Fármacos antiepilépticos usados en el embarazo y sus consecuencias sobre los resultados fetales: una revisión de la literatura / Antiepileptic drugs used in pregnancy and their consequences on fetal outcomes: a review of the literature

Los riesgos teratogénicos ocasionados por la exposición intrauterina a fármacos antiepilépticos (FAE) son conocidos, por lo que su prescripción se mantiene bajo estricto control. Describir los efectos adversos fetales de la exposición a FAE durante la gestación, reportados en la literatura durante el período 2016-2022. Revisión sistematizada de estudios que reportaron los efectos adversos fetales inducidos por la exposición a FAE en mujeres embarazadas en tratamiento por diagnósticos neurológicos, principalmente de epilepsia. La búsqueda se realizó en PubMed, Cochrane, Web of Science, SCOPUS, Biblioteca Virtual en Salud, Lilacs y SciELO. Se identificaron 37 artículos distribuidos en 13 países de Asia, Europa, América del Norte y Oceanía. Se observaron resultados perinatales adversos, tanto físicos como cognitivos, en la mayoría de los estudios. Los fármacos identificados como los más utilizados en los últimos años fueron valproato, topiramato, carbamazepina, lamotrigina y levetiracetam. Los FAE tienen potencial teratogénico en distintos grados de riesgo, provocando anomalías congénitas o efectos adversos en múltiples sistemas del cuerpo humano, siendo los sistemas nervioso, circulatorio y osteomuscular los más afectados.

The teratogenic risks caused by intrauterine exposure to antiepileptic drugs (AED) are known, so their prescription is kept under strict control. To describe the fetal adverse effects AED exposure during gestation, reported in the literature during the period 2016-2022. Systematized review of studies that reported fetal adverse effects induced for the exposure to AED in pregnant women in treatment for neurological diagnoses, mainly epilepsy. The search was carried out in PubMed, Cochrane, Web of Science, SCOPUS, Virtual Health Library, Lilacs and SciELO. 37 articles distributed in thirteen countries in Asia, Europe, North America and Oceania were identified. Adverse perinatal outcomes, both physical and cognitive, were observed in most studies. The most common drugs identified were valproate, topiramate, carbamazepine, lamotrigine and levetiracetam. AED have teratogenic potential in different degrees of risk, causing congenital anomalies or adverse effects in multiple systems of the human body, being the nervous, circulatory and musculoskeletal systems the most affected.

Genetic epidemiology of rare diseases in San Luis Province, Argentine

Objectives: Genetic epidemiologic studies in populations of the world are scarce and this medical information is of special value for clinical geneticists. The purpose of this work was to know and to implicate the geographical environments with the genetic diseases found in patients attending a genetic consulter, according to the type of work, place of residence, or environment characteristic in the province of San Luis, Argentine. Material and Methods: Clinical genetics consultations during 2014–January 2019 were analyzed for all patients derived to the primary consultation center, and nearby hospitals in San Luis. A total of 448 patients were registered and examined once a week at the Central Hospital of San Luis. The reasons of the derivate medical consultations were divided into major malformations (MMal), neurodevelopment diseases, and genetic counseling. In addition, possible environmental risk factors such as urban or rural origin, the working activity of parents in manufacturing houses or mines, and drug consumption during pregnancy were also considered. The prevalence of genetic diseases was calculated for all eight province departments and compared with the province’s apparent prevalence. Results: In the whole sample (n = 448), the major proportion of patients came from the city. Patients with MMals were the most abundant and significantly higher than the other categories. The prevalence of MMals distributed approximately similarly in all departments of the province, with exception of two of them. No association was found between types of work or drug abuse with MMals in this sample. Conclusion: Of all types of genetic diseases, the most prevalent was the MMals. Regarding its prevalence, except for two departments, each department’s prevalence had a similar distribution. Most of the affected patients with this type of genetic condition were found in the city and not in other regions of supposed risk

Controle e utilização da talidomida: adequados à ampliação do uso e mitigação do risco de teratogenicidade no Brasil? / Thalidomide control and use: are these appropriate to extend the use and mitigate the risk of teratogenicity in Brazil?

Resumo Estudo de utilização de medicamento que descreve o controle da talidomida no Brasil e sua utilização em Minas Gerais. Questionário online foi enviado às unidades federativas do Brasil para coleta de dados de distribuição, dispensação, cadastro de usuários e eventos adversos da talidomida. Dados de distribuição (2011-2018) e dispensação (2015-2018) de Minas Gerais foram obtidos pelo sistema de gerenciamento da assistência farmacêutica. Análise de variância e teste de Tukey foram empregados para comparações dos dados. Das 16 unidades federativas participantes, 100% e 50% utilizavam sistema eletrônico para distribuição e dispensação, respectivamente, e cerca de 43% cadastravam usuários. Sistemas de notificação de eventos adversos eram escassos. Houve redução de 44% na distribuição em Minas Gerais no período. A dispensação manteve-se constante (média 0,0004 DDD/1000 hab./dia) e ocorreu principalmente para eritema nodoso hansênico e mieloma múltiplo. O uso off-label (2,2%) foi crescente. A maioria dos usuários era do sexo masculino (idade média 56 anos). Das mulheres, 30% estavam em idade fértil. A vigilância da talidomida é um desafio em saúde pública. Apesar da ampliação do uso e obrigatoriedade de controle, não há padronização em nível nacional e a notificação de eventos adversos é incipiente.

