INTRODUÇÃO: A restrição do crescimento intrauterino (RCIU) é conhecida como uma condição na qual o feto não consegue desenvolver todo o seu potencial de crescimento intrínseco. Crianças com RCIU em idade escolar têm prejuízos no aprendizado, memória, atenção e cognição em geral, e maior predisposição a transtornos psicológicos como Transtorno de Déficit de Atenção e Hiperatividade (TDAH), quando comparados com crianças não restritas. OBJETIVO: este estudo busca encontrar modificações neurobiológicas encefálicas, em ratos Wistar adolescentes, que possam explicar os efeitos, em parâmetros comportamentais, de neuroplasticidade e memória, da RCIU por redução da pressão de perfusão uterina (RPPU). MÉTODOS: ratas Wistar prenhes de 75 dias de idade foram submetidas à RPPU no dia gestacional 14, período que corresponde ao inicio da fase de rápido crescimento, diferenciação e maturação em ratos, por meio da colocação de um clipe na artéria aorta abdominal descendente antes da bifurcação para as artérias ilíacas e um clipe em cada artéria ovariana. O grupo Sham foi submetido à laparotomia exploratória sem a RPPU e o grupo controle não foi submetido a nenhum procedimento cirúrgico. Ratos Wistar de 30 dias, provenientes de mães submetidas à RPPU, Sham ou Controles, foram submetidos ao Teste de Campo Aberto, para avaliação da atividade locomotora e exploratória, e no 32º dia pós-natal (DPN) foram submetidos ao teste de Reconhecimento do Novo Objeto para avaliar a memória de longo prazo. Os encéfalos da prole foram coletados no 34º DPN e conservados para análise. A Técnica de imunoistoquímica foi realizada para mensurar a expressão de marcadores celulares neurais: NeuN (neurônios maduros) GFAP (astrócito) no córtex pré-frontal e estriado da prole. RESULTADOS: a RPPU causou diminuição no peso ao nascimento no grupo RCIU e Sham, porém não houve diferença no peso entre os grupos no 30º DPN. A RPPU aumentou significativamente a duração da gestação no grupo RCIU em um dia. Os animais restritos apresentaram aumento na atividade exploratória no teste de campo aberto. RCIU e Sham apresentaram déficit de memória no teste de reconhecimento do novo objeto. Associado a essas alterações comportamentais, a RCIU levou a o aumento significativo na expressão de NeuN no CPF e de GFAP no estriado no 34º DPN. CONCLUSÃO: a RPPU produz alterações na gravidez causando maior duração da ges-tação e RCIU na prole, conduzindo a modificações comportamentais e de memória, assim como a nível encefálico celular, promovendo novas perspectivas sobre as consequências do modelo em ratos de RCIU-RPPU. São necessários mais estudos para desvendar se essas modificações continuam presente na vida adulta dos ratos. / INTRODUCTION: Intrauterine growth restriction (IUGR) is known as a condition where the fetus cannot develop its intrinsic growth potential. IUGR Children in early scholar age have impaired learning abilities, memory, attention and cognitive deficit in general; also, they are in higher risk of psychological disorders as Attention Deficit and Hyperactivity Disorder (ADHD) when compared with non-IUGR children. OBJECTIVE: The study aims to find neurobiologi-cal brain modifications, in adolescent Wistar rats, that could clarify these memory and behav-ioral impairments in a rat animal model of IUGR by Reduced Uterine Perfusion Pressure (RUPP). METHODS: 75 days-old pregnant Wistar rats were underwent to RUPP procedure on 14th gestational day, period where the fast growing, differentiation and maturation phase begins in rats, by putting one clip at the abdominal descendent aorta before iliac bifurcation and one clip in each ovarian artery. The Sham group underwent exploratory laparotomy procedure without the RUPP and the control group was not exposed to any surgical procedure. 30 days old Wistar rats from RUPP, Sham, and Control mothers were exposed to the Open Field Test to assess the locomotor and exploratory activity and, at 32th postnatal day (PND), to the Novel Object Recognition test to assess the long-term memory. Offspring brains were collected at 34th PND and preserved for analysis. Immunohistochemistry technique was performed to measure the expression of neural cells markers: NeuN (mature neurons) and GFAP (astrocytes) in prefrontal cortex and striatum on the offspring. RESULTS: RUPP caused a decreased birth weight in IUGR and Sham group, however there was no difference between birth weight at 30th PND. RUPP significantly increased gestation in 1 day in IUGR rats. IUGR animals had greater exploratory, locomotor activity in the Open Field test. IUGR and Sham showed memory deficit in the Novel Object Recognition test. Associated to those behavioral modifications, the RUPP leaded to a significant increase in expression of NeuN and GFAP marker in prefrontal cortex and striatum at PND34. CONCLUSIONS: The RUPP dis-turbs pregnancy increasing gestation length and inducing IUGR in the offspring; which leads to behavioral and memory modifications, also, in a brain cellular level, promoting new insight about the IUGR-RUPP rat model consequences. Further analysis are needed to find whether this changes are still present in adult life.

