Introdução: O comportamento motor é primordial e se manifesta em todas as fases da vida. No entanto, algumas crianças apresentam atrasos marcantes na aquisição de habilidades motoras que podem acarretar em dificuldades futuras. Evidências da literatura têm sugerido que os fatores presentes no período pré-natal e de nascimento, tais como a restrição do crescimento intrauterino (RCIU) e o nascimento pré-termo (PT) podem atuar de maneira significativa no curso do desenvolvimento motor (DM) ao longo do tempo. Contudo, os resultados apresentados por estudos que investigaram o impacto do PT, RCIU e da associação PT e RCIU no DM ainda são contraditórios, merecendo mais investigações. Objetivo: Investigar o efeito das condições de nascimento PT e/ou RCIU no DM infantil. Método: Foram estudadas 1006 crianças pertencentes a uma coorte iniciada durante o pré-natal (22-25 semanas de gestação) em 2010, acompanhada no nascimento e reavaliada no segundo ano de vida em 2011/2013. As crianças foram classificadas em T-NRCIU (termo e não restrito); T-RCIU (termo + restrição do crescimento intrauterino); PT-NRCIU (pré-termo + não restrito) e PT-RCIU (pré-termo + restrição do crescimento intrauterino) para verificar o efeito do PT, RCIU e associações das condições (PT-RCIU) no desempenho motor. Por meio da bateria de testes \"Bayley Scales of Infant and Toddler Development Third Edition - screening\" foi avaliado o desempenho obtido na subescala motora fina (SMF) e motora grossa (SMG). Utilizou-se modelo de regressão linear múltipla para verificar associação entre PT e/ou RCIU com o escore de desempenho motor e calculou-se o risco relativo por meio de modelo de regressão de Poisson para verificar a associação entre as condições de nascimento e a classificação motora. Os modelos foram ajustados para as covariáveis maternas (hipertensão e/ou diabetes gestacional, utilização de álcool e/ou tabaco na gestação, nível de atividade física, escolaridade, idade e classe econômica) e da criança (crescimento fetal e sexo). Resultados: As crianças do grupo PT-RCIU apresentaram escores inferiores ao do grupo T-NRCIU nas SMF (coeficiente ? = -2,54, IC 95% -3,78; -1,30, p<0,001) e SMG (? = -1,62, IC95% -2,77; -0,47, p=0,006). Ainda, o grupo PT-RCIU esteve associado a maiores riscos de atrasos no desenvolvimento de habilidade motora fina (RR = 3,04, IC95% 1,36; 6,78, p=0,007) e grossa (RR = 2,97, IC95% 1,38; 6,40, p=0,005). Para os demais grupos, não foram observadas diferenças em relação ao grupo de referência. Conclusão: A RCIU e a prematuridade, desassociadas, não estiveram relacionadas ao baixo desempenho e aos atrasos motores. No entanto, a associação das duas condições, PT e RCIU, influenciou negativamente o desempenho motor e aumentou os riscos de atrasos motores no segundo ano de vida. / Introduction: The motor behavior is paramount and manifests itself in all phases of life. However, some children have marked delays in acquiring motor skills that may lead to future difficulties. Evidence from the literature has suggested that prenatal and birth factors such as intrauterine growth restriction (IUGR) and preterm birth (PT) may play a significant role in the course of motor development (MD). However, the results presented by studies investigating the impact of PT, IUGR and PT and IUGR association in MD are still contradictory, deserving further investigation. Objective: to investigate the effect of PT and / or IUGR on infant motor development (fine and gross motor skills) among 2 years old children. Method: We studied 1006 children belonging to a cohort started during the prenatal evaluation (22nd - 25th weeks gestational age), followed at birth in 2010 and reexamined in the second year of life in 2011/2013. The children were classified in T-NIUGR (term and not restricted); T-IUGR (term + intrauterine growth restriction); PT-NIUGR (preterm + not restricted) and PT-IUGR (preterm + intrauterine growth restriction) to verify the interaction between PT and IUGR in the infant motor performance. The performance of the fine motor (SMF) and gross motor subscale (SMG) was evaluated using the Bayley Scales of Infant and Toddler Development Third Edition screening. A multiple linear regression model was used to verify the association between PT and IUGR with the motor performance score and the relative risk was calculated using a Poisson regression model to verify the association between the birth conditions and the motor classification. The models were adjusted for maternal covariables (hypertension and / or gestational diabetes, alcohol and / or tobacco use during gestation, physical activity level, schooling, age and economic class) and the child (fetal growth and sex). Results: The children in the PT-IUGR group had lower motor performance than the T-NIUGR group in SMF (coefficient ? = -2.54, CI 95% -3.78, -1.30, p <0.001) and SMG ? = -1.62, 95% CI -2.77, -0.47, p = 0.006). Furthermore, the PT-IUGR group was associated with greater risks of delays in the development of fine motor skills (RR = 3.04, 95% CI 1.36; 6.78, p=0.007) and gross motor skills (RR = 2.97, 95% CI, 1.38; 6.40, p = 0.005). No difference could be observed between the other groups and T-NIUGR. Conclusion: The isolated effect of IUGR and prematurity, were not associated with poor performance and motor delays. However, the association of the two conditions, PT and IUGR, negatively influenced motor performance and increased the risk of motor delays in the second year of life.

