Validation study of obstetric hospitalization data held on the Brazilian National Health System Hospital Information System for maternal morbidity surveillance: Brazil, 2021-2022.

OBJECTIVE: To validate the Brazilian National Health System Hospital Information System (SIH/SUS) for maternal morbidity surveillance. METHODS: This was a cross-sectional study conducted in 2021/2022, taking as its reference a national study on maternal morbidity (MMG) conducted in 50 public and 28 private hospitals; we compared SIH/SUS and MMG data for hospitalization frequency, reason and type of discharge and calculated sensitivity, specificity, positive and negative likelihood ratios for seven diagnoses and four procedures. RESULTS: Hospitalizations identified on SIH/SUS (32,212) corresponded to 95.1% of hospitalizations assessed by MMG (33,867), with lower recording on SIH/SUS (85.5%) for private hospitals [10,036 (SIH/SUS)]; 11,742 (MMG)]; compared to MMG, SIH/SUS had a lower proportion of hospitalizations due to "complications during pregnancy" (9.7% versus 16.5%) as well as under-recording of all diagnoses and procedures assessed, except "ectopic pregnancy". CONCLUSION: Better recording of diagnoses and procedures on SIH/SUS is essential for its use in maternal morbidity surveillance.

Essential Oil of Piper marginatum (Piperaceae) Against Monogeneans, and Its Hematological and Histopathological Effects on Colossoma macropomum.

PURPOSE: This study investigated the anthelmintic efficacy of therapeutic baths with the essential oil of Piper marginatum Jacq against the monogeneans Anacanthorus spathulatus Kritsky, Thatcher & Kayton, 1979, Notozothecium janauachensis Belmont-Jégu, Domingues & Laterça 2004, Mymarothecium boegeri Cohen & Kohn, 2005 and Linguadactyloides brinkmanni Thatcher & Krytsky, 1983 in Colossoma macropomum Cuvier, 1818, and its hematological and histopathological effects on this fish. METHODS: Short six therapeutic baths with 100 mg/L of the essential oil of P. marginatum and two control groups (water from the cultivation tank and water from the cultivation tank + 70% alcohol) were used for 20 min every two days. RESULTS: The therapeutic baths with 100 mg/L of the essential oil of P. marginatum had efficacy of 42.8% against monogeneans of C. macropomum gills. Toxicity was low for C. macropomum, because there were few physiological and histopathological changes that did not compromise the functioning of the gills of this fish. CONCLUSION: Short therapeutic baths with 100 mg/L of the essential oil of P. marginatum had low efficacy for controlling monogeneans in C. macropomum and thus cannot be recommended.

Desfechos neonatais adversos e fatores associados entre gestantes com diabetes mellitus gestacional e de risco habitual / Neonatal adverse outcomes and associated factors among pregnant women with gestational and usual risk of diabetes mellitus

Objetivo: Avaliar os desfechos neonatais adversos e fatores associados entre gestantes com diabetes mellitus gestacional e de risco gestacional habitual. Métodos: Estudo transversal, de âmbito nacional e de base hospitalar, conduzido entre fevereiro de 2011 e outubro de 2012. Foram excluídas as mulheres com gestações múltiplas ou natimortos. As informações foram coletadas via questionário padronizado, cartão de pré-natal e/ou prontuário. Resultados: Das 12.712 puérperas avaliadas, 1.915 tinham diabetes mellitus gestacional e 10.797 foram classificadas em risco gestacional habitual. Verificou-se que 74,1% das mulheres com diabetes receberam assistência pré-natal adequada/mais que adequada em relação a 65% das mulheres com risco gestacional habitual. Em contrapartida, o grupo das mulheres com diabetes foi composto em sua maioria por mulheres acima de 35 anos, com hipertensão prévia, excesso de peso pré-gestacional e ganho de peso gestacional excessivo, multíparas, com histórico de cesárea e abortos. Os desfechos "prematuridade" e "nascimento de recém-nascido grande para idade gestacional" foram superiores entre as mulheres com diabetes. Conclusão: As mulheres com diabete detiveram condições demográficas, antecedentes clínicos/obstétricos e desfechos neonatais mais desfavoráveis em relação às mulheres de risco gestacional habitual. Apesar disso, o pré-natal foi um dos fatores que exerceu extrema importância para que outros desfechos negativos (óbito neonatal e o Apgar<5) não fossem superiores entre as mulheres com diabete sem relação às de risco gestacional habitual. Portanto, reitera-se o papel do pré-natal entre as mulheres brasileiras, sobretudo as de alto risco gestacional.

Objective: To assess adverse neonatal outcomes and associated factors between pregnant women with gestational diabetes mellitus and usual gestational risk. Methods: Cross-sectional, nationwide, hospital-based study, conducted from February 2011 to October 2012. Women with multiple pregnancies or stillbirths were excluded. Information was collected using a standardized questionnaire, prenatal card and/or medical records. Results: Out of a total of 12,712 postpartum women evaluated, 1,915 had gestational diabetes mellitus and 10,797 were classified as usual gestational risk. It was observed that 74.1% of diabetics received adequate/more than adequate prenatal care compared to 65% of women with usual gestational risk. On the other hand, the group of diabetics was composed mostly of women over 35 years of age, with underlying hypertension, pre-gestational excess weight and excess gestational weight gain who were multiparous, with history of cesarean deliveries and abortions. The outcomes of "prematurity" and "birth of large-sized newborn" for the gestational age were higher among diabetics. Conclusion: Diabetic women had more unfavorable demographic conditions, clinical/obstetric history and neonatal outcomes compared to women with usual gestational risk. Nevertheless, prenatal care was a factor of extreme importance to prevent other negative outcomes (neonatal death and Apgar <5) to increase among diabetic women compared to those with usual gestational risk. Therefore, the role of prenatal care among Brazilian women is reiterated, especially among the high gestational risk women.