Introdução: A gravidez na adolescência é considerada um problema de saúde pública pela alta prevalência e morbimortalidade para a mãe e filho, principalmente em adolescentes mais jovens. Objetivo: Analisar a associação entre os fatores para neonatos pequenos para a idade gestacional. Metodologia: Estudo transversal com uma amostra de 364 puérperas adolescentes com idade menor ou igual a 15 anos, que tiveram parto na maternidade do Hospital da Santa Casa de Misericórdia do Pará (Brasil) entre Fevereiro de 2012 a Março de 2013. As adolescentes foram divididas em dois grupos: grupo com neonato pequeno para a idade gestacional (PIG) e grupo com não pequeno para a idade gestacional (NPIG). Foram coletados dados sócio-demográficos, clínicos, de assistencia ao pré-natal, do parto, do puerpério e aferidas medidas antropométricas (prega triciptal e circunferência do braço). Utilizou-se o teste t-Student para comparação das variáveis contínuas entre amostras independentes e o teste do X2 para comparação de variáveis categóricas. Regressão de Poisson foi realizada para controle de fatores de confusão (análise multivariada). Resultados: No período de estudo, 8.153 mulheres tiveram partos naquela maternidade e dessas 487 (5,97%) eram adolescentes ≤15 anos, sendo 364 incluídas no estudo. A proporção de RN PIGs foi de 34,61%. O grupo de RNs PIG realizou menor número de consultas pré-natais (p=0,037), maior prevalência de estado nutricional classificado como “muito baixo peso” (p<0,001) e maior prevalência de parto vaginal (p=0,023) diferindo significativamente do grupo NPIG. O estado nutricional e parto normal permaneceram significativos mesmo após ajuste de fatores de confusão. O risco de prevalência para nascimento de RN PIG foi 30% maior no grupo de mães classificadas como “muito baixo peso” através da escala de referencia de Frisancho para avaliação do estado nutricional. (RP 1,30 IC 95% 1,13-1,50) (p<0,001). Conclusão: Em nosso estudo, 15.4% das adolescentes ≤ 15 anos apresentava circunferência braquial compatível com o diagnóstico “muito baixo peso” pela escala de Frisancho, demonstrando elevada prevalência de baixo estado nutricional materno nessa faixa etária. O nascimento de RN PIG em adolescentes ≤ 15 anos de idade está independentemente associado ao estado nutricional materno classificado como “muito baixo peso” pela medida da circunferência braquial. / Introducion: Adolescent pregnancy is considered a public health problem by the high prevalence, morbidity and mortality for mother and child, especially in younger adolescents. Objective: This study aimed to analyze the factors associated to the birth of small for gestational age. Methodology: Cross-sectional study with a sample of 364 postpartum adolescents younger or equal to 15 years old, who gave birth in the maternity of Hospital da Santa Casa de Misericórdia of Pará (Brazil) between February 2012 and March 2013. The adolescents were divided into two groups: those who gave birth to small for gestational age (SGA) and those who gave birth to non-small for gestational age (NSGA). Socio-demographic, clinical, prenatal care, delivery and postpartum data were collected and anthropometric measures were taken (triceps skinfold and mid-arm circumference). The Student’s t test was used to compare continuous variables in independent samples and the X2 test to compare categorical variables. Poisson regression was performed to control confounding factors (multivariate analysis). Results: During the study period, 8,153 women gave birth at that maternity, 487 (5.97%) were adolescents ≤ 15 years, from these 364 were enrolled in the study. The proportion of SGA was 34.61%. The group SGA held fewer prenatal visits (p = 0.037), higher prevalence of nutritional status classified as "very low weight" (p <0.001) and vaginal delivery (p = 0.023),significantly different from the group NSGA. The nutritional status and vaginal delivery remained significant even after adjustment for confounders. The prevalence risk for SGA birth was 30% higher in the group of mothers classified as "very low weight” by Frisancho reference scale for assessment of nutritional status. (PR 1.30 95% CI 1.13 to 1.50) (p <0.001). Conclusion: In our study, 15.4% of adolescents ≤ 15 years had arm circumference compatible with the "very low weight" condition, demonstrating the high prevalence of poor maternal nutrition status in this group. The birth of SGA among adolescents ≤ 15 years of age is independently associated to maternal nutritional status classified as "very low weight" by the mid-arm circumference measure.

Introdução: A gravidez na adolescência é considerada um problema de saúde pública pela alta prevalência e morbimortalidade para a mãe e filho, principalmente em adolescentes mais jovens. Objetivo: Analisar a associação entre os fatores para neonatos pequenos para a idade gestacional. Metodologia: Estudo transversal com uma amostra de 364 puérperas adolescentes com idade menor ou igual a 15 anos, que tiveram parto na maternidade do Hospital da Santa Casa de Misericórdia do Pará (Brasil) entre Fevereiro de 2012 a Março de 2013. As adolescentes foram divididas em dois grupos: grupo com neonato pequeno para a idade gestacional (PIG) e grupo com não pequeno para a idade gestacional (NPIG). Foram coletados dados sócio-demográficos, clínicos, de assistencia ao pré-natal, do parto, do puerpério e aferidas medidas antropométricas (prega triciptal e circunferência do braço). Utilizou-se o teste t-Student para comparação das variáveis contínuas entre amostras independentes e o teste do X2 para comparação de variáveis categóricas. Regressão de Poisson foi realizada para controle de fatores de confusão (análise multivariada). Resultados: No período de estudo, 8.153 mulheres tiveram partos naquela maternidade e dessas 487 (5,97%) eram adolescentes ≤15 anos, sendo 364 incluídas no estudo. A proporção de RN PIGs foi de 34,61%. O grupo de RNs PIG realizou menor número de consultas pré-natais (p=0,037), maior prevalência de estado nutricional classificado como “muito baixo peso” (p<0,001) e maior prevalência de parto vaginal (p=0,023) diferindo significativamente do grupo NPIG. O estado nutricional e parto normal permaneceram significativos mesmo após ajuste de fatores de confusão. O risco de prevalência para nascimento de RN PIG foi 30% maior no grupo de mães classificadas como “muito baixo peso” através da escala de referencia de Frisancho para avaliação do estado nutricional. (RP 1,30 IC 95% 1,13-1,50) (p<0,001). Conclusão: Em nosso estudo, 15.4% das adolescentes ≤ 15 anos apresentava circunferência braquial compatível com o diagnóstico “muito baixo peso” pela escala de Frisancho, demonstrando elevada prevalência de baixo estado nutricional materno nessa faixa etária. O nascimento de RN PIG em adolescentes ≤ 15 anos de idade está independentemente associado ao estado nutricional materno classificado como “muito baixo peso” pela medida da circunferência braquial. / Introducion: Adolescent pregnancy is considered a public health problem by the high prevalence, morbidity and mortality for mother and child, especially in younger adolescents. Objective: This study aimed to analyze the factors associated to the birth of small for gestational age. Methodology: Cross-sectional study with a sample of 364 postpartum adolescents younger or equal to 15 years old, who gave birth in the maternity of Hospital da Santa Casa de Misericórdia of Pará (Brazil) between February 2012 and March 2013. The adolescents were divided into two groups: those who gave birth to small for gestational age (SGA) and those who gave birth to non-small for gestational age (NSGA). Socio-demographic, clinical, prenatal care, delivery and postpartum data were collected and anthropometric measures were taken (triceps skinfold and mid-arm circumference). The Student’s t test was used to compare continuous variables in independent samples and the X2 test to compare categorical variables. Poisson regression was performed to control confounding factors (multivariate analysis). Results: During the study period, 8,153 women gave birth at that maternity, 487 (5.97%) were adolescents ≤ 15 years, from these 364 were enrolled in the study. The proportion of SGA was 34.61%. The group SGA held fewer prenatal visits (p = 0.037), higher prevalence of nutritional status classified as "very low weight" (p <0.001) and vaginal delivery (p = 0.023),significantly different from the group NSGA. The nutritional status and vaginal delivery remained significant even after adjustment for confounders. The prevalence risk for SGA birth was 30% higher in the group of mothers classified as "very low weight” by Frisancho reference scale for assessment of nutritional status. (PR 1.30 95% CI 1.13 to 1.50) (p <0.001). Conclusion: In our study, 15.4% of adolescents ≤ 15 years had arm circumference compatible with the "very low weight" condition, demonstrating the high prevalence of poor maternal nutrition status in this group. The birth of SGA among adolescents ≤ 15 years of age is independently associated to maternal nutritional status classified as "very low weight" by the mid-arm circumference measure.

