Organ volume measurements: comparison between MRI and autopsy findings in infants following sudden unexpected death.

OBJECTIVE: To assess the accuracy of a semiautomated 3D volume reconstruction method for organ volume measurement by postmortem MRI. METHODS: This prospective study was approved by the institutional review board and the infants' parents gave their consent. Postmortem MRI was performed in 16 infants (1 month to 1 year of age) at 1.5 T within 48 h of their sudden death. Virtual organ volumes were estimated using the Myrian software. Real volumes were recorded at autopsy by water displacement. The agreement between virtual and real volumes was quantified following the Bland and Altman's method. RESULTS: There was a good agreement between virtual and real volumes for brain (mean difference: -0.03% (-13.6 to +7.1)), liver (+8.3% (-9.6 to +26.2)) and lungs (+5.5% (-26.6 to +37.6)). For kidneys, spleen and thymus, the MRI/autopsy volume ratio was close to 1 (kidney: 0.87±0.1; spleen: 0.99±0.17; thymus: 0.94±0.25), but with a less good agreement. For heart, the MRI/real volume ratio was 1.29±0.76, possibly due to the presence of residual blood within the heart. The virtual volumes of adrenal glands were significantly underestimated (p=0.04), possibly due to their very small size during the first year of life. The percentage of interobserver and intraobserver variation was lower or equal to 10%, but for thymus (15.9% and 12.6%, respectively) and adrenal glands (69% and 25.9%). CONCLUSIONS: Virtual volumetry may provide significant information concerning the macroscopic features of the main organs and help pathologists in sampling organs that are more likely to yield histological findings.

Fetal laser therapy: applications in the management of fetal pathologies.

Fetoscopic coagulation of placental anastomoses is the treatment of choice for severe twin-to-twin transfusion syndrome. In the present day, fetal laser therapy is also used to treat amniotic bands, chorioangiomas, sacrococcygeal teratomas, lower urinary tract obstructions and chest masses, all of which will be reviewed in this article. Amniotic band syndrome can cause limb amputation by impairing downstream blood flow. Large chorioangiomas (>4 cm), sacrococcygeal teratomas or fetal hyperechoic lung lesions can lead to fetal compromise and hydrops by vascular steal phenomenon or compression. Renal damage, bladder dysfunction and lastly death because of pulmonary hypolasia may be the result of megacystis caused by a posterior urethral valve. The prognosis of these pathologies can be dismal, and therapy options are limited, which has brought fetal laser therapy to the forefront. Management options discussed here are laser release of amniotic bands, laser coagulation of the placental or fetal tumor feeding vessels and laser therapy by fetal cystoscopy. This review, largely based on case reports, does not intend to provide a level of evidence supporting laser therapy over other treatment options. Centralized evaluation by specialists using strict selection criteria and long-term follow-up of these rare cases are now needed to prove the value of endoscopic or ultrasound-guided laser therapy.

Dificuldades para a identificação da causa do óbito fetal: como resolver?

OBJETIVO: Identificar as causas dos óbitos fetais (OF) e avaliar as causas deste desfecho. Propor o emprego do sistema Relevant Condition of Death (ReCoDe) na elucidação das causas de OF para minimizar o número de causas desconhecidas. MÉTODOS: Estudo transversal relacionado às mortes fetais atendidas em um hospital universitário especializado do Sul do Brasil, de Janeiro de 2000 a dezembro de 2009. Os dados foram coletados das Declarações de Óbito, dos prontuários maternos e dos laudos de estudo dos fetos e anexos, sendo os achados comparados. A análise dos dados foi realizada pelo programa SPSS versão 17.0. RESULTADOS: Foram incluídos neste estudo 111 fetos e suas respectivas mães. A comparação entre o diagnóstico das causas encontradas nos laudos do exame dos fetos e anexos e o diagnóstico clínico foi de 74 (66,7%) e 73 (65,8%), respectivamente. Em 48,7% dos casos, ambas encontraram uma potencial causa e 16,2% permaneceram desconhecidas. Utilizando-se a classificação ReCoDe, somente 9,9% dos OFs ficaram como "não classificados". CONCLUSÕES: Os laudos da autópsia fetal e exame anatomopatológico e as avaliações clínicas não apresentaram diferenças significativas na identificação da causa do OF. Ao se comparar os resultados do ReCoDe com as causas de óbito da clínica/patologia, verificou-se que ela é uma ferramenta importante no esclarecimento da causa mortis, reduzindo a quantidade daqueles OFs que permaneceram sem uma possível etiologia.