Metazoan parasite fauna of detritivorous and omnivorous fishes from Amapá Lake, in western Brazilian Amazon / Fauna parasitária de metazoários em peixes detritívoros e onívoros do Lago Amapá, na Amazônia Ocidental brasileira

Abstract Despite being an important component of the freshwater ecosystems and an important factor controlling wild fish populations, Amazonian fish parasites have been poorly studied. Here, we analyzed the fauna of metazoan parasites from 10 detritivorous and omnivorous fish species from Amapá Lake in the western Amazon. Of 159 fish specimens examined, 73.6% were parasitized by one or more species of metazoan parasites. A total of 5,260 parasites (24 Monogenea, 14 Nematoda, 10 Digenea, 2 Acanthocephala, and 6 Crustacea) were identified. Aggregated dispersion pattern of parasites was observed. There was a predominance of endohelminth species that presented a similar pattern regarding the level of component communities (i.e., a low species number, low diversity and dominance of a single species, mainly the digeneans and nematodes in their larval stages). Five species of parasites presented correlation with the body size of the hosts. In the fish community, the presence of endoparasites in the larval and adult stages suggests that these are intermediate, paratenic and definitive hosts, reflecting their detritivorous or omnivorous feeding habits. The trophic level and diet had an influence on the structuring of endohelminth communities and infracommunities. Lastly, 38% of the metazoan parasite species were new records for examined hosts.

Resumo Apesar de ser um importante componente dos ecossistemas de água doce e um importante fator controlador das populações naturais de peixes, os parasitos de peixes amazônicos ainda são pouco estudados. Foi analisada a fauna de parasitos metazoários em 10 espécies de peixes detritívoros e onívoros do Lago Amapá na Amazônia ocidental. Dos 159 espécimes de peixes examinados, 73,6% estavam parasitados por uma ou mais espécies de parasitos metazoários. Um total de 5.260 parasitos (24 Monogenea, 14 Nematoda, 10 Digenea, 2 Acanthocephala e 6 Crustacea) foram identificados. Houve um padrão de dispersão agregado de parasitos. Houve predominância de espécies de endohelmintos que apresentaram padrão semelhante quanto ao nível de comunidades componentes, ou seja, baixo número de espécies, baixa diversidade e dominância de uma única espécie, principalmente os digenéticos e nematoides em estágio larval. Cinco espécies de parasitos apresentaram correlação com o tamanho corporal dos hospedeiros. Na comunidade de peixes, a presença de endoparasitos em fase larval e adulta sugere que esses são hospedeiros intermediários, paratênicos e definitivos, refletindo seus hábitos alimentares detritívoros ou onívoros. O nível trófico e dieta influenciaram na estruturação das comunidades e infracomunidades de endohelmintos. Por fim, 38% das espécies de parasitos metazoários foram novos registros para os hospedeiros examinados.

Protocolo do Nascer no Brasil II: Pesquisa Nacional sobre Aborto, Parto e Nascimento / Protocolo del Nacer en Brasil II: Encuesta Nacional sobre Aborto, Parto y Nacimiento / Protocol of Birth in Brazil II: National Research on Abortion, Labor and Childbirth

Resumo: Com o passar do tempo, o Brasil vem apresentando avanços na assistência obstétrica em hospitais públicos e privados; no entanto, ainda existem pontos frágeis que necessitam de atenção. O Ministério da Saúde, ciente dessa necessidade, financiou a segunda versão da pesquisa Nascer no Brasil. Os objetivos gerais são: avaliar a assistência pré-natal, ao parto e nascimento, ao puerpério e ao aborto, comparando com os resultados do Nascer no Brasil I, e analisar os principais determinantes da morbimortalidade perinatal; avaliar a estrutura e processos assistenciais dos serviços de obstetrícia e neonatologia das maternidades; analisar os conhecimentos, atitudes e práticas de profissionais de saúde que prestam assistência ao parto e ao aborto; e identificar as principais barreiras e facilitadores para essa assistência no país. Com escopo nacional e amostra probabilística em dois estágios (1-hospitais e 2-mulheres), dividida em 59 estratos, foram selecionados 465 hospitais com total planejado de, aproximadamente, 24.255 mulheres, 2.205 por motivo de aborto e 22.050 por motivo de parto. A coleta de dados, realizada por meio de seis instrumentos eletrônicos, ocorre durante a internação hospitalar para o parto ou aborto, com duas ondas de seguimento, aos dois e quatro meses. Com o intuito de expandir o número de casos de morbidade materna grave, mortalidade materna e perinatal, três estudos caso controle foram incorporados ao Nascer no Brasil II. O trabalho de campo foi iniciado em novembro de 2021 com término previsto para 2023. Os resultados permitirão comparar a atenção atual ao parto e ao nascimento com a retratada no primeiro inquérito e, com isso, avaliar os avanços alcançados no decorrer desses 10 anos.

Resumen: Aunque Brasil ha presentado avances en la atención obstétrica en hospitales públicos y privados, todavía hay puntos débiles que necesitan atención. El Ministerio de Salud, consciente de esta necesidad, financió la segunda versión de la encuesta Nacer en Brasil. Los objetivos generales son: evaluar la atención prenatal, el parto y el nacimiento, el puerperio y el aborto, comparando con los resultados del Nacer en Brasil I, y analizar los principales determinantes de la morbimortalidad perinatal; evaluar la estructura y los procesos de atención de los servicios de obstetricia y neonatología en las maternidades; analizar los conocimientos, prácticas y actitudes de los profesionales de la salud que brindan atención para el parto y el aborto; e identificar las principales barreras y facilitadores para esta atención en el país. Tiene un alcance nacional y muestra probabilística en dos etapas (1-hospitales y 2-mujeres), la cual se dividió en 59 estratos; y se seleccionaron 465 hospitales con un total planificado de aproximadamente 24.255 mujeres, de las cuales 2.205 tuvieron procedimientos por aborto y 22.050 por parto. Para la recolección de datos se aplicó seis instrumentos electrónicos, que se realizó durante la hospitalización por parto o aborto, con dos rondas de seguimiento, a los dos y cuatro meses. Con el fin de ampliar el número de casos de morbilidad materna grave, mortalidad materna y perinatal, se incorporaron tres estudios de casos y controles en Nacer en Brasil II. El trabajo de campo comenzó en noviembre de 2021 y finalizará en 2023. Los resultados nos permitirán evaluar la atención al parto y al nacimiento actual con lo que se retrató en la primera encuesta, de esta manera se podrá evaluar los avances alcanzados a lo largo de estos 10 años.

