Consideraciones actuales sobre los teratógenos y sus efectos durante el embarazo / Current considerations on the teratogens and their effects during pregnancy

Introducción: El desarrollo alcanzado por la teratología como ciencia y las observaciones clínicas efectuadas por los científicos, permitieron establecer sus principios, representados por una serie de factores que determinan la capacidad de un agente de provocar trastornos congénitos, los cuales resultan actualmente de gran utilidad e importancia en la formación del profesional de la salud y repercuten en el Programa de Atención Materno Infantil. Objetivo: Describir los agentes teratógenos asociados a la aparición de defectos congénitos. Métodos: Se realizó una revisión bibliográfica acerca de los agentes teratógenos y sus posibles efectos teratogénicos en las bases de datos LILACS, SciELO, Clinicalkey y Google Académico, así como en la plataforma Biblioteca Virtual en Salud. Resultados: Las consecuencias de la exposición al teratógeno dependen, entre otras cosas, del momento en que se encuentre el proceso de gestación. Existen múltiples agentes teratógenos y algunos factores de riesgo que frecuentemente concomitan con ellos, por lo que se deben considerar en la prevención primaria para disminuir alteraciones y defectos congénitos por estas noxas ambientales. Consideraciones finales: El conocimiento de los efectos de los agentes teratógenos permite valorar el posible daño al feto.

Introduction: The development reached by teratology as science and the clinical observations made by the scientists, allowed to establish their principles, represented by a series of factors that determine the capacity of an agent to cause congenital dysfunctions, which are at the moment of great utility and importance in the training of health professional and rebound in the Infantile Maternal Care Program. Objective: To describe the teratogen agents associated with the appearance of congenital defects. Methods: A literatura review was carried out about the teratogen agents and their possible teratogenic effects in the LILACS, SciELO, Clinicalkey databases and Academic Google, as well as in the platform Virtual Library in Health. Results: The consequences of the exhibition to the teratogen depend, among other things, of the moment in which is the gestation process. There are multiple teratogen agents and some risk factors that frequently concomitan with them, for what should be considered in the primary prevention to diminish alterations and congenital defects for these environmental noxas. Final considerations: The knowledge of the effects of the agents teratogen allows to value the possible damage to the fetus.

Isotretinoin exposure in pregnant women in Korea

OBJECTIVE: Isotretinoin is a notorious teratogen otherwise used for the treatment of acne vulgaris. Some countries, including those in North America and the European Union, implemented the pregnancy prevention program (PPP); however, no PPP has yet been established in South Korea. So the aim of this study was to evaluate the rate of pregnant women exposed to isotretinoin among the callers of the Korean Mother Safe Counseling Center. METHODS: This is a prospective cohort study. We evaluated the demographic characteristics, obstetric history, and isotretinoin exposure of pregnant women based on the mother safe registry from April 2010 to July 2016. RESULTS: Among 22,374 callers, 650 (2.9%) pregnant women were exposed to isotretinoin. The mean age was 29.0±4.4 years in the isotretinoin-exposed group and 32.0±4.2 years in the unexposed group (P < 0.001). Moreover, the incidence of pregnancies within 30 days after isotretinoin discontinuation or during isotretinoin intake was 78.9% (513/650). The median duration of isotretinoin exposure was 18 (1–4,231) days. Furthermore, from 2011 to 2015, the incidence of isotretinoin exposure was 2.9±1.2 pregnancies per 10,000 births in South Korea. CONCLUSION: Approximately 80% of pregnant women are exposed to isotretinoin within the recommended 30 days of contraception or during pregnancy. Therefore, the PPP has to be established in South Korea.

Malformações congênitas: principais etiologias conhecidas, impacto populacional e necessidade de monitoramento / Birth defects: main known etiologies, population impact and the need for monitoring

