Repercussões maternas, reprodutivas e perinatais do tratamento com extrato aquoso de folhas de Bauhinia forficata (Pata-de-vaca) na prenhez de ratas não-diabéticas e diabéticas

Pós-graduação em Ginecologia, Obstetrícia e Mastologia - FMB

Diagnosi prenatale delle malformazioni fetali: ecografia e risonanza magnetica a confronto in 11 anni di esperienza

Obiettivo: Valutare l’accuratezza reciproca dell’ecografia “esperta” e della risonanza magnetica nelle diagnosi prenatale delle anomalie congenite. Materiali e metodi: Sono stati retrospettivamente valutati tutti i casi di malformazioni fetali sottoposte a ecografia “esperta” e risonanza magnetica nel nostro Policlinico da Ottobre 2001 a Ottobre 2012. L’età gestazionale media all’ecografia e alla risonanza magnetica sono state rispettivamente di 28 e 30 settimane. La diagnosi ecografica è stata confrontata con la risonanza e quindi con la diagnosi postnatale. Risultati: sono stati selezionati 383 casi, con diagnosi ecografica o sospetta malformazione fetale “complessa” o anamnesi ostetrica positiva infezioni prenatali, valutati con ecografia “esperta”, risonanza magnetica e completi di follow up. La popolazione di studio include: 196 anomalie del sistema nervoso centrale (51,2%), 73 difetti toracici (19,1%), 20 anomalie dell’area viso-collo (5,2%), 29 malformazioni del tratto gastrointestinale (7,6%), 37 difetti genito-urinari (9,7%) e 28 casi con altra indicazione (7,3%). Una concordanza tra ecografia, risonanza e diagnosi postnatale è stata osservata in 289 casi (75,5%) ed è stata maggiore per le anomalie del sistema nervoso centrale 156/196 casi (79,6%) rispetto ai difetti congeniti degli altri distretti anatomici 133/187 (71,1%). La risonanza ha aggiunto importanti informazioni diagnostiche in 42 casi (11%): 21 anomalie del sistema nervoso centrale, 2 difetti dell’area viso collo, 7 malformazioni toraciche, 6 anomalie del tratto gastrointestinale, 5 dell’apparato genitourinario e 1 caso di sospetta emivertebra lombare. L’ecografia è stata più accurata della risonanza in 15 casi (3,9%). In 37 casi (9,7%) entrambe le tecniche hanno dato esito diverso rispetto agli accertamenti postnatali. Conclusioni: l’ecografia prenatale rimane a tutt’oggi la principale metodica di imaging fetale. In alcuni casi complessi e/o dubbi sia del sistema nervoso centrale sia degli altri distretti anatomici la risonanza può aggiungere informazioni rilevanti.

Polybrominated diphenyl ethers: Potential human exposure through household dust and dryer lint

This MPH thesis consists of (1) literature review of the relatively new synthetic persistent organic pollutants (POP), polybrominated diphenyl ethers (PBDEs), a type of flame retardant posing a potential public health hazard, (2) Presentation of data on PBDE levels in dryer lint from Dallas, TX and Hamburg, Germany. ^ PBDEs are used as additive fire retardants in plastics, polyurethane foam and electronic equipment to reduce flammability and thus save life and property. PBDEs have been widely used beginning in the 1970s. They resemble polychlorinated biphenyls (PCBs) in structure and toxicity. PBDEs are found in environmental sediments, sludges, and wildlife and even in human blood, milk and tissues. ^ PBDEs, due to their lipophilicity, accumulate in fat and other tissues and biomagnify up the food chain, with increasing concentrations. Animal studies have suggested potential health effects including thyroid disruption, permanent learning and memory impairment, fetal malformations, developmental neurotoxicity and, at high doses, possibly cancer. ^ PBDE levels are increasing in blood and breast milk in North America, but PBDEs intake unlike PCBs appears to be not primarily through food; food PBDE levels in the U.S. are not markedly higher than in Europe yet U.S. human blood and milk levels are much higher. For this reason various exposure pathways including PBDE contaminated dust and air have been studied to better characterize routes of PBDE intake into humans. ^ The scientific literature on PBDE levels in household dust reports higher PBDE concentration in dust than that found in dryer lint; levels in the U.S are elevated compared to other countries with congeners such as BDE 47, 99, 100 and 209 predominating. The United Kingdom has elevated BDE 209 due to high usage of Deca commercial mixture. These studies suggest that indoor PBDE contamination through household dust could be a potential source of PBDE exposure and body burden especially in young children. ^ PBDE levels in dryer lint from U.S ranged from 321 to 3073 ng/g (Mean: 1138 ng/g, Median: 803 ng/g) and from Germany were from 330 to 2069 ng/g (Median: 71ng/g, Mean: 361 ng/g). High median levels in U.S samples indicate contamination of lint with PBDEs although the source of the PBDEs in lint may be from dryer electrical components or air deposition onto clothes, lint may be one source of PBDE exposure to humans. ^

