregnancy BMI. This may contribute to the reduction of fetal macrosomia as one of its associated complications.4 . Interventions should contribute to weight gains adjusted to the pre-pregnancy BMI and motivate mothers to improve the selection, portion size and preparation of foods with low caloric density and higher nutritional value, favoring the prevention of micro-nutrients deficit risk and the management of anxiety face food, to achieve the proposed goals.Prenatal control programs and professionals responsible for the care of pregnant woman are called to take the lead in this matter. A differential and contextualized care must be devised. Interventions for pregnant women with excess weight should include: education and nutritional care, physical activity according to maternal health, empowerment of women around their prenatal care and, especially, their weight gain and dietary interventionsA limitation of this study is the collection of data from secondary sources, which may affect their quality. pre-pregnancy BMI and weight gain in pregnancy are modifiable risk factors that are susceptible to nutritional intervention and can contribute to minimizing adverse perinatal outcomes. This analysis contributes to the discussion about maternal excess weight and macrosomia in newborns, as aspects of paramount importance given the weight gain in women of childbearing age worldwide, and the deleterious effects of macrosomia in the short-, medium-, and long-term health. The results of this study are of great relevance for the department of Antioquia and the rest of the country, and they are expected to be taken as input at the national level to declare macrosomia at birth as an indicator of public health. 1 . Un informe realizado por la Organización de las Naciones Unidas en el 2015 expone que una de cada cuatro mujeres en edad adulta es obesa2 . La situación no es diferente en Colombia: la prevalencia de sobrepeso y obesidad en la población adulta es 55,2% en mujeres frente a 45,6% en hombres3 .Las cifras de exceso de peso han tenido un aumento en la población mundial en las últimas décadas. Según el reporte del Panorama de Seguridad Alimentaria y Nutricional en América Latina y el Caribe se evidenció cómo el sobrepeso y la obesidad en más de 20 países del continente fue 10 puntos porcentuales mayor en mujeres que en hombres en el 20163 . Otros estudios observacionales en muestras representativas de gestantes en países como Perú4 , Brasil5 y Uruguay6 , muestran prevalencias de exceso de peso de 63,8%, 47,5% y 32,6%, respectivamente.Cada vez más mujeres inician la gestación en exceso de peso. La Encuesta Nacional de la Situación Nutricional en Colombia de 2015 indica que 39,9% de las gestantes de todos los grupos de edad presentaron exceso de peso  en el país7 . En Colombia, se realizó una investigación a partir del Registro de Nacido Vivo del Departamento Administrativo de Estadísticas Vitales de los años 2002 a 2011, entre los cuales se registraron cerca de 6.000.000 nacimientos. El bajo peso al nacer fue 3,8%, mientras la macrosomía alcanzó 4,5%, en los recién nacidos (RN) a término8 .Este panorama afecta directamente el peso al nacer. Un estudio realizado en 23 países mostró una prevalencia de macrosomía de 4,5% y de 5,4% en América Latina. En países desarrollados, esta osciló entre 5% y 20%, y se ha reportado un aumento de 15-25% en las últimas tres décadas9 ; además de mayor admisión a la unidad de cuidados intensivos neonatales, alteraciones respiratorias y muerte neonatal10 .El binomio exceso de peso-gestación puede marcar el origen de una gama de enfermedades. Diversos mecanismos parecen confluir en la programación metabólica y la transferencia generacional de la obesidad y sus comorbilidades asociadas: inflamación, estrés oxidativo, desórdenes neurohormonales, modificaciones epigenéticas, calidad de la microbiota materna, macrosomía y mayor adiposidad fetal10 . Un estudio analítico realizado con más de 3.000 madres en Buga, Colombia, entre 2005 y 2015, mostró correlaciones entre obesidad materna, preeclampsia, eclampsia y diabetes gestacional. Los hijos de madres con diabetes gestacional y obesidad fueron significativamente de mayor peso al nacer11 .Los