Abstract Drug utilization research to describe the control of thalidomide in Brazil and its use in Minas Gerais state. An online questionnaire was sent to the Brazilian federative units to collect data concerning distribution, dispensation, user registration, and thalidomide adverse events. Distribution (2011-2018) and dispensing (2015-2018) data in Minas Gerais were obtained through the pharmaceutical care management system. Analysis of variance and Tukey test were used for data comparisons. Of the 16 participating federative units, 100% and 50% used electronic distribution and dispensing systems, respectively, and about 43% registered users. Adverse event reporting systems were scarce. A 44% reduction was observed in the distribution in Minas Gerais for the period. Dispensing remained constant (mean 0.0004 DDD/1,000 inhabitants/day) and occurred mainly for erythema nodosum leprosum and multiple myeloma. Off-label use (2.2%) was increasing. Most users were male (mean age 56 years) and thirty percent of women were of childbearing age. Thalidomide surveillance is a public health challenge. Despite the increased use and mandatory control, there is no national standardization, and adverse event reporting is incipient.

Malformaciones congénitas relacionadas con los agentes teratógenos / Congenital malformations related to teratogenic agents

Los agentes teratógenos constituyen un problema social, pues no todos los pacientes que nacen con alguna malformación congénita logran bienestar absoluto, pues arrastran secuelas que repercuten en la calidad de vida. Muchas drogas, medicamentos y sustancias químicas atraviesan la barrera placentaria y causan efectos adversos sobre el embrión o el feto. Se realizó una actualización en cuanto a la toxicología del desarrollo prenatal. Se revisaron 186 resúmenes bibliográficos de PubMed, Scielo,Foxitsoftware, Latinsalud, Infomed y libros de la especialidad de embriología, de los que se seleccionaron 64 con criterios de relevancia científica, actualidad y autor. Se desecharon 31 repetidos y quedaron solo 35, en las cuales se centró el trabajo. Todo esto evidenció la existencia de diversas drogas, medicamentos, sustancias químicas, exposiciones ocupacionales y del medio ambiente que constituyen embriotóxicos, capaces de producir defectos congénitos con riesgo de mortalidad durante la vida intrauterina, en el período perinatal y las etapas tempranas de la vida.

Teratogenic agents have become a social problem. Many drugs, medications and chemical substances can cross the placental barrier, with adverse effects on embryo or fetus. Patients born with congenital malformations have sequelae that influence their life quality. A bilbliographic rewiew about antenatal toxicology trough Latinsalud, Infomed and embryology books. We picked a group of 64 with scientific criteria, publication and author. We discarded 31 repeated, checked 186 bibliographic PubMed's summaries, Scielo, foxitsoftware themselves. Finally there were only 35 publications, in which various drugs, medications, chemical substances, occupational and the ambient- midway expositions were considered capable toxics to produce congenital defects, with a high mortality range during the intrauterine life, in the perinatal period and in premature life stages.

Life Without Limbs: Tetra-amelia

Amelia is defined as the complete absence of the skeletal parts of a limb. Tetra- amelia, is the absence of all thefour limbs is a very rare condition with an incidence range of 1.5–4/100,000 births. Many factors causingvarious limb defects are genetic, environmental (teratogens), vascular compromise by amniotic bands andconditions like oligohydraminos and maternal diabetes. Point mutation in the WNT gene plays a major role incausing limb defects.

Uso de fármacos durante el embarazo / Drug use during pregnancy

La información sobre seguridad de fármacos en la gestación es abundante, pero existe poca evidencia científica, por razones éticas muy pocos ensayos clínicos se han realizado y publicado. Todo esto ha traído como consecuencia que se sobredimensione el peligro de los fármacos en el embarazo, limitando su uso razonable en enfermedades crónicas de gestantes, y, en el otro extremo, que se prescriba la medicación libremente desconociendo el verdadero riesgo que implica administrarlos en el momento y en la dosis inadecuada. La presente revisión describe la manera en que los cambios fisiológicos en el embarazo modifican considerablemente la farmacocinética de la medicación. Se evalúa el verdadero riesgo potencial de teratogénesis de los fármacos, los criterios específicos para considerarlos como factor etiológico. Se comenta la clasificación de la Administración de Alimentos y Medicamentos estadounidense (FDA, por sus siglas en inglés), los criterios de su clasificación, sus limitaciones, su limitada vigencia actual y la propuesta de nuevas reglas para etiquetar los fármacos en donde considera evaluación clínica, exposición inadvertida y riesgo disponible. Se realiza la descripción de los riesgos de la medicación de más frecuente uso en las patologías más comunes en el embarazo. Se comenta la correcta manera de informar a la paciente expuesta a supuestos teratógenos, con la finalidad de no afectar la percepción del riesgo. Hay que considerar que los fármacos prescritos con mayor frecuencia se pueden administrar con relativa seguridad durante el embarazo, indicando los que sean estrictamente necesarios, restringiéndolos en el primer trimestre, prefiriendo los de seguridad comprobada, utilizando la menor dosis eficaz durante el menor tiempo posible, evitando utilizar varios fármacos y vigilando sus efectos colaterales y complicaciones