Abstract: Brazil has made advances in obstetric care in public and private hospitals; however, weaknesses in this system still require attention. The Brazilian Ministry of Health, aware of this need, funded the second version of the Birth in Brazil survey. This study aimed to evaluate: prenatal, labor and birth, postpartum, and abortion care, comparing the results with those of Birth in Brazil I; and analyze the main determinants of perinatal morbidity and mortality; evaluate the care structure and processes of obstetrics and neonatology services in maternity hospitals; analyze the knowledge, practices, and attitudes of health professionals who provide birth and abortion care; and identify the main barriers and facilitators related to care of this nature in Brazil. With a national scope and a 2-stage probability sample: 1-hospitals and 2-women, stratified into 59 strata, 465 hospitals were selected with a total planned sample of around 24,255 women - 2,205 for abortion reasons and 22,050 for labor reasons. Data collection was conducted using six electronic instruments during hospital admission for labor or abortion, with two follow-up waves, at two and four months. In order to expand the number of cases of severe maternal morbidity, maternal and perinatal mortality, three case control studies were incorporated into Birth in Brazil II. The fieldwork began in November 2021 and is scheduled to end in 2023. It will allow a comparison between current labor and birth care results and those obtained in the first study and will evaluate the advances achieved in 10 years.

Mortalidade perinatal, morbidade materna grave e near miss materno: protocolo de um estudo integrado à pesquisa Nascer no Brasil II / Mortalidad perinatal, morbilidad materna severa y near miss materna: protocolo de un estudio integrado con la encuesta Nacer en Brasil II / Perinatal mortality, severe maternal morbidity and maternal near miss: protocol of a study integrated with the Birth in Brazil II survey

Resumo: O Brasil apresenta elevada morbimortalidade materna e perinatal. Casos de morbidade materna grave, near miss materno e óbitos perinatais são indicadores importantes de saúde e compartilham dos mesmos determinantes sociais, tendo estreita relação com as condições de vida e qualidade da assistência perinatal. Este artigo pretende apresentar o protocolo de estudo que visa estimar a taxa de mortalidade perinatal e a incidência de morbidade materna grave e near miss materno no país, assim como identificar seus determinantes. Trata-se de estudo transversal integrado à pesquisa Nascer no Brasil II, realizada entre 2021 e 2023. Serão incluídas neste estudo 155 maternidades públicas, mistas e privadas, com mais de 2.750 partos por ano, participantes do Nascer no Brasil II. Nessas maternidades, será realizada coleta retrospectiva de dados de prontuário materno e neonatal de todas as internações ocorridas num período de 30 dias, com aplicação de uma ficha de triagem para identificação de casos de morbidade materna e de óbito perinatal. Dados de prontuário de todos os casos identificados serão coletados após a alta hospitalar, utilizando instrumento padronizado. Casos de morbidade materna grave e near miss materno serão classificados por meio da definição adotada pela Organização Mundial da Saúde. Será estimada a taxa de mortalidade perinatal e a incidência de morbidade materna grave e near miss materno. Os casos serão comparados a controles obtidos na pesquisa Nascer no Brasil II, pareados por hospital e duração da gestação, visando a identificação de fatores associados aos desfechos negativos. Espera-se que os resultados deste artigo contribuam para o conhecimento sobre a morbidade materna e a mortalidade perinatal no país, bem como para a elaboração de estratégias de melhoria do cuidado.

Resumen: Brasil tiene una alta morbimortalidad materna y perinatal. Los casos de morbilidad materna severa, maternal near miss y muertes perinatales son importantes indicadores de salud y comparten los mismos determinantes sociales, y tienen una estrecha relación con las condiciones de vida y la calidad de la asistencia perinatal. Este artículo pretende presentar el protocolo de estudio que tiene como objetivo estimar la tasa de mortalidad perinatal y la incidencia de morbilidad materna severa y maternal near miss en el país, así como identificar sus determinantes. Se trata de un estudio transversal integrado a la investigación Nacer en Brasil II, realizada entre el 2021 y el 2023. Este estudio incluirá 155 maternidades públicas, mixtas y privadas, con más de 2.750 partos al año, que participan en el Nacer en Brasil II. En estas maternidades, se realizará una recopilación retrospectiva de datos de las historias clínicas maternas y neonatales de todas las hospitalizaciones ocurridas en un período de 30 días, con la aplicación de un formulario de triaje para identificar casos de morbilidad materna y de muerte perinatal. Los datos de las historias clínicas de todos los casos identificados se recopilarán tras el alta hospitalaria, mediante un instrumento estandarizado. Los casos de morbilidad materna severa y maternal near miss se clasificarán por medio de la definición adoptada por la Organización Mundial de la Salud. Se estimará la tasa de mortalidad perinatal y la incidencia de morbilidad materna severa y maternal near miss. Los casos se compararán con los controles obtenidos en el estudio Nacer en Brasil II, emparejados por hospital y duración del embarazo, para identificar factores asociados con desenlaces negativos. Se espera que los resultados de este artículo contribuyan al conocimiento sobre la morbilidad materna y la mortalidad perinatal en el país, así como a la elaboración de estrategias para mejorar el cuidado.

Abstract: Brazil presents high maternal and perinatal morbidity and mortality. Cases of severe maternal morbidity, maternal near miss, and perinatal deaths are important health indicators and share the same determinants, being closely related to living conditions and quality of perinatal care. This article aims to present the study protocol to estimate the perinatal mortality rate and the incidence of severe maternal morbidity and maternal near miss in the country, identifying its determinants. Cross-sectional study integrated into the research Birth in Brazil II, conducted from 2021 to 2023. This study will include 155 public, mixed and private maternities, accounting for more than 2,750 births per year, participating in the Birth in Brazil II survey. We will collect retrospective data from maternal and neonatal records of all hospitalizations within a 30-day period in these maternities, applying a screening form to identify cases of maternal morbidity and perinatal deaths. Medical record data of all identified cases will be collected after hospital discharge, using a standardized instrument. Cases of severe maternal morbidity and maternal near miss will be classified based on the definition adopted by the World Health Organization. The perinatal deaths rate and the incidence of severe maternal morbidity and maternal near miss will be estimated. Cases will be compared to controls obtained in the Birth in Brazil II survey, matched by hospital and duration of pregnancy, in order to identify factors associated with negative outcomes. Results are expected to contribute to the knowledge on maternal morbidity and perinatal deaths in Brazil, as well as the development of strategies to improve care.