OBJETIVOS: Este artigo tem por objetivo revisar as causas, o impacto dos defeitos congênitos na morbimortalidade infantil e a importância da sua vigilância, bem como apresentar como nossa comunidade acadêmica está inserida neste monitoramento. MÉTODOS: Foi realizada uma revisão da literatura nas bases de dados Medline/PubMed e Scielo, incluindo publicações de janeiro de 2010 até maio de 2018, em português e inglês. As palavras-chave utilizadas foram: "birth defects", "etiology", "infant mortality", "teratogens", "congenital abnormalities", "defeitos congênitos", "ECLAMC", "genética". Foram incluídos também livros-textos e artigos relevantes na área, independente da data de publicação, assim como sites eletrônicos de relevância. Adicionalmente, descrevemos o funcionamento do programa de monitoramento de defeitos congênitos do Hospital São Lucas da PUCRS, vinculado ao Estudo Colaborativo Latino Americano de Malformações Congênitas (ECLAMC). RESULTADOS: 971 artigos foram localizados com as combinações das palavras-chave, destes 21 foram utilizados na revisão. No conteúdo da revisão incluímos as etiologias conhecidas dos defeitos congênitos, dentre elas, estão as genéticas, multifatoriais e teratógenos físicos, químicos e biológicos. Esses dados estão resumidos das tabelas 1 a 5 deste artigo. Com relação ao monitoramento de defeitos congênitos, o ECLAMC- PUCRS avaliou 3981 recém-nascidos no período de agosto de 2016 a dezembro de 2017, e a taxa observada de malformações foi de 3,77%. CONCLUSÃO: Os defeitos congênitos são uma causa importante de morbimortalidade em todos os países, inclusive no Brasil. A compreensão de suas etiologias contribui para o aconselhamento genético das famílias, para o estabelecimento do prognóstico e intervenções terapêuticas, assim como para sua prevenção.

OBJECTIVE: This article aims to review the impact of birth defects on infant morbidity and mortality and the importance of their surveillance, to review their causes, as well as to show how our academic community is included in this monitoring. METHODS: a literature review was conducted in the Medline / PubMed and Scielo databases, including publications from January 2010 to May 2018, in Portuguese and English. The keywords used were: "birth defects", "etiology", "infant mortality", "teratogens", "congenital abnormalities", "congenital defects", "ECLAMC", "genetics". Also included were textbooks and relevant articles in the area, regardless the date of publication, as well as relevant electronic sites. Additionally, we describe the operation of the congenital defect monitoring program of the São Lucas Hospital of PUCRS, linked to the Latin American Collaborative Study of Congenital Malformations (ECLAMC). RESULTS: 971 articles were found using the keywords, from those 21 were used in the review. In the content of the review we include the known etiologies of the congenital defects, among which are the genetic, multifactorial, and physical, chemical and biological teratogens. These data are summarized in Tables 1-5 of this article. With regard to the monitoring of congenital defects, ECLAMC-PUCRS evaluated 3981 newborns from August 2016 to December 2017, and the observed malformation rate was 3.77%. CONCLUSION: Congenital defects are an important cause of morbidity and mortality in all countries, including Brazil. Understanding their etiologies contributes to the genetic counseling of families, to the establishment of prognosis and therapeutic interventions, as well as to their prevention.

Dengue y factores teratogénicos. Reporte de un paciente / Dengue and Teratogenic Factors. Report of a Patient

Se reportó un caso de aborto espontáneo producido entre la décima y oncena semanas de gestación en una gestante durante la epidemia de dengue que afectó la ciudad de Holguín, en el año 2015. El objetivo fue realizar el análisis de los factores teratogénicos que incidieron en el fracaso gestacional. La transmisión transplacentaria de la infección por el virus dengue al embriofeto, que provocó alteraciones en el proceso metabólico del desarrollo embriofetal fue el factor teratogénico primario, potencializados en forma sinérgica por la prolongada exposición febril que afectó la gestante, con la formación de un hematoma retroplacentario y la producción secundaria de un grado variable de insuficiencia placentaria, que ulteriormente condujo al desprendimiento placentario abortivo. La terapéutica farmacológica empleada (dipirona, gravinol, omeprazol, difenhidramina y benadrilina) por la insuficiente actividad enzimática microsómica y citosólica, característica en este estadio del desarrollo de la concepción, suele haber interrumpido o dificultado la actividad farmacocinética embriofetal, que actuó en calidad de coteratógeno en este estadio del desarrollo e incidió en el desarrollo de la concepción para producir el aborto espontáneo.