There is plenty of information about drug safety during pregnancy, but there is little scientific evidence on this topic. Due to ethical reasons, very scarce clinical assays have been conducted and published. This situation has resulted in the exaggeration of drug risk during pregnancy, thus limiting its reasonable use for chronic diseases in pregnant women. At the other extreme, it has resulted in the careless prescription of drugs not acknowledging the real risk involved in administering them in the inappropriate dose and moment. This review article describes how physiological changes during pregnancy modify significantly the pharmacokinetics of drugs. The real potential risk of drug-induced teratogenesis and the specific criteria for considering them an etiological factor are evaluated. The U.S. Food and Drug Administration (FDA) pregnancy categories' criteria, limitations, and limited current validity are discussed, as well as its proposal of new regulations on drug labeling, considering clinical evaluations, unnoticed exposure, and risks. The risks associated with the most frequently used drugs for the most common diseases during pregnancy are described. The correct way to tell the patient exposed to suspected teratogens is discussed, in order to avoid affecting risk perception. It should be considered that the administration of the most frequently prescribed drugs is relatively safe during pregnancy. Nevertheless, only those strictly necessary must be prescribed, their consumption must be limited during the first trimester, those proven safety must be preferred, the minimum effective dose during the shortest time possible must be used, the administration of several drugs must be avoided, and side effects and complications must be monitored

Endocarcinoma gástrico y embarazo reporte de dos casos y revisión de la literatura / Gastric carcinoma and pregnancy report of two clinical cases and review of the literature / Endocarcinoma gástrica e gravidez relatório de dois casos e revisão da literatura

RESUMEN La incidencia de cáncer durante la gestación es de 1: 1000 a 2000 embarazos, siendo los más frecuentes el de cérvix, mama, ovario, melanoma, tiroides, colon y hematológicos como linfoma y leucemia. A pesar de ser una entidad poco frecuente en el embarazo, se ha visto una tendencia a aumentar en los últimos años debido al incremento progresivo de la edad materna en el momento de la concepción. El carcinoma gástrico es una patología aún menos frecuente, siendo su incidencia durante la gestación de aproximadamente 0.016% a 0.026% en las series de casos de Japón, país con la mayor prevalencia de enfermedad. La cirugía es el tratamiento oncológico menos controversial durante la gestación. En los últimos años, ha cobrado importancia la quimioterapia adyuvante con antineoplásicos de tipo antimetabolito como el 5 fluoracilo (5 - FU), medicamento que ha demostrado mejoría de la supervivencia en pacientes gestantes con adenocarcinoma gástrico. Desafortunadamente, el 96.7% de los casos son diagnosticados en estadios avanzados, pues su presentación clínica suele confundirse con las manifestaciones propias de la primera mitad de la gestación como son las nauseas y el vomito. Presentamos dos casos clínicos, el de una gestante de 34 años con embarazo de 19 semanas y 3 días al momento del diagnóstico de un carcinoma gástrico Bormann III, llevada a laparotomía con intención curativa a las 21 semanas con hallazgo intraoperatorio de enfermedad metastásica avanzada y tumor ovárico izquierdo sugestivo de tumor de Krukenberg, a quien se le inicia a las 23 semanas quimioterapia paliativa con esquema FOLFIRI el cual recibió hasta la finalización de la gestación a las 33 semanas por restricción del crecimiento intrauterino y posteriormente durante el puerperio; y el de una gestante de 31 años con embarazo de 26 semanas y 6 días quien se ingresa para estudio de emesis persistente durante la gestación con confirmación diagnóstica de adenocarcinoma gástrico Bormann III asociado a Restricción del crecimiento intrauterino que fue llevada a cesárea a las 34 semanas y en el puerperio a gastrectomía total con vaciamiento ganglionar del area celiaca y reconstrucción en Y de Roux. El objetivo de realizar estos reportes surge de la carencia de guias de manejo respecto a dicha entidad durante la gestación debido a la poca frecuencia de presentación de la misma. Es frecuente encontrar discrepancias entre los conceptos en cuanto a conductas médicas se refiere. Disponemos de reportes y series de casos que orientan el manejo hacia un enfoque interdisciplinario dirigido a sopesar los riesgos y beneficios derivados de implementar o no un tratamiento durante la gestación siendo pocos los casos exitosos reportados en la literatura.

ABSTRACT Incidence of cancer during pregnancy is 1 in 1000. The most frequent carcinomas are the cervix, breast, ovaries, melanoma, thyroid, colon and hematological such as lymphoma and leukemia. Although cancer is not frequently associated with pregnancy, there has been a tendency to increase in recent years due to the progressive increase in maternal age at conception. Gastric carcinoma during pregnancy is a rare pathology, with an incidence of 0.016% to 0.026% in the series of cases from Japan, one of the countries with the greatest prevalence of this disease. Surgery is the least controversial type of oncologic treatment during pregnancy. In the last years, the adjuvant chemotherapy with antimetabolite drugs like the 5-fluoracile has gained relevance because it has demonstrated to improve survival in pregnant patients with gastric carcinoma. Unfortunately, the 96.7% of cases are diagnosed in advanced states because its symptoms can be misinterpreted as pregnancy induced nausea and vomiting characteristic of first half of pregnancy. We present two Clinical cases. The case of a 34 years old pregnant woman with 19 weeks and 3 days of gestation at the time of diagnosis of a gastric carcinoma in Bormann III stage, she was laparotomized with curative intentions at 21 weeks of gestation with intraoperative findings consistent with advanced metastatic disease and left-sided ovarian tumor suggestive of Krukenberg tumor. At 23 weeks palliative chemotherapy with FOLFIRI was initiated and it was continued until the end of gestation at 33 weeks and later in the puerperium; and the case of a 31 years old pregnant woman with 26 weeks and 6 days of gestation, she was admitted for the study of persistent vomiting during pregnancy with diagnostic confirmation of gastric adenocarcinoma Bormann III associated with intrauterine growth restriction, she was carried cesarean at 34 weeks. In the postpartum she was carried total gastrectomy with lymph node dissection of the celiac area and Roux-Y reconstruction. The objective of this report arises from the absence of clinical randomized studies about the management of this entity during pregnancy in consequence of the few cases available in the literature. This has been a cause of discrepancies between medical staff regarding therapeutics. There are some available literature series and case reports that guide management to a multidisciplinary approach in pursuit of more benefits and less risk in the context of the pregnant patient, with little cases reported as successful.