INTRODUÇÃO: A associação entre restrição do crescimento fetal (RCF) e alterações renais envolvem questões como a relação entre a redução da vascularização renal nesses fetos e a hemodinâmica fetal durante a gestação que, até o momento, não estão suficientemente exploradas. Considerando que a causa primária da redução nefrônica nesses fetos seria o hipofluxo renal causado pela redistribuição da hemodinâmica fetal frente a estímulos hipoxêmicos, seria de esperar que a gravidade do acometimento fetal levasse a menor vascularização renal em fetos com RCF. OBJETIVOS: Este estudo objetivou avaliar fetos com restrição de crescimento fetal e, assim, (1) descrever o índice de pulsatilidade das artérias renais, o volume renal e os índices de vascularização renal, bem como (2) verificar correlações entre os achados dopplervelocimétricos das artérias umbilicais, da artéria cerebral média e do ducto venoso e o índice de pulsatilidade das artérias renais, o volume renal e os índices de vascularização renal (IV, IF, IVF) e entre o índice de pulsatilidade das artérias renais, o volume renal, os índices de vascularização e o índice de líquido amniótico. MÉTODOS: Oitenta e um fetos com RCF foram avaliados por Power Doppler tridimensional, no sentido de se determinarem dados relativos ao índice de pulsatilidade das artérias renais, o volume renal, os índices de vascularização renal, os índices de pulsatilidade das artérias umbilicais, da artéria cerebral média e do ducto venoso, e o índice de líquido amniótico. Os valores identificados foram submetidos a análises estatísticas com o intuito de se determinarem eventuais correlações entre os parâmetros renais avaliados. RESULTADOS: O índice de pulsatilidade das artérias renais variou entre 1,50 e 3,44, com mediana de 2,39 + 0,41; o volume renal variou de 1,90 a 18,90, com mediana de 8,54 + 3,43; o IV renal variou de 0,05 a 7,75, com mediana de 1,57 + 1,58; o IF variou de 19,04 a 40,0, com mediana de 28,29 + 5,06; e o IVF variou de 0,03 a 5,18, com mediana de 0,96 + 1,3. Não houve correlação entre o índice de pulsatilidade das artérias renais e o índice de pulsatilidade das artérias umbilicais, da artéria cerebral média e do ducto venoso; tampouco foi observada correlação entre o volume renal e o índice de pulsatilidade das artérias umbilicais, da artéria cerebral média e do ducto venoso. O IV renal e o IVF renal foram negativamente correlacionados com o índice de pulsatilidade do ducto venoso, e positivamente correlacionados com o índice de líquido amniótico. Não houve correlação entre os índices de vascularização e os achados dopplervelocimétricos das artérias umbilicais e da artéria cerebral média, nem entre o índice de pulsatilidade das artérias renais, do volume renal e do IF renal com o ILA. CONCLUSÕES: O índice de pulsatilidade do ducto venoso se mostrou melhor preditor de alterações nos índices de vascularização renal, indicando que essas alterações se tornam mais evidentes em fetos com RCF com maior comprometimento hemodinâmico / INTRODUCTION: The association between intrauterine growth restriction (IUGR) and renal alterations refers to issues such as the relation between reduced renal vascularization in these fetuses and the fetal hemodynamics during pregnancy, which were not sufficiently investigated so far. Considering that the primary cause of nefrons reduction in these fetuses would be the renal hypoflow caused by the redistribution of the fetal hemodynamics resulting from hypoxic stimuli, it would be expected that the severety of the fetal impairment could result in worse renal vascularization in IUGR fetuses. OBJECTIVES: This study aimed at evaluating IUGR fetuses in order to (1) describe the pulsatility index of renal arteries, the renal volume and the renal vascularization indexes, as well as (2) verify correlations of the doppler findings in the umbilical arteries, middle cerebral artery, and venous duct with the pulsatility index of the renal arteries, the renal volume, and the renal vascularization indexes (VI, FI, VFI), and of the pulsatility index of the renal arteries, the renal volume, and the renal vascularization indexes with the amniotic liquid index. METHODS: 81 fetuses with IUGR were assessed with tridimentional power doppler in order to determine data regarding the pulsatility index of the renal arteries, the renal volume, the renal vascularization indexes, the pulsatility indexes of umbilical arteries, middle cerebral artery and venous duct, and the amniotic liquid index. Data were undertaken to statistical analysis for establishing eventual correlations among such assessed parameters. RESULTS: Pulsatility index of renal arteries ranged from 1.50 to 3.44 (median of 2.39 + 0.41); renal volume ranged from 1.90 to 18.90 (median of 8.54 + 3.43); renal VI ranged from 0.05 to 7.75 (median of 1.57 + 1.58); renal FI ranged from 19.04 to 