riesgos del exceso de peso en la madre incluyen preeclampsia, tromboembolismo venoso, hipertensión, diabetes gestacional, hemorragia posparto y mayor probabilidad de parto vaginal asistido o cesárea12 . Sin embargo, el incremento en las cifras de obesidad femenina y de macrosomía sustenta la necesidad de que esta sea considerada un indicador importante en la atención y vigilancia prenatal por sus efectos deletéreos a corto, mediano y largo plazo en la salud del neonato.Son escasos los estudios centrados en la macrosomía en el ámbito nacional. La evidencia científica se ha enfocado en las complicaciones obstétricas y el estudio de las alteraciones metabólicas materno-fetales. Además, el análisis de riesgo de eventos en salud pública en los RN se ha centrado en el bajo peso al nacerLa presente investigación tuvo como propósito analizar factores clínicos y ganancia de peso en gestantes y su asociación con la macrosomía fetal.Estudio analítico de casos y controles, anidado en una cohorte definida de RN en una institución de segundo nivel referente de la atención en salud del suroeste del departamento de Antioquia entre 2010–2017, y sus madres, quienes realizaron control prenatal en la misma institución o en otras de municipios cercanos. Las fuentes de información fueron el registro de parto, la ficha del Centro Latinoamericano de Perinatología (CLAP) y la historia clínica materna.casos del estudio. Los mismos criterios de inclusión fueron aplicados para el grupo de controles , excepto el peso al nacer, el cual se definió como un peso entre 3.000 y 3.999 g, considerado como adecuado.Los criterios de selección fueron: edad de la madre entre 15 y 45 años, control prenatal en la institución o instituciones de municipios cercanos, mínimo 90% de los datos en la ficha CLAP o la historia clínica, un dato de peso pregestacional o antes de la semana 14, uno ≥ a la semana 36 y los datos antropométricos del neonato. Se excluyeron las madres con embarazos múltiples, diabetes previa a la gestación y RN con enfermedades congénitas. Se identificaron los RN macrosómicos con peso ≥ 4.000 g, como criterio de inclusión específico para el grupo de A partir de la población censal de RN en la institución, se obtuvieron 300 neonatos macrosómicos, de los cuales 61 cumplieron los criterios de selección. Se realizó emparejamiento de casos y controles 1:1   . Se conSe estudiaron aspectos como índice de masa corporal (IMC) pregestacional, ganancia de peso y patologías durante la gestación. En el neonato se recolectaron los datos de sexo, peso, longitud, perímetro cefálico y edad gestacional al nacimiento, la cual se clasificó según los datos reportados en la historia clínica, por fecha de la última menstruación o ecografía del primer trimestre.13 . El IMC pregestacional en la embarazada menor de 19 años se realizó por medio del indicador IMC para la edad; para las mayores de 19 años, se realizó la clasificación según el indicador IMC para la edad gestacional, basado en el estándar propuesto por Atalah et al.14 : enflaquecida inferior a 20 kg/m2, normal 20–24,9 kg/m2, sobrepeso 25–29,9 kg/m2y obesidad ≥ 30 kg/m2. Ambos estándares acogidos por la norma nacional.Para el plan análisis, se consideró la clasificación del estado nutricional de las gestantes de acuerdo a la edad, según la Resolución 2465 de 2016 del Ministerio de Salud y Protección Social de la República de Colombia2. La ganancia de peso en adultas se clasifico así: enflaquecidas 12-18 kg, peso adecuado 10–13 kg, sobrepeso 7–10 kg y obesidad 6–7 kg15 . En adolescentes, se clasificó como: enflaquecidas entre 12–20 kg, peso adecuado entre 12,5–17 kg, sobrepeso entre 7,5–12,5 kg y en las obesas menos de 7 kg16 . Se definió ganancia inadecuada por déficit la inferior a los rangos de peso recomendados; ganancia excesiva de peso la que superó la recomendación; y ganancia adecuada la que se mantuvo dentro de los rangos especificados.La meta de ganancia de peso se calculó de acuerdo al peso pregestacional saludable equivalente a un IMC de 22,5 kg/m17 .Para la clasificación de la ganancia de peso total, se calculó la diferencia entre el último peso previo al parto registrado en la semana 36 o semanas posteriores y el peso pregestacional