INTRODUÇÃO: A restrição do crescimento intrauterino (RCIU) é conhecida como uma condição na qual o feto não consegue desenvolver todo o seu potencial de crescimento intrínseco. Crianças com RCIU em idade escolar têm prejuízos no aprendizado, memória, atenção e cognição em geral, e maior predisposição a transtornos psicológicos como Transtorno de Déficit de Atenção e Hiperatividade (TDAH), quando comparados com crianças não restritas. OBJETIVO: este estudo busca encontrar modificações neurobiológicas encefálicas, em ratos Wistar adolescentes, que possam explicar os efeitos, em parâmetros comportamentais, de neuroplasticidade e memória, da RCIU por redução da pressão de perfusão uterina (RPPU). MÉTODOS: ratas Wistar prenhes de 75 dias de idade foram submetidas à RPPU no dia gestacional 14, período que corresponde ao inicio da fase de rápido crescimento, diferenciação e maturação em ratos, por meio da colocação de um clipe na artéria aorta abdominal descendente antes da bifurcação para as artérias ilíacas e um clipe em cada artéria ovariana. O grupo Sham foi submetido à laparotomia exploratória sem a RPPU e o grupo controle não foi submetido a nenhum procedimento cirúrgico. Ratos Wistar de 30 dias, provenientes de mães submetidas à RPPU, Sham ou Controles, foram submetidos ao Teste de Campo Aberto, para avaliação da atividade locomotora e exploratória, e no 32º dia pós-natal (DPN) foram submetidos ao teste de Reconhecimento do Novo Objeto para avaliar a memória de longo prazo. Os encéfalos da prole foram coletados no 34º DPN e conservados para análise. A Técnica de imunoistoquímica foi realizada para mensurar a expressão de marcadores celulares neurais: NeuN (neurônios maduros) GFAP (astrócito) no córtex pré-frontal e estriado da prole. RESULTADOS: a RPPU causou diminuição no peso ao nascimento no grupo RCIU e Sham, porém não houve diferença no peso entre os grupos no 30º DPN. A RPPU aumentou significativamente a duração da gestação no grupo RCIU em um dia. Os animais restritos apresentaram aumento na atividade exploratória no teste de campo aberto. RCIU e Sham apresentaram déficit de memória no teste de reconhecimento do novo objeto. Associado a essas alterações comportamentais, a RCIU levou a o aumento significativo na expressão de NeuN no CPF e de GFAP no estriado no 34º DPN. CONCLUSÃO: a RPPU produz alterações na gravidez causando maior duração da ges-tação e RCIU na prole, conduzindo a modificações comportamentais e de memória, assim como a nível encefálico celular, promovendo novas perspectivas sobre as consequências do modelo em ratos de RCIU-RPPU. São necessários mais estudos para desvendar se essas modificações continuam presente na vida adulta dos ratos. / INTRODUCTION: Intrauterine growth restriction (IUGR) is known as a condition where the fetus cannot develop its intrinsic growth potential. IUGR Children in early scholar age have impaired learning abilities, memory, attention and cognitive deficit in general; also, they are in higher risk of psychological disorders as Attention Deficit and Hyperactivity Disorder (ADHD) when compared with non-IUGR children. OBJECTIVE: The study aims to find neurobiologi-cal brain modifications, in adolescent Wistar rats, that could clarify these memory and behav-ioral impairments in a rat animal model of IUGR by Reduced Uterine Perfusion Pressure (RUPP). METHODS: 75 days-old pregnant Wistar rats were underwent to RUPP procedure on 14th gestational day, period where the fast growing, differentiation and maturation phase begins in rats, by putting one clip at the abdominal descendent aorta before iliac bifurcation and one clip in each ovarian artery. The Sham group underwent exploratory laparotomy procedure without the RUPP and the control group was not exposed to any surgical procedure. 30 days old Wistar rats from RUPP, Sham, and Control mothers were exposed to the Open Field Test to assess the locomotor and exploratory activity and, at 32th postnatal day (PND), to the Novel Object Recognition test to assess the long-term memory. Offspring brains were collected at 34th PND and preserved for analysis. Immunohistochemistry technique was performed to measure the expression of neural cells markers: NeuN (mature neurons) and GFAP (astrocytes) in prefrontal cortex and striatum on the offspring. RESULTS: RUPP caused a decreased birth weight in IUGR and Sham group, however there was no difference between birth weight at 30th PND. RUPP significantly increased gestation in 1 day in IUGR rats. IUGR animals had greater exploratory, locomotor activity in the Open Field test. IUGR and Sham showed memory deficit in the Novel Object Recognition test. Associated to those behavioral modifications, the RUPP leaded to a significant increase in expression of NeuN and GFAP marker in prefrontal cortex and striatum at PND34. CONCLUSIONS: The RUPP dis-turbs pregnancy increasing gestation length and inducing IUGR in the offspring; which leads to behavioral and memory modifications, also, in a brain cellular level, promoting new insight about the IUGR-RUPP rat model consequences. Further analysis are needed to find whether this changes are still present in adult life.