RESUMO A incidência de câncer durante a gravidez é de 1 em 1000. Os carcinomas mais freqüentes são o colo do útero, mama, ovários, melanoma, tireóide, cólon e hematológicos, como linfoma e leucemia. Embora o câncer não seja freqüentemente associado à gravidez, houve tendência de aumento nos últimos anos devido ao aumento progressivo da idade materna na concepção. O carcinoma gástrico durante a gravidez é uma patologia rara, com incidência de 0,016% a 0,026% na série de casos do Japão, um dos países com maior prevalência desta doença. A cirurgia é o tipo menos controverso de tratamento oncológico durante a gravidez. Nos últimos anos, a quimioterapia adjuvante com fármacos antimetabolitos como a 5-fluoracile ganhou relevância porque demonstrou melhorar a sobrevida em gestantes com carcinoma gástrico. Infelizmente, os 96,7% dos casos são diagnosticados em estados avançados porque seus sintomas podem ser mal interpretados, pois a náusea e os vômitos induzidos pela gravidez são característicos da primeira metade da gravidez. A presentamos dois casos clínicos. O caso de uma mulher grávida de 34 anos com 19 semanas e 3 dias de gestação no momento do diagnóstico de carcinoma gástrico no estádio Bormann III, foi laparotomizada com intenções curativas às 21 semanas de gestação com achados intraoperatórios consistentes com doença metastática avançada e tumor de ovário esquerdo sugestivo de tumor de Krukenberg. Às 23 semanas, iniciou-se a quimioterapia paliativa com FOLFIRI e continuou até o final da gestação às 33 semanas e mais tarde no puerpério; e o caso de uma mulher grávida de 31 anos com 26 semanas e 6 dias de gestação, foi admitida para o estudo de vômitos persistentes durante a gravidez com confirmação diagnóstica de adenocarcinoma gástrico Bormann III associado à restrição de crescimento intra-uterino, foi realizada cesariana às 34 semanas. No pós-parto foi transportada gastrectomia total com dissecção dos linfonodos da área celíaca e reconstrução Roux-Y. O objetivo deste relatório decorre da ausência de estudos clínicos randomizados sobre o manejo dessa entidade durante a gravidez em conseqüência dos poucos casos disponíveis na literatura. Esta foi uma causa de discrepâncias entre a equipe médica em relação à terapêutica. Existem algumas séries de literatura disponíveis e relatos de casos que orientam o gerenciamento para uma abordagem multidisciplinar em busca de mais benefícios e menos risco no contexto da paciente grávida, com pequenos casos relatados como bem sucedidos.

Teratogens: a public health issue - a Brazilian overview

Abstract Congenital anomalies are already the second cause of infant mortality in Brazil, as in many other middle-income countries in Latin America. Birth defects are a result of both genetic and environmental factors, but a multifactorial etiology has been more frequently observed. Here, we address the environmental causes of birth defects - or teratogens - as a public health issue and present their mechanisms of action, categories and their respective maternal-fetal deleterious effects. We also present a survey from 2008 to 2013 of Brazilian cases involving congenital anomalies (annual average of 20,205), fetal deaths (annual average of 1,530), infant hospitalizations (annual average of 82,452), number of deaths of hospitalized infants (annual average of 2,175), and the average cost of hospitalizations (annual cost of $7,758). Moreover, we report on Brazilian cases of teratogenesis due to the recent Zika virus infection, and to the use of misoprostol, thalidomide, alcohol and illicit drugs. Special attention has been given to the Zika virus infection, now proven to be responsible for the microcephaly outbreak in Brazil, with 8,039 cases under investigation (from October 2015 to June 2016). From those cases, 1,616 were confirmed and 324 deaths occurred due to microcephaly complications or alterations on the central nervous system. Congenital anomalies impact life quality and raise costs in specialized care, justifying the classification of teratogens as a public health issue.

2．Points for Evaluation of the Revised Risk Minimization Plans on Thalidomide and its Derivatives / 薬剤疫学

Thalidomide and the derivatives, lenalidomide and pomalidomide, are the most potent teratogenic medicines. Thalidomide Education and Risk Management System （TERMS®）and RevMate® for lenalidomide and pomalidomide have been operated with a goal of no exposed embryo to the drugs. The TERMS®and the RevMate®, a centralized management system, were revised in 2016 according to a request by a patient group. After the revision, the patient self-check sheet on adherence to conception prevention is primarily confirmed by his/her doctor, and the content of the completed sheet is sent to the management center in the pharmaceutical company after dispensing of the drug. The points for evaluation of the revised system will be as follows. (1) Has an appropriate procedure in accordance with the revised system been established in respective hospitals? (2) The rate of non-compliance with the procedure by the doctors or pharmacists, (3) Effect on awareness and behavior of the patients. Questionnaire studies of the patients, doctors, and pharmacists have been performed by the third-party committees.