40.0 (median of 28.29 + 5.06); and renal VFI ranged from 0.03 to 5.18 (median of 0.96 + 1.3. There was no correlation between the pulsatility index of renal arteries and the pulsatility indexes of the umbilical arteries, middle cerebral artery, and venous duct; correlations were not observed as well between the renal volume and the pulsatility indexes of the umbilical arteries, middle cerebral artery, and venous duct. Renal VI and VFI correlated negatively with the pulsatility index of the venous duct, and positively with the amniotic liquid index. There was no correlation betweem renal vascularization indexes and doppler findings in umbilical arteries and in middle cerebral artery, neither between pulsatility index of renal arteries, renal volume and renal FI and the amniotic liquid index. CONCLUSION: The pulsatility index of the venous duct was better predictive of alterations in renal vascularization index, suggesting that such alterations are more evident in IUGR fetuses with more severe hemodynamic impairments

OBJETIVO: Avaliar o comportamento alimentar de recém-nascidos (RN) pequenos (PIG) e grandes (GIG) para a idade gestacional através de questionário específico e comparar com RN adequados para a idade gestacional (AIG). METODOLOGIA: Estudo de coorte prospectivo, cuja primeira fase consistiu na realização de uma entrevista para coleta de dados da mãe da gestação e do parto, bem como de dados socioeconômicos, com mães que tiveram seus filhos a termo no Hospital de Clínicas de Porto Alegre. Na segunda fase do estudo foi aplicado o questionário Baby Eating Behaviour Questionnaire (BEBQ) através de contato por telefone, com 1 mês do nascimento. RESULTADOS: Foram avaliados 126 RN (43 AIG, 43 PIG e 40 GIG). As análises não demonstraram diferenças significativas nos principais dados demográficos e perinatais em relação aos diferentes grupos de estudo. No entanto, foi observada uma maior escolaridade em mães de RN PIG (p=0,004) e uma menor prevalência de aleitamento materno exclusivo até a alta hospitalar em RN GIG (p=0,002). A análise de variância não encontrou diferença significativa entre os grupos em relação aos domínios do BEBQ, mesmo quando corrigido por sexo do RN. CONCLUSÃO: O estudo demonstrou que alterações do comportamento alimentar ainda não estão presentes com 1 mês de vida, sugerindo que não são inatas, e sim desenvolvidas com o passar do tempo. O estudo tem como limitação as avaliações do crescimento baseadas em registros de terceiros. / OBJECTIVE: To evaluate feeding behavior of infants born small (SGA) and large (LGA) for gestational age using a questionnaire, and compare them with infants born adequate for gestational age (AGA). METHODS: Prospective cohort study was carried out in which the first phase consisted of an interview about gestation and delivery, as well as socioeconomic data, with mothers who had their babies born at term in the Hospital de Clínicas de Porto Alegre. In the second phase of the study, the Baby Eating Questionnaire (BEBQ) was applied through telephone interview 1 month of birth. RESULTS: 126 infants (43 AGA, 43 SGA and 40 LGA) with a mean gestational age of 39.4 weeks were assessed. The analyses did not show significant differences in the main demographic and perinatal data between the different study groups. However, a higher level of schooling was observed in mothers of SGA infants (p = 0.004) and a lower prevalence of exclusive breastfeeding in the LGA (p = 0.002). The analysis of variance found no significant difference between the groups in any of the BEBQ domains, even when corrected for the sex of the baby. CONCLUSION: This study demonstrated that changes in feeding behavior are not yet present at 1 month of age, suggesting that they are not innate, but developed over time. The study is limited to growth assessments based on third-party records.

L’insuffisance placentaire est une pathologie grave avec un diagnostic souvent trop tardif empêchant la mise en place de thérapeutiques efficaces. Le but de ce travail de Thèse est de développer chez la rate gestante et de transposer à l’Homme des outils d’IRM fonctionnelle (IRMf) placentaire qui permettrait une quantification de la perfusion placentaire en pratique clinique.Matériels et méthodes : Trois études en IRMf font partie de cette Thèse.Les deux premières ont été réalisées sur un modèle murin. Une séquence dynamique avec injection d’un agent de contraste (DCE) a été développée avec une particule de fer de type SPIO dans un modèle chirurgical d’hypoperfusion placentaire chronique, avec mesure de la perfusion placentaire f en ml/min/100ml et de la fraction volumique (Vb) en %. Une autre technique d’IRMf a été développée avec l’Arterial Spin Labeling (ASL) permettant d’estimer la perfusion placentaire en ml/min/100g sans injection de produit de contraste exogène. La dernière étude était une