INTRODUÇÃO: A restrição do crescimento intrauterino (RCIU) é conhecida como uma condição na qual o feto não consegue desenvolver todo o seu potencial de crescimento intrínseco. Crianças com RCIU em idade escolar têm prejuízos no aprendizado, memória, atenção e cognição em geral, e maior predisposição a transtornos psicológicos como Transtorno de Déficit de Atenção e Hiperatividade (TDAH), quando comparados com crianças não restritas. OBJETIVO: este estudo busca encontrar modificações neurobiológicas encefálicas, em ratos Wistar adolescentes, que possam explicar os efeitos, em parâmetros comportamentais, de neuroplasticidade e memória, da RCIU por redução da pressão de perfusão uterina (RPPU). MÉTODOS: ratas Wistar prenhes de 75 dias de idade foram submetidas à RPPU no dia gestacional 14, período que corresponde ao inicio da fase de rápido crescimento, diferenciação e maturação em ratos, por meio da colocação de um clipe na artéria aorta abdominal descendente antes da bifurcação para as artérias ilíacas e um clipe em cada artéria ovariana. O grupo Sham foi submetido à laparotomia exploratória sem a RPPU e o grupo controle não foi submetido a nenhum procedimento cirúrgico. Ratos Wistar de 30 dias, provenientes de mães submetidas à RPPU, Sham ou Controles, foram submetidos ao Teste de Campo Aberto, para avaliação da atividade locomotora e exploratória, e no 32º dia pós-natal (DPN) foram submetidos ao teste de Reconhecimento do Novo Objeto para avaliar a memória de longo prazo. Os encéfalos da prole foram coletados no 34º DPN e conservados para análise. A Técnica de imunoistoquímica foi realizada para mensurar a expressão de marcadores celulares neurais: NeuN (neurônios maduros) GFAP (astrócito) no córtex pré-frontal e estriado da prole. RESULTADOS: a RPPU causou diminuição no peso ao nascimento no grupo RCIU e Sham, porém não houve diferença no peso entre os grupos no 30º DPN. A RPPU aumentou significativamente a duração da gestação no grupo RCIU em um dia. Os animais restritos apresentaram aumento na atividade exploratória no teste de campo aberto. RCIU e Sham apresentaram déficit de memória no teste de reconhecimento do novo objeto. Associado a essas alterações comportamentais, a RCIU levou a o aumento significativo na expressão de NeuN no CPF e de GFAP no estriado no 34º DPN. CONCLUSÃO: a RPPU produz alterações na gravidez causando maior duração da ges-tação e RCIU na prole, conduzindo a modificações comportamentais e de memória, assim como a nível encefálico celular, promovendo novas perspectivas sobre as consequências do modelo em ratos de RCIU-RPPU. São necessários mais estudos para desvendar se essas modificações continuam presente na vida adulta dos ratos. / INTRODUCTION: Intrauterine growth restriction (IUGR) is known as a condition where the fetus cannot develop its intrinsic growth potential. IUGR Children in early scholar age have impaired learning abilities, memory, attention and cognitive deficit in general; also, they are in higher risk of psychological disorders as Attention Deficit and Hyperactivity Disorder (ADHD) when compared with non-IUGR children. OBJECTIVE: The study aims to find neurobiologi-cal brain modifications, in adolescent Wistar rats, that could clarify these memory and behav-ioral impairments in a rat animal model of IUGR by Reduced Uterine Perfusion Pressure (RUPP). METHODS: 75 days-old pregnant Wistar rats were underwent to RUPP procedure on 14th gestational day, period where the fast growing, differentiation and maturation phase begins in rats, by putting one clip at the abdominal descendent aorta before iliac bifurcation and one clip in each ovarian artery. The Sham group underwent exploratory laparotomy procedure without the RUPP and the control group was not exposed to any surgical procedure. 30 days old Wistar rats from RUPP, Sham, and Control mothers were exposed to the Open Field Test to assess the locomotor and exploratory activity and, at 32th postnatal day (PND), to the Novel Object Recognition test to assess the long-term memory. Offspring brains were collected at 34th PND and preserved for analysis. Immunohistochemistry technique was performed to measure the expression of neural cells markers: NeuN (mature neurons) and GFAP (astrocytes) in prefrontal cortex and striatum on the offspring. RESULTS: RUPP caused a decreased birth weight in IUGR and Sham group, however there was no difference between birth weight at 30th PND. RUPP significantly increased gestation in 1 day in IUGR rats. IUGR animals had greater exploratory, locomotor activity in the Open Field test. IUGR and Sham showed memory deficit in the Novel Object Recognition test. Associated to those behavioral modifications, the RUPP leaded to a significant increase in expression of NeuN and GFAP marker in prefrontal cortex and striatum at PND34. CONCLUSIONS: The RUPP dis-turbs pregnancy increasing gestation length and inducing IUGR in the offspring; which leads to behavioral and memory modifications, also, in a brain cellular level, promoting new insight about the IUGR-RUPP rat model consequences. Further analysis are needed to find whether this changes are still present in adult life.