A case of spontaneous abortion occurred between the tenth and eleventh weeks of gestation in a pregnant woman during the dengue epidemic that affected the city of Holguín in 2015. The objective of this was to analyze of the teratogenic factors that affected the gestational failure. The transplacental transmission of dengue virus infection to embryofeto, which caused alterations in the metabolic process of the embryofoetal development, was the primary teratogenic factor, together with the prolonged febrile exposure that affected the pregnant woman, with the formation of a retroplacental hematoma, and secondary variable degree of placental insufficiency, causing the abortion. Dipyrone, gravinol, omeprazole, diphenhydramine and benadryline were the pharmacological therapy used, due to the insufficient microsomal and cytosolic enzymatic activity, characteristic at this stage of conception development, has usually interrupted or hindered the embryofoetal pharmacokinetic activity, acting as coteratogen, influenced in the development of conception to produce embryolethal effects, producing the spontaneous abortion.

Reproductive Toxic Chemicals at Work and Efforts to Protect Workers' Health: A Literature Review

A huge number of chemicals are produced and used in the world, and some of them can have negative effects on the reproductive health of workers. To date, most chemicals and work environments have not been studied for their potential to have damaging effects on the workers' reproductive system. Because of the lack of information, many workers may not be aware that such problems can be related to occupational exposures. Newly industrialized countries such as Republic of Korea have rapidly amassed chemicals and other toxicants that pose health hazards, especially to the reproductive systems of workers. This literature review provides an overview of peer-reviewed literature regarding the teratogenic impact and need for safe handling of chemicals. Literature searches were performed using PubMed, Google Scholar, and ScienceDirect. Search strategies were narrowed based on author expertise and 100 articles were chosen for detailed analysis. A total of 47 articles met prespecified inclusion criteria. The majority of papers contained studies that were descriptive in nature with respect to the Medical Subject Headings (MeSH) terms and keywords: “reproductive and heath or hazard and/or workplace or workers or occupations.” In the absence of complete information about the safe occupational handling of chemicals in Republic of Korea (other than a material safety data sheet), this review serves as a valuable reference for identifying and remedying potential gaps in relevant regulations. The review also proposes other public health actions including hazard surveillance and primary prevention activities such as reduction, substitution, ventilation, as well as protective equipment.

Necessity of Research for Safe Drug use in Pregnant Women

The thalidomide tragedy in the 1960s has resulted in a perpetuation of a certain perception amongst physicians and pregnant women that the use of medication during pregnancy is a potential teratogen. Consequently, physicians hesitate in prescribing medication to pregnant women. In addition, pregnant women often refuse medication despite therapeutic necessity because of this existing perception. Recently there have been frequent adverse pregnancy outcomes related to the recurrence of chronic diseases, such as hypertension and diabetes, following pregnancy in older women. And there are lots of unnecessary termination of pregnancy due to the of information of medication exposed to medication following over 50% of unintended pregnancy. In light of this, better dissemination of information regarding the safe usage of medication for pregnant women is required. This would not only be cost-effective in terms of medical expenditure, but also prove beneficial for the treatment of diseases. In addition, Korea needs to adapt to the increasing changes of the international information system regarding supporting the safe usage of medication during pregnancy. An example of this is shown by the recent changes to the labeling of medication by the United States Food and Drug Administration. The new labeling includes information on the risk of usage, rather than just an arbitrary alphabetic classification of B, C, D, or X. Furthermore, this information is limited in Korea because of the lack of research, which in turn is due to several limitations on ethics and methodology, as well as present regulations on the research of pregnant women. From this, we can learn that government support is critical for the establishment of research so that we can alter the perception that all medication is harmful to pregnant women.

Drugs in pregnancy and lactation.

Drug use during pregnancy and lactation is an almost inevitable event. Some of the drugs may have adverse effects on the baby on exposure. It is therefore necessary for the physician to be aware of the changes in pharmacokinetics and pharmacodynamics during pregnancy. Knowledge about the known teratogens and drugs safe to be used during pregnancy is essential on the part of the prescribing physician. There are many factors affecting drug passage into the milk and thus affecting the child in some cases. There are also some drugs affecting lactation. All this data needs to be carefully studied by the physician.