recherche translationnelle. Elle a consisté au développement de séquences de DCE avec injection de chélate de gadolinium, pour obtenir la perfusion f en ml/min/100ml et la fraction volumique en %. Nous avons également étudié, au décours de cette étude, la pharmacocinétique materno-fœtale du chélate de gadolinium.Résultats : Chez l’animal en DCE avec SPIO, notre étude nous a permis de montrer qu'il était possible d'utiliser l’effet T1 des SPIO pour caractériser la microcirculation placentaire par f=159,4 ml/min/100ml (+/- 54,6) et Vb =39,2% (+/- 11,9) pour 31 placentas « normaux ». En cas de RCIU, f diminue significativement pour les 23 placentas étudiés (f= 108,1 ml/min/100ml +/- 41, p=0,004), alors que la fraction volumique placentaire n'est pas modifiée (Vb=42,8% +/- 16,7, p=0,24). L’ASL nous a permis d’estimer la perfusion placentaire pour 47 placentas en condition physiologique, avec une perfusion estimée à 146,8 ml/min/100g (+/- 70,1).Chez l’Homme, 14 placentas ont été étudiés avec une perfusion placentaire globale estimée à 183 ml/min/100ml (+/-144) et nous avons également mis en évidence deux types de cinétique de rehaussement placentaire (précoce et intense et plus tardif et moins intense). La pharmacocinétique nous a permis d'étudier quantitativement le passage du chélate de gadolinium chez le fœtus. Ce passage est faible: par rapport à la concentration initiale du Dotarem®, la concentration sanguine fœtale correspond à 18,1x10-6 %, la concentration dans le liquide amniotique à 242,8 x10-6 % et 0,3 % de la dose initiale de Dotarem® est présente dans le placenta environ 70 heures après l’injection.Conclusion : Ce travail illustre la variété des techniques d'IRM fonctionnelle disponibles pour l'étude du placenta. La perfusion placentaire peut être quantifiée en DCE avec un agent particulaire à base de fer (SPIO) ou sans injection de produit de contraste en ASL chez le rat. L’étude de la perfusion placentaire chez l'Homme est possible en DCE avec les chélates de gadolinium.Mots clés : IRM, DCE, chélates de Gadolinium, ASL, perfusion placentaire, grossesse, placenta, retard de croissance intra-utérin. / Placental insufficiency is a serious medical condition with a diagnosis made usually too late to prevent introduction of effective therapies. The aim of this thesis is to develop, in pregnant rats and translate to humans, functional MRI (fMRI) tools allowing quantification of placental perfusion in clinical practice.Materials and Methods: Three studies using fMRI are part of this thesis. The first two were performed on a murine model. A dynamic sequence with injection of a contrast agent (DCE) has been developed with an iron oxide particle (SPIO) in a surgical model of chronic placental hypoperfusion with placental perfusion measurement (f) in ml / min / 100 ml and placental fractionnal volume (Vb) in %. Another technique of fMRI was developed with Arterial Spin Labeling (ASL) to estimate placental perfusion in ml / min / 100g without injection of contrast media.The latest study was a translational research. It consisted in the development of a dynamic sequence with injection of gadolinium chelate, in order to obtain perfusion (f) in ml / min / 100 ml and placental fractionnal volume (Vb) in %. We also studied maternal and fetal pharmacokinetics of gadolinium chelate.Results: In animals with SPIO DCE, our study allowed us to show that it is possible to use the T1 effect of SPIO to characterize the placental microcirculation by f = 159.4 ml / min / 100ml (+ / - 54.6) and Vb = 39.2% (11.9 +/-) for 31 « normal » placentas. In case of IUGR, f decreases significantly for the 23 examined placentas (f = 108.1 ml / min / 100ml +/- 41, p = 0.004), whereas the volume fraction placenta is not modified (Vb = 42 +/- 16.7 8 %, p = 0.24). ASL has allowed us to estimate placental perfusion for 47 placentas under physiological conditions, with an estimated perfusion of 146.8 ml / min / 100 g (70.1 +/-).In humans, 14 placentas were studied with an estimated perfusion of 183 ml / min / 100ml (+/- 144) and we also identified two types of placental kinetic enhancement (early and intense and later and less intense). Pharmacokinetics have allowed us to study quantitatively the transfer of gadolinium chelate in the fetus. This transfer is low compared to the initial concentration of Dotarem® : fetal blood concentration is 18.1x10-6%, concentration in amniotic fluid is 242.8 x10-6 % and 0.3% of the Dotarem® initial dose is present in the placenta approximately 70 hours after injection.Conclusion: This study illustrates the variety of functional MRI techniques available for placental study. Placental perfusion can be quantified by DCE with an iron oxide particle (SPIO) or without injection of contrast in ASL, in a rat model. The study of placental perfusion in humans is also possible in DCE with gadolinium chelates.