Polybrominated diphenyl ether (PBDE) exposure in North Americans: Cause for concern?

Polybrominated diphenyl ethers (PBDEs) are brominated flame retardants (BFRs) that have been widely produced and used as flame retardants since the 1970’s in many consumer products such as carpet and drape linings, plastics used in electronics, computer and television casings and polyurethane foam used in chairs, sofas and mattresses. PBDEs are persistent organic pollutants (POPs), which, by definition, are toxic in nature, persistent in the environment and accumulative in living organisms. Animal studies have found PBDEs to cause health defects such as fetal malformations, delayed onset of puberty, decreased sperm count, behavioral changes, permanent learning and memory impairment, endocrine disruption, as well as cancer at high doses. Recent research involving humans reported that elevated breast milk PBDEs levels in their mothers are associated with cryptorchidism (absence of one or both testes from the scrotum) in newborn boys and adverse birth outcomes as well as elevated serum PBDE levels in mothers are associated with low sperm count in young men. There are three commonly manufactured PBDE commercial mixtures: Penta-, Octa-, and Deca-BDEs. Two of them (Octa- and Penta-BDEs) have been banned by the European Union and are being voluntarily phased out in the United States. However, Deca continues to be manufactured, used, and imported in the United States. This MPH thesis consists of a literature review of peer reviewed scientific articles concerned with PBDEs in the environment and in humans, as well as a discussion concerning different routes of exposure to PBDEs and their blood, milk and tissue levels as surrogates for body burdens in North Americans and in people from other countries. Results of this literature review shows PBDE levels in human blood, milk and tissues are higher in North Americans than people from other countries worldwide. To date, the highest level of PBDEs was found in a toddler’s blood in a California study. Despite the fact that PBDEs are associated with adverse health effects, and highest levels of PBDEs in North Americans, Deca-BDE is still manufactured, used and imported in the United States. There is an urgent need of new federal regulatory policy to ban completely the production, importation and use of all commercial mixtures of PBDEs.^