Introdução: A gravidez na adolescência é considerada um problema de saúde pública pela alta prevalência e morbimortalidade para a mãe e filho, principalmente em adolescentes mais jovens. Objetivo: Analisar a associação entre os fatores para neonatos pequenos para a idade gestacional. Metodologia: Estudo transversal com uma amostra de 364 puérperas adolescentes com idade menor ou igual a 15 anos, que tiveram parto na maternidade do Hospital da Santa Casa de Misericórdia do Pará (Brasil) entre Fevereiro de 2012 a Março de 2013. As adolescentes foram divididas em dois grupos: grupo com neonato pequeno para a idade gestacional (PIG) e grupo com não pequeno para a idade gestacional (NPIG). Foram coletados dados sócio-demográficos, clínicos, de assistencia ao pré-natal, do parto, do puerpério e aferidas medidas antropométricas (prega triciptal e circunferência do braço). Utilizou-se o teste t-Student para comparação das variáveis contínuas entre amostras independentes e o teste do X2 para comparação de variáveis categóricas. Regressão de Poisson foi realizada para controle de fatores de confusão (análise multivariada). Resultados: No período de estudo, 8.153 mulheres tiveram partos naquela maternidade e dessas 487 (5,97%) eram adolescentes ≤15 anos, sendo 364 incluídas no estudo. A proporção de RN PIGs foi de 34,61%. O grupo de RNs PIG realizou menor número de consultas pré-natais (p=0,037), maior prevalência de estado nutricional classificado como “muito baixo peso” (p<0,001) e maior prevalência de parto vaginal (p=0,023) diferindo significativamente do grupo NPIG. O estado nutricional e parto normal permaneceram significativos mesmo após ajuste de fatores de confusão. O risco de prevalência para nascimento de RN PIG foi 30% maior no grupo de mães classificadas como “muito baixo peso” através da escala de referencia de Frisancho para avaliação do estado nutricional. (RP 1,30 IC 95% 1,13-1,50) (p<0,001). Conclusão: Em nosso estudo, 15.4% das adolescentes ≤ 15 anos apresentava circunferência braquial compatível com o diagnóstico “muito baixo peso” pela escala de Frisancho, demonstrando elevada prevalência de baixo estado nutricional materno nessa faixa etária. O nascimento de RN PIG em adolescentes ≤ 15 anos de idade está independentemente associado ao estado nutricional materno classificado como “muito baixo peso” pela medida da circunferência braquial. / Introducion: Adolescent pregnancy is considered a public health problem by the high prevalence, morbidity and mortality for mother and child, especially in younger adolescents. Objective: This study aimed to analyze the factors associated to the birth of small for gestational age. Methodology: Cross-sectional study with a sample of 364 postpartum adolescents younger or equal to 15 years old, who gave birth in the maternity of Hospital da Santa Casa de Misericórdia of Pará (Brazil) between February 2012 and March 2013. The adolescents were divided into two groups: those who gave birth to small for gestational age (SGA) and those who gave birth to non-small for gestational age (NSGA). Socio-demographic, clinical, prenatal care, delivery and postpartum data were collected and anthropometric measures were taken (triceps skinfold and mid-arm circumference). The Student’s t test was used to compare continuous variables in independent samples and the X2 test to compare categorical variables. Poisson regression was performed to control confounding factors (multivariate analysis). Results: During the study period, 8,153 women gave birth at that maternity, 487 (5.97%) were adolescents ≤ 15 years, from these 364 were enrolled in the study. The proportion of SGA was 34.61%. The group SGA held fewer prenatal visits (p = 0.037), higher prevalence of nutritional status classified as "very low weight" (p <0.001) and vaginal delivery (p = 0.023),significantly different from the group NSGA. The nutritional status and vaginal delivery remained significant even after adjustment for confounders. The prevalence risk for SGA birth was 30% higher in the group of mothers classified as "very low weight” by Frisancho reference scale for assessment of nutritional status. (PR 1.30 95% CI 1.13 to 1.50) (p <0.001). Conclusion: In our study, 15.4% of adolescents ≤ 15 years had arm circumference compatible with the "very low weight" condition, demonstrating the high prevalence of poor maternal nutrition status in this group. The birth of SGA among adolescents ≤ 15 years of age is independently associated to maternal nutritional status classified as "very low weight" by the mid-arm circumference measure.

Une croissance intra-utérine insuffisante représente, avec la prématurité et les malfor-mations congénitales, une des principales causes de morbidité et de mortalité néonatales. Ces pathologies sont liées entre elles, les nouveau-nés prématurés étant souvent atteints de RCIU (RCIU). Les études épidémiologiques récentes ont montré que le RCIU était associé à une augmentation de la morbidité respiratoire dès la période néonatale, avec, en particulier, une augmentation du risque de dysplasie broncho-pulmonaire (DBP), principale séquelle respira-toire de la prématurité. La DBP est caractérisée par des anomalies du développement alvéo-laire et vasculaire, considérées comme les conséquences d’agressions multiples sur un poumon immature. La physiopathologie exacte reste encore largement méconnue. Nous nous sommes intéressés dans ce travail au lien entre RCIU et DBP avec un abord expérimental et clinique. Alors que les études épidémiologiques sont relativement concordantes sur le lien entre RCIU et DBP, les études expérimentales, montrent des résultats divers