<b>2．Points for Evaluation of the Revised Risk Minimization Plans on Thalidomide and its </b><b>Derivatives </b> / 薬剤疫学

<p>Thalidomide and the derivatives, lenalidomide and pomalidomide, are the most potent teratogenic medicines. Thalidomide Education and Risk Management System （TERMS^®）and RevMate^® for lenalidomide and pomalidomide have been operated with a goal of no exposed embryo to the drugs. The TERMS^®and the RevMate^®, a centralized management system, were revised in 2016 according to a request by a patient group. After the revision, the patient self-check sheet on adherence to conception prevention is primarily confirmed by his/her doctor, and the content of the completed sheet is sent to the management center in the pharmaceutical company after dispensing of the drug. The points for evaluation of the revised system will be as follows. (1) Has an appropriate procedure in accordance with the revised system been established in respective hospitals? (2) The rate of non-compliance with the procedure by the doctors or pharmacists, (3) Effect on awareness and behavior of the patients. Questionnaire studies of the patients, doctors, and pharmacists have been performed by the third-party committees.</p><p></p>

Fenocopia del síndrome de larsen asociado al uso de misoprostol: reporte de caso / Phenocopy of larsen syndrome associated with misoprostol use: a case report

Resumen: el misoprostol es un análogo de la prostaglandina E1 con diversas utilidadesterapéuticas incluyendo el tratamiento de la úlcera péptica. En el campo de la obstetricia es ampliamente utilizado para la inducción del trabajo de parto en escenarios específicos, abortos médicos e incluso emergencias obstétricas como el sangrado posparto. Su amplia distribución en el mercado farmacéutico ha llevadoa que sea usado de manera indiscriminada con fines abortivos, desconociendo su potencial teratogénico durante la gestación. En este manuscrito se presenta el caso de un recién nacido, hijo de madre de 17 años, expuesto prenatalmente a misoprostol en dosis de 1.000 mcg vía vaginal y 1.800 mcg vía oral entre las semanas cuatro y 16 de gestación, que presentaba marcadas malformaciones articulares clínicamente compatibles con el síndrome de Larsen, entidad caracterizadapor la presencia de dislocaciones de cadera, rodilla y codos, y deformidades en pie equino varo; además de hipertelorismo, frente prominente y puente nasal deprimido. Después de un estudio clínico y paraclínico se descartaron las posibles entidades genéticas y se demostró que las anomalías presentadas eran una fenocopia del síndrome de Larsen causadas por el efecto teratogénico del misoprostol.En conclusión, el misoprostol es un medicamento teratogénico contraindicado durante el embarazo, que causa un amplio espectro de anomalías congénitas que producen fenocopias de diversas entidades genéticas. Esta situación hace que el paciente expuesto requiera un abordaje y estudio adecuado para llegar a un diagnósticoetiológico correcto que lleve a la mejor conducta terapéutica, con manejo inter y multidisciplinario.

Abstract: misoprostol is an analogue of prostaglandin E1 with various therapeutic utilities, including treatment for peptic ulcer. In the obstetrics field is widely used for induction of labor in specific scenarios, medical abortions, and even obstetric emergencies, such as postpartum bleeding. Its wide distribution in the pharmaceuticalmarket has facilitated another indiscriminate uses like non-medical abortion,ignoring their teratogenic potential during gestation. In this manuscript, it present the case of a newborn, born to a mother of 17 years, who was exposed prenatally to a misoprostol dose of 1,000 μg by vaginal route and 1,800 μg per mouth, between weeks four and 16 of gestation, that showed marked articular malformations clinically compatible with Larsen syndrome. This entity is characterizedby the presence of dislocations of the hip, knee and elbows, deformitiesin equine foot Varus, in addition to hypertelorism, prominent forehead, and depressed nasal bridge. After a clinical study are discarded the possible genetic entities and it was demonstrated that the abnormalities were a imitation of Larsen syndrome caused by the teratogenic effect of misoprostol. In conclusion, misoprostolis a teratogenic drug contraindicated during pregnancy that causes a broad spectrum of congenital abnormalities that can cause imitation of several entities of genetic origin. This situation makes that exposed patient requires an appropriateapproach and clinical study to reach a correct a etiological diagnosis, leading to a better therapeutic approach with an inter and multidisciplinary management.

Algunas consideraciones actuales sobre las malformaciones en el desarrollo del sistema osteomioarticular / Some current considerations on the malformations in the development of the osteomyoarticular system

En el desarrollo del sistema osteomioarticular desempeñan una función determinante los mecanismos morfogenéticos básicos: inducción, migración, proliferación, diferenciación y apoptosis, los cuales son detectados por la acción de diversos agentes teratógenos que ocasionan la aparición de diversas anomalías, que también pueden ser provocadas por mutaciones en genes específicos como los de caja homeótica, por factores de crecimiento fibroblástico y por sus receptores. A causa del aumento de la incidencia de estas alteraciones a nivel mundial, y específicamente en la provincia de Santiago de Cuba, en los últimos años, se realizó una revisión bibliográfica para profundizar acerca de las malformaciones congénitas de dicho sistema, su origen, sus características y la forma de prevenirlas. Se concluyó que algunos de los teratógenos más perjudiciales son muy utilizados en Cuba y existe desconocimiento en los sectores más vulnerables de la población acerca de este tema.