registrado a la semana 14 o menos. Si el nacimiento ocurrió después de la semana en la cual se registró el último peso de la madre, se proyectó la ganancia de peso de acuerdo al percentil de ganancia de cada gestante. La estatura materna mayor a 1,55 m se consideró como punto de corte para el riesgo de macrosomía al nacer de acuerdo con estudios previosSe elaboró un instrumento sistematizado en el programa Epi Info versión 7.2.1.0 para la recolección de la información. La recolección estuvo a cargo de personal previamente capacitado y estandarizado. El análisis descriptivo incluyó distribuciones absolutas y relativas, e indicadores de resumen como media aritmética, desviación estándar, cuartiles y rango intercuartílico. Se estableció el criterio de normalidad para algunas variables sociodemográficas y clínicas por medio de la prueba de Shapiro Wilk. Se utilizó la prueba U- Mann Whitney o la prueba t-Student para dos muestras independientes para determinar la relación entre la macrosomía y algunos aspectos sociodemográficos y clínicos cuantificables. La relación entre los aspectos sociodemográficos y los antecedentes clínicos con la macrosomía se definió mediante la prueba Chi cuadrado de independencia de Pearson o la prueba exacta de Fisher. Se evaluó la fuerza de asociación por medio de la razón de proporción (RP) con sus respectivos intervalos del 95% de confianza (IC95%) .Se aplicó un modelo parsimonioso que seleccionó las variables que mejor explicaron el efecto de la macrosomía, por un modelo lineal generalizado (GML) de regresión de Poisson con varianza robusta. El procesamiento estadístico de datos se realizó en el Software SPSS versión 23.La investigación fue aprobada por el comité de ética de la Facultad de Enfermería de la Universidad de Antioquia. Las instituciones en las que se realizó el proceso de recolección de datos dieron su aval y autorización para la revisión de las fuentes de datos. Se consideró una “investigación con riesgo mínimo”, con estricta custodia y confidencialidad de la información, de acuerdo con la Ley Estatutaria 1581 de 2012 y la Resolución Número 1995 de 1999.En ambos grupos, la mediana de edad fue 24 años y 75,4% de las participantes se encontraban entre los 19 y 34 años; el nivel educativo predominante  fue secundaria-universitaria; 74,6% tenían nivel socioeconómico bajo; 82% estaban afiliadas al régimen subsidiado de salud; y 68% contaban con presencia de compañero (casadas o en unión libre).El 59,8% de las madres fueron multíparas, 18,0% tuvieron abortos previos y 78,7% realizaron seis o más controles prenatales. Presentaron antecedente familiar de hipertensión arterial 50%, y 26,2% de diabetes mellitus. La preeclampsia previa fue 6,2% y durante la gestación 2,5%. La amenaza de parto pretérmino alcanzó 27,8% y la ruptura prematura de membranas 5,7%.La edad gestacional promedio al nacimiento del RN fue 39 semanas en ambos grupos, con un promedio de peso al nacer en el grupo de casos de 4120 gramos, mientras que en los controles 3334 gramos. La media de longitud al nacimiento fue 52,3 y 50 cm en los casos y en los controles respectivamente. La media del perímetro cefálico en los casos fue 36 y en los controles 34,5 cm. El sexo predominante en los RN fue el masculino con 60,7%, frente a 39,3% del sexo femenino, con una distribución similar entre los grupos. En cuanto al tipo de parto, 63% de los RN macrosómicos nacieron por cesárea.La mediana del peso pregestacional de las gestantes fue 60,7 Kg; 65,1 kg en los casos y 57,8 kg en los controles. La media de estatura fue 1,57 m. La mediana del IMC pregestacional en los casos fue 26,6 kg/m2 y 23,2 kg/m2 en los controles. El peso promedio al finalizar la gestación en los casos fue 78,5 kg y 68,8 kg en los controles. La mitad de las madres inició la gestación con peso adecuado; 28,7% con sobrepeso, 15,6% con obesidad y 5,7% en bajo peso. La media de ganancia de peso fue 12,2 kg.De las gestantes que presentaron IMC pregestacional en exceso, 64,8% tuvieron niños macrosómicos, y en las gestantes con IMC adecuado 38,2% . La macrosomía fue 1,6 veces más probable en las gestantes con IMC pregestacional en exceso frente a las que no lo tuvieron . El 63,9% tuvieron estatura > 1,55 