tant sur le développement pulmonaire qu’au niveau moléculaire. Nous avons donc voulu identifier, dans un premier temps, un modèle de RCIU reproduisant les anomalies du développement alvéolaire observées chez l’Homme en utilisant trois modèles précédemment validés chez le rat : un modèle de res-triction protidique per-gestationnelle , un modèle de ligature unilatérale de l’artère utérine, un modèle d’injection d’un inhibiteur chimique de la NO synthase, le L NAME. Seule la restric-tion protidique anténatale permet de reproduire à long terme des lésions de l’alvéolisation proches de celles observées dans la DBP. En revanche, dans ce modèle, les modifications des principaux gènes identifiés précédemment dans les anomalies le développement alvéolaire ne sont pas observées, que ce soit avant, pendant ou après l’alvéolisation. Ce résultat nous a ame-né à entreprendre une étude multigénique qui a permis d’identifier plusieurs voies modifiées pendant l’alvéolisation dans ce modèle. Parmi celles-ci, les gènes impliqués dans la contractili-té et l’adhésion cellulaire, l’immunité ou la voie des « Peroxisome Proliferator-Activated Re-ceptor ». Dans la partie clinique de cette étude, nous avons évalué le risque de DBP chez les extrêmes prématurés atteints de RCIU dont les mères présentaient des signes de pathologie vasculaire de la grossesse (prééclampsie). Cette étude rétrospective unicentrique sur 184 en-fants a permis de comparer des enfants atteints de RCIU à des enfants eutrophes pris en charge de manière homogène. Le RCIU d’origine vasculaire multiplie le risque de DBP par 6. Un marqueur précoce de l’évolution vers une DBP est un taux de plaquettes bas à la naissance, évoquant le rôle d’un taux élevé de facteurs anti-angiogéniques circulants. Une étude est en cours pour corréler les facteurs anti-angiogéniques circulants présents chez les mères pré-éclamptiques au devenir respiratoire, en particulier à l’évolution vers une DBP, de leurs nou-veau-nés d’âge gestationnel inférieur à 30 semaines d’aménorrhée. En conclusion, nous avons montré expérimentalement que seule la restriction protidique anténatale chez le rat reproduisait les troubles de l’alvéolisation comparables à ceux observés dans la DBP. De nouvelles voies moléculaires potentiellement impliquées dans les anomalies de l’alvéolisation ont été mises en évidence. Par ailleurs, le rôle de facteurs anti-angiogéniques d’origine maternelle comme fac-teurs de développement d’une DBP est en cours d’évaluation. / Insufficient intrauterine growth is with prematurity and congenital malformations, a major cause of neonatal morbidity and mortality. These conditions are interrelated, the preterm infants often suffered of intrauterine growth restriction (IUGR). Recent epidemiological stud-ies showed that IUGR was associated with increased respiratory morbidity as soon as the ne-onatal period, with an increased risk of bronchopulmonary dysplasia (BPD), the main respira-tory sequelae of prematurity. BPD is characterized by impaired alveolar and vascular devel-opment and is the consequence of multiple insults on an immature lung. The exact pathophysi-ology is still largely unknown. We study in this work the relationship between IUGR and DBP with an experimental and clinical approach. While epidemiological studies are relatively concordant on the relationship between IUGR and BPD, experimental studies showed various results in lung development and molecular process. We wanted to identify, at first, a model of IUGR reproducing impaired alveolar development observed in humans using three previously validated models in rats: a model of per-gestational protein restriction, a model of unilateral ligation uterine artery, an injection pattern of a chemical inhibitor of NO synthase, L NAME. Only antenatal protein restriction can reproduce long-term impaired alveolarization as those observed in BPD. However, in this model, changes in key genes previously identified in pathological alveolar development are not observed before, during or after alveolarization. This result led us to perform a genome-wide analysis which identified several modified path-ways during alveolarization. Among these, the genes involved in the “cardiac contractility”, “cell adhesion molecules”, “immunity”, “molecular adhesion” or the "Peroxisome Proliferator-Activated Receptor" pathways. In the clinical part of this study, we evaluated the risk of BPD in extreme preterm infants with IUGR whose mothers had evidence of vascular disease of pregnancy (preeclampsia). This single-center retrospective study of 184 children was used to compare children with IUGR in adjusted for gestational age children. The vascular IUGR increases the risk of DBP by 6. An early marker of progression to BPD is a low platelet count at birth, referring to the role of high levels of circulating anti-angiogenic factors. A study is ongoing to correlate circulating anti-angiogenic factors present in preeclamptic mothers to res-piratory outcome and particularly BDP, in newborn younger than 30 weeks of gestational age at birth. In conclusion, we have shown experimentally that only prenatal protein restriction in rats reproduced impaired alveolarization comparable to those observed in the BPD. New mo-lecular pathways potentially involved in the impaired alveolarization were highlighted. More-over, the role of placental anti-angiogenic factors leading to development of BPD is evaluat-ed.

