O Diabetes melito gestacional (DMG) está relacionado ao crescimento fetal exagerado. Entender a influência do controle glicêmico no padrão do crescimento fetal auxilia na identificação dos fetos com maior risco de desvios da normalidade. Objetivo: comparar o crescimento fetal em pacientes com DMG segundo o controle glicêmico. Método: estudo retrospectivo com 89 gestantes da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo no período de maio de 2005 a junho de 2011. Foram incluídas apenas pacientes com gestações únicas e com DMG diagnosticado pelo teste de tolerância oral à glicose de 100 gramas ou 75 gramas, sem doenças maternas que interferem no ganho de peso fetal, sem malformações fetais ou tabagismo. Todas as gestantes realizaram retornos semanais no pré-natal especializado, dieta para diabetes, controle glicêmico diário e uso de insulina quando necessário. Foi introduzida insulina quando 30% ou mais das glicemias capilares aferidas em uma semana eram superiores a: jejum> 95 mg/dl, 1hora pós-prandial> 140 mg/dl ou 2 horas pós-prandial> 120 mg/dl. As gestantes foram divididas para análise dos dados em dois grupos: se apresentassem menos de 30% de hiperglicemias em todas as glicemias capilares aferidas eram alocadas no grupo 1 (n= 65), e caso contrário no grupo 2 (n=24). Elas realizaram três ultrassonografias (USG): USG 0 (entre 18 a 24 semanas), USG 1 (início do tratamento do DMG) e USG 2 (final do tratamento). Foram analisadas as médias dos percentis do peso e da circunferência abdominal fetal para avaliação do padrão do crescimento fetal, e o ganho de peso fetal entre os USG. Resultados: Não houve diferenças quanto à: idade materna e índice de massa corpórea pré-gestacional; ganho de peso materno no pré-natal; idade gestacional do diagnóstico do DMG e do início do tratamento; idade gestacional da realização das USG. As médias glicêmicas foram de 98,7 mg/dl no grupo 1 e de 111,9 mg/dl no grupo 2 (p<0,001). O uso de insulina foi de 16,9% vs. 87,5%; p<0, 001 nos grupos 1 e 2, respectivamente. O valor da hemoglobina glicada no diagnóstico de DMG foi maior no grupo 2 (5,52% vs. 5,93%; p<0,001). Os percentis do peso fetal foram semelhantes entre os grupos no USG 0 e no USG 1, porém significativamente maiores no grupo 2 no USG 2 (p=0,02). Os percentis da circunferência abdominal fetal foram significativamente maiores no grupo 2 no USG 1 e USG 2. O grupo 2 apresentou um maior ganho de peso fetal (27,53 gramas/dia vs. 33,43gramas/dia; p=0,001) e um maior peso ao nascer (3247g. vs. 3499g.; p=0,025). Conclusões: O controle glicêmico influenciou no peso fetal, as gestantes que apresentaram mais de 30% de hiperglicemia durante o pré-natal apresentaram maior velocidade de ganho de peso fetal durante o tratamento e recém-nascidos com maior peso ao nascer. O percentil da circunferência abdominal fetal parece modificar antes que o percentil do peso fetal e seria um marcador mais sensível de alterações no potencial de crescimento fetal. / Gestational diabetes (GDM) is related to overgrowth fetal. Objective: To evaluate fetal growth in patients with gestational diabetes (GD) according to glycemic control. Methods: Eighty-nine pregnant women seen at the Obstetric Clinic of the University Hospital, University of São Paulo School of Medicine, between May 2005 and June 2011 were studied retrospectively. The study included non-smoking women with singleton pregnancies and GD diagnosed by the 100- or 75-g oral glucose tolerance test. The patients had no maternal disease interfering with fetal weight gain and there were no fetal malformations. All women attended weekly specialized prenatal care, consumed a diabetes diet, performed daily glycemic control, and used insulin when necessary. Insulin was introduced when >=30% of the capillary glucose measurements obtained in one week were >95 mg/dl (fasting), >140 mg/dl (1 h postprandial), or >120 mg/dl (2 h postprandial). The women were divided into two groups according to the frequency of hyperglycemic episodes in all capillary glucose measurements obtained during treatment: group 1 (n = 65, <=30%), and group 2 (n = 24, >30%). Ultrasound (US) was performed at three time points for the comparison of mean fetal weight and abdominal circumference percentiles and fetal weight gain (g/day): US0 (18 to 24 weeks), US1 (at the beginning of treatment of GD), and US2 (at the end of treatment) Results: The two groups did not differ in terms of maternal age, pregestational BMI, prenatal maternal weight gain, gestational age at the diagnosis of GD, time of onset of treatment, or gestational age at US. Mean glycemia was 98.7 mg/dl in group 1 and 111.9 mg/dl in group 2 (p<0.001). Insulin was used by 16.9% of the patients of group 1 vs. 87.5% of group 2 (p<0.001). HbA1c at diagnosis of GD was higher in group 2 (5.52% vs. 5.93%; p<0.001). Fetal weight percentiles were similar in the two groups at US0 and US1, but significantly higher in group 2 at US2 (p=0.02). Abdominal circumference percentiles were significantly higher in group 2 at US1 and US2. Fetal weight gain (27.5 vs. 33.4 g/day; p=0.001) and birthweight (3247 vs. 3499 g; p=0.025) were higher in group 2. Conclusions: The pattern of fetal growth in patients with GD varies according to glycemic control. The fetal growth velocity and newborn birthweight were higher in women who presented >30% of hyperglycemic episodes during treatment of GD. The abdominal circumference percentile seems to change before the weight percentile and would be a more sensitive marker of altered fetal growth.