Transferência transplacentária de anticorpos em gestações gemelares

Há poucos dados na literatura sobre o transporte transplacentário de imunoglobulinas em gestações múltiplas. O objetivo deste estudo foi observar fatores que influenciam a concentração de imunoglobulina G (IgG) no cordão umbilical dos neonatos e a transferência transplacentária de IgG total e de IgG contra o Streptococcus grupo B (EGB), e lipopolissacarídeos (LPS) de Klebsiella spp. e Pseudomonas spp.. Métodos: estudo prospectivo realizado no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo no período de 2012 a 2013. Foram coletadas amostras de sangue materno e de cordão umbilical no momento do parto. Os critérios de inclusão foram gestações gemelares com ausência de sinais de infecção por HIV, citomegalovírus, Hepatites B e C, toxoplasmose e rubéola e ausência de doenças autoimunes, malformação fetal e síndromes genéticas. A análise multivariada foi realizada para avaliar a associação entre os níveis de IgG em cordão umbilical e as taxas de transferência de anticorpos com a concentração materna de IgG, a corionicidade da gestação, a presença de insuficiência placentária, a restrição de crescimento intrauterino, a idade gestacional de nascimento, o peso de nascimento, o tabagismo, a doença materna e a via de parto. Resultados: a concentração de IgG total em cordão umbilical apresentou correlação positiva com os níveis maternos séricos de IgG total e a idade gestacional do parto. Os níveis de IgG total em cordão umbilical foram significativamente menores em gestações monocoriônicas quando comparadas às dicoriônicas. A taxa de transferência de IgG total apresentou correlação positiva com a idade gestacional do parto, mas negativa com as concentrações maternas de IgG total. As concentrações de IgG contra EGB e LPS de Klebsiella spp. e Pseudomonas spp. apresentaram associação com os níveis maternos de IgG específicos contra esses antígenos e com o diabetes. Os níveis de IgG contra LPS de Klebsiella spp. também foram associados com o peso de nascimento e com hipertensão materna. As taxas de transferência de IgG contra EGB e LPS de Pseudomonas spp. apresentaram correlação com os níveis maternos de IgG específicos contra os antígenos referidos. A taxa de transferência de IgG contra EGB também esteve associada com a idade gestacional do parto, enquanto a taxa de transferência de IgG contra LPS de Pseudomonas spp. apresentou correlação com diabetes. Não houve correlação entre a taxa de transferência de IgG contra a LPS de Klebsiella spp. com nenhum fator analisado. Conclusão: em gestações gemelares, a concentração total de IgG em cordão umbilical foi influenciada pela concentração materna de IgG total, pela idade gestacional do parto e pela corionicidade placentária. As concentrações de IgG total foram significativamente menores em gestações monocoriônicas que em dicoriônicas. As concentrações séricas de IgG contra EGB e LPS de Klebsiella spp. e Pseudomonas spp. em cordão umbilical apresentaram associação com os níveis maternos de IgG específicos contra esses antígenos e com a presença de diabetes. Todos os outros parâmetros estudados apresentaram diferentes associações com as concentrações de IgG e com as taxas de transferências de IgG específicas contra cada antígeno investigado

Quando a oftalmologia diagnostica uma patologia sistémica : a propósito de um caso clínico

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Should valproate be taken during pregnancy?

The Australian Registry of Antiepileptic Drug Use in Pregnancy includes 172 instances in which women took sodium valproate, with or without other antiepileptic drugs, during pregnancy. These pregnancies resulted in a substantially higher (p < 0.05) rate of malformed offspring (15.1%) compared with 348 pregnant women who took antiepileptic drugs other than valproate (2.3%) and 40 pregnancies in epileptic women who took no antiepileptic drugs (2.5%). At valproate doses of 1400 mg and below per day, the mean rate of pregnancies with fetal malformations was 6.42% and did not seem to be dose-dependent. At higher valproate doses, the mean rate of pregnancy with fetal malformation was 33.9% and appeared to increase with increasing drug dosage. This finding suggests the need for reappraisal of the use of valproate in women who may become pregnant or are pregnant whilst the drug is taken. The therapeutic policy adopted may depend on whether valproate doses below 1400 mg per day are regarded as safe for the fetus. This study indicates that the risk of malformation associated with such doses was just statistically significantly (p < 0.05) higher than that associated with other antiepileptic drugs. Various possible clinical scenarios are discussed.

EXAMINATION OF THE EFFECTS OF VALPROIC ACID EXPOSURE OR P300 PROTEIN INHIBITION ON THE BALANCE OF APOPTOSIS AND PROLIFERATION IN P19 EMBRYONAL CARCINOMA CELLS

Valproic acid (VPA), a commonly-used anticonvulsant drug, is associated with increased risk of fetal malformations, including neural tube defects (NTDs). Previous in vivo studies determined that VPA-exposed embryos with a NTD had altered expression of several proteins regulated by p300, a histone acetyltransferase (HAT) protein. p300 is capable of acetylating histones and non-histone proteins through its HAT activity, allowing it to transcriptionally regulate genes as well as modulate the stability and activity of specific proteins. NFκB, Stat3 and Egr1, all of which function as transcription factors, are regulated by p300 through its HAT activity. Together, these proteins all play an important role in maintaining the balance of apoptosis, proliferation and differentiation, the regulation of which is extremely important for proper embryonic development. The studies in this thesis utilized P19 embryonal carcinoma (EC) cells in order to determine the effects of VPA exposure on the expression of p300 and the aforementioned transcription factors, as well as apoptosis and proliferation, in vitro. P19 EC cells were exposed to C646, a selective p300 inhibitor, in order to assess whether the effects observed as a result of VPA exposure were due to p300 protein degradation. It was found that VPA exposure for 24 hours in P19 EC cells in vitro resulted in a significant decrease in p300 protein expression. VPA exposure also significantly decreased NFκB protein expression, while resulting in increased Stat3 protein expression. However, Stat3 acetylation and phosphorylation, which both contribute to Stat3 activation, were significantly decreased as a result of VPA exposure. p300 inhibition resulted in a significant decrease in NFκB, similar to what was observed as a result of VPA exposure, which suggests that VPA-mediated degradation of p300 may play a role in reduced NFκB protein expression following VPA exposure. Conversely, Stat3 protein expression, acetylation and phosphorylation were not significantly changed as a result of p300 inhibition, suggesting that p300 degradation does not play a role in VPA’s effects on Stat3 protein expression and activation. VPA exposure also resulted in a significant increase in apoptosis, while p300 inhibition did not significantly increase apoptosis. These data suggest that p300 degradation plays a role in VPA-mediated teratogenicity, and that VPA may target other cellular mechanisms in order to exert its teratogenic effects.

Prenatal detection of congenital renal malformations by fetal ultrasonographic examination: an analysis of 709,030 births in 12 European countries.

The study was performed to evaluate the prevalence of prenatal ultrasound diagnoses for renal anomalies in 20 registries of 12 European countries, and to compare the different prenatal scanning policies. Standardized data were acquired from 709,030 livebirths, stillbirths, and induced abortions during the study period of 2.5 years and transmitted for central analysis. At least one renal malformation was diagnosed in 1130 infants and fetuses. Prenatal diagnosis (PD) was given in 81.8% of all cases, 29% of these pregnancies were terminated. The highest detection rate was reported for unilateral multicystic dysplastic kidneys with 97% (102/105). An early diagnosis was documented for exstrophy of bladder at a mean gestational age of 18.5 weeks. Dilatations of the upper urinary tract were seen late in pregnancy at 28.3 weeks. Terminations of pregnancies (TOP) were performed in 67% (58/86) of the detected bilateral renal agenesis/dysgenesis, but only 4% of the unilateral multicystic dysplastic renal malformations (4/102). In about 1/3 of the cases, renal malformations are within the category of associated malformations, which include multiple non-syndromal malformations, chromosomal aberrations, and non-chromosomal syndromes. Renal malformations were detected in 2/3 of the associated category by the first prenatal ultrasound scan. Detection rates vary in the different countries of the European community due to diverse policies, ethical, and religious background. Countries with no routine ultrasound show the lowest rates in detection, and termination of pregnancy. Prenatally detected renal malformations should result in a careful examination for further anomalies. Prenatal ultrasound fulfills the needs of screening examinations and is a good tool in detecting lethal and severe renal malformations.

Follow-up of Pregnant Women With Autoimmune Hepatitis The Disease Behavior Along With Maternal and Fetal Outcomes

Goals: To assess maternal and fetal outcomes and clinical management of pregnancy in patients with autoimmune hepatitis (AIH). Background: There is a paucity of information about maternal and fetal outcomes, and AIH activity during pregnancy and in the postpartum period. There is no consensus about the administration of azathioprine during pregnancy and breastfeeding. Study: Retrospective analysis of 54 pregnancies (3 still in progress) in 39 AIH patients. Results: The median age at conception was 24 years, and 68.4% of women had liver cirrhosis. Before conception and in early pregnancy, azathioprine and prednisone were administered in 48.1%, but treatment regimen vas usually changed further to 20 mg/d prednisone and 20.4%, were off treatment. There were 36 livebirths, and fetal loss rates were 29.4% (13 miscarriages, 1 stillbirth, and 1 ectopic pregnancy). Preterm birth rate was 11.8%. In 2 cases, there was acute fetal distress; and in 2 others congenital malformations (3.9%). The rate of serious maternal complication was 7.8%, with no deaths. There were no flares in 41.2% pregnancies, but aminotransferase elevations occurred in 54.9%, 31.4% of which were true AIH relapses, only registered in the postpartum period. Conclusions: Despite the high fetal miscarriage rate, pregnancy in AIH was safe. Patients needed careful monitoring, especially in the postpartum period because of relapses. There was no evidence of a cause and effect relationship among azathioprine administration and premature births and congenital abnormalities, but more studies are necessary. Higher doses of prednisone may be an alternative option for those who prefer azathioprine withdrawal during pregnancy.