Abstract Children born preterm are prone to acute brain insults related to subsequent neurodevelopmental impairments. However, the role of specific biomarkers and perinatal clinical factors in the pathogenesis of brain injury and neurodevelopmental sequelae has remained poorly understood. The present study evaluated whether specific immunoproteins at birth predict the risk of intraventricular hemorrhage (IVH) and whether their receptors are localized at the bleeding site. We further investigated whether children who went on to develop cerebral palsy (CP) could be identified on the basis of blood immunoproteins collected during the perinatal period. The association between single nucleotide polymorphisms in the chemokine CCL18 gene and susceptibility to CP was also studied. Finally, we investigated the association of pre- and postnatal factors with cognitive outcomes in very preterm-born schoolchildren without impairments. The present study revealed that a low concentration of CCL18 in cord blood was an independent risk factor of IVH in very preterm infants. The CCL18 receptor, CCR3, was detectable in the periventricular area and in the neurons of the hippocampus in preterm infants already at 23 weeks of gestation. We also identified a cluster of cord blood cytokines that was associated with the risk of CP. In addition, inflammatory cytokine levels were associated with CP risk on days 1 and 7 after birth. The genetic study showed that both IVH and the CCL18 polymorphism independently and additively had an influence on CP susceptibility. Our study further demonstrated that schoolchildren born very preterm without CP or cognitive impairment had poorer performance in visuospatial–sensorimotor skills and in attention–executive functions than term-born children. Fetal growth restriction was an independent risk factor of compromised neurocognitive outcome in very preterm children predicting difficulties in language, memory and learning. In conclusion, specific cytokines and cytokine clusters serve as biomarkers of different pathways involved in damage to the brain structures and in the pathogenesis of CP. In addition, genetic factors can affect these processes. Further, fetal growth restriction and prematurity play important roles in neurocognitive development later in life. / Tiivistelmä Hyvin ennenaikaisina syntyneet lapset ovat alttiita akuuteille aivovaurioille sekä myöhemmin ilmeneville kehityshäiriöille. Eri välittäjäaineiden sekä raskaudenaikaisten ja syntymänjälkeisten kliinisten tekijöiden vaikutusta aivojen vaurioherkkyyteen sekä neurologiseen ja neurokognitiiviseen kehitykseen ei kuitenkaan ole tutkittu riittävästi. Tässä tutkimuksessa tarkasteltiin, ennustaako jokin napaverestä tutkituista sytokiineista aivoverenvuotoa hyvin ennenaikaisesti syntyneillä vastasyntyneillä. Lisäksi selvitettiin, onko sytokiinin spesifinen reseptori osoitettavissa vuotoherkällä alueella aivoissa. Tutkimme myös, ennustaako jokin napaveren immunoproteiini-profiilin komponentti CP-vamman syntyä joko itsenäisesti tai yhdessä muiden perinataalisten riskitekijöiden kanssa sekä lisääkö tietyn sytokiinin (CCL18) geneettinen vaihtelu CP-vamman riskiä hyvin ennenaikaisesti syntyneillä lapsilla. Lisäksi selvitimme, vaikuttavatko raskaudenaikaiset tekijät ja vastasyntyneisyyskauden sairaudet neurokognitiiviseen kehitykseen kouluiässä. Tämän tutkimuksen mukaan napaveren matala CCL18-kemokiinipitoisuus oli itsenäinen aivoverenvuodon riskitekijä. CCR3-reseptori, johon CCL18 sitoutuu, oli osoitettavissa sekä vuotoherkällä alueella että hermosoluissa 23. raskausviikon iästä lähtien. Havaitsimme myös, että tietyt napaveren sytokiiniryppäät ja yksittäisten tulehdusvastevälittäjäaineiden pitoisuudet 1. ja 7. elinpäivänä olivat yhteydessä CP-riskiin. Lisäksi havaitsimme yhteyden CCL18-kemokiinin geneettisen vaihtelun ja aivoverenvuodon sekä CP-vamman kehittymisen välillä. Tutkimuksemme mukaan hyvin ennenaikaisesti syntyneet koululaiset, joilla ei ollut CP- tai kehitysvammaa, suoriutuivat täysiaikaisina syntyneitä verrokkeja heikommin visuaalista hahmotusta ja sensomotoriikkaa sekä tarkkaavuutta ja toiminnanohjausta mittaavissa testeissä. Lisäksi havaitsimme sikiöaikaisen kasvuhäiriön ennustavan itsenäisesti heikkoa suoritusta kieltä, muistia ja oppimista testaavissa tehtävissä ennenaikaisesti syntyneillä lapsilla. Tietyt sytokiinit ja sytokiiniryppäät ovat yhteydessä aivovauriomekanismeihin. Nämä mekanismit saattavat yhdessä perinnöllisen alttiuden kanssa vaikuttaa myös CP-vamman syntyyn. Sikiöaikainen kasvuhäiriö ja ennenaikaisuus vaikuttavat lapsen myöhempään neurokognitiiviseen kehitykseen.

MicroRNA (miRNA) are small non-coding 21-23 nucleotides long one strand RNAs. They are among the major posttranscriptional regulators of gene expression that regulate both physiological and pathological processes. Some of microRNAs, amount of their expression respectively, are specific only for certain type of tissue or pathological condition. The hypothesis for my diploma thesis was that gene expression of 28 cardiovascular disease associated microRNAs (miR-1-3p, miR-16-5p, miR-17-5p, miR- 20a-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-29a-3p, miR-92a-3p, miR-100-5p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181-5p, miR-195-5p, miR- 199a-5p, miR-210-3p, miR-221-3p, miR-342-3p, miR-499a-5p, miR-574-3p) would differ in umbilical cord blood between groups of women with physiological pregnancies (FG), gestational hypertension (GH), preeclampsia (PE) and fetal growth restriciton (FGR). The studied cohort consisted of 184 pregnant women involving 44 controls, 47 GH pregnancies, 56 PE pregnancies and 37 FGR pregnancies. Relative quantification of microRNAs was performed by quantitative real-time PCR. Results showed a trend to miR-195-5p down-regulation in umbilical cord blood of GH patients. On the other hand, mild PE...