INTRODUÇÃO: A associação entre restrição do crescimento fetal (RCF) e alterações renais envolvem questões como a relação entre a redução da vascularização renal nesses fetos e a hemodinâmica fetal durante a gestação que, até o momento, não estão suficientemente exploradas. Considerando que a causa primária da redução nefrônica nesses fetos seria o hipofluxo renal causado pela redistribuição da hemodinâmica fetal frente a estímulos hipoxêmicos, seria de esperar que a gravidade do acometimento fetal levasse a menor vascularização renal em fetos com RCF. OBJETIVOS: Este estudo objetivou avaliar fetos com restrição de crescimento fetal e, assim, (1) descrever o índice de pulsatilidade das artérias renais, o volume renal e os índices de vascularização renal, bem como (2) verificar correlações entre os achados dopplervelocimétricos das artérias umbilicais, da artéria cerebral média e do ducto venoso e o índice de pulsatilidade das artérias renais, o volume renal e os índices de vascularização renal (IV, IF, IVF) e entre o índice de pulsatilidade das artérias renais, o volume renal, os índices de vascularização e o índice de líquido amniótico. MÉTODOS: Oitenta e um fetos com RCF foram avaliados por Power Doppler tridimensional, no sentido de se determinarem dados relativos ao índice de pulsatilidade das artérias renais, o volume renal, os índices de vascularização renal, os índices de pulsatilidade das artérias umbilicais, da artéria cerebral média e do ducto venoso, e o índice de líquido amniótico. Os valores identificados foram submetidos a análises estatísticas com o intuito de se determinarem eventuais correlações entre os parâmetros renais avaliados. RESULTADOS: O índice de pulsatilidade das artérias renais variou entre 1,50 e 3,44, com mediana de 2,39 + 0,41; o volume renal variou de 1,90 a 18,90, com mediana de 8,54 + 3,43; o IV renal variou de 0,05 a 7,75, com mediana de 1,57 + 1,58; o IF variou de 19,04 a 40,0, com mediana de 28,29 + 5,06; e o IVF variou de 0,03 a 5,18, com mediana de 0,96 + 1,3. Não houve correlação entre o índice de pulsatilidade das artérias renais e o índice de pulsatilidade das artérias umbilicais, da artéria cerebral média e do ducto venoso; tampouco foi observada correlação entre o volume renal e o índice de pulsatilidade das artérias umbilicais, da artéria cerebral média e do ducto venoso. O IV renal e o IVF renal foram negativamente correlacionados com o índice de pulsatilidade do ducto venoso, e positivamente correlacionados com o índice de líquido amniótico. Não houve correlação entre os índices de vascularização e os achados dopplervelocimétricos das artérias umbilicais e da artéria cerebral média, nem entre o índice de pulsatilidade das artérias renais, do volume renal e do IF renal com o ILA. CONCLUSÕES: O índice de pulsatilidade do ducto venoso se mostrou melhor preditor de alterações nos índices de vascularização renal, indicando que essas alterações se tornam mais evidentes em fetos com RCF com maior comprometimento hemodinâmico / INTRODUCTION: The association between intrauterine growth restriction (IUGR) and renal alterations refers to issues such as the relation between reduced renal vascularization in these fetuses and the fetal hemodynamics during pregnancy, which were not sufficiently investigated so far. Considering that the primary cause of nefrons reduction in these fetuses would be the renal hypoflow caused by the redistribution of the fetal hemodynamics resulting from hypoxic stimuli, it would be expected that the severety of the fetal impairment could result in worse renal vascularization in IUGR fetuses. OBJECTIVES: This study aimed at evaluating IUGR fetuses in order to (1) describe the pulsatility index of renal arteries, the renal volume and the renal vascularization indexes, as well as (2) verify correlations of the doppler findings in the umbilical arteries, middle cerebral artery, and venous duct with the pulsatility index of the renal arteries, the renal volume, and the renal vascularization indexes (VI, FI, VFI), and of the pulsatility index of the renal arteries, the renal volume, and the renal vascularization indexes with the amniotic liquid index. METHODS: 81 fetuses with IUGR were assessed with tridimentional power doppler in order to determine data regarding the pulsatility index of the renal arteries, the renal volume, the renal vascularization indexes, the pulsatility indexes of umbilical arteries, middle cerebral artery and venous duct, and the amniotic liquid index. Data were undertaken to statistical analysis for establishing eventual correlations among such assessed parameters. RESULTS: Pulsatility index of renal arteries ranged from 1.50 to 3.44 (median of 2.39 + 0.41); renal volume ranged from 1.90 to 18.90 (median of 8.54 + 3.43); renal VI ranged from 0.05 to 7.75 (median of 1.57 + 1.58); renal FI ranged from 19.04 to 40.0 (median of 28.29 + 5.06); and renal VFI ranged from 0.03 to 5.18 (median of 0.96 + 1.3. There was no correlation between the pulsatility index of renal arteries and the pulsatility indexes of the umbilical arteries, middle cerebral artery, and venous duct; correlations were not observed as well between the renal volume and the pulsatility indexes of the umbilical arteries, middle cerebral artery, and venous duct. Renal VI and VFI correlated negatively with the pulsatility index of the venous duct, and positively with the amniotic liquid index. There was no correlation betweem renal vascularization indexes and doppler findings in umbilical arteries and in middle cerebral artery, neither between pulsatility index of renal arteries, renal volume and renal FI and the amniotic liquid index. CONCLUSION: The pulsatility index of the venous duct was better predictive of alterations in renal vascularization index, suggesting that such alterations are more evident in IUGR fetuses with more severe hemodynamic impairments

