Analysis of parameters of haemostasis in pre-eclamptic, normotensive pregnant and non-pregnant women.

Pregnancy is characterized by a state of heightened coagulation, which is exacerbated in pathological conditions such as pre-eclampsia (PET). PET is further associated with abnormal maternal inflammation and increased circulating microparticles (MP); however, a mechanistic link between these pathological features has never been established. It is proposed in this thesis that abnormal maternal inflammation is causally linked to pro-coagulant trophoblast MP shedding via a mechanism mediated by the pro-inflammatory cytokine tumour necrosis factor alpha (TNF), thereby contributing to maternal coagulopathies associated with PET. Using thromboelastography (TEG) and standard laboratory tests, haemostatic function was evaluated in PET and normotensive subjects at delivery and post-partum. Furthermore, the effects of the menstrual cycle and oral contraceptive (OC) use on haemostatic function were assessed in non-pregnant subjects in order to understand their influence on post-partum haemostasis. Plasma TNF and pro-coagulant MP levels were evaluated in the pregnant subjects. Using chorionic villi explants from human term placentas, MPs were quantified after TNF administration. The pro-coagulant potential of placental MPs was evaluated by TEG by spiking whole-blood with medium containing MPs from chorionic villi. TEG identified increased whole-blood coagulability in PET subjects at delivery, demonstrating its increased sensitivity over standard laboratory tests at identifying haemostatic alterations associated with PET. Haemostatic alterations were normalized by six weeks post-partum. TEG also identified cyclic haemostatic variations associated with OC use. Chorionic villi treated with TNF (1 ng/ml) shed significantly more MPs than untreated placentas. MPs from chorionic villi increased the coagulability of whole-blood. Together, results provide evidence supporting the concept that abnormal maternal inflammation is causally linked to the development of maternal coagulopathies in pregnancy complications. Moreover, TEG may be superior to standard laboratory tests in evaluating haemostasis in pregnant and non-pregnant subjects.

Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women

Aims/hypothesis: Elevated anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), a soluble form of vascular endothelial growth factor receptor, and endoglin, a co-receptor for TGFß1, confer high risk of pre-eclampsia in healthy pregnant women. In this multicentre prospective study, we determined levels of these and related factors in pregnant women with type 1 diabetes, a condition associated with a fourfold increase in pre-eclampsia.
Methods: Maternal serum sFlt1, endoglin, placental growth factor (PlGF) and pigment epithelial derived factor were measured in 151 type 1 diabetic and 24 healthy non-diabetic women at each trimester and at term.
Results: Approximately 22% of the diabetic women developed pre-eclampsia, primarily after their third trimester visit. In women with pre-eclampsia (diabetic pre-eclampsia, n?=?26) vs those without hypertensive complications (diabetic normotensive, n?=?95), significant changes in angiogenic factors were observed, predominantly in the early third trimester and prior to clinical manifestation of pre-eclampsia. Serum sFlt1 levels were increased approximately twofold in type 1 diabetic pre-eclampsia vs type 1 diabetic normotensive women at the third trimester visit (p?<?0.05) and the normal rise of PlGF during pregnancy was blunted (p?<?0.05). Among type 1 diabetic women, third trimester sFlt1 and PlGF were inversely related (r2?=?42%, p?<?0.0001). Endoglin levels were increased significantly in the diabetic group as a whole vs the non-diabetic group (p?<?0.0001).
Conclusions/interpretation: Higher sFlt1 levels, a blunted PlGF rise and an elevated sFlt1/PlGF ratio are predictive of pre-eclampsia in pregnant women with type 1 diabetes. Elevated endoglin levels in women with type 1 diabetes may confer a predisposition to pre-eclampsia and may contribute to the high incidence of pre-eclampsia in this patient group.

Known risk factors for violence predict 12-month-old infants' aggressiveness with peers

This study tested the hypothesis that 12-month-old infants' use of force against peers is associated with known risk factors for violence. We conducted a prospective longitudinal study, which included laboratory observations of firstborn British infants (N = 271) during simulated birthday parties. No gender differences in aggressiveness were observed. The infants' observed aggressiveness was significantly correlated with mothers' mood disorder during pregnancy and with mothers' history of conduct problems. Infants' observed aggressiveness was correlated with parents' ratings of infants' anger and aggression, which were also predicted by mothers' mood disorder and history of conduct problems. Our findings indicate that infants at risk for serious aggression can already be identified when the motor ability to use physical force first enters the human repertoire.

Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents

Reproductive disorders that are common/increasing in prevalence in human males may arise because of deficient androgen production/action during a fetal 'masculinization programming window'. We identify a potentially important role for Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) in Leydig cell (LC) steroidogenesis that may partly explain this. In rats, fetal LC size and intratesticular testosterone (ITT) increased ~3-fold between e15.5-e21.5 which associated with a progressive decrease in the percentage of LC expressing COUP-TFII. Exposure of fetuses to dibutyl phthalate (DBP), which induces masculinization disorders, dose-dependently prevented the age-related decrease in LC COUP-TFII expression and the normal increases in LC size and ITT. We show that nuclear COUP-TFII expression in fetal rat LC relates inversely to LC expression of steroidogenic factor-1 (SF-1)-dependent genes (StAR, Cyp11a1, Cyp17a1) with overlapping binding sites for SF-1 and COUP-TFII in their promoter regions, but does not affect an SF-1 dependent LC gene (3β-HSD) without overlapping sites. We also show that once COUP-TFII expression in LC has switched off, it is re-induced by DBP exposure, coincident with suppression of ITT. Furthermore, other treatments that reduce fetal ITT in rats (dexamethasone, diethylstilbestrol (DES)) also maintain/induce LC nuclear expression of COUP-TFII. In contrast to rats, in mice DBP neither causes persistence of fetal LC COUP-TFII nor reduces ITT, whereas DES-exposure of mice maintains COUP-TFII expression in fetal LC and decreases ITT, as in rats. These findings suggest that lifting of repression by COUP-TFII may be an important mechanism that promotes increased testosterone production by fetal LC to drive masculinization. As we also show an age-related decline in expression of COUP-TFII in human fetal LC, this mechanism may also be functional in humans, and its susceptibility to disruption by environmental chemicals, stress and pregnancy hormones could explain the origin of some human male reproductive disorders.

PAPP-A y β-hCG libre como predictores de preeclampsia y bajo peso al nacer en una población latina

Introducción: La Preeclampsia ocurre entre el 2-7% de los embarazos. Previos estudios han sugerido la asociación entre los niveles alterados de PAPP-A y la β-hCG libre con el desarrollo de Preeclampsia (PE) y/o Bajo Peso al Nacer (BPN). Metodología: El diseño del estudio es de Prueba Diagnóstica con enfoque de casos y controles. Las mediciones séricas de PAPP-A y la β-hCG libre, fueron realizadas entre la semana 11-13.6 días durante 2 años. Resultados: La cohorte incluyó 399 pacientes, la incidencia de PE fue de 2,26% y de BPN fue de 14.54%. El punto de corte del percentil 10 fue MoM PAPP-A: 0,368293 y MoM β-hCG libre: 0,412268; la especificidad en PE leve fue de 90,5 y para BPN de 90. Los MoM de la β-hCG libre, la edad y el peso materno se comportan como factores de riesgo, mientras que mayores valores de MoM de la PAPP-A y mayor número de partos factores de protección. Para el BPEG severo la edad materna y la paridad se comportan como factores de riesgo, mientras que un aumento promedio de los valores de los MoM de la PAPP-A y la β-hCG libre, como factores de protección en el desarrollo de BPEG Severo. Conclusiones: Existe una relación significativa entre los valores alterados de PAPP-A y de β-hCG libre, valorados a la semana 11 a 13 con la incidencia de Preeclampsia y de Bajo Peso al nacer en fetos cromosómicamente normales, mostrando unos niveles significativamente más bajos a medida que aumentaba la severidad de la enfermedad.