Mortalidade materna: protocolo de um estudo integrado à pesquisa Nascer no Brasil II / Mortalidad materna: protocolo de un estudio integrado a la encuesta Nacer en Brasil II / Maternal mortality: protocol of a study integrated to the Birth in Brazil II survey

Resumo: O Estudo da Mortalidade Materna conduz uma investigação hospitalar dos óbitos maternos ocorridos em 2020/2021 nas maternidades amostradas na pesquisa Nascer no Brasil II, com os seguintes objetivos: estimar o sub-registro da mortalidade materna e calcular um fator de correção e a razão de mortalidade materna (RMM) corrigida; validar as causas de mortalidade materna informadas na declaração de óbito (DO); e analisar os fatores associados à mortalidade materna. O Nascer no Brasil II inclui aproximadamente 24.255 puérperas distribuídas em 465 hospitais públicos, privados e mistos com ≥ 100 partos de nascidos vivos/ano nas cinco macrorregiões do país. Os dados do Estudo da Mortalidade Materna serão preenchidos utilizando o mesmo questionário do Nascer no Brasil II, a partir da consulta aos prontuários hospitalares. Obstetras treinados preencherão uma nova DO (DO refeita) a partir de análise independente desse questionário, comparando aos dados oficiais. A base de dados dos óbitos investigados será relacionada com os óbitos constantes no Sistema de Informações sobre Mortalidade do Ministério da Saúde, permitindo a estimativa do sub-registro e cálculo da RMM corrigida. Para o cálculo da confiabilidade das causas de morte, serão utilizados os testes kappa e kappa ajustado à prevalência com intervalo de 95% de confiança. Um estudo de caso-controle para estimar os fatores de risco para mortalidade materna será desenvolvido com os óbitos investigados (casos) e os controles obtidos na pesquisa Nascer no Brasil II, utilizando-se modelos de regressão logística múltipla condicional. Espera-se contribuir para a correção do sub-registro da mortalidade materna e para a melhor compreensão dos fatores determinantes da persistência de RMM elevada no Brasil.

Resumen: El Estudio de Mortalidad Materna evalúa las muertes maternas ocurridas en 2020-2021 en las muestras de maternidades del encuesta Nacer en Brasil II con los objetivos de estimar el subregistro de mortalidad materna y calcular el factor de corrección y la tasa de mortalidad materna corregida (TMM); validar las causas de mortalidad materna reportadas en el certificado de defunción (CD); y analizar los factores asociados a la mortalidad materna. La Nacer en Brasil II incluye aproximadamente 24.250 mujeres puerperales, distribuidas en 465 hospitales públicos, privados y mixtos con ≥ 100 nacidos vivos/año en las cinco macrorregiones de Brasil. Los datos de Estudio de Mortalidad Materna se completarán con la información del cuestionario Nacer en Brasil II a partir de una búsqueda de los registros médicos hospitalarios. Los obstetras capacitados completarán un nuevo CD (CD rehecho) desde un análisis independiente de este cuestionario, comparándolo con los datos oficiales. La base de datos de muertes investigadas se relacionará con las muertes que constan en el Sistema de Informaciones sobre la Mortalidad del Ministerio de Salud para permitir la estimación del subregistro y el cálculo de la TMM corregida. Para calcular la exactitud de las causas de muerte, se utilizarán las pruebas kappa y kappa ajustada a la prevalencia con un intervalo de 95% de confianza. Un estudio de casos y controles se aplicará para estimar los factores de riesgo de las mortalidad materna con las muertes investigadas (casos) y los controles obtenidos en el estudio Nacer en Brasil II utilizando modelos de regresión logística múltiple condicional. Se espera que este estudio pueda contribuir a la corrección del subregistro de la mortalidad materna y a una mejor comprensión de los determinantes de la persistencia de alta TMM en Brasil.

Abstract: The Maternal Mortality Study conducts a hospital investigation of maternal deaths that occurred in 2020/2021 in the maternity hospitals sampled by the Birth in Brazil II survey, with the following objectives: estimate the maternal mortality underreporting; calculate a correction factor and the corrected (MMR); validate the causes of maternal mortality reported in the death certificate (DC); and analyze the factors associated with maternal mortality. The Birth in Brazil II includes approximately 24,250 puerperal women distributed in 465 public, private, and mixed hospitals with ≥ 100 live births/year in the five macroregions of Brazil. The Maternal Mortality Study data will be completed using the same Birth in Brazil II questionnaire, from the consultation of hospital records. Trained obstetricians will fill out a new DC (redone DC) from independent analysis of this questionnaire, comparing it to official data. The database of the investigated deaths will be related to the deaths listed in the Mortality Information System of the Brazilian Ministry of Health, allowing the estimation of underreporting and calculation of the corrected MMR. To calculate the reliability of the causes of death, the kappa test and prevalence-adjusted kappa with 95% confidence interval will be used. A case-control study to estimate the risk factors for maternal mortality will be developed with the investigated deaths (cases) and the controls obtained in the Birth in Brazil II survey, using conditional multiple logistic regression models. We expect this research to contribute to the correction of the underreporting of maternal mortality and to a better understanding of the determinants of the persistence of a high MMR in Brazil.

Prevalence and factors associated with the perception of perineal laceration: a cross-sectional study with data from the Nascer no Brasil Survey, 2011 and 2012 / Prevalencia y factores asociados a la percepción de laceración perineal: estudio transversal con datos de la Encuesta Nascer no Brasil, 2011 y 2012 / Prevalência e fatores associados à percepção da laceração perineal: estudo transversal com dados do Inquérito Nascer no Brasil, 2011 e 2012

Abstract Objective: To describe the prevalence of perineal laceration, based on the self-reported perception of postpartum women, and to analyze factors associated with its occurrence in Brazil. Methods: This was a cross-sectional study conducted with 23,894 postpartum women, excluding twin pregnancies, cesarean sections, and births with episiotomies, between 2011 and 2012. Prevalence ratios (PR) and 95% confidence intervals (95%CI) of association between the event and maternal, fetus/newborn, obstetric and clinical management characteristics were estimated in hierarchical Poisson regression models. Results: Out of 4,606 postpartum women, 49.5% (95%CI 46.1;42.9) self-reported perineal laceration. Being an adolescent (PR = 1.12; 95%CI 1.02;1.25), primipara (PR = 1.47; 95%CI 1.33;1.63), having had excessive gestational weight gain (PR = 1.17; 95%CI 1.07;1.29) and having undergone the Kristeller maneuver (PR = 1.18; 95%CI 1.08;1.29) increased the proportion of the outcome. Conclusion: The results found call for prenatal care and adjustments to childbirth care so as to be in accordance with current recommendations.