Abstract Fetal alcohol syndrome (FAS) is a common cause of mental retardation and is attributable to the teratogenic effects of alcohol exposure in utero in individuals with genetic susceptibility. The Coloured communities from the Western and Northern Cape regions have some of the highest recorded incidence rates (~70 affected children per 1000 live births) in the world. The candidate genes selected for this study belong to the family of alcohol dehydrogenase genes that code for enzymes which metabolise alcohol. The ADH1B and ADH1C genes have previously been examined in the Western Cape Coloured community and the enzyme encoded by the allele ADH1B*2 was significantly associated with protection against the development of FAS. ADH4, a new candidate gene, was selected due to its role in both the alcohol and retinol metabolic pathways. A case-control genetic association study was performed to examine the potential roles of the ADH1B, ADH1C and ADH4 genes in the etiology of FAS in two Coloured populations from the Northern and Western Cape. Single nucleotide polymorphisms found within the candidate genes were typed by PCR-based methods in samples from the FAS children, their mothers and controls. Significant associations were observed in the Western Cape cohort but were not replicated in the Northern Cape. Allelic association tests revealed that ADH1B*2 may be a protective marker as it occurred more commonly in the controls than the mothers (p= 0.038). The alleles of the polymorphic variant, ADH4.8, have been shown to influence the promoter activity of ADH4 (the ‘A’ allele has been shown to increase the activity of the promoter when compared to the ‘C’ allele as the same position). The alleles of this polymorphic marker were significantly associated with the risk for FAS. The ‘A’ allele was shown to occur more commonly in the mothers and FAS-affected children (p= 0.002 and 0.035 respectively) when compared to the controls, suggesting a role in disease susceptibility while the ‘C’ allele was shown to occur more commonly in the controls. Itwas also observed that ADH1B and ADH4.8 when examined together in a haplotype demonstrated an association with susceptibility to the disease. While the 2-C haplotype (ADH1B-ADH4.8) was shown to be associated with protection against the development of FAS, the 1-A haplotype was associated with increased susceptibility. The results suggest that mothers with the common ADH1B*1 allele and presumably a normal ADH1B function but an increased level of ADH4 (allele ‘A’) as a result of the promoter mutation, will, when the blood alcohol concentration is high, have an increased risk of having a child with FAS. Conversely when the mothers have a faster alcohol metabolising rate due to the allele ADH1B*2 and normal levels of ADH4 protein (allele ‘C’), the circulating alcohol in the blood is removed efficiently resulting in maternal protection against developing the disease. This study has also highlighted the genetic diversity within individuals of the South African Coloured population. Haplotype analysis and logistic regression revealed that the Western and Northern Cape Coloured communities are genetically different and as a result, the samples could not be pooled for analysis. Although the two groups of controls were genetically diverse, haplotype analysis revealed that the sample of mothers and FAS-affected children were not statistically different between the provinces thus possibly suggesting a similar genetic etiology for the disease. The results from this study suggest that the ADH genes do play a role in the pathogenesis of FAS.