Evaluation of prenatal ultrasound diagnosis of fetal abdominal wall defects by 19 European registries.

OBJECTIVES: To evaluate the current effectiveness of routine prenatal ultrasound screening in detecting gastroschisis and omphalocele in Europe. DESIGN: Data were collected by 19 congenital malformation registries from 11 European countries. The registries used the same epidemiological methodology and registration system. The study period was 30 months (July 1st 1996-December 31st 1998) and the total number of monitored pregnancies was 690,123. RESULTS: The sensitivity of antenatal ultrasound examination in detecting omphalocele was 75% (103/137). The mean gestational age at the first detection of an anomaly was 18 +/- 6.0 gestational weeks. The overall prenatal detection rate for gastroschisis was 83% (88/106) and the mean gestational age at diagnosis was 20 +/- 7.0 gestational weeks. Detection rates varied between registries from 25 to 100% for omphalocele and from 18 to 100% for gastroschisis. Of the 137 cases of omphalocele less than half of the cases were live births (n = 56; 41%). A high number of cases resulted in fetal deaths (n = 30; 22%) and termination of pregnancy (n = 51; 37%). Of the 106 cases of gastroschisis there were 62 (59%) live births, 13 (12%) ended with intrauterine fetal death and 31 (29%) had the pregnancies terminated. CONCLUSIONS: There is significant regional variation in detection rates in Europe reflecting different policies, equipment and the operators' experience. A high proportion of abdominal wall defects is associated with concurrent malformations, syndromes or chromosomal abnormalities, stressing the need for the introduction of repeated detailed ultrasound examination as a standard procedure. There is still a relatively high rate of elective termination of pregnancies for both defects, even in isolated cases which generally have a good prognosis after surgical repair.

Prenatally engineered autologous amniotic fluid stem cell-based heart valves in the fetal circulation.

Prenatal heart valve interventions aiming at the early and systematic correction of congenital cardiac malformations represent a promising treatment option in maternal-fetal care. However, definite fetal valve replacements require growing implants adaptive to fetal and postnatal development. The presented study investigates the fetal implantation of prenatally engineered living autologous cell-based heart valves. Autologous amniotic fluid cells (AFCs) were isolated from pregnant sheep between 122 and 128 days of gestation via transuterine sonographic sampling. Stented trileaflet heart valves were fabricated from biodegradable PGA-P4HB composite matrices (n = 9) and seeded with AFCs in vitro. Within the same intervention, tissue engineered heart valves (TEHVs) and unseeded controls were implanted orthotopically into the pulmonary position using an in-utero closed-heart hybrid approach. The transapical valve deployments were successful in all animals with acute survival of 77.8% of fetuses. TEHV in-vivo functionality was assessed using echocardiography as well as angiography. Fetuses were harvested up to 1 week after implantation representing a birth-relevant gestational age. TEHVs showed in vivo functionality with intact valvular integrity and absence of thrombus formation. The presented approach may serve as an experimental basis for future human prenatal cardiac interventions using fully biodegradable autologous cell-based living materials.

Detection of Congenital Anomalies by Fetal Ultrasonographic Examination across Europe.