In the development of the osteomyoarticular system, the basic morphogenetical mechanisms play an important role: induction, migration, proliferation, differentiation and apoptosis, which are detected by the action of different teratogenic agents which cause the emergence of diverse anomalies, that can also be caused by mutations in specific genes as those of the homeotic skeletal cage, by factors of fibroblastic growth and by their receptors. Due to the increase in the incidence of these changes at world level and specifically in Santiago de Cuba province, in the last years, a literature review was carried out to deepen on the congenital malformations of this system, their origin, their characteristics and the way of preventing them. It was concluded that some of the most harmful teratogens are very used in Cuba and ignorance exists in the population's most vulnerable sectors about this topic.

Analysis of agreement between Visual Analogue Scales (VAS) and numerical questions to assess perception of teratogenic risks in treatment with drugs and radiotherapy in women / Análise de concordância entre as escalas visual analógica (VAS) e questões numéricas para avaliar a percepção de riscos teratogênicos em tratamento com medicamentos e radioterapia em mulheres

To evaluate the agreement between Visual Analogue Scales (VAS) and numerical questions as a way of assessing the perception of teratogenic risk of treatment with drugs and radiotherapy. Methods: the sample comprised 144 pregnant and 143 non-pregnant women consecutively recruited at public health centers in Porto Alegre, in the State of Rio Grande do Sul, from February to August 2011. The perception of risk for congenital malformations in the general population and the perceptions of teratogenic risk for exposure to acetaminophen, meto-clopramide, misoprostol and radiotherapy were measured using VAS and numerical questions. The agreement between the results of the two techniques was tested using a Bland-Altman plot. Results: the medians for the perceptions measured using VAS were higher than those obtained using numerical questions for all variables. The perception of risk for acetaminophen showed the lower bias of the two techniques (bias=13.17; p<0.001) and exposure to radiotherapy, the higher (bias=25.02; p<0.001). Conclusion: there was no agreement between the measurements obtained using the two techniques for any of the risk perceptions under study. Risk perceptions were higher using VAS, for all kinds of exposure. Studies should be conducted to assess whether there is overestimation in other situations and social contexts owing to the use of VAS...

Avaliar a concordância entre Escalas Visuais Analógicas (EVA) e perguntas numéricas para aferir a percepção de risco teratogênico de medicamentos e radioterapia. Métodos: a amostra foi constituída por 144 gestantes e 143 não gestantes recrutadas consecutivamente em centros públicos de saúde de Porto Alegre, RS, entre fevereiro e agosto de 2011. A percepção de risco de malformações congênitas na população geral e as percepções de risco teratogênico das exposições a paracetamol, metoclo-pramida, misoprostol e radioterapia na gestação foram aferidas por EVA e perguntas numéricas. A concordância entre as duas técnicas foi avaliada pela análise gráfica de Bland-Altman Resultados: as medianas das percepções de risco teratogênico medidas por EVA foram superiores às obtidas através da pergunta numérica, para todas as variáveis. A percepção de risco ao paracetamol apresentou o menor viés entre as duas técnicas de aferição (viés=13,17; p<0,001) e a exposição à radioterapia, o maior (viés=25,02;p<0,001). Conclusões: não houve concordância entre as duas técnicas, para nenhuma das percepções de risco estudadas. As percepções de risco foram maiores para EVA, para todas as exposições. Sugerimos a realização de estudos que avaliem se também ocorre superestimação em outras situações e contextos sociais, em função do uso de EVA...

Teratogen exposure and congenital ocular abnormalities in Brazilian patients with Möbius sequence / Exposição à teratógenos e anormalidades oculares congênitas em pacientes brasileiros portadores da sequência de Möbius

Purpose: To assess the sociodemographic profiles, teratogen exposures, and ocular congenital abnormalities in Brazilian patients with Möbius sequence. Method: Forty-four patients were recruited from the Brazilian Möbius Sequence Society. This cross-section comprised 41 patients (age, mean ± standard deviation, 9.0 ± 5.5 years) who fulfilled the inclusion criteria. The parent or caregiver answered a questionnaire regarding sociodemographic data and pregnancy history. Patients underwent ophthalmological assessments. They were subdivided into groups according to misoprostol exposure during pregnancy, and the two groups were compared. Results: Mothers/caregivers reported unplanned pregnancies in 36 (88%) cases. Of these, 19 (53%) used misoprostol during their first trimesters. A stable marital status tended to be more frequent in the unexposed group (P=0.051). Incomplete elementary school education was reported by two (11%) mothers in the exposed group and by three (14%) mothers in the unexposed group (P=0.538). The mothers' gestational exposures to cocaine, marijuana, alcohol, and cigarettes were similar in both groups (P=0.297, P=0.297, P=0.428, and P=0.444, respectively). One (5%) case of Rubella infection during pregnancy was found in the unexposed group. The main malformations in the exposed and unexposed groups were the following: strabismus (72% and 77%, respectively), lack of emotional tearing (47% and 36%, respectively), and lagophthalmos (32% and 41%, respectively). Conclusion: Stable marital statuses tended to be more frequent among mothers that did not take misoprostol during pregnancy. Exposures to other teratogens and the main ocular abnormalities were similar in both groups. .