Renal blood flow and micropuncture studies were conducted in late gestation fetal sheep (gestational age 134 - 141 days; term 150 days) and neonatal lambs (8 - 18 days after birth) to study the forces involved in glomerular filtration (GFR) and characterize the tubuloglomerular feedback (TGF) system during development. These studies required the kidney to be immobilized so stable models in acutely prepared anaesthetized animals were developed. Fetuses were studied in a heated water bath exteriorized from the uterus but with an intact umbilical circulation. The lower GFR in fetuses than lambs was found to be due to both lower net filtration pressures (P<0.001) and a lower ultrafiltration coefficient (P<0.001). TGF was present at both ages, but in fetuses the sensitivity was higher (P<0.001) and reactivity was lower (P<0.001). The reduction in TGF sensitivity between fetal and neonatal life may facilitate the increase in renal blood flow and GFR which occurs at this time. In both fetuses and lambs the sensitivity of the TGF curve was reduced by volume expansion (P<0.001, P<0.05) and reactivity was reduced in lambs (P<0.001). Furosemide abolished TGF at both ages. In both fetuses and lambs, TGF reactivity was increased by inhibition of neuronal nitric oxide synthase (nNOS; P<0.01, P<0.001) and in lambs, TGF sensitivity was increased (P<0.01). This indicates that nitric oxide produced by the macula densa modulates TGF during development. In offspring destined to become hypertensive due to maternal dexamethasone treatment in early gestation TGF sensitivity tended to be enhanced in fetal life and was enhanced in lambs (P<0.01). Increased TGF sensitivity may contribute to the development of hypertension in this model of developmental programming. The effects of nNOS inhibition were attenuated in these animals, suggesting that they have low tonic production of nitric oxide by the macula densa. In fetuses whose mothers had been subtotally nephrectomized prior to mating to induce maternal mild renal impairment, GFR was increased (P<0.01) but net filtration pressure was reduced (P<0.001) so the ultrafiltration coefficient was increased (P<0.001). TGF sensitivity was normal and the effects of nNOS inhibition were similar to normal fetuses.

The chronic and severe executive functioning (EF) and self regulation deficits experienced by children with fetal alcohol spectrum disorders (FASD) are well documented and EF and self regulation have been identified as core targets for intervention. The goals of this dissertation were to: (i) examine the effects of a self regulation treatment for children with FASD on a range of EF measures (ii) examine neural markers of treatment outcome and determine if functional magnetic resonance imaging (fMRI) can differentiate treatment responders from nonresponders; (iii) determine if treatment effects generalize to child compliance and qualitatively examine the treatment process. Twenty-five children with FASD participated. Using a wait-list control design children were assigned to an immediate treatment (TXT; n = 12) or delayed treatment control (DTC; n = 13) condition. All children received an evaluation of EF and fMRI at baseline and 12-week follow-up. Parents also completed questionnaires assessing EF and behavior as well as a feedback questionnaire upon completion of treatment. A subset of parents tracked compliance over the course of their child’s therapy. For the TXT group only, parent questionnaires were readministered at 6 month follow-up. At 12-week follow-up, children in the TXT group displayed significant improvements in inhibitory control and social cognition. Additionally, parents reported improved behavioral and emotional regulation. This improvement, along with a further improvement in parent-rated inhibitory control, was maintained at the 6-month follow-up. Neuroplastic changes were also observed as the TXT group showed increased BOLD response in the right prefrontal cortex (PFC) and left caudate on a task of inhibitory control. When treatment responders were compared to nonresponders a pattern of increased BOLD response was found bilaterally in the PFC and left caudate. Compliance tracking revealed that self regulation therapy generalized to improved child compliance at home. Qualitative analysis indicated that perceived clinician competence, caregiver insight about child’s problems and caregiver perceptions of child’s insight about their problems, were the most commonly endorsed themes by caregivers. Results from this research signify that children with FASD are responsive to psychotherapy and following a brief intervention, showed improvements in self regulatory abilities that generalize to other EF areas and parent-reported behaviors.