Study of embryotoxicity of mentha piperita L. during organogenesis in balb/c mice / Estudio de la embriotoxicidad de mentha piperita L. durante la organogénesis en ratones balb/c

Mentha piperita (Labiatae), commonly known as peppermint is a native Iranian herb which is used in folk medicine for various purposes. This study was carried out to reveal the teratogenic effect of Mentha piperita on mice fetuses. In this experimental study, pregnant Balb/c mice divided to four groups. Case group received 600 (treatment I) and 1200 (treatment II) mg/kg/day the hydroalcoholic extract of Mentha piperita during 6-15 of gestational days and one control group received normal saline during GD6-GD15 by gavages and other control group did not receive any matter during 6-15 of gestational days. Mice sacrificed at GD18 and embryos were collected. Macroscopic observation was done by stereomicroscope. 20 fetuses of each group were stained by Alizarin red-S and Alcian blue staining method. The Mean weight of fetuses decreased in treatment groups rather than control (P<0.05) but CRL there was no significant difference between treatments and controls groups. In the treatment I (600 mg/kg/day) and treatment II (1200 mg/kg/day), normal saline and control group, no gross congenital malformations were observed in fetuses. Treated fetuses also had no delayed bone ossification as determined by Alizarin red-S and Alcian blue staining method. This study showed that the hydroalcoholic extract of Mentha piperita (600 and 1200 mg/kg/day) has no teratogenic effect in mice fetuses if used continuously during embryonic period.

Mentha piperita (Labiatae), comúnmente conocida como menta, es una hierba nativa de Irán, que se utiliza en la medicina tradicional para diversos fines. Este estudio fue realizado para descubrir el efecto teratogénico de la Mentha piperita en fetos de ratones. Los ratones Balb/c preñadas fueron divididas en cuatro grupos. Los grupos recibieron 600 (tratamiento I) y 1200 (tratamiento II) mg/kg/día del extracto hidroalcohólico de Mentha piperita durante los días 6-15 de gestación (DG), mientras que un grupo control recibió solución salina normal durante los DG 6-15 vía oral y otro grupo control sano no recibió substancia durante los DG 6-15. Los ratones fueron sacrificados el DG 18, recolectando los fetos. Se realizó la observación macroscópica mediante un estereomicroscopio. 20 fetos de cada grupo se tiñeron por el método de rojo de alizarina-S y azul de Alcián. La media de peso de los fetos disminuyó más en los grupos de tratamientos que los controles (p <0,05), pero CRL no presentó diferencias significativas entre los tratamientos y los grupos control. En los fetos del grupos tratamiento I (600 mg/kg/día), tratamiento II (1200 mg/kg/día), solución salina normal y control no se observó ninguna malformación congénita grave. Los fetos tratados tampoco tuvieron osificación ósea retrasada según lo determinado por el método de rojo de alizarina-S y azul de Alcián. Este estudio mostró que el extracto hidroalcohólico de Mentha piperita (600 y 1200 mg/kg/día) no tiene efectos teratogénicos en fetos de ratones al ser utilizado continuamente durante el período embrionario.

Síndrome alcohólico fetal / Fetal Alcohol Syndrome

Recientemente se ha comentado mucho en la opinión pública el nivel del alcohol permitido legalmente, e incluso ha sido motivo de modificaciones en nuestra ley de tránsito, y es que el alcohol se ha convertido en la droga m s usada en el mundo, la cual genera problemas de tipo social, psicológico y de salud pública. El consumo de alcohol durante el embarazo puede causar defectos en varios órganos y sistemas del organismo, sobre todo si la madre lo ingiere en grandes cantidades, pero no está  demostrado que beber pocas cantidades del mismo sea inocuo. Los efectos que el consumo del mismo le produce a los embriones ha sido demostrado en la literatura desde 1973, sin embargo su uso y abuso siguen tan altos, como alta es la cantidad de ni¤os que nacen con síndrome alcohólico fetal cada día...

Effects of quinazolinones on Balb/C mice embryonic livers.