LEITE, F. Influência da restrição de crescimento intra-uterino na idade da menarca: estudo da coorte de nascidos vivos de Ribeirão Preto de 1978/9. 2008. 85 p. Dissertação (Mestrado) apresentada à Faculdade de Medicina de Ribeirão Preto/USP. A idade da menarca é um marco da puberdade e, quando antecipada, parece estar associada a um maior risco de desenvolvimento de câncer de mama, síndrome metabólica e obesidade. É possível que alterações no ambiente intrauterino, como a restrição de crescimento do feto, levem a interferências no sistema hipotálamo-hipófise-gonadal resultando em alterações na idade da menarca. Em vista da controvérsia dos fatores que influenciam na idade da menarca, este estudo testou a hipótese da associação entre restrição de crescimento intra-uterino (baixo peso ao nascer, pequeno para idade gestacional, restrição intra-uterina de Kramer) e antecipação da idade da menarca. Em uma sub-amostra foi testada a possível interação entre a restrição de crescimento intra-uterino e o índice de massa corpórea. Para esse estudo foram utilizadas informações coletadas nos seguimentos de 1987/9 e 2004/5 de 1056 meninas nascidas em Ribeirão Preto, provenientes do estudo de coorte dos nascidos vivos em Ribeirão Preto de 1978/9. Menarca antecipada foi definida como primeiro sangramento vaginal ocorrido antes dos 12 anos de idade. Análise univariada foi seguida de análise bivariada e multivariada por meio de modelo generalizado empregando distribuição de Poisson para estimativa de riscos relativos e erro padrão por meio de método robusto. Os fatores de confusão controlados foram idade, escolaridade e situação conjugal da mãe, número de irmãos, comprimento ao nascer, prematuridade e índice de massa corpórea (apenas para a subamostra). Em média, a menarca ocorreu aos 12,3 anos (DP=1,5). A ocorrência de menarca antecipada foi de 27,7% (n= 293) para a coorte inteira e de 29,1% (n= 172) na sub-amostra. Foi encontrada associação negativa entre restrição de crescimento intra-uterino, seja representado por baixo peso ao nascer (Risco Relativo, RR= 0,47; Intervalo de Confiança de 95%, IC95%: 0,26-0,84), pequeno para idade gestacional (RR = 0,57;IC95%:0,37-0,89) ou restrição de Kramer (RR= 0,65; IC95%:0,47-0,92), com a antecipação da idade da menarca. Os resultados foram semelhantes na análise da sub-amostra, porém sem significância estatística. Quando o índice de massa corpórea foi considerado na análise da sub-amostra, não houve modificação dos resultados. Desta forma, este estudo demonstrou associação negativa entre restrição de crescimento intra-uterino e antecipação da idade da menarca, ou seja, a restrição de crescimento foi fator de proteção da menarca antecipada. / LEITE, F. Influence of intrauterine growth restriction on the age of menarche: the cohort study of live births of Ribeirao Preto in 1978/9. 2008. 85 p. Dissertation (Master) submitted to the Faculty of Medicine of Ribeirao Preto/USP. This study tested the hypothesis of association between intrauterine growth restriction and early age of menarche. For this study, follow-up data (n = 1056) from the population based livebirth cohort study of Ribeirao Preto of 19789 were analyzed. Early menarche was defined as having the first menstrual event before 12 years-old and intrauterine growth restriction was defined by three measurements: low birthweight (< 2500grs), small for gestational age (< 10% Williams growth curve) and fetal growth ratio (< 0.85 mean weight for gestational age). Relative risks were estimated by generalized estimation equations (Poisson distribution) with robust method for estimation of standard errors. Analyzes were adjusted for maternal age, education and marital status, number of siblings, birth length and preterm. Body mass index was tested as intervenient or interaction factor in a subsample of the cohort examined at 9 yrs-old. The mean age of menarche was 12.3 years (Standard Deviation = 1.5). Early menarche was observed for 27.7% for the entire cohort and 29.1% for the sub-sample. Negative association was observed between intrauterine growth restriction and early menarche. The adjusted relative risks and respective confidence intervals (95% CI) for low birth weight, small for gestational age and fetal growth ratio were respectively: 0.47 (95% CI: 0.26-0.84), 0.57 (95% CI: 0,37-0,89), and 0.65 (95%CI: 0,47-0, 92). No evidence that body mass index was an intermediate or interaction factor was observed. Thus, this study showed a negative association between intrauterine growth restriction and anticipation of age of menarche.

The geometry of an organ’s vascular system determines the blood flow distribution to tissues for exchange of gas and nutrients by determining its vascular resistance. The importance of vascular geometry is evident in the placenta, where insufficient fetoplacental vascularity elevates vascular resistance thereby impairing perfusion, leading to one of the most common and severe pregnancy complications, intrauterine growth restriction (IUGR). The mouse is becoming a widely used model for human placental development due to the increasing availability of mouse models thought to have a placental defect. Vascular geometry can now be imaged and quantified using micro-computed tomography (micro-CT) and results used to estimate resistance to blood flow. This thesis first describes the implementation of contrast agent perfusion and micro-CT imaging of the mouse fetoplacental vasculature throughout late gestation. Application of a vascular segmentation technique is then described and evaluated for quantification of the arterial fetoplacental tree. Normal fetoplacental vascular development in late gestation is described for two common mouse strains, CD1 and C57Bl6 (B6). In B6 placentas, both late gestational capillary growth and thinning of the interhaemal membrane were blunted relative to CD1. Analysis of CD1 and B6 tree geometry revealed a constant number of arterial segments throughout late gestation in both strains but expansion of arterial diameters in B6 only, resulting in decreased B6 arterial resistance and shear stress in late gestation. Strain dependence shows the importance of genetics in fetoplacental vascular development. Quantification of the arterial tree in a mouse model of maternal pre-pregnancy exposure to chemicals commonly found in cigarettes revealed an increase in vascular tortuousity and a reduced number of arteriole sized vessels. This led to an increase in vascular resistance and a predicted decrease in blood flow, which could contribute to the observed reduction in fetal weights. In future studies, the methods described herein can be used in phenotyping numerous mouse models which currently are suspected to have a placental vascular defect.

