Sicco A. Scherjon

Nonexpanded primary lung and bone marrow-derived mesenchymal cells promote the engraftment of umbilical cord blood-derived CD34 + cells in NOD/SCID mice

OBJECTIVE Previously, we have found that human culture-expanded fