Homing of placenta-derived mesenchymal stem cells after perinatal intracerebral transplantation in a rat model

The aim of this study is to assess early homing of placenta-derived stem cells after perinatal intracerebral transplantation in rats.

Perinatal care at the limit of viability between 22 and 26 completed weeks of gestation in Switzerland. 2011 revision of the Swiss recommendations

Perinatal care of pregnant women at high risk for preterm delivery and of preterm infants born at the limit of viability (22-26 completed weeks of gestation) requires a multidisciplinary approach by an experienced perinatal team. Limited precision in the determination of both gestational age and foetal weight, as well as biological variability may significantly affect the course of action chosen in individual cases. The decisions that must be taken with the pregnant women and on behalf of the preterm infant in this context are complex and have far-reaching consequences. When counselling pregnant women and their partners, neonatologists and obstetricians should provide them with comprehensive information in a sensitive and supportive way to build a basis of trust. The decisions are developed in a continuing dialogue between all parties involved (physicians, midwives, nursing staff and parents) with the principal aim to find solutions that are in the infant's and pregnant woman's best interest. Knowledge of current gestational age-specific mortality and morbidity rates and how they are modified by prenatally known prognostic factors (estimated foetal weight, sex, exposure or nonexposure to antenatal corticosteroids, single or multiple births) as well as the application of accepted ethical principles form the basis for responsible decision-making. Communication between all parties involved plays a central role. The members of the interdisciplinary working group suggest that the care of preterm infants with a gestational age between 22 0/7 and 23 6/7 weeks should generally be limited to palliative care. Obstetric interventions for foetal indications such as Caesarean section delivery are usually not indicated. In selected cases, for example, after 23 weeks of pregnancy have been completed and several of the above mentioned prenatally known prognostic factors are favourable or well informed parents insist on the initiation of life-sustaining therapies, active obstetric interventions for foetal indications and provisional intensive care of the neonate may be reasonable. In preterm infants with a gestational age between 24 0/7 and 24 6/7 weeks, it can be difficult to determine whether the burden of obstetric interventions and neonatal intensive care is justified given the limited chances of success of such a therapy. In such cases, the individual constellation of prenatally known factors which impact on prognosis can be helpful in the decision making process with the parents. In preterm infants with a gestational age between 25 0/7 and 25 6/7 weeks, foetal surveillance, obstetric interventions for foetal indications and neonatal intensive care measures are generally indicated. However, if several prenatally known prognostic factors are unfavourable and the parents agree, primary non-intervention and neonatal palliative care can be considered. All pregnant women with threatening preterm delivery or premature rupture of membranes at the limit of viability must be transferred to a perinatal centre with a level III neonatal intensive care unit no later than 23 0/7 weeks of gestation, unless emergency delivery is indicated. An experienced neonatology team should be involved in all deliveries that take place after 23 0/7 weeks of gestation to help to decide together with the parents if the initiation of intensive care measures appears to be appropriate or if preference should be given to palliative care (i.e., primary non-intervention). In doubtful situations, it can be reasonable to initiate intensive care and to admit the preterm infant to a neonatal intensive care unit (i.e., provisional intensive care). The infant's clinical evolution and additional discussions with the parents will help to clarify whether the life-sustaining therapies should be continued or withdrawn. Life support is continued as long as there is reasonable hope for survival and the infant's burden of intensive care is acceptable. If, on the other hand, the health car...

Copeptin concentration in cord blood in infants with early-onset sepsis, chorioamnionitis and perinatal asphyxia