Resumen Objetivo: Describir la prevalencia de laceración perineal, a partir de la percepción autoinformada de puérperas, y analizar los factores asociados a su aparición en Brasil. Métodos: Estudio transversal entre 2011 y 2012, con 23.894 puérperas, excluyendo embarazos gemelares, cesáreas y partos con episiotomías. Se estimaron razones de prevalencia (RP) e intervalos de confianza del 95% (IC95%) de la asociación entre el evento y las características maternas, feto/recién nacido, obstétricas y de manejo clínico en modelos de regresión jerárquica de Poisson. Resultados: Entre 4.606 mujeres en posparto, el 49,5%(IC95%:46,1;42,9) informó laceración perineal. Ser adolescente (RP = 1,12; IC95% 1,02;1,25), primipara (RP = 1,47; IC95% 1,33;1,63), haber tenido aumento excesivo de peso gestacional (RP = 1,17; IC95% 1,07;1,29) y haber sido sometido a la maniobra de Kristeller (RP = 1,18; IC95% 1,08;1,29) aumentó la proporción de resultados. Conclusión: Los resultados encontrados requieren atención prenatal y ajustes en la atención del parto de acuerdo con las recomendaciones actuales.

Resumo Objetivo: Descrever a prevalência da laceração perineal segundo a percepção autorrelatada da puérpera, e analisar os fatores associados à sua ocorrência no Brasil. Métodos: Estudo transversal conduzido em 23.894 puérperas, excluindo-se gestações gemelares, cesarianas e partos com episiotomias entre 2011 e 2012. Razões de prevalência (RP) e intervalos de confiança de 95% (IC95%) da associação entre o evento e as características maternas, feto/recém-nato, obstétricas e manejo clínico foram estimadas em modelos de regressão de Poisson hierarquizados. Resultados: Entre 4.606 puérperas, 49,5% (IC95% 46,1;42,9) autorrelataram laceração perineal. Ser adolescente (RP = 1,12; IC95% 1,02;1,25), primípara (RP = 1,47; IC95% 1,33;1,63), ter tido ganho de peso gestacional excessivo (RP = 1,17; IC95% 1,07;1,29) e ter sido submetida à manobra de Kristeller (RP = 1,18; IC95% 1,08;1,29) elevaram a proporção do desfecho. Conclusão: Os resultados encontrados demandam atenção pré-natal e adequações na assistência ao parto conforme recomendações vigentes.

Validation study of obstetric hospitalization data held on the Brazilian National Health System Hospital Information System for maternal morbidity surveillance: Brazil, 2021-2022 / Estudio de validación de internaciones obstétricas en el Sistema de Información Hospitalaria del Sistema Único de Salud para vigilancia de la morbilidad materna: Brasil, 2021-2022 / Estudo de validação das internações obstétricas no Sistema de Informações Hospitalares do Sistema Único de Saúde para a vigilância da morbidade materna: Brasil, 2021-2022

ABSTRACT Objective To validate the Brazilian National Health System Hospital Information System (SIH/SUS) for maternal morbidity surveillance. Methods This was a cross-sectional study conducted in 2021/2022, taking as its reference a national study on maternal morbidity (MMG) conducted in 50 public and 28 private hospitals; we compared SIH/SUS and MMG data for hospitalization frequency, reason and type of discharge and calculated sensitivity, specificity, positive and negative likelihood ratios for seven diagnoses and four procedures. Results Hospitalizations identified on SIH/SUS (32,212) corresponded to 95.1% of hospitalizations assessed by MMG (33,867), with lower recording on SIH/SUS (85.5%) for private hospitals [10,036 (SIH/SUS)]; 11,742 (MMG)]; compared to MMG, SIH/SUS had a lower proportion of hospitalizations due to "complications during pregnancy" (9.7% versus 16.5%) as well as under-recording of all diagnoses and procedures assessed, except "ectopic pregnancy". Conclusion Better recording of diagnoses and procedures on SIH/SUS is essential for its use in maternal morbidity surveillance.

RESUMEN Objetivo Validar el Sistema de Información Hospitalaria del Sistema Único de Salud (SIH/SUS) para vigilancia de la morbilidad materna. Métodos Estudio transversal, 2021/2022, utilizando como referencia datos de estudio nacional de morbilidad materna (MMG) realizado en 50 hospitales públicos y 28 privados; comparando: frecuencia, motivo y tipo de alta de internaciones en SIH/SUS y MMG y calculando sensibilidad, especificidad y razones de probabilidad positivos y negativos para siete diagnósticos y cuatro procedimientos. Resultados Las internaciones identificadas en SIH/SUS (32.212) correspondieron al 95,1% de internaciones evaluadas en MMG (33.867), observándose menor registro en SIH/SUS (85,5%) en hospitales privados [10.036 (SIH/SUS)]; 11.742 (MMG)]; comparado con MMG, SIH/SUS tuvo menor proporción de internaciones por "complicaciones durante el embarazo" (9,7% vs 16,5%), así como subregistro de todos los diagnósticos y procedimientos evaluados, excepto "embarazo ectópico". Conclusión Mejor registro de diagnósticos y procedimientos en SIH/SUS es fundamental para su uso en la vigilancia de la morbilidad materna.

RESUMO Objetivo Validar o Sistema de Informações Hospitalares do Sistema Único de Saúde (SIH/SUS) para vigilância da morbidade materna. Métodos Estudo transversal, de 2021-2022, utilizando-se como referência dados de estudo nacional sobre morbidade materna (MMG) realizado em 50 hospitais públicos e 28 privados; foram comparados frequência, motivo e tipo de saída das internações, segundo SIH/SUS e MMG, e calculadas sensibilidade, especificidade, razão de verossimilhança positiva e negativa para sete diagnósticos e quatro procedimentos. Resultados Internações identificadas no SIH/SUS (32.212) corresponderam a 95,1% das internações avaliadas no MMG (33.867), tendo-se observado menor registro no SIH/SUS (85,5%) em hospitais privados [10.036 (SIH/SUS); 11.742 (MMG)]; comparado ao MMG, o SIH/SUS apresentou menor proporção de internações por "intercorrências na gestação" (9,7% versus 16,5%), bem como sub-registro de todos os diagnósticos e procedimentos avaliados, exceto "gestação ectópica". Conclusão Melhor registro de diagnósticos e procedimentos no SIH/SUS é essencial para sua utilização na vigilância da morbidade materna.

Maternal health surveillance panel: a tool for expanding epidemiological surveillance of women's health and its determinants / Painel de vigilância da saúde materna: uma ferramenta para ampliação da vigilância epidemiológica da saúde das mulheres e seus determinantes

ABSTRACT Objective: To present the methodology used in the development of two products for maternal health surveillance and its determinants and discuss their possible uses. Methods: Based on a theoretical model of the determinants of maternal death and databases of Brazilian health information systems, two free products were developed: an interactive panel "surveillance of maternal health" and an educational material "Aparecida: a story about the vulnerability of Brazilian women to maternal death", both available on the website of the Brazilian Obstetric Observatory. Results: More than 30 indicators were calculated for the period 2012-2020, containing information on socioeconomic conditions and access to health services, reproductive planning, prenatal care, delivery care, conditions of birth and maternal mortality and morbidity. The indicators related to severe maternal morbidity in public hospitalizations stand out, calculated for the first time for the country. The panel allows analysis by municipality or aggregated by health region, state, macro-region and country; historical series analysis; and comparisons across locations and with benchmarks. Information quality data are presented and discussed in an integrated manner with the indicators. In the educational material, visualizations with national and international data are presented, aiming to help in the understanding of the determinants of maternal death and facilitate the interpretation of the indicators. Conclusion: It is expected that the two products have the potential to expand epidemiological surveillance of maternal health and its determinants, contributing to the formulation of health policies and actions that promote women's health and reduce maternal mortality.

RESUME Objetivo: Apresentar a metodologia utilizada no desenvolvimento de dois produtos para a vigilância da saúde materna e seus determinantes e discutir as suas possíveis utilizações. Métodos: A partir de modelo teórico dos determinantes do óbito materno e bases de dados dos sistemas de informação em saúde brasileiros, foram desenvolvidos dois produtos gratuitos: um painel interativo denominado "Vigilância da saúde materna" e um material educativo chamado "Aparecida: uma história sobre a vulnerabilidade da mulher brasileira à morte materna", ambos disponíveis no site do Observatório Obstétrico Brasileiro. Resultados: Foram calculados mais de 30 indicadores para o período 2012-2020, contendo informações sobre condições socioeconômicas e de acesso a serviços de saúde, planejamento reprodutivo, assistência pré-natal, assistência ao parto, condições de nascimento e mortalidade e morbidade materna. Destacam-se os indicadores relacionados à morbidade materna grave em internações públicas, calculados pela primeira vez para o país. O painel permite análises por município ou agregadas por região de saúde, unidade da federação, macrorregião e país; análises de série histórica; e comparações entre localidades e com padrões de referência. Dados de qualidade da informação são apresentados e discutidos de forma integrada aos indicadores. No material educativo, visualizações com dados nacionais e internacionais são apresentadas, visando auxiliar na compreensão dos determinantes do óbito materno e facilitar a interpretação dos indicadores. Conclusão: Espera-se que os produtos tenham o potencial de ampliar a vigilância epidemiológica da saúde materna e seus determinantes, contribuindo para a formulação de políticas e ações de saúde que promovam a saúde das mulheres e reduzam a mortalidade materna.

Essential oil of Piper hispidum (Piperaceae) has efficacy against monogeneans, and effects on hematology and gill histology of Colossoma macropomum.

This study investigated for the first time the effectiveness of therapeutic baths with essential oil (EO) of Piper hispidum against monogeneans Anacanthorus spathulatus, Notozothecium janauachensis, Mymarothecium boegeri and Linguadactyloides brinkmanni from the gills of Colossoma macropomum, as well as the hematological and histological effects on this fish. In therapeutic baths, 100 mg/L of P. hispidum essential oil and two control groups (water from the culture tank and water from the culture tank with 70% alcohol) were exposed for 1 h/day, with intervals of 48 hours for 3 days, and three replicates each were used. Therapeutic baths with 100 mg/L of P. hispidum essential oil had an efficacy of 78.6% against monogeneans. The toxicity of this essential oil was low, since there were a few physiological and histopathological changes that did not compromise the functioning of the gills of the fish. Therefore, 100 mg/L of P. hispidum essential oil was effective for controlling monogeneans in C. macropomum, when short therapeutic baths were used without compromising the health of the exposed fish.

Structure and thermal behavior of biobased vitrimer of lactic acid and epoxidized canola oil.

Biobased vitrimers were obtained from epoxidized canola oil (ECO) and lactic acid (LA) using zinc acetate (ZnAc) and ZnAl-layered double hydroxide (ZnAl) in the proportions of 1 and 2 wt% as transesterification catalysts. Reactions containing ECO and LA showed an average enthalpy of cure of approximately 85 mJ mg-1 and materials cured in the presence of the catalysts showed lower enthalpies of cure and decrease in the material gel content. ECO-LA reaction generated materials with rubber-like properties with Tg ranging from -15 °C to -23 °C, where the material without a catalyst showed the higher Tg value. The presence of catalysts gave the material vitrimer properties, with the softening point associated with transesterification reactions and topology freezing temperature transition at temperatures (Tv) between 195-235 °C.

Efficacy of Carapa guianensis oil (Meliaceae) against monogeneans infestations: a potential antiparasitic for Colossoma macropomum and its effects in hematology and histopathology of gills.

This study evaluated the efficacy of therapeutic baths with Carapa guianensis (andiroba) oil against monogeneans of Colossoma macropomum (tambaqui), as well as the hematological and histological effects on fish. Among the fatty acids identified in C. guianensis oil, oleic acid (53.4%) and palmitic acid (28.7%) were the major compounds, and four limonoids were also identified. Therapeutic baths of 1 hour were performed for five consecutive days, and there was no fish mortality in any of the treatments. Therapeutic baths using 500 mg/L of C. guianensis oil had an anthelmintic efficacy of 91.4% against monogeneans. There was increase of total plasma protein and glucose, number of erythrocytes, thrombocytes, leukocytes, lymphocytes and number of monocytes and decrease in mean corpuscular volume. Histological changes such as epithelium detachment, hyperplasia, lamellar fusion and aneurysm were found in the gills of tambaqui from all treatments, including controls with water of culture tank and water of culture tank plus iso-propyl alcohol. Therapeutic baths with 500 mg/L of C. guianensis oil showed high efficacy and caused few physiological changes capable of compromising fish gill function. Results indicate that C. guianensis oil has an anthelmintic potential for control and treatment of infections by monogeneans in tambaqui.