Maternal undernutrition and the offspring kidney: from fetal to adult life

Maternal dietary protein restriction during pregnancy is associated with low fetal birth weight and leads to renal morphological and physiological changes. Different mechanisms can contribute to this phenotype: exposure to fetal glucocorticoid, alterations in the components of the renin-angiotensin system, apoptosis, and DNA methylation. A low-protein diet during gestation decreases the activity of placental 11ß-hydroxysteroid dehydrogenase, exposing the fetus to glucocorticoids and resetting the hypothalamic-pituitary-adrenal axis in the offspring. The abnormal function/expression of type 1 (AT1R) or type 2 (AT2R) AngII receptors during any period of life may be the consequence or cause of renal adaptation. AT1R is up-regulated, compared with control, on the first day after birth of offspring born to low-protein diet mothers, but this protein appears to be down-regulated by 12 days of age and thereafter. In these offspring, AT2R expression differs from control at 1 day of age, but is also down-regulated thereafter, with low nephron numbers at all ages: from the fetal period, at the end of nephron formation, and during adulthood. However, during adulthood, the glomerular filtration rate is not altered, due to glomerulus and podocyte hypertrophy. Kidney tubule transporters are regulated by physiological mechanisms; Na+/K+-ATPase is inhibited by AngII and, in this model, the down-regulated AngII receptors fail to inhibit Na+/K+-ATPase, leading to increased Na+ reabsorption, contributing to the hypertensive status. We also considered the modulation of pro-apoptotic and anti-apoptotic factors during nephrogenesis, since organogenesis depends upon a tight balance between proliferation, differentiation and cell death.

The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Three-Dimensional Ultrasonographic Assessment of Fetal Total Lung Volume as a Prognostic Factor in Primary Pleural Effusion

Objectives-The purpose of this study was to predict perinatal outcomes using fetal total lung volumes assessed by 3-dimensional ultrasonography (3DUS) in primary pleural effusion.Methods-Between July 2005 and July 2010, total lung volumes were prospectively estimated in fetuses with primary pleural effusion by 3DUS using virtual organ computer-aided analysis software. The first and last US examinations were considered in the analysis. The observed/expected total lung volumes were calculated. Main outcomes were perinatal death (up to 28 days of life) and respiratory morbidity (orotracheal intubation with mechanical respiratory support >48 hours).Results-Twelve of 19 fetuses (63.2%) survived. Among the survivors, 7 (58.3%) had severe respiratory morbidity. The observed/expected total lung volume at the last US examination before birth was significantly associated with perinatal death (P < .01) and respiratory morbidity (P < .01) as well as fetal hydrops (P < .01) and bilateral effusion (P = .01).Conclusions-Fetal total lung volumes may be useful for the prediction of perinatal outcomes in primary pleural effusion.

Maternal undernutrition and the offspring kidney: from fetal to adult life

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

Mixture of vitamin C, hesperidin and piperidol exposure in pregnancy: Maternal-fetal repercussions

To evaluate the reproductive performance and the development of their offspring on rat pregnancy. Wistar pregnant rats were gavaged with 0 mg/kg wb/day (control group, n = 20) and 166.5 mg/kg/day of a mixture of vitamin C, hesperidin and piperidol (experimental group, n = 20) during the organogenic period (from day 5 to 14 of pregnancy; positive vaginal smear = day 0). The female rats were killed on day 21 of pregnancy. The number of implantations, resorptions (dead embryos), and live/dead fetuses were counted for the analysis of the postimplantation loss rates. There was neither alteration in maternal reproductive performance, but it was verified an increase of the number of fetuses presenting dilated urether, hydronephrosis, and reduced ossification of skull due to the treatment of female rats with a mixture of vitamin C, hesperidin and piperidol, these abnormalities were considered transitory and may not interfere on offspring development. It was not verified other type of major malformation neither the appearance of fetuses presenting atrophy of upper limbs that it could be associated to use of this drug.