Objectives: Birth defects are a major health burden. Primary prevention is at present emerging, i.e. folate supplementation. When it is not possible, as is still the case for most birth defects, research is needed to determine how an optimal provision of prenatal diagnosis and use of services can be achieved. Ultrasound scans in the midtrimester of pregnancy are now a routine part of antenatal care in most European countries. The objective of this study was to evaluate the prenatal diagnosis of congenital anomalies by fetal ultrasonographic examination across Europe. Methods: Data from 20 registries of congenital malformations in 12 European countries were included. The prenatal ultrasound screening programs in the countries ranged from no routine screening to 3 fetal scans offered, including 2 for biometric purposes and 1 for search of congenital anomalies, the anomaly scan. Results: There were 8,126 cases with congenital anomalies with an overall prenatal detection rate of 44.3%. Termination of pregnancy was performed in 1,657 cases (21.8%). There was significant variation in the prenatal detection rate between regions with the lowest detection rate in registries of countries without routine fetal screening (Denmark and The Netherlands) and the highest detection rate in registries of countries with at least 1 anomaly scan (France, Germany, Italy, Spain, UK). However, there were large variations among the registries with a high detection rate. There were significant differences in the prenatal detection rate and proportion of induced abortions between isolated anomalies and associated anomalies (chromosomal aberrations, recognized syndromes, and multiple without chromosomal aberrations or recognized syndromes). Conclusions: Prenatal detection rate of congenital anomalies by fetal scan varies significantly between registries of European countries even with the same screening policy. Prenatal detection of congenital anomalies is significantly higher when associated malformations are present. The rate of induced abortions varies between registries of countries even with the same detection rate of congenital anomalies. The variation described may be due to cultural and policy differences. Copyright 2002 S. Karger AG, Basel

Prenatal diagnosis of dysmorphic syndromes by routine fetal ultrasound examination across Europe.

OBJECTIVES: Ultrasound scan in the mid-trimester of pregnancy is now a routine part of prenatal care in most European countries. The objective of this study was to evaluate the prenatal diagnosis of dysmorphic syndromes by fetal ultrasound examination. METHODS: Data from 20 registries of congenital malformations in 12 European countries were included in the study. RESULTS: There were 2454 cases with congenital heart diseases, 479 of which were recognized syndromes, including 375 chromosomal anomalies and 104 syndromes without chromosomal anomalies. Fifty-one of the 104 were detected prenatally (49.0%). One hundred and ninety-two of 1130 cases with renal anomalies were recognized syndromes, including 128 chromosomal anomalies and 64 syndromes without chromosomal anomalies; 162 of them (84.4%) were diagnosed prenatally, including 109 chromosomal anomalies and 53 non-chromosomal syndromes. Fifty-four of the 250 cases with limb defects were recognized syndromes, including 16 chromosomal syndromes and 38 syndromes without chromosomal anomalies; 21 of these 54 syndromes were diagnosed prenatally (38.9%), including 9 chromosomal syndromes. There were 243 cases of abdominal wall defects including 57 recognizable syndromes, 48 with omphalocele and 9 with gastroschisis; 48 were diagnosed prenatally (84.2%). Twenty-six of the 187 cases with diaphragmatic hernia had recognized syndromes, including 20 chromosomal aberrations and 6 syndromes without chromosomal anomalies. Twenty-two of them (84.6%) were detected prenatally. Sixty-four of 349 cases with intestinal anomalies were recognized syndromes; 24 were diagnosed prenatally (37.5%). There were 553 cases of cleft lip and palate (CL(P)) and 198 of cleft palate (CP) including 74 chromosomal anomalies and 73 recognized non-chromosomal syndromes. Prenatal diagnosis was made in 51 cases of CL(P) (53.7%) and 7 of CP (13.7%). Twenty-two of 188 anencephalic cases were syndromic and all were diagnosed prenatally. Of 290 cases with spina bifida, 18 were recognized syndromes, and of them 17 were diagnosed prenatally. All 11 syndromic encephaloceles were diagnosed prenatally. CONCLUSIONS: Around 50% of the recognized syndromes which are associated with major congenital anomalies (cardiac, renal, intestinal, limb defects, abdominal wall defects and oral clefts) can be detected prenatally by the anomaly scan. However the detection rate varies with the type of syndrome and with the different countries' policies of prenatal screening.