PREPARE: A Stepped-Wedge Cluster-Randomized Trial to Evaluate Whether Risk Stratification Can Reduce Preterm Deliveries Among Patients With Suspected or Confirmed Preterm Preeclampsia.

BACKGROUND: Early delivery in preterm preeclampsia may reduce the risks for the patient, but consequences of prematurity may be substantial for the baby. This trial evaluated whether the implementation of a risk stratification model could safely reduce prematurity. METHODS: This was a stepped-wedge cluster-randomized trial in seven clusters. Patients presenting with suspected or confirmed preeclampsia between 20+0 and 36+6 gestational weeks were considered eligible. At the start of the trial, all centers were allocated in the preintervention phase, and patients enrolled in this phase were managed according to local treatment guidance. Subsequently, every 4 months, 1 randomly allocated cluster transitioned to the intervention. Patients enrolled in the intervention phase had sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio and preeclampsia integrated estimate of risk assessments performed. If sFlt-1/PlGF ≤38 and preeclampsia integrated estimate of risk <10%, patients were considered low risk and clinicians received recommendations to defer delivery. If sFlt-1/PlGF >38 and preeclampsia integrated estimate of risk ≥10%, patients were considered not low risk, and clinicians received recommendations to increase surveillance. The primary outcome was the proportion of patients with preterm preeclampsia delivered prematurely out of total deliveries. RESULTS: Between March 25, 2017 and December 24, 2019, 586 and 563 patients were analyzed in the intervention and usual care groups, respectively. The event rate was 1.09% in the intervention group, and 1.37% in the usual care group. After prespecified adjustments for variation between and within clusters over time, the adjusted risk ratio was 1.45 ([95% CI, 1.04-2.02]; P=0.029), indicating a higher risk of preterm deliveries in the intervention group. Post hoc analysis including calculation of risk differences did not show evidence of statistical differences. Abnormal sFlt-1/PlGF was associated with a higher rate of identifying preeclampsia with severe features. CONCLUSIONS: The introduction of an intervention based on biomarkers and clinical factors for risk stratification did not lead to reductions in preterm deliveries. Further training on the interpretation of disease severity in preeclampsia and the development of additional risk stratification is needed before adoption into clinical practice. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03073317.

Brazilian Black Women are at Higher Risk for COVID-19 Complications: An Analysis of REBRACO, a National Cohort / Mulheres negras brasileiras correm maior risco de complicações da COVID-19: uma análise do REBRACO, uma coorte nacional

Abstract Objective To evaluate the impact of the race (Black versus non-Black) on maternal and perinatal outcomes of pregnant women with COVID-19 in Brazil. Methods This is a subanalysis of REBRACO, a Brazilian multicenter cohort study designed to evaluate the impact of COVID-19 on pregnant women. From February2020 until February 2021, 15 maternity hospitals in Brazil collected data on women with respiratory symptoms. We selected all women with a positive test for COVID-19; then, we divided them into two groups: Black and non-Black women. Finally, we compared, between groups, sociodemographic, maternal, and perinatal outcomes. We obtained the frequency of events in each group and compared them using X2 test; p-values < 0.05 were considered significant. We also estimated the odds ratio (OR) and confidence intervals (CI). Results 729 symptomatic women were included in the study; of those, 285 were positive for COVID-19, 120 (42.1%) were Black, and 165 (57.9%) were non-Black. Black women had worse education (p = 0.037). The timing of access to the health system was similar between both groups, with 26.3% being included with seven or more days of symptoms. Severe acute respiratory syndrome (OR 2.22 CI 1.17-4.21), intensive care unit admission (OR 2.00 CI 1.07-3.74), and desaturation at admission (OR 3.72 CI 1.41-9.84) were more likely to occur among Black women. Maternal death was higher among Black women (7.8% vs. 2.6%, p = 0.048). Perinatal outcomes were similar between both groups. Conclusion Brazilian Black women were more likely to die due to the consequences of COVID-19.

Resumo Objetivo Avaliar o impacto da raça (negra versus não negra) nos desfechos maternos e perinatais de gestantes com COVID-19 no Brasil. Métodos Esta é uma subanálise da REBRACO, um estudo de coorte multicêntrico brasileiro desenhado para avaliar o impacto da COVID-19 em mulheres grávidas. De fevereiro de 2020 a fevereiro de 2021, 15 maternidades do Brasil coletaram dados de mulheres com sintomas respiratórios. Selecionamos todas as mulheres com teste positivo para COVID-19; em seguida, as dividimos em dois grupos: mulheres negras e não negras. Finalmente, comparamos, entre os grupos, os resultados sociodemográficos, maternos e perinatais. Obtivemos a frequência dos eventos em cada grupo e comparamos usando o teste X2; Valores de p <0,05 foram considerados significativos. Também estimamos o odds ratio (OR) e os intervalos de confiança (IC). Resultados 729 mulheres sintomáticas foram incluídas no estudo; desses, 285 foram positivos para COVID-19, 120 (42,1%) eram negros e 165 (57,9%) não eram negros. As mulheres negras apresentaram pior escolaridade (p = 0,037). O tempo de acesso ao sistema de saúde foi semelhante entre os dois grupos, com 26,3% incluídos com sete ou mais dias de sintomas. Síndrome respiratória aguda grave (OR 2,22 CI 1,17-4,21), admissão em unidade de terapia intensiva (OR 2,00 CI 1,07-3,74) e dessaturação na admissão (OR 3,72 CI 1,41-9,84) foram mais prováveis de ocorrer entre mulheres negras. A mortalidade materna foi maior entre as negras (7,8% vs. 2,6%, p = 0,048). Os resultados perinatais foram semelhantes entre os dois grupos. Conclusão Mulheres negras brasileiras tiveram maior probabilidade de morrer devido às consequências da COVID-19.

Protective Effects of Kefir Against Unpredictable Chronic Stress Alterations in Mice Central Nervous System, Heart, and Kidney.