The vulnerable male, or the sex ratio among fetal deaths in Brazil

Some studies indicate the existence of innate male vulnerabilities, especially during the perinatal period. The current study is a cross-sectional analysis of fetal mortality in Brazil according to sex from 2000 to 2009, stratified by maternal characteristics (age, schooling, and gestational age), using Ministry of Health data (DATASUS). The analysis included all fetal deaths from 2000 to 2009, except when the sex of the fetus was not recorded. The male/female sex ratio (SR) for all fetal deaths was 1.188. Analysis of maternal characteristics showed that the SR was statistically higher (p < 0.01) in mothers that were younger (10-14 years), had no formal schooling, and with gestational age < 22 weeks. The study showed a statistically higher-than-expected SR (p < 0.01) for 13 underlying causes of death and a lower SR for two others. The results suggest a potential innate male vulnerability.

Three-Dimensional Ultrasonographic Assessment of Fetal Total Lung Volume as a Prognostic Factor in Primary Pleural Effusion

Objectives-The purpose of this study was to predict perinatal outcomes using fetal total lung volumes assessed by 3-dimensional ultrasonography (3DUS) in primary pleural effusion. Methods-Between July 2005 and July 2010, total lung volumes were prospectively estimated in fetuses with primary pleural effusion by 3DUS using virtual organ computer-aided analysis software. The first and last US examinations were considered in the analysis. The observed/expected total lung volumes were calculated. Main outcomes were perinatal death (up to 28 days of life) and respiratory morbidity (orotracheal intubation with mechanical respiratory support >48 hours). Results-Twelve of 19 fetuses (63.2%) survived. Among the survivors, 7 (58.3%) had severe respiratory morbidity. The observed/expected total lung volume at the last US examination before birth was significantly associated with perinatal death (P < .01) and respiratory morbidity (P < .01) as well as fetal hydrops (P < .01) and bilateral effusion (P = .01). Conclusions-Fetal total lung volumes may be useful for the prediction of perinatal outcomes in primary pleural effusion.

Nuclear Transfer with Apoptotic Bovine Fibroblasts: Can Programmed Cell Death Be Reprogrammed?

Cell death by apoptosis is considered to be irreversible. However, reports have indicated that its reversibility is possible if the cells have not yet reached the "point of no return.'' In order to add new information about this topic, we used cells at different moments of apoptotic process as nuclear donors in somatic cell nuclear transfer (SCNT) in order to test if programmed cell death can be reversed. Adult bovine fibroblasts were treated with 10 mu M of staurosporine (STP) for 3 h and analyzed for phosphatidylserine externalization (Annexin assay) and presence of active caspase-9. Annexin-positive (Anx +) and Caspase-9-positive (Casp-9 +) cells were isolated by FACS and immediately transferred into enucleated in vitro matured bovine oocytes. After STP treatment, 89.9% of cells were Anx + (4.6% in control cells; p < 0.01) and 24.9% were Casp-9 + (2.4% in control cells; p < 0.01). Fusion and cleavage were not affected by the use apoptotic cells (p > 0.05). Also, the use of Anx + cells did not affect blastocyst production compared to control (26.4% vs. 22.9%, respectively; p > 0.05). However, blastocyst formation was affected by the use of Casp-9 + cells (12.3%; p < 0.05). These findings contribute to the idea of that apoptosis is reversible only at early stages. Additionally, we hypothesize that the "point of no return'' for apoptosis may be located around activation of Caspase-9.