Factores de riesgo para morbilidad materna extrema en gestantes

Introducción: La morbilidad materna extrema es un término usado para definir cualquier condición obstétrica severa que amenaza la vida y requiere una intervención médica urgente con el fin de prevenir la probable muerte materna. Con el presente estudio se pretendió evaluar los factores de riesgo para morbilidad materna extrema en las gestantes del Hospital Universitario Mayor. Metodología Se realizó un estudio de casos y controles, comparando pacientes con MME y sin MME en una relación de 1:1. Se realizó un muestreo aleatorio simple teniendo en cuenta 95% de la población apareadas por diagnóstico de ingreso. Resultados Se incluyeron un total de 110 pacientes (55 en cada grupo). Ambas poblaciones fueron comprables. Ser de estrato socioeconómico bajo (p 0,000), haber tenido 2 o menos partos (p 0,000), ser tipo de sangre negativo (p0.000) realizar entre 0-3 controles prenatales (p 0,000), tener antecedente de preeclampsia (p 0,000), hipotiroidismo (p 0,000), o trastorno bipolar (p 0,000), son factores de riesgo significativos para presentar MME. Entre los factores protectores están tener más de tres partos OR 0,60 (IC95%: 0,17-0,82, p=0,00) y 7 o más controles prenatales OR 0,23 (IC95%: 0,09-0,55, p=0,000). Resultados concordantes con la literatura Discusión: Es importante dar a conocer los resultados del presente estudio para promover las campañas de prevención primaria, secundaria y terciaria con el fin de evitar las altas complicaciones que se pueden presentar en las mujeres en edad fértil de nuestra población.

Effect of heparin and fractionated heparin on trophoblast invasion

BACKGROUND: Heparin can significantly reduce pregnancy complications in women with certain thrombophilias, such as antiphospholipid syndrome. Recent reports suggest that heparin may act by mechanisms other than anticoagulation. However, the effect of heparin on trophoblast biology in the absence of thrombophilia has not been extensively investigated. Therefore, this study aimed to evaluate trophoblast invasion, using an established cell line and primary extravillous trophoblasts (EVTs), following exposure to heparin and fractionated heparin. METHODS: An EVT cell line (SGHPL-4) was used to study invasion in the presence of hepatocyte growth factor (HGF) and varying concentrations of fractionated and unfractionated heparin. These experiments were repeated using first trimester primary EVTs. RESULTS: Both forms of heparin significantly reduced HGF-induced invasion in the SGHPL-4 cell line. This suppression of invasion appeared to be dose-dependent for fractionated heparin. In primary EVT cells, fractionated heparin also demonstrated significant suppression of invasion. CONCLUSIONS: Heparin has the potential to reduce trophoblast invasion in cell lines and first trimester EVT cells. This article highlights the need for further evaluation of these medications in vitro and in vivo, especially when used in the absence of thrombophilic disorders.

'Ultrasound is an invaluable third eye, but it can't see everything' : a qualitative study with obstetricians in Australia

Background: Obstetric ultrasound has come to play a significant role in obstetrics since its introduction in clinical care. Today, most pregnant women in the developed world are exposed to obstetric ultrasound examinations, and there is no doubt that the advantages of obstetric ultrasound technique have led to improvements in pregnancy outcomes. However, at the same time, the increasing use has also raised many ethical challenges. This study aimed to explore obstetricians' experiences of the significance of obstetric ultrasound for clinical management of complicated pregnancy and their perceptions of expectant parents' experiences. Methods: A qualitative study was undertaken in November 2012 as part of the CROss-Country Ultrasound Study (CROCUS). Semi-structured individual interviews were held with 14 obstetricians working at two large hospitals in Victoria, Australia. Transcribed data underwent qualitative content analysis. Results: An overall theme emerged during the analyses, 'Obstetric ultrasound - a third eye', reflecting the significance and meaning of ultrasound in pregnancy, and the importance of the additional information that ultrasound offers clinicians managing the surveillance of a pregnant woman and her fetus. This theme was built on four categories: I:'Everyday-tool' for pregnancy surveillance, II: Significance for managing complicated pregnancy, III: Differing perspectives on obstetric ultrasound, and IV: Counselling as a balancing act. In summary, the obstetricians viewed obstetric ultrasound as an invaluable tool in their everyday practice. More importantly however, the findings emphasise some of the clinical dilemmas that occur due to its use: the obstetricians' and expectant parents' differing perspectives and expectations of obstetric ultrasound examinations, the challenges of uncertain ultrasound findings, and how this information was conveyed and balanced by obstetricians in counselling expectant parents. Conclusions: This study highlights a range of previously rarely acknowledged clinical dilemmas that obstetricians face in relation to the use of obstetric ultrasound. Despite being a tool of considerable significance in the surveillance of pregnancy, there are limitations and uncertainties that arise with its use that make counselling expectant parents challenging. Research is needed which further investigates the effects and experiences of the continuing worldwide rapid technical advances in surveillance of pregnancies.