Heterocyclic compounds such as quinazolinones have variety of biological and pharmacological properties (anticancer, antiinflammatory, antimicrobial, antimalaria, etc.). Effects of two new quinazolinones viz., 4(3H)-quinazolinone-2-propyl-2-phenylethyl (QPPE) and 4(3H)quinazolinone-2-ethyl-2-phenylethyl (QEPE) were investigated on Balb/C mice embryos livers—the major organ of metabolism and detoxification of drugs and toxins. Histological and pathological studies demonstrated QPPE and QEPE as producers of toxic metabolites after biotransformation, creating necrosis, fatty changes, increase in the number of band cells, hepatocytes’ diameters and alkaline phosphatase, in addition to sinusoid dilation, hemorrhages and hyperemia. Transmission electron micrographs showed lipid droplets in hepatocytes’ cytoplasm, necrosis, vacuolization, cytoplasm disintegration, disfigured and swollen mitochondria, irregular and abnormal nuclei, nuclei with heterochromatin, condensed chromatins, myelin figures and autophages in injured hepatocytes. In conclusion, QPPE and QEPE make toxic components after biotransformation injuring membranes and creating inflammatory reactions. They also disturb metabolism of lipids pathways and cause the appearances of lipid droplets in hepatocytes.

Pregnancy Outcomes after Peri-conceptional Medication Exposure; 10 Years Experience: Study for Application of Reproductive Toxicity Information / 대한주산의학회잡지

PURPOSE: In Korea, pregnancy termination is frequently reported among women who took medications for an acute or chronic disease during pregnancy, for fear of teratogenic risk. We have previously shown that a service providing evidence-based information is helpful for women who week counseling to make a rational decision regarding their pregnancies. This study aimed to evaluate whether termination of pregnancy based on such perceptions, is justified using the 'DRug Exposure and risk Assessment in Moms' (DREAM) registry. METHODS: The study included 5,032 consenting pregnant women from the clinic and call center at the Korean Motherisk Program, from November 1999 to October 2008. The DREAM registry recorded the pregnancy outcomes (preterm birth, low birth weight, intrauterine fetal death, and congenital anomaly) of 3,328 women. RESULTS: Among women exposed to medications, time of exposure ranged from 3.5-4.6 weeks of gestation. There were 1,308 different drugs prescribed to these women. The drug most frequently prescribed was acetaminophen followed by chlorpheniramine maleate, and pseudoephedrine. There were 4.7% (n=156/3,328) women who underwent a voluntary abortion for fear of birth defects. We compared frequency of birth defects between exposed women and unexposed pregnant women in our institution during gestation. The frequency of major congenital malformations was 2.5% (n=74/2,977) in exposed group and 2.9% (n=75/2,573) in unexposed group (P=0.32). There was no statistically significant difference between exposed and control group in the rate of preterm births, intrauterine fetal death and low-birth weight babies. CONCLUSION: We did not observe increased risk of congenital malformations and adverse pregnancy outcomes in a population of pregnant women exposed to a variety of medications. Therefore these medications are not considered teratogen.

Antiteratogenic effects of caffeine on external, visceral, and skeletal anomalies of rat foetuses.

This study reports the antiteratogenic effects of caffeine on various anomalies on Charles Foster rat foetuses. The antiteratogenic activity of caffeine was assessed against two teratogens, cyclophosphamide and tolbutamide, both having different teratogenic potentials. External, visceral, and skeletal anomalies were assessed among the foetuses of both control and treated groups. Controls showed 2.5%, 0.0% and 5% external, visceral, and skeletal anomalies respectively. The offspring of caffeine-treated females showed 2.43% and 4.36% of external and visceral anomalies, while there were no skeletal anomalies. Foetuses of females treated with caffeine-tolbutamide combination showed 4.34% and 9.09% external and skeletal anomalies, which were comparatively higher than the control and caffeine-treated subgroups. However, no visceral anomalies were seen in this group. The offspring from dams treated with tolbutamide showed the highest incidence of external, visceral, and skeletal anomalies (10%, 4.6% and 13.04%) respectively. This preliminary study reveals that caffeine at dose levels of 12.5 mg/kg body weight has a protective effect on tolbutamide-treated foetuses. No foetuses could be obtained for the study of anomalies from the cyclophosphamide-treated dams because of total resorption.