El presente trabajo estudiará el Valor Predictivo del Monitoreo Electrónico Fetal en el Diagnóstico de Distocia Funicular. Para ello se analizaron 1332 registros cardiotocográficos anteparto de los cuales ' ) 11 presentaron Signos Sugestivos de Distocia Funicular y estos fueron evaluados para determinar las características cardiotocográficos (línea de base, variabilidad y Dip III) y la validación de pruebas diagnosticas, en el Instituto Materno Perinatal en el periodo marzo - mayo del 2002. La naturaleza del estudio es Prospectiva, longitudinal, correlacional, no experimental con un nivel de confianza del 95%, Para la validación de la prueba diagnóstica estimamos la Sensibilidad (62.20%), Especificidad (92.29%), Valor Predictivo Positivo (76,841/6) y Valor Predictivo Negativo (84.52%); según nuestras estadísticas la distocia funicular representa un 29.80% del total de pacientes que asisten a la Unidad de Medicina Fetal del Instituto Materno Perinatal y además encontramos un resultado perinatal del 0.64% de depresión neonatal teniendo en cuenta el puntaje Apgar. Los resultados del presente trabajo son: 1) Las medidas de valoración diagnóstica de una prueba como son la Sensibilidad, Especificidad, Valor Predictivo Positivo y Valor Predictivo Negativo. 2) La incidencia de Depresión Neonatal es baja cuando existe signos sugestivos de distocia funicular en el trazado cardiotocográfico.

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 140-164). Available also in a digital version from Dissertation Abstracts.

A serious consequence of maternal consumption of alcohol during pregnancy is the fetal alcohol syndrome (FAS): characterized by growth deficiency (both pre- and post-natal), craniofacial dysmorphology and central nervous system (CNS) dysfunction. However, in the absence of the characteristic facial features, and without confirmed history of alcohol exposure, clinical diagnosis remains a significant challenge. Recently, the term fetal alcohol spectrum disorders (FASD) has been adopted to encompass all diagnoses relating to a history of prenatal alcohol exposure. The purpose of this study was to test the following three general hypotheses: Children with FASD 1) demonstrate specific deficits in oculomotor control that can be measured using saccadic eye movement tasks, 2) display specific deficiencies in multiple domains of executive function that can be determined using standardized neuropsychological tasks, and 3) reveal deficits in oculomotor control that correlate with deficiencies in executive function as measured using standardized neuropsychological tasks. A preliminary study revealed significant deficits in saccadic eye movement tasks and provided the foundation for a large, multi-centered study assessing oculomotor control and neuropsychological function in children with FASD. A mobile laboratory was created, which facilitated recruitment of 92 control subjects and 89 subjects with FASD. We found significant evidence for oculomotor deficits across multiple outcome measures following the saccadic eye movement experiments, especially for oculomotor tasks that probe aspects of executive function. Additionally, children with FASD exhibited performance deficits in neuropsychological tasks that assess planning, attention, spatial working memory and strategy; cognitive skills also included within the domain of executive function. Finally, significant correlations between these two objective measures were found for children with FASD, which were not evident in the control sample. These findings are consistent with significant frontal lobe dysfunction. This is an exciting area of research that may hold promise in developing effective screening tools that can assist in the diagnosis of individuals with a history of prenatal alcohol exposure. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2008-08-28 15:41:20.595