The geometry of an organ’s vascular system determines the blood flow distribution to tissues for exchange of gas and nutrients by determining its vascular resistance. The importance of vascular geometry is evident in the placenta, where insufficient fetoplacental vascularity elevates vascular resistance thereby impairing perfusion, leading to one of the most common and severe pregnancy complications, intrauterine growth restriction (IUGR). The mouse is becoming a widely used model for human placental development due to the increasing availability of mouse models thought to have a placental defect. Vascular geometry can now be imaged and quantified using micro-computed tomography (micro-CT) and results used to estimate resistance to blood flow. This thesis first describes the implementation of contrast agent perfusion and micro-CT imaging of the mouse fetoplacental vasculature throughout late gestation. Application of a vascular segmentation technique is then described and evaluated for quantification of the arterial fetoplacental tree. Normal fetoplacental vascular development in late gestation is described for two common mouse strains, CD1 and C57Bl6 (B6). In B6 placentas, both late gestational capillary growth and thinning of the interhaemal membrane were blunted relative to CD1. Analysis of CD1 and B6 tree geometry revealed a constant number of arterial segments throughout late gestation in both strains but expansion of arterial diameters in B6 only, resulting in decreased B6 arterial resistance and shear stress in late gestation. Strain dependence shows the importance of genetics in fetoplacental vascular development. Quantification of the arterial tree in a mouse model of maternal pre-pregnancy exposure to chemicals commonly found in cigarettes revealed an increase in vascular tortuousity and a reduced number of arteriole sized vessels. This led to an increase in vascular resistance and a predicted decrease in blood flow, which could contribute to the observed reduction in fetal weights. In future studies, the methods described herein can be used in phenotyping numerous mouse models which currently are suspected to have a placental vascular defect.

Altered DNA methylation may lead to suboptimal fetal programming, increasing the risk of adverse pregnancy outcomes such as small for gestational age (SGA); however, few studies have examined the associations between DNA methylation, prenatal exposures, and fetal outcomes. Cross-sectional data from a larger, ongoing study were used to assess the impact of prenatal smoking on gene specific methylation of umbilical cord blood derived DNA and to investigate the association between gene-specific methylation and risk of SGA. The association between gene-specific DNA methylation and birthweight was also assessed. Maternal and infant covariates were abstracted from medical records, cigarette smoke exposure was determined by measuring cotinine in umbilical cord blood plasma, and the Illumina Infinium Methylation27 assay was used to assess CpG site specific methylation. Methylation was represented by a beta value ranging from 0 to 1. Gene-level methylation was calculated by averaging the methylation levels over the CpG sites interrogated in that gene. Logistic regression was used to generate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between SGA and methylation of CYP1A1, HIF1A, GSTT1, and GSTM1 and the association between cotinine level and hypermethylation of CYP1A1, HIF1A, GSTT1, and GSTM1. DNA was considered hypermethylated if the beta value was greater than or equal to the 75th percentile. Univariate and multivariable linear regression were used to examine the association between birthweight and methylation of the IGF1 and IGF2 gene. The analyses included 90 singleton births. A 0.10 unit increase in methylation of GSTT1 increased the risk of SGA almost 3-fold (OR=2.69, 95%CI=1.34, 5.43). A 5ng/ml increase in cotinine level increased the risk of hypermethylation of GSTT1 (OR=1.18, 95%CI=1.02, 1.37). Birthweight did not appear to be impacted by methylation of IGF2 (β=0.07, 95%CI=-2.91, 3.05), but a one standard deviation increase in methylation of IGF1 was associated with a 3.63% decrease in birthweight (95%CI= -6.49, -0.78). No differences in DNA methylation by prenatal vitamin intake were detected. These findings suggest that DNA methylation plays a critical role in fetal growth and may mediate the risk of SGA and low birthweight.