Pregnancy Outcome after Exposure of Suspected Teratogens in Early Pregnancy / 대한산부인과학회잡지

OBJECTIVE: To compare the risk of congenital anomaly after exposure to suspected teratogens in early pregnancy with the known baseline risk to the geneneral population. METHODS: From September 1999 to August 2001, we counseled about the teratogenic risk of the fetus by relevant medical literatures after assessment of type, amount, and time of exposure for 302 pregnant women exposed to suspected teratogens such as drugs, radiation, alcohol, and cigarette smoking. We followed up on the pregnancy outcome with the rate of termination of pregnancy and incidence of congenital anomaly. RESULTS: Among a total of 302 cases, 253 pregnant women (83.8%) delivered, 15 (5%) were aborted spontaneously, 34 (11.3%) were terminated. 297 pregnant women (98.3%) were lastly exposed to drugs in mean 5.3 +/- 0.2 gestational weeks. Medicines taken were gastrointestinal drugs (23%), NSAIDs (18.3%), antibiotics (16.2%), antihistamines (10.8%) in the order of frequency. 74 pregnant women (24.5%) were exposed to radiation in mean 5.1 +/- 0.5 gestational weeks. The mean dose was 234.60 mrem. 113 pregnant women (37.3%) lastly drank alcohol in mean 4.5 +/- 0.4 gestational weeks and the mean amount was 1.55 oz. 36 pregnant women (11.9%) lastly smoked in mean 4.4 +/- 0.3 gestational weeks and the mean amount was 7.3 cigarettes/day. We found structural anomalies in 5 cases (Polydactylyl, Ileal agenesis, Both ear mass, Left ectopic kidney, Meningomyelocele) and 1 chromosomal abnormality case (Trisomy18). CONCLUSION: The rate of fetal structural anomaly was 2% in this study and is not more than baseline risk of general population. Therefore, evidence-based teratogenic risk counseling may prevent unnecessary pregnancy termination.

A Case of Fetal Alcohol Syndrome / 대한소아신경학회지

The teratogenic effects of alcohol have been recognized in fetal alcohol syndrome (FAS). FAS is a collection of signs and symptoms seen in some children exposed to alcohol in the prenatal period. An 8 month-old-male with an alcoholic mother was diagnosed as a case of FAS according to the following : 1) early-onset intrauterine growth retardation and persistent postnatal growth failure 2) psychomotor retardation 3) craniofacial dysmorphism. Early diagnosis and continued education are advantageous at all levels, benefiting both the individual and all of society. We present this case with a brief review of related literatures.

Experimental Study on the Effects of Cabarmazepine on the Neurulation in Early Chick Embryos and Immunohistochemical Staining for Fibronectin

Teratogenic effects of carbamazepine, an anticonvulsant, on the neurulation of the explanted early chick embryos were studied utilizing the punched-out filter paper explantation and culture technique. Fresh fertilized white leghorn hen eggs were incubated for 20-30 hours in an egg incubator. The Hamburger and Hamilton stage 4-11 chick embryos were explanted using the punched-out filter paper explantation technique and cultured in the CO2 cell culture incubator for 6-10 hours. They were randomly divided into a control group and an experimental group. The experimental group was divided into five subgroups according to the carbamazepine concentrations of 20micrometer 40micrometer 100micrometer 200micrometer 400micrometer with which the Ham's F-10 culture media were treated. The morphological characteristics and the incidences of teratogenic effects on the neurulation of early chick embryos in the control and experimental groups were compared with each other using the stereomicroscope and the electron microscope. The chick embryos of the same developmental stage were selected from the control and experimental groups, and immunohistochemical staining for fibronectin was done by the double-bridge PAP method. The results were as follows. 1) Of the 41 chick embryos cultured in the Ham's F-10 media without carbamazepine, 38 embryos(92.7%) developed normally, and 3 embryos(7.3%) developed abnormally. In contrast, among the 98 embryos cultured in the carbamazepine-treated media, 54 embryos(55.1%) developed abnormally. The frequent anomalous features were deformities of the neural folds, failure of neural tube closure, derangement of somites, and developmental arrest. 2) The frequency and severity of abnormal embryos increased in dose-dependent fashion. The embryos cultured in the media treated each with 20micrometer 40micrometer 100micrometer 200micrometer 400micrometer of carbamazepine developed abnormally in 12.5%, 21.1%, 60.0%, 81.0%, 86.4% respectively. 3) The scanning electron microscopic findings in neuroepithelial cells of abnormally developed embryos were flattened and smooth cellular surface with diminished surface blebs and microvilli, and size irregularity of the cells. On transmission electron microscope, underdevelopment of intracellular microfilaments was seen, but there was no significant change in the intracellular organelle. 4) The immunohistochemical stainability of the extracellular fibronectin at the basal side of the neuroepithelium was decreased in the carbamazepine-treated embryos.