m; sin embargo, no se hallaron diferencias estadísticas entre los grupos respecto a esta variable    .En las gestantes con excesiva ganancia de peso, 71,2% presentaron RN macrosómicos. El riesgo de macrosomía se incrementó 3,6 veces en las gestantes que tuvieron ganancias excesivas de peso, en comparación con las que tuvieron ganancia adecuada o deficiente    De las mujeres con exceso de peso pregestacional, 63% tuvieron ganancia de peso excesiva y 24,1% una ganancia de peso adecuada; se hallaron diferencias estadísticamente significativas entre el IMC pregestacional y la clasificación de la ganancia de peso   .De las gestantes con diabetes gestacional, 88,9% presentaron niños macrosómicos. La macrosomía fue 43,3% en aquellas que no presentaron diabetes. El riesgo de macrosomía fue dos veces mayor en gestantes con diabetes gestacional, frente a las que no la presentaron    .De las participantes con exceso de peso pregestacional (n = 54), 31,5% presentaron diabetes; de las que no presentaron exceso de peso pregestacional (n = 68), 1,5% la presentaron; se hallaron diferencias estadísticamente significativas entre el IMC pregestacional y la presencia de diabetes en la madre . La ganancia de peso no mostró asociación con la diabetes gestacional   .Las variables que mejor explicaron la macrosomía fueron la ganancia de peso gestacional y la diabetes gestacional en el modelo final de regresión múltiple. La probabilidad de ser macrosómico incrementó 3,5 veces en las gestantes con ganancia de peso excesiva  frente a las gestantes con ganancia de peso adecuada o insuficiente. Así mismo, fue dos veces más probable que gestantes con diabetes gestacional  tuviesen un hijo macrosómico, frente a las que no desarrollan esta enfermedad   .Factores maternos como el exceso de peso pregestacional, la ganancia de peso excesiva y la diabetes durante la gestación, incrementan la probabilidad de macrosomía en el neonato. El sobrepeso y la obesidad al iniciar la gestación fueron factores de riesgo para la ganancia de peso excesiva y la aparición de la diabetes gestacional.3 , en la que se encontró que 39,9% de ellas presentaron exceso de peso.El exceso de peso cambia el medio ambiente intrauterino y conlleva a un riesgo mayor de complicaciones obstétricas y neonatales. En el presente estudio, casi la mitad de las gestantes presentó sobrepeso u obesidad pregestacional. Esto está en consonancia con los resultados de la Encuesta Nacional de la Situación Nutricional en Colombia del año 20157 . Otros estudios realizados en países como Camerún18 , EEUU19 , Líbano20 , Uruguay6 , Perú17 , Argentina21 y Paraguay22 , mostraron asociación entre el exceso de peso pregestacional y la macrosomía, tal como el presente estudio. El exceso de peso pregestacional ha contribuido al aumento de la prevalencia de macrosomía en diferentes países, en algunos casos, independientemente de la ganancia de peso en el embarazo7 . La evidencia es contundente en la relación entre el IMC y su efecto en el peso al nacer23 .Se ha evidenciado la relación entre el exceso de peso pregestacional y la macrosomía del neonato, las cuales son condiciones asociadas a un incremento del riesgo de mortalidad perinatal y morbilidad neonatal. Una investigación realizada por Koyanagi et al. en 23 países concluyó que el IMC pregestacional en exceso se asocia con un peso al nacer > 4000 g24 .Las gestantes con exceso de peso pregestacional superaron las recomendaciones de ganancia en el presente estudio. Múltiples investigaciones en diferentes países coinciden con dichos hallazgos y exponen que el sobrepeso u obesidad pregestacional implican una mayor posibilidad de superar las ganancias de peso recomendadas, lo que agrava el panorama en este grupo de gestantes26 . Eso puede generar un feto de mayor peso al nacimiento, incluso en mujeres sin exceso de peso pregestacional22 . Una revisión de expertos publicada en el 2016 expone que las mujeres presentaron mayor probabilidad de macrosomia cuando tuvieron variaciones excesivas del IMC. Lo anterior muestra la necesidad de realizar una estricta vigilancia a la ganancia de peso, de manera especial en aquellas mujeres con exceso pregestacional. Ellas requieren una atención diferenciada