Maternal postpartum adjustment in Victoria's south west : a rural perspective

Aims & Rationale/Objectives
This study examined maternal postpartum adjustment in the first 12 months. Firstly, we were interested in examining whether Parental Functioning would be affected by living or not living in a major South West regional centre. Secondly, we were interested in whether Parental Functioning would differ as a function of infants being under or over 6 months of age. Thirdly, we were interested in whether Parental Functioning would differ as a function of pregnancy and birth complications. Finally, we were interested in whether postpartum perceptions of Role Competence/Satisfaction and Social Support would be associated with the Postnatal Depression.

Methods
The (preliminary) sample included 69 rural mothers recruited from across five shire regions within South West Victoria. Indicators of Parental Functioning were assessed using self-report questionnaires. Demographic and medical information was also collected. Respondents to the study were mailed a questionnaire pack which was returned in a reply-paid envelope.

Principal Findings
The results regarding geographical location were non-significant. There were significant differences in Wellbeing but not Role Competence/Satisfaction, or Social Support as a function of infant age. There were significant differences in Wellbeing, Role Competence/Satisfaction, and Social Connectedness (but not actual social support) as a function of Pregnancy Complications but not Birth Complications. Finally, Role Competence/Satisfaction and Social Connectedness (but not actual social support) significantly contributed to the variance in Postnatal Depression.

Discussion
Findings suggest that mothers did not differ as a function of their geographical location. Overall, mothers had higher levels of parental functioning when their infants were over 6 months of age, and also, if they did not experience pregnancy complications (physical, emotional, both). Additionally, findings suggest that perceptions of competence in and satisfaction with the parenting role, and also feelings of 'connectedness' to social others, are protective factors against the development of postpartum adjustment disorders.

Implications
Given that depressive episodes are common during childbearing years, and have both short- and long-term developmental effects on the infant, these findings support a need for the development and examination of a perinatal and infant mental health programme for rural mothers and infants.

Hipertireoidismo na gravidez: repercussões materno-fetais

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Oxidative stress status of highly prolific sows during gestation and lactation

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Mola Completa em Gravidez Gemelar: relato de Caso

A gravidez gemelar na qual coexistem um feto normal e uma mola completa é um evento raro. Complicações clínicas e aumento de risco de malignização são de importância nesta patologia. Este trabalho descreve um caso de diagnóstico tardio em decorrência da presença do feto. Este diagnóstico foi feito no momento da resolução da gestação e confirmado por estudo histopatológico e citometria de fluxo. A resolução da gestação foi por via transpélvica em decorrência de hemorragia uterina maciça. O seguimento pós-molar evidenciou a persistência de níveis elevados de bhCG, obtendo-se remissão completa da doença com o uso do metotrexato. À luz deste caso, discutem-se o diagnóstico, a história natural e a conduta desta rara intercorrência na clínica obstétrica.

Fatores de risco para macrossomia fetal em gestações complicadas por diabete ou por hiperglicemia diária

OBJETIVO: identificar fatores de risco para a macrossomia fetal na população de gestantes portadoras de diabete ou hiperglicemia diária. MÉTODOS: estudo retrospectivo, tipo caso-controle, incluindo 803 pares de mães e recém-nascidos desta população específica, distribuídos em dois grupos: macrossômicos (casos, n=242) e não macrossômicos (controles, n=561). Foram comparadas variáveis relativas à idade, paridade, peso e índice de massa corporal (IMC), ganho de peso (GP), antecedentes de diabete, hipertensão arterial e tabagismo, tipo e classificação do diabete e indicadores do controle glicêmico no terceiro trimestre. As médias foram avaliadas pelo teste F e as variáveis categorizadas foram submetidas à análise univariada, utilizando-se o teste do chi². Os resultados significativos foram incluídos no modelo de regressão múltipla, para identificação do risco independente de macrossomia, considerando-se OR, IC 95% e valor de p. Para todas as análises foi estabelecido o limite de significância estatística de 5% (p<0,05). RESULTADOS: observou-se associação significativa entre macrossomia e GP maior que 16 kg, IMC >25 kg/m², antecedentes pessoais, obstétricos e, especificamente, o de macrossomia, classificação nos grupos de Rudge (IB e IIA + IIB), média glicêmica (MG) >120 mg/dL e média de glicemia pós-prandial >130 mg/dL no terceiro trimestre. Na análise de regressão múltipla, o GP >16 kg (OR=1,79; IC 95%: 1,23-1,60), o IMC >25 kg/m² (OR=1,83; IC 95%: 1,27-2,64), o antecedente pessoal de diabete (OR=1,56; IC 95%: 1,05-2,31) e de macrossomia (OR=2,37; IC 95%: 1,60-3,50) e a MG >120 mg/dL no terceiro trimestre (OR=1,78; IC 95%: 1,13-2,80) confirmaram risco independente para macrossomia nestas gestações de risco. CONCLUSÃO: o GP superior a 16 kg, o IMC maior ou igual a 25 kg/m², a MG superior a 120 mg/dL no terceiro trimestre e a presença de antecedentes pessoais de diabete ou de macrossomia foram identificados como fatores de risco para macrossomia fetal em gestantes portadoras de diabete ou de hiperglicemia diária.