Kefir is a probiotic mixture with anxiolytic and antioxidant properties. Chronic stress can lead to anxiety disorders and increase oxidative damage in organs such as the heart and kidney. In this study, we examined whether kefir ameliorates the anxiety-like behavior of mice submitted to chronic unpredictable stress (CUS) by modulating brain-derived neurotrophic factor (BDNF) and corticosterone levels and whether kefir modifies the oxidative parameters in the heart and kidney of mice. Male Swiss mice received kefir (0.3 mL/100 g/day) or milk for 30 days (gavage). On the 10th day, the mice were submitted to CUS. Behavioral analysis was performed using the elevated plus maze and forced swimming tests. BDNF levels were analyzed in brain tissues. Heart and kidney superoxide dismutase (SOD), catalase, glutathione (GSH), thiobarbituric acid reactive substances (TBARS), 3-nitrotyrosine, metalloproteinase-2 (MMP-2), and plasma corticosterone were evaluated. Kefir reverted the CUS-induced decrease in the time spent in the open arms, the increase in grooming frequency, and decrease in the head dipping frequency, but not the reduced immobility time. CUS decreased the cerebellum BDNF levels and increased corticosterone levels, which were restored by Kefir. Neither catalase and SOD activities nor GSH, TBARS, 3-nitrotyrosine, and MMP-2 were modified by CUS in the heart. In the kidney, CUS increased 3-nitrotyrosine and MMP-2. Kefir increased the antioxidant defense in the heart and kidney of control and CUS mice. These results suggest that kefir ameliorated CUS-induced anxiety-like behavior by modulating brain BDNF and corticosterone levels. Kefir also increased the antioxidant defense of mice heart and kidney.

In Vitro and In Vivo Cell-Interactions with Electrospun Poly (Lactic-Co-Glycolic Acid) (PLGA): Morphological and Immune Response Analysis.

Random electrospun three-dimensional fiber membranes mimic the extracellular matrix and the interfibrillar spaces promotes the flow of nutrients for cells. Electrospun PLGA membranes were analyzed in vitro and in vivo after being sterilized with gamma radiation and bioactivated with fibronectin or collagen. Madin-Darby Canine Kidney (MDCK) epithelial cells and primary fibroblast-like cells from hamster's cheek paunch proliferated over time on these membranes, evidencing their good biocompatibility. Cell-free irradiated PLGA membranes implanted on the back of hamsters resulted in a chronic granulomatous inflammatory response, observed after 7, 15, 30 and 90 days. Morphological analysis of implanted PLGA using light microscopy revealed epithelioid cells, Langhans type of multinucleate giant cells (LCs) and multinucleated giant cells (MNGCs) with internalized biomaterial. Lymphocytes increased along time due to undegraded polymer fragments, inducing the accumulation of cells of the phagocytic lineage, and decreased after 90 days post implantation. Myeloperoxidase+ cells increased after 15 days and decreased after 90 days. LCs, MNGCs and capillaries decreased after 90 days. Analysis of implanted PLGA after 7, 15, 30 and 90 days using transmission electron microscope (TEM) showed cells exhibiting internalized PLGA fragments and filopodia surrounding PLGA fragments. Over time, TEM analysis showed less PLGA fragments surrounded by cells without fibrous tissue formation. Accordingly, MNGC constituted a granulomatous reaction around the polymer, which resolves with time, probably preventing a fibrous capsule formation. Finally, this study confirms the biocompatibility of electrospun PLGA membranes and their potential to accelerate the healing process of oral ulcerations in hamsters' model in association with autologous cells.

Visible Light Photoelectrochemical Sensor for Dopamine: Determination Using Iron Vanadate Modified Electrode.

This study reports a facile approach for constructing low-cost and remarkable electroactivity iron vanadate (Fe-V-O) semiconductor material to be used as a photoelectrochemical sensor for dopamine detection. The structure and morphology of the iron vanadate obtained by the Successive Ionic Adsorption and Reaction process were critically characterized, and the photoelectrochemical characterization showed a high photoelectroactivity of the photoanode in visible light irradiation. Under best conditions, dopamine was detected by chronoamperometry at +0.35 V vs. Ag/AgCl, achieving two linear response ranges (between 1.21 and 30.32 µmol L-1, and between 30.32 and 72.77 µmol L-1). The limits of detection and quantification were 0.34 and 1.12 µmol L-1, respectively. Besides, the accuracy of the proposed electrode was assessed by determining dopamine in artificial cerebrospinal fluid, obtaining recovery values ranging from 98.7 to 102.4%. The selectivity was also evaluated by dopamine detection against several interferent species, demonstrating good precision and promising application for the proposed method. Furthermore, DFT-based electronic structure calculations were also conducted to help the interpretation. The dominant dopamine species were determined according to the experimental conditions, and their interaction with the iron vanadate photoanode was proposed. The improved light-induced DOP detection was likewise evaluated regarding the charge transfer process.

Nicotine exposure through breastfeeding affects brain-derived neurotrophic factor and synaptic proteins levels in the brain of stressed adult female mice.

Nicotine has been used during pregnancy and lactation as a tobacco harm reduction strategy. However, it is unclear whether nicotine exposure during a critical development period negatively impacts stress responses in adulthood. This study investigated how nicotine, administered via breastfeeding, affects the brain-derived neurotrophic factor (BDNF), synaptic proteins levels, and anxiety-like behavior in adult female mice subjected to stress. Female Swiss mice were exposed to saline or nicotine (8 mg/kg/day) through breastfeeding between their fourth and 17th postnatal days (P) via implanted osmotic mini pumps. The unpredictable chronic mild stress (UCMS) protocol was performed during their adulthood (P65) for 10 consecutive days, followed by the elevated plus maze (EPM) test 1 day after the protocol. Animals were euthanized and their blood, collected for plasma corticosterone measurements and their brain structures, dissected for BDNF and synaptic proteins analyses. We found no significant differences in corticosterone levels between groups (Saline/Non-stress, Nicotine/Non-stress, Saline/Stress, and Nicotine/Stress). The UCMS protocol hindered weight gain. Mice exposed to nicotine through breastfeeding with or without the UCMS protocol in adulthood showed higher grooming and head dipping frequency; decreased BDNF levels in cerebellum and striatum; increased postsynaptic density protein 95 (PSD-95), synapsin I, and synaptophysin levels in cerebellum; and decreased PSD-95 and synapsin I levels in brainstem. Our results indicate that nicotine exposure through breastfeeding leads to long-lasting behavioral effects and synaptic protein changes, most of which were independent of the UCMS protocol, even after a long nicotine-free period, highlighting the importance of further studies on nicotine exposure during development.