que contribuya a alcanzar una ganancia ajustada a su peso pregestacional27 .La ganancia excesiva de peso gestacional fue la variable de mayor efecto en la probabilidad de un recién nacido con macrosomía, según los hallazgos de la presente investigación. Otros autores han reportado resultados similares y exponen que las mujeres obesas y con sobrepeso tuvieron mayores proporciones de ganancia de peso total28 . Adicionalmente, la prevalencia de diabetes es mayor en las gestantes con exceso de peso, respecto a las gestantes con IMC normal, y aumenta conforme se incrementa el IMC. Las mujeres con IMC > 25 tienen hasta seis veces más probabilidades de desarrollarla y mayor riesgo de diagnósticos simultáneos de hipertensión gestacional y diabetes posterior a la gestación11 .Otro aspecto asociado a la aparición de la macrosomía fue la diabetes mellitus gestacional. Los estados de hiperglicemia se asocian de manera lineal con el aumento del peso del recién nacido30 . El presente estudio indica que el exceso de peso pregestacional y la ganancia de peso excesiva tienen un marcado efecto en la aparición de la macrosomía, que es independiente de otras variables.La macrosomía se presentó en mayor proporción en neonatos de madres jóvenes, con nivel educativo secundaria o universitario, con una o sin gestas previas y con baja proporción de diabetes gestacional. Las variables maternas asociadas con la macrosomía en el neonato son la edad > 35 años, nivel educativo bajo, mayor número de hijos, pocos controles prenatales y diabetes pregestacional o que se desarrolla durante la gestaciónPara contener la propagación de la epidemia del exceso de peso, es necesario que la mujer reciba una intervención integral antes, durante y después de la gestación. Dentro de las estrategias para mejorar la salud sexual y reproductiva en Colombia, es prioritario establecer una guía o protocolo que contenga las directrices dirigidas a los tomadores de decisiones, generadores de políticas en salud pública, instituciones prestadoras de salud y grupos interprofesionales en todos los niveles de atención. Esas directrices deben ser orientadas hacia la prevención e intervención oportuna del exceso de peso en la mujer y la prevención de la ganancia de peso gestacional excesiva en las gestantes independiente de su IMC pregestacional. Eso puede contribuir a la reducción de la macrosomía fetal como una de sus complicaciones asociadas.4 . Las Intervenciones deben contribuir a ganancias de peso ajustadas al IMC pregestacional, a motivar a las madres para mejorar la selección, el tamaño de las porciones y la preparación de los alimentos de baja densidad calórica y mayor valor nutricional, favorecer la prevención del riesgo de déficit de micronutrientes y el manejo de la ansiedad frente a la alimentación para alcanzar las metas propuestas.Los programas de control prenatal y los profesionales encargados de la atención de la gestante están llamados a tomar el liderazgo de este asunto. Es necesario generar una atención diferencial y contextualizada. Las intervenciones para gestantes con exceso de peso deben incluir: educación y atención nutricional, actividad física de acuerdo con la salud materna, empoderamiento de la mujer en torno a su cuidado prenatal y, en especial, a su ganancia de peso e intervenciones dietéticasUna limitación de este estudio es la toma de los datos de fuentes secundarias, que pueden incidir sobre la calidad de los mismos. El IMC pregestacional y la ganancia de peso en el embarazo constituyen factores de riesgo modificables que son susceptibles de intervención nutricional y que pueden contribuir a minimizar los resultados perinatales adversos. Este análisis contribuye a la discusión en torno al exceso de peso materno y la macrosomía en el neonato, como aspectos de trascendental importancia dado el aumento de peso en las mujeres en edad fértil en el ámbito mundial, y los efectos deletéreos de la macrosomía en la salud a corto, mediano y largo plazo. Los resultados de este estudio son de gran relevancia para el departamento de Antioquia y el resto del país, y se espera sean tomados como insumo en el ámbito nacional para declarar la macrosomía al nacer como un indicador de salud pública.