Objetivo: Descrever o perfil sóciodemográfico, exposição à teratógenos e anormalidades oculares congênitas em pacientes brasileiros portadores da sequência de Möbius Método: Quarenta e quatro pacientes recrutados da Sociedade Brasileira de Sequência de Möbius foram examinados. Este estudo transversal incluiu 41 pacientes que preencheram os critérios de inclusão do estudo (média das idades: 9,0 ± 5,5 anos). Mãe/responsável dos pacientes responderam a um questionário sobre perfil sóciodemográfico e história gestacional. Foi realizado exame oftalmológico de todos os pacientes. Eles foram agrupados em dois grupos de acordo com a exposição ao misoprostol durante a gestação e seus dados foram comparados. Resultados: Mães/responsáveis referiram gravidez indesejada em 36 (88%) dos casos. Destas, 19 (53%) fizeram uso de misoprostol no primeiro trimestre de gestação. Houve uma tendência do grupo de mães não expostas ao misoprostol de terem um estado civil estável (P=0,051). Duas (11%) mães do grupo de expostas ao misoprostol relataram primeiro grau incompleto e três (14%) do grupo de não expostas (P=0,538). A exposição das mães à cocaína, maconha, álcool e cigarro foi similar em ambos os grupos (P=0,297, P=0,297, P=0,428, P=0,444, respectivamente). Houve um caso (5%) de Rubéola no grupo de mães não expostas. As principais malformações associadas nos pacientes expostos e não expostos foram, respectivamente: estrabismo (72% e 77%), e diminuição da lágrima emocional (47% e 36%) e lagoftalmia (32% and 41%). Conclusão: Estado civil estável foi mais frequente em mães que não fizeram uso de misoprostol durante a gestação. Exposição à outros ...

Klippel-Trenaunay Syndrome and Gestational Trophoblastic Neoplasm.

Background: Klippel-Trenaunay syndrome is a non-heritable venous malformation with bone and soft tissue hypertrophy and cutaneous nevi. Case characteristics: Neonate with Klippel Trenaunay syndrome born to a mother with past history of Gestational trophoblastic neoplasm. Observation: Antenatally, a fetal vascular malformation was identified ultrasonologically at 29 weeks gestation. Acute myeloid leukemia was diagnosed in mother at 33 weeks gestation. Message: A rare association of Klippel Trenaunay syndrome and gestational trophoblastic neoplasm with the possible role of either hyperglycosylated Human Chorionic Gonadotropin or chemotherapy as a link is highlighted.

Asociación VACTERL y síndrome de Moebius en un recién nacido expuesto prenatalmente a misoprostol / VACTERL association and Moebius syndrome in a newborn girl prenatally exposed to misoprostol

El misoprostol, un análogo sintético de la prostaglandina E1, se ha asociado a un aumento en el riesgo de ocurrencia del síndrome de Moebius (parálisis congénita del VII par craneal que puede estar asociada a compromiso de otros pares craneales o incluso de otros sistemas) y defectos de las extremidades de tipo transversal-terminal en embarazos en que las madres utilizan este medicamento durante el primer trimestre de gestación. Se ha propuesto la perturbación vascular como mecanismo teratogénico del misoprostol. La asociación VACTERL es la coocurrencia estadísticamente no aleatoria de defectos vertebrales, anomalías vasculares, atresia anal, anomalías cardíacas, fístula traqueoesofágica con atresia esofágica, displasia renal y radial y anomalías de las extremidades diferentes a las radiales. No existe evidencia de una causa unificadora de la coocurrencia de las malformaciones VACTERL, por lo que esta condición se sigue denominando asociación y no síndrome. Se presenta el caso de una niña recién nacida con asociación VACTERL y síndrome de Moebius asociados a exposición prenatal a misoprostol en el primer trimestre del embarazo y, dado el mecanismo teratogénico del misoprostol, se propone un origen vascular de la asociación VACTERL.

Misoprostol, a synthetic analogue of prostaglandin E1, has been associated with an increased risk of occurrence of the Moebius syndrome (congenital paralysis of the seventh cranial nerve that may be associated with involvement of other cranial nerves or of other systems) and crossterminal limb defects in pregnancies in which mothers used this drug during the first trimester of pregnancy. Vascular disruption has been proposed as a teratogenic mechanism of misoprostol. The VACTERL association is the statistically non-random co-occurrence of vertebral defects, vascular anomalies, anal atresia, cardiac abnormalities, tracheo-esophageal fistula with esophageal atresia, radial and renal dysplasia, and other limb anomalies. There is no evidence for a unifying cause for the co-occurrence of VACTERL malformations, so this condition is still called an association and not a syndrome. We report the case of a newborn girl with VACTERL association and Moebius syndrome associated with prenatal exposure to misoprostol in the first trimester of pregnancy. Given the teratogenic mechanism of misoprostol, we propose a vascular origin for VACTERL association.