Background Vasopressin is one of the most important physiological stress and shock hormones. Copeptin, a stable vasopressin precursor, is a promising sepsis marker in adults. In contrast, its involvement in neonatal diseases remains unknown. The aim of this study was to establish copeptin concentrations in neonates of different stress states such as sepsis, chorioamnionitis and asphyxia. Methods Copeptin cord blood concentration was determined using the BRAHMS kryptor assay. Neonates with early-onset sepsis (EOS, n = 30), chorioamnionitis (n = 33) and asphyxia (n = 25) were compared to a control group of preterm and term (n = 155) neonates. Results Median copeptin concentration in cord blood was 36 pmol/l ranging from undetectable to 5498 pmol/l (IQR 7 - 419). Copeptin cord blood concentrations were non-normally distributed and increased with gestational age (p < 0.0001). Neonates born after vaginal compared to cesarean delivery had elevated copeptin levels (p < 0.0001). Copeptin correlated strongly with umbilical artery pH (Spearman's Rho -0.50, p < 0.0001), umbilical artery base excess (Rho -0.67, p < 0.0001) and with lactate at NICU admission (Rho 0.54, p < 0.0001). No difference was found when comparing copeptin cord blood concentrations between neonates with EOS and controls (multivariate p = 0.30). The highest copeptin concentrations were found in neonates with asphyxia (median 993 pmol/l). Receiver-operating-characteristic curve analysis showed that copeptin cord blood concentrations were strongly associated with asphyxia: the area under the curve resulted at 0.91 (95%-CI 0.87-0.96, p < 0.0001). A cut-off of 400 pmol/l had a sensitivity of 92% and a specifity of 82% for asphyxia as defined in this study. Conclusions Copeptin concentrations were strongly related to factors associated with perinatal stress such as birth acidosis, asphyxia and vaginal delivery. In contrast, copeptin appears to be unsuitable for the diagnosis of EOS.

Therapeutic hypothermia in term infants after perinatal encephalopathy: The last 5 years in Switzerland

Background: Therapeutic hypothermia (TH) following perinatal asphyxial encephalopathy in term infants improves mortality and neurodevelopmental outcome. In Europe, most neonatal units perform active cooling whereas in Switzerland passive cooling is predominantly used. Aims: (i) To determine how many infants were cooled within the last 5 years in Switzerland, (ii) to assess the cooling methods, (iii) to evaluate the variation of temperature of different cooling methods, and (iv) to evaluate the use of neuromonitoring. Study design: Retrospective cohort study. Patients: Notes of all cooled term infants between March 2005 and December 2010 in 9 perinatal and two paediatric intensive care centres were retrospectively reviewed. Active cooling was compared to passive cooling alone and to passive cooling in combination with gel packs. Results: 150 infants were cooled. Twenty-seven (18.2%) were cooled actively, 34 (23%) passively and 87 (58.8%) passively in combination with gel packs. Variation of temperature was significantly different between the three methods. Passive cooling had a significant higher variation of temperature (SD of 0.89) than both passive cooling in combination with gel packs (SD of 0.79) and active cooling (SD of 0.76). aEEG before TH was obtained in 35.8% of the infants and 86.5% had full EEG. One cUS was performed in 95.3% and MRI in 62.2% of the infants. Conclusion: Target temperature can be achieved with all three cooling methods. Passive cooling has the highest variation of temperature. Neuromonitoring should be improved in Swiss neonatal and paediatric intensive care units. Our results stress the importance of national registries.

Placental mesenchymal stem cells as potential autologous graft for pre- and perinatal neuroregeneration

OBJECTIVE: Mesenchymal stem cells (MSCs) have a broad differentiation potential. We aimed to determine if MSCs are present in fetal membranes and placental tissue and to assess their potential to differentiate into neurogenic and mesodermal lineages. STUDY DESIGN: MSCs isolated from first and third trimester chorion and amnion and first trimester chorionic villi and characterized morphologically and by flourescence-activated cell sorting analysis. Their ability to mature under different culture conditions into various cells of mesodermal and neuroectodermal cell lines was assessed by immuno- and cytochemical staining. RESULTS: Independent of gestational age, cells isolated from fetal membranes and placenta showed typical MSC phenotype (positive for CD166, CD105, CD90, CD73, CD49e, CD44, CD29, CD13, MHC I; negative for CD14, CD34, CD45, MHC II) and were able to differentiate into mesodermal cells expressing cell markers/cytologic staining consistent with mature chondroblasts, osteoblasts, adipocytes, or myocytes and into neuronal cells presenting markers of various stages of maturation. The differentiation pattern was mainly dependent on cell type. CONCLUSION: Mesenchymal cells from chorion, amnion, and villous stroma can be differentiated into neurogenic, chondrogenic, osteogenic, adipogenic, and myogenic lineage. Placental tissue obtained during prenatal chorionic villous sampling or at delivery might be an ideal source for autologous stem cell graft for peripartum neuroregeneration and other clinical issues.