Malformação arteriovenosa uterina após doença trofoblástica gestacional

OBJETIVO: investigar a presença e resultados de malformações vasculares uterinas (MAVU) após doença trofoblástica gestacional (DTG). MÉTODOS: estudo retrospectivo com inclusão de casos diagnosticados entre 1987 e 2004; 2764 pacientes após DTG foram acompanhadas anualmente com ultra-sonografia transvaginal e Doppler colorido no Centro de Neoplasia Trofoblástica Gestacional da Santa Casa da Misericórdia (Rio de Janeiro, RJ, Brasil). Sete pacientes tiveram diagnóstico final de MAVU baseado em análise ultra-sonográfica - índice de pulsatilidade (IP), índice de resistência (IR) e velocidade sistólica máxima (VSM) - e achados de imagens de ressonância nuclear magnética (RNM). Dosagens negativas de beta-hCG foram decisivas para estabelecer o diagnóstico diferencial com DTG recidivante. RESULTADOS: a incidência de MAVU após DTG foi 0,2% (7/2764). Achados ultra-sonográficos de MAVU: IP médio de 0,44±0,058 (extremos: 0,38-0,52); IR médio de 0,36±0,072 (extremos: 0,29-0,50); VSM média de 64,6±23,99 cm/s (extremos: 37-96). A imagem de RNM revelou útero aumentado, miométrio heterogêneo, espaços vasculares tortuosos e vasos parametriais com ectasia. A apresentação clínica mais comum foi hemorragia transvaginal, presente em 52,7% (4/7) dos casos. Tratamento farmacológico com 150 mg de acetato de medroxiprogesterona foi empregado para controlar a hemorragia, após a estabilização hemodinâmica. Permanecem as pacientes em seguimento, assintomáticas até hoje. Duas pacientes engravidaram com MAVU, com gestações e partos exitosos. CONCLUSÃO: presente sangramento transvaginal em pacientes com beta-hCG negativo e história de DTG, deve-se considerar a possibilidade de MAVU e solicitar avaliação ultra-sonográfica com dopplervelocimetria. O tratamento conservador é a melhor opção na maioria dos casos de MAVU pós-DTG.

Insulinoterapia na prenhez de ratas diabéticas: repercussões fetais e placentárias

O objetivo deste trabalho foi estudar as repercussões feto-placentárias da insulinoterapia na prenhez de ratas diabéticas. A droga diabetogênica foi aloxana na dose de 42 mg/kg de peso por via intravenosa. Formaram-se cinco grupos experimentais: controle (G1, n=12); diabete moderado não-tratado (G2, n=10); diabete moderado tratado com insulina (G3, n=11); diabete grave não-tratado (G4, n=12) e diabete grave tratado com insulina (G5, n=10). Foram obtidos 634 recém-nascidos e respectivas placentas. O resultado perinatal do tratamento com insulina teve relação direta com a qualidade do controle glicêmico. O tratamento inadequado do diabete moderado determinou níveis de hiperglicemia moderada nos recém-nascidos, não interferiu com o peso corporal dos filhotes e diminuiu a proporção de recém-nascidos grandes para a idade da prenhez (GIP). O controle adequado do diabete grave normalizou a glicemia dos recém-nascidos, aumentou o peso dos filhotes e diminuiu a proporção de recém-nascidos pequenos para a idade da prenhez (PIP). A administração de doses adequadas de insulina no grupo de ratas diabéticas grave diminuiu o peso das placentas mas sem modificar o índice placentário.