Use of psychotropic medications during pregnancy: perception of teratogenic risk among physicians in two Latin American countries

Objective: Pregnant women and their health care professionals commonly believe that use of medications during pregnancy may be harmful to the unborn fetus. The objective of this study was to evaluate the risk perception of psychotropic drug use in pregnancy among physicians in different medical specialties. Method: This was a convenience survey conducted at outpatient clinics in the cities of Recife, Brazil, and La Plata, Bahía Blanca, and Buenos Aires, Argentina. Physicians who agreed to participate were asked to rate their perception of teratogenic risk among different classes of drugs, which included antidepressants, antipsychotics, anticonvulsants, and benzodiazepines. Results: Two hundred and thirty-eight physicians completed the survey (response rate, 98%). These included psychiatrists, obstetricians, neurologists, cardiologists, gastroenterologists, and general practitioners. Among different specialties, a minority of psychiatrists perceived psychotropic drugs to be highly teratogenic (antidepressants, 12.5%; antipsychotics, 15%; benzodiazepines, 25%) as compared with other specialties (p < 0.003 for each drug class). There was no difference in perceived risk of antiepileptic drugs among specialties, including psychiatrists. Conclusion: The risk associated with use of psychotropic drugs in pregnancy was overestimated by physicians of all medical specialties, except psychiatry. All physicians should be aware of the safety/risk of psychotropic agents in pregnancy, as they may be required to give advice and/or prescribe these drugs to pregnant women. .

Factores de riesgo prenatales relacionados con la aparición de las cardiopatías congénitas / Prenatal risk factors related to the onset of congenital heart disease

Las cardiopatías congénitas constituyen defectos estructurales y/o funcionales del corazón y los grandes vasos, están relacionadas con la primera causa de muerte en niños menores de 1 año. Se realizó un estudio observacional, analítico, de casos y controles con el objetivo de identificar los factores de riesgo prenatales relacionados con la aparición de las cardiopatías congénitas en el territorio San Antonio de los Baños, La Habana, Cuba, de enero del 2000 a diciembre del 2009. El universo estuvo constituido por 89 gestantes cuyo producto de concepción tuvo cardiopatías congénitas. El 66,3 porciento de los casos con cardiopatías congénitas tenían algún familiar con esta patología, se identificó asociación entre la ingestión de medicamentos teratogenos y la presencia de las cardiopatías congénitas. Las edades extremas de la vida no constituyen factor de riesgo para tener hijos con cardiopatías congénitas

Congenital heart defects are structural and / or functional defects of the heart and great vessels; they are related to the first cause of death in children younger than 1 year old. We performed an observational, analytical, case-control study with to identify prenatal risk factors related to the occurrence of congenital heart disease in the territory of San Antonio de los Baños, Havana, Cuba from December 2009 to January 2000. The sample consisted of 89 pregnant women whose product of conception had congenital heart disease. 66.3 percent of cases with congenital heart disease had a relative with this disease; association was found between teratogens- medication intake and the presence of congenital heart disease. Extreme life ages are not a risk factor for having children with congenital heart disease

Gestación exitosa después de exposición inadvertida a ciclofosfamida durante el primer trimestre en una paciente con lupus activo: reporte de caso / Successful pregnancy after inadvertent exposure to cyclophosphamide in the first trimester in a patient with active lupus: case report

La ciclofosfamida se debe evitar durante el embarazo por sus efectos teratogénicos reconocidos. Los embriones o fetos de madres que requieren el uso de ciclofosfamida, o que se exponen inadvertidamente a la misma, tienen usualmente un desenlace adverso. En muy raras ocasiones se han informado gestaciones exitosas a pesar del uso de este medicamento durante el embarazo. Presentamos un nuevo caso de gestación exitosa en una mujer con lupus activo renal y neurosiquiátrico quien tuvo exposición a la ciclofosfamida durante el primer trimestre de su gestación.

Cyclophosphamide should be avoided during pregnancy because of its known teratogenic effects. Embryos or fetuses of mothers who require the use of this drug or who have been inadvertently exposed to it usually have an adverse outcome. However, successful pregnancies have occasionally been reported despite the use of cyclophosphamide during it. We report a new case of successful pregnancy in a woman with active renal and neuropsychiatric lupus who had exposure to cyclophosphamide during the first trimester of pregnancy.

Essence of preconception counseling and care

Since the 1980's, prenatal care for pregnant women and their babies has improved maternal and neonatal health. However, despite prenatal care, the rate of some complications, such as major fetal anomalies, preterm labor, and low birth weight have not improved. Only 10.3% of Korean women of childbearing age take folic acid supplementation and approximately 14% still consume alcohol during pregnancy. Because in Korea about 50% of pregnancies are unintended, those women have higher exposure rates to alcohol, drugs, and ionizing radiation. Because most fetal anomalies occur between 5 to 10 gestational weeks, the initial prenatal care provided at 7 to 8 gestational weeks is too late to prevent fetal anomalies. Preconception care may identify and modify adverse health, behavioral, and social outcomes for women and their unborn babies. Recently, a number of preconception interventions have been reported to have evidence-based effectiveness in improving pregnancy outcomes. These include folic acid supplementation, avoiding alcohol intake, smoking cessation, counseling on potentially teratogenic drugs, infection control, immunizations, and control of chronic diseases such as diabetes, hypothyroidism, obesity. For the improvement of maternal and fetal health, guidelines for preconception care must be developed in Korea. All health care providers should understand the clinical importance of evidence-based preconception care.