Perinatal adaptation in mammals: the impact of metabolic rate

Mammalian birth is accompanied by profound changes in metabolic rate that can be described in terms of body size relationship (Kleiber's rule). Whereas the fetus, probably as an adaptation to the low intrauterine pO2, exhibits an "inappropriately" low, adult-like specific metabolic rate, the term neonate undergoes a rapid metabolic increase up to the level to be expected from body size. A similar, albeit slowed, "switching-on" of metabolic size allometry is found in human preterm neonates whereas animals that are normally born in a very immature state are able to retard or even suppress the postnatal metabolic increase in favor of weight gain and O2 supply. Moreover, small immature mammalian neonates exhibit a temporary oxyconforming behavior which enhances their hypoxia tolerance, yet is lost to the extent by which the size-adjusted metabolic rate is "locked" by increasing mitochondrial density. Beyond the perinatal period, there are no other deviations from metabolic size allometry among mammals except in hibernation where the temporary "switching-off" of Kleiber's rule is accompanied by a deep reduction in tissue pO2. This gives support to the hypothesis that the postnatal metabolic increase represents an "escape from oxygen" similar to the evolutionary roots of mitochondrial respiration, and that the overall increase in specific metabolic rate with decreasing size might contribute to prevent tissues from O2 toxicity.

Perinatal stem-cell and gene therapy for hemoglobinopathies

Most genetic diseases of the lymphohematopoietic system, including hemoglobinopathies, can now be diagnosed early in gestation. However, as yet, prenatal treatment is not available. Postnatal therapy by hematopoietic stem cell (HSC) transplantation from bone marrow, mobilized peripheral blood, or umbilical cord blood is possible for several of these diseases, in particular for the hemoglobinopathies, but is often limited by a lack of histocompatible donors, severe treatment-associated morbidity, and preexisting organ damage that developed before birth. In-utero transplantation of allogeneic HSC has been performed successfully in various animal models and recently in humans. However, the clinical success of this novel treatment is limited to diseases in which the fetus is affected by severe immunodeficiency. The lack of donor cell engraftment in nonimmunocompromised hosts is thought to be due to immunologic barriers, as well as to competitive fetal marrow population by host HSCs. Among the possible strategies to circumvent allogeneic HLA barriers, the use of gene therapy by genetically corrected autologous HSCs in the fetus is one of the most promising approaches. The recent development of strategies to overcome failure of efficient transduction of quiescent hematopoietic cells using new vector constructs and transduction protocols opens new perspectives for gene therapy in general, as well as for prenatal gene transfer in particular. The fetus might be especially susceptible for successful gene therapy approaches because of the developing, expanding hematopoietic system during gestation and the immunologic naiveté early in gestation, precluding immune reaction towards the transgene by inducing tolerance. Ethical issues, in particular regarding treatment safety, must be addressed more closely before clinical trials with fetal gene therapy in human pregnancies can be initiated.

Levoatrial cardinal vein in mitral atresia and closed foramen ovale: prenatal diagnosis and perinatal management

A levoatrial cardinal vein is a rare cardiovascular anomaly that may be present in malformed hearts with severe left heart obstruction and restrictive interatrial communication. We report the prenatal diagnosis at 23 weeks of a fetus with mitral atresia, double-outlet right ventricle, premature closure of the foramen ovale and a levoatrial cardinal vein draining into the innominate vein. In a prior examination performed elsewhere the levoatrial cardinal vein had been interpreted as an aortic arch perfused retrogradely, and hypoplastic left heart syndrome with aortic atresia had been diagnosed. Prenatal management, induction at 38 weeks and postnatal examinations and treatment are reported. To the best of our knowledge, this is the first reported prenatal diagnosis of this embryological vessel, presenting a potential pitfall for prenatal echocardiography.