Σκοπός: Να αξιολογηθεί ο λόγος αγόρια/κορίτσια (sex ratio) στα παιδιά καπνιστριών και μη καπνιστριών μητέρων, σε σχέση με τη σειρά γέννησης των παιδιών (τόκος). Να αξιολογηθεί το αποτέλεσμα του καπνίσματος της μητέρας κατά την εγκυμοσύνη στην εμβρυική ανάπτυξη σε σχέση με τον τόκο την ηλικία και τον αριθμό των τσιγάρων που κάπνιζαν οι μητέρες ανά ημέρα κατά την εγκυμοσύνη και το φύλο των παιδιών. Σχεδιασμός: Προοπτική μελέτη. Τόπος: Πανεπιστημιακό Γενικό Νοσοκομείο Πατρών. Αντικείμενο: Μελετήθηκαν 2.108 τελοιόμηνα νεογνά που γεννήθηκαν από το 1993 έως και το 2002, 665 νεογνά καπνιστριών μητέρων και 1.443 νεογνά μη καπνιστριών μητέρων. Αποτελέσματα: Ο λόγος αγόρια/κορίτσια στο σύνολο των νεογνών που μελετήθηκε ήταν 1,09. Η υπεροχή των αγοριών στα παιδιά των καπνιστριών και μη καπνιστριών μητέρων ήταν 1,26 και 1,03 αντίστοιχα. Στα παιδιά των καπνιστριών μητέρων που ήταν τόκων 1, 2 και ≥3 ήταν 1,47, 1,35 και 0,92 αντίστοιχα, ενώ στα παιδιά των μη καπνιστριών μητέρων ήταν 1,04, 1,00 και 1,03 αντίστοιχα. Η στατιστική ανάλυση παλινδρόμησης έδειξε ότι η πιθανότητα για γέννηση αγοριού από καπνίστριες μητέρες ήταν σημαντικά μεγαλύτερη στις πρωτότοκες παρά στους τόκους ≥3, ανεξάρτητα από την ηλικία της μητέρας. Αντίστροφα, η σειρά γέννησης των παιδιών δεν επηρέασε τον λόγο αγόρια/κορίτσια στις μη καπνίστριες μητέρες. Αυξανομένου του τόκου στα νεογνά των μη καπνιστριών μητέρων παρατηρήθηκε μια σταδιακή αύξηση της ανάπτυξης ενώ στα νεογνά μη καπνιστριών μητέρων παρατηρήθηκε μια σταδιακή μείωση της ανάπτυξης. Αυτό το αποτέλεσμα ήταν περισσότερο εμφανές στα αγόρια. Ένα σημαντικά αρρνητικό αποτέλεσμα στην αύξηση παρατηρήθηκε από την στην συσχέτιση του καπνίσματος με τον τόκο (p=0,0013) και, με το φύλο και τον τόκο (p=0,001). Υπήρχε μια σημαντική αρρνητική συσχέτιση ανάμεσα στον αριθμό των τσιγάρων που καπνίζονταν ανά ημέρα και της αύξησης η δύναμη της οποίας αυξανόταν με την αύξηση του τόκου, κυρίως στα αγόρια. Συμπεράσματα: Οι πρωτότοκες μητέρες που κάπνιζαν κατά την εγκυμοσύνη γέννησαν σημαντικά περισσότερα αγόρια απ’ ότι κορίτσια, ενώ μητέρες με τόκους ≥3 γέννησαν περισσότερα κορίτσια. Δευτερότοκες γυναίκες που κάπνιζαν λιγότερα από 10 τσιγάρα την ημέρα γέννησαν σημαντικά περισσότερα αγόρια, αλλά ο λόγος αγόρια/κορίτσια ελαττώθηκε όταν κάπνιζαν ≥10 τσιγάρα την ημέρα. Το κάπνισμα της μητέρας κατά την κύηση προκαλεί καθυστέρηση στην εμβρυική αύξηση, κυρίως στα αγόρια, ένα αποτέλεσμα που ενισχύεται με τον τόκο αλλά είναι ανεξάρτητο από την ηλικία της μητέρας. / Objective: To assess the sex ratio in offspring of smoking and nonsmoking mothers in relationship to the parity. To examine the effect of maternal smoking during pregnancy on fetal growth in relationship to maternal parity, age and number of cigarettes smoked/day, and offspring’s gender. Design: Prospective study. Setting: University hospital. Subjects: Were studied 2018 term singleton neonates born form 1993 to 2002, 665 from smoking and 1443 from nonsmoking mothers. Main outcome measures: Secondary sex ratio in regard to maternal periconseptual smoking and parity. Results: The male preponderance in the offspring of smoking and nonsmoking mothers was 0.558 and 0.506, respectively (p=0.031). In the smoking women parity 1, 2 and 3 it was 0.596, 0.574 and 0.462, respectively, whereas in the nonsmoking it was 0.511, 0.500 and 0.508, respectively (p=0.02, 0.04 and 0.64, respectively). Logistic regression analysis showed that the possibility for a boy to be delivered by mothers who smoked was significantly greater in primiparous than in party ≥3, independently of the maternal age. Conversely, parity did not affect the sax ratio in the offspring of the nonsmoking mothers. With increasing parity, in the neonates of nonsmoking mothers there was a gradual increase of growth, whereas in neonates of smoking mothers there was a gradual decrease of growth. This effect was more pronounced in males. A significant negative main effect on growth resulted from the interaction of smoking with parity (p=0,013), and with gender and parity (p=0,001). There was a significant negative correlation between number of cigarettes smoked per day and growth, the strength of which increased with parity, mainly in males. Conclusions: Among women who smoked in the periconceptual period, significantly more male than female offspring are born from primiparous, whereas parity >3 give birth to more female offspring; women parity 2 give birth to significantly more male, but the sex ratio declines when they smoked ≥10 cigarettes/day. Maternal smoking during pregnancy causes a delay in getal growth, which is greater in male offspring, an effect that is enhanced with parity but is independent of maternal age.