ObjectifLe diagnostic prénatal (DPN) a pour but de détecter des pathologies foetales in utero. L’objectif de ce travail était de mettre au point et d’appliquer les techniques d’exploration chromosomique en prénatal. Nous avons, tout d’abord, validé et évalué une plateforme de séquençage basée sur la technologie des semi-conducteurs, Ion Proton®, pour le dépistage prénatal non-invasif (DPNI) des principales aneuploïdies en routine clinique, puis évalué l’intérêt de l’Analyse Chromosomique sur Puces à ADN (ACPA) dans le diagnostic prénatal des retards de croissance intra-utérin (RCIU) foetaux. Matériel et Méthodes Nous avons inclus prospectivement 2505 patientes enceintes analysées par huit laboratoires hospitalo-universitaires de génétique : 695 grossesses à haut risque pour la trisomie 21 (risque ≥1/250 ou avec anomalie échographique) dans une étude de validation de la technique du test ADN libre circulant (ADNlc), et 1810 grossesses à risque, sans anomalie échographique, en routine clinique. Les issues de grossesses étaient toutes disponibles dans l’étude de validation et pour 521 grossesses dans l’étude en routine clinique. L’ADNlc extrait d’échantillons plasmatiques était séquencé, puis les données étaient analysées à l’aide du logiciel WISECONDOR. Les résultats des tests ADNlc étaient comparés aux caryotypes foetaux ou 7 aux données à la naissance. Nous avons aussi évalué le taux d’échec et comparé trois méthodes d’évaluation de la fraction foetale (FF) (RASSF1A, DEFRAG et SANEFALCON). Nous avons rétrospectivement inclus tous les foetus référés pour un prélèvement invasif pour RCIU et étudié les résultats de technique d’hybridation in situ en fluorescence (FISH), caryotypes et ACPA. Résultats Les résultats des deux cohortes de l’étude sur l’ADNlc étaient cohérents et les âges gestationnels n’étaient pas significativement différents ; les données ont été combinées afin d’étoffer la cohorte à analyser. Respectivement, la sensibilité et la spécificité étaient de : 98.3% (95% IC, 93.5–99.7%) et 99.9% (95% IC, 99.4–100%) pour la trisomie 21; 96.7% (95% IC, 80.9–99.8%) et 100% (95% IC, 99.6–100%) pour la trisomie 18 ; et 94.1% (95% IC, 69.2–99.7%) et 100% (95% IC, 99.6–100%) pour la trisomie 13. Le taux de non rendus était de 1.2% initialement puis après réanalyse de 0.6%. L’estimation de la FF avec les méthodes RASSF1A et DEFRAG étaient comparables, toutes deux compatibles avec une utilisation en routine clinique. Parmi les 162 foetus RCIU (78 associés et 84 isolés) inclus dans l’étude ACPA, 15 avaient une FISH pathologique : 10 RCIU associés et cinq RCIU isolés. Parmi 143 foetus étudiés par ACPA, 10 (7%) présentaient un variant du nombre de copies (CNV), tous étaient des RCIUs associés (10/65 soit 15.4%; 95 IC: 8.4%‐26.2%), versus 0/78 dans le groupe RCIUs isolés (95% IC: 0%‐5.6%). Six foetus (4.2%) ont présenté des variants de signification inconnue (VSI) (trois RCIU associés et trois RCIU isolés). Conclusion : Notre étude évaluant le test ADNlc utilisant la technologie des semi-conducteurs est la première étude clinique à rapporter les issues de grossesses dans une population aussi large. La plateforme est performante pour le DPNI des principales aneuploïdies. Notre protocole robuste est facilement applicable en routine clinique. Notre étude souligne une augmentation de rendement diagnostique de l’ACPA de 6.1% (4/65) par rapport au caryotype pour le DPN des foetus présentant un RCIU associé. Aucun CNV pathogène n’a été mis en évidence dans le groupe RCIU isolé. L’ADNlc pourrait-il supplanter l’ACPA dans cette population de RCIU isolé ? Le développement du test ADNlc a permis de limiter le nombre de prélèvements invasifs et donc leurs complications [...]. / ObjectivePrenatal diagnosis allows to detect fetal pathologies in-utero. The goal of this work was both technical development and application of the chromosomal exploration technics in prenatal diagnosis. First, we aimed to validate and evaluate the performance metrics of the highthroughput semiconductor sequencing platform, Ion Proton®, in non-invasive prenatal genetic screening (NIPS) for common fetal aneuploidies in a clinical setting and, then to evaluate the diagnostic utility of prenatal diagnosis using the chromosomal microarray analysis (CMA) for fetuses presenting with isolated or associated intrauterine growth restriction (IUGR). Methods : First, regarding NIPS, a prospective cohort study including 2505 pregnant women from eight academic genetics laboratories (695 high risk pregnancies for trisomy 21 (risk ≥1/250 or with ultrasound anomalies) in a validation study, and 1810 such pregnancies, without ultrasound anomalies, in a real-life NIPS clinical setting) was conducted. An outcome was available for all cases in the validation cohort and for 521 in the clinical cohort. Cell-free DNA from plasma samples was sequenced using the Ion Proton sequencer, and sequencing data were analyzed using the open-access software, WISECONDOR. Performance metrics for detection 10 of trisomies 21, 18 and 13 were calculated based on either fetal karyotype result or clinical data collected at birth. We also evaluated the failure rate and compared three methods of fetal fraction quantification (RASSF1A assay, and DEFRAG and SANEFALCON software). Then, regarding the CMA study, we retrospectively included all fetuses with IUGR referred for prenatal testing and studied by rapid fluorescence in situ hybridization (FISH), karyotype, and CMA. Results :In the NIPS study, results from both cohorts were consistent and their gestational age was not significantly different, so their data were combined to increase the sample size for analysis. Sensitivities and specificities, respectively, were as follows: for trisomy 21, 98.3% (95% CI, 93.5–99.7%) and 99.9% (95% CI, 99.4–100%); for trisomy 18, 96.7% (95% CI, 80.9–99.8%) and 100% (95% CI, 99.6–100%); and for trisomy 13, 94.1% (95% CI, 69.2–99.7%) and 100% (95% CI, 99.6–100%). Our failure rate was 1.2% initially and as low as 0.6% after retesting some of the failed samples. Fetal fraction estimation by the RASSF1A assay was consistent with DEFRAG results, and both were adequate for routine diagnosis. Among the 162 IUGR fetuses (78 associated and 84 isolated IUGR) included in the CMA study, 15 had an abnormal FISH result: 10 associated and five isolated fetal IUGRs. Among the 143 fetuses studied by CMA, 10 (7%) presented pathogenic copy number variations (CNVs). All 10 were in the associated fetal IUGR group (10/65 or 15.4%; 95% confidence interval [CI]: 8.4%‐26.2%) versus 0/78 in the isolated fetal IUGR group (95% CI: 0%‐5.6%). Six fetuses (4.2%) carried variants of unknown significance (VOUS) (three associated and three isolated fetal IUGRs). Conclusion: We described one of the largest studies evaluating Ion Proton-based NIPS and the first clinical study reporting pregnancy outcome in a large series of patients. This platform is highly efficient in detecting the three most common trisomies. Our protocol is robust and can be implemented easily in any medical genetics’ laboratory. Our second study highlighted the added value of CMA in the case of associated fetal IUGR with an incremental yield of 6.1% (4/65) over karyotyping. No pathogenic CNVs were reported in the isolated fetal IUGR group. Could NIPS supplant CMA in isolated fetal IUGR? The development of the NIPS test has reduced prenatal invasive testing and therefore its complications [...].