Defects in embryonic hindbrain development and fetal resorption resulting from vitamin A deficiency in the rat are prevented by feeding pharmacological levels of all-trans-retinoic acid

Vitamin A is required for reproduction and normal embryonic development. We have determined that all-trans-retinoic acid (atRA) can support development of the mammalian embryo to parturition in vitamin A-deficient (VAD) rats. At embryonic day (E) 0.5, VAD dams were fed purified diets containing either 12 μg of atRA per g of diet (230 μg per rat per day) or 250 μg of atRA per g of diet (4.5 mg per rat per day) or were fed the purified diet supplemented with a source of retinol (100 units of retinyl palmitate per day). An additional group was fed both 250 μg of atRA per g of diet in combination with retinyl palmitate. Embryonic survival to E12.5 was similar for all groups. However, embryonic development in the group fed 12 μg of atRA per g of diet was grossly abnormal. The most notable defects were in the region of the hindbrain, which included a loss of posterior cranial nerves (IX, X, XI, and XII) and postotic pharyngeal arches as well as the presence of ectopic otic vesicles and a swollen anterior cardinal vein. All embryonic abnormalities at E12.5 were prevented by feeding pharmacological amounts of atRA (250 μg/g diet) or by supplementation with retinyl palmitate. Embryos from VAD dams receiving 12 μg of atRA per g of diet were resorbed by E18.5, whereas those in the group fed 250 μg of atRA per g of diet survived to parturition but died shortly thereafter. Equivalent results were obtained by using commercial grade atRA or atRA that had been purified to eliminate any potential contamination by neutral retinoids, such as retinol. Thus, 250 μg of atRA per g of diet fed to VAD dams (≈4.5 mg per rat per day) can prevent the death of embryos at midgestation and prevents the early embryonic abnormalities that arise when VAD dams are fed insufficient amounts of atRA.

Mortalidade fetal e infantil na cidade de Surubim, Pernambuco

Enquadramento: Com a redução global da mortalidade infantil no Brasil, o componente perinatal passou a exercer maior influência neste indicador, sendo necessário, portanto, um maior enfoque nas análises dessa componente. Objectivo: Levantar o perfil da mortalidade infantil e fetal e a evitabilidade destes óbitos, no município de Surubim, Pernambuco, no período de Junho de 2011 a Dezembro de 2014. Métodos: Estudo retrospectivo com enfoque descritivo, cuja a amostra foi de 56 óbitos investigados com base em 53 Fichas de Investigação da Secretaria de Saúde de Surubim. Este número corresponde a 66,66% dos casos entre 2011 e 2014 em fetos e menores de um ano, residentes de Surubim, Pernambuco. Utilizados como fontes de dados, os Bancos do Sistema de Informações sobre Mortalidade (SIM) e o Sistema de Informações sobre Nascidos Vivos (SINASC) do Ministério da Saúde (DATASUS), ambos com boa cobertura e qualidade satisfatória das informações, e Fichas usadas pelo Grupo Técnico de Investigação do Óbito do Município. Resultados: Em 2011, 23 óbitos (11 fetais e 12 infantis), 07 investigados, 1 fetal e 6 infantis; em 2012, 26 óbitos (12 fetais e 14 infantis), 23 investigados, 9 fetais e 14 infantis; em 2013, 17 óbitos (11 fetais e 6 infantis), 14 investigados, 9 fetais e 5 infantis; e em 2014, 19 óbitos (7 fetais e 12 infantis), 12 investigados, 4 fetais e 8 infantis. A Taxa de Mortalidade Infantil e Fetal para o período foi de 13,8/1000nv e 12,6/1000nv(2011), 15/1000nv e 13/1000nv(2012), 7/1000nv e 12,7/1000nv(2013),13/1000nv e 8/1000nv(2014)nv. 60,61% dos óbitos fetais e 91,3% dos óbitos infantis foram por causas evitáveis. Inconclusivos 06, não evitáveis 02 fetais e 07 Infantis. Conclusão:Consideram-se necessárias mudanças no processo de trabalho da equipe de saúde, capacitação da equipe multidisciplinar na perspectiva de trabalho colaborativo de maior equidade e efetividade clínica de forma a dotar a assistência à mulher fértil, à mulher grávida, à puérpera,ao feto e ao recém-nascido,com vistas à redução da mortalidade infantil e neonatal precoce por causas evitáveis. Palavras-chave: mortalidade infantil, mortalidade neonatal precoce, evitabilidade.