Spontaneous foetal loss is the most common complication of pregnancy, affecting up to 20% of recognized pregnancies and recurring in 1-3% of cases. Abnormal maternal inflammation and systemic maternal coagulopathies are associated with foetal loss; however, the causal role of inflammation in the development of obstetric coagulopathies has not been determined. Further, questions remain as to whether maternal systemic coagulopathies are associated with placental haemostatic alterations and what role these local alterations play in foetal outcome. We hypothesized that abnormal maternal inflammation during pregnancy is causally linked to maternal coagulopathies and that these coagulopathies are associated with impaired utero-placental blood flow preceding foetal death. To induce inflammation-mediated fetal death, we administered lipopolysaccharide (LPS; 100-µg/kg) to Wistar rats on gestational day 14.5 and characterized the systemic maternal coagulation status 1hr post LPS administration using thromboelastograpy. Utero-placental haemostatic alterations were analyzed by periodic acid Schiff staining (PAS) and immunohistochemistry for fibrin/fibrinogen. Spiral arteriole peak flow velocity was determined by Doppler ultrasound. To determine causality between abnormal maternal inflammation, coagulopathies, and placental hemodynamics, the TNF -inhibitor etanercept (Enbrel®) was administered six hours prior to LPS administration. Systemic maternal coagulopathies were evident in 82% of LPS-treated dams and were associated with specific placental haemostatic alterations as well as reduced utero-placental blood flow. Etanercept administration prevented the development of systemic coagulopathies and placental haemostatic alterations. Furthermore, etanercept maintained normal spiral arteriole peak flow velocity. This study demonstrated that abnormal maternal inflammation is causally linked to systemic coagulopathies specific to pregnancy. Moreover, we showed that inflammation-induced systemic coagulopathies are associated with placental haemostatic alterations and reduced utero-placental blood flow preceding foetal death. Modulation of maternal inflammation may thus be useful in the prevention of coagulopathies associated with complications of pregnancy. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2011-08-01 14:29:12.489

Some previous work has suggested that fetal rejection may be a cause of spontaneous abortion in humans. The aim of the work presented, therefore, was to determine the influence of maternal alloantibody formation against paternal B lymphocytes, detected by the erythrocyte antibody rosette inhibition (EAI) assay, on the outcome of semi-allogeneic pregnancies. Preliminary studies indicated that EA rosette inhibition was a suitable assay for these investigations, because it detected alloantibodies directed to any major histocompatibility complex (MHC) antigen, irrespective of the ability of the antibody to fix complement; this was an important consideration because alloantibodies induced by pregnancy are often only weakly lytic. In humans it was found that antibodies to paternal B lymphocytes occurred significantly more commonly in normal primigravid and multigravid pregnancies when compared with pregnancies of similar gestation which aborted. These antibodies were shown to be directed to MHC encoded antigens by family studies, but were not removed by platelet absorption, strongly suggesting that they were not class I MHC antigens. Studies in inbred rats demonstrated that these paternal antigens were encoded by the RT1A region of the rat MHC alone. Maternal alloantibody responses to RT1A antigens appeared to be suppressive because studies using the rat kidney allograft model showed that multiparous rats with EAI antibodies to paternal strain cells enjoyed prolonged graft survival. It was also found that pregnancies in which the paternal strain differed only by RT1A antigens induced a suppressive immune response in the mother. These results suggest that immune responses to MHC encoded antigens, possibly unique, may prevent fetal rejection in some instances.

Alcohol consumption during pregnancy is detrimental to the developing nervous system of the unborn offspring. The hippocampus, one of the two brain regions where neurogenesis persists into adulthood, is particularly sensitive to the teratogenic effects of alcohol. The present study examined the effects of alcohol exposure throughout all three trimester equivalents on the stages of adult neurogenesis. Prenatal and early postnatal alcohol exposure (PPAE) altered cell proliferation in adult but not adolescent animals and increased early neuronal differentiation without affecting cell survival in both age groups. The levels of brain-derived neurotrophic factor (BDNF) were not affected by PPAE in the dentate gyrus but were significantly decreased in the Cornu ammonis region of the hippocampus. These results might explain the functional deficits seen in this hippocampal sub-region. This study identified that voluntary wheel running increased cell proliferation, differentiation and survival as well as BDNF expression in both PPAE and control animals. / Graduate