Beyond maternal death: improving the quality of maternal care through national studies of ‘near-miss’ maternal morbidity

Knight M, Acosta C, Brocklehurst P, Cheshire A, Fitzpatrick K, Hinton L, Jokinen M, Kemp B, Kurinczuk JJ, Lewis G, Lindquist A, Locock L, Nair M, Patel N, Quigley M, Ridge D, Rivero-Arias O, Sellers S, Shah A on behalf of the UKNeS coapplicant group. Background Studies of maternal mortality have been shown to result in important improvements to women’s health. It is now recognised that in countries such as the UK, where maternal deaths are rare, the study of near-miss severe maternal morbidity provides additional information to aid disease prevention, treatment and service provision. Objectives To (1) estimate the incidence of specific near-miss morbidities; (2) assess the contribution of existing risk factors to incidence; (3) describe different interventions and their impact on outcomes and costs; (4) identify any groups in which outcomes differ; (5) investigate factors associated with maternal death; (6) compare an external confidential enquiry or a local review approach for investigating quality of care for affected women; and (7) assess the longer-term impacts. Methods Mixed quantitative and qualitative methods including primary national observational studies, database analyses, surveys and case studies overseen by a user advisory group. Setting Maternity units in all four countries of the UK. Participants Women with near-miss maternal morbidities, their partners and comparison women without severe morbidity. Main outcome measures The incidence, risk factors, management and outcomes of uterine rupture, placenta accreta, haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, severe sepsis, amniotic fluid embolism and pregnancy at advanced maternal age (≥ 48 years at completion of pregnancy); factors associated with progression from severe morbidity to death; associations between severe maternal morbidity and ethnicity and socioeconomic status; lessons for care identified by local and external review; economic evaluation of interventions for management of postpartum haemorrhage (PPH); women’s experiences of near-miss maternal morbidity; long-term outcomes; and models of maternity care commissioned through experience-led and standard approaches. Results Women and their partners reported long-term impacts of near-miss maternal morbidities on their physical and mental health. Older maternal age and caesarean delivery are associated with severe maternal morbidity in both current and future pregnancies. Antibiotic prescription for pregnant or postpartum women with suspected infection does not necessarily prevent progression to severe sepsis, which may be rapidly progressive. Delay in delivery, of up to 48 hours, may be safely undertaken in women with HELLP syndrome in whom there is no fetal compromise. Uterine compression sutures are a cost-effective second-line therapy for PPH. Medical comorbidities are associated with a fivefold increase in the odds of maternal death from direct pregnancy complications. External reviews identified more specific clinical messages for care than local reviews. Experience-led commissioning may be used as a way to commission maternity services. Limitations This programme used observational studies, some with limited sample size, and the possibility of uncontrolled confounding cannot be excluded. Conclusions Implementation of the findings of this research could prevent both future severe pregnancy complications as well as improving the outcome of pregnancy for women. One of the clearest findings relates to the population of women with other medical and mental health problems in pregnancy and their risk of severe morbidity. Further research into models of pre-pregnancy, pregnancy and postnatal care is clearly needed.

Feasibility And Reproducibility Of Diffusion-weighted Magnetic Resonance Imaging Of The Fetal Brain In Twin-twin Transfusion Syndrome.

The aim of this study is to test the feasibility and reproducibility of diffusion-weighted magnetic resonance imaging (DW-MRI) evaluations of the fetal brains in cases of twin-twin transfusion syndrome (TTTS). From May 2011 to June 2012, 24 patients with severe TTTS underwent MRI scans for evaluation of the fetal brains. Datasets were analyzed offline on axial DW images and apparent diffusion coefficient (ADC) maps by two radiologists. The subjective evaluation was described as the absence or presence of water diffusion restriction. The objective evaluation was performed by the placement of 20-mm(2) circular regions of interest on the DW image and ADC maps. Subjective interobserver agreement was assessed by the kappa correlation coefficient. Objective intraobserver and interobserver agreements were assessed by proportionate Bland-Altman tests. Seventy-four DW-MRI scans were performed. Sixty of them (81.1%) were considered to be of good quality. Agreement between the radiologists was 100% for the absence or presence of diffusion restriction of water. For both intraobserver and interobserver agreement of ADC measurements, proportionate Bland-Altman tests showed average percentage differences of less than 1.5% and 95% CI of less than 18% for all sites evaluated. Our data demonstrate that DW-MRI evaluation of the fetal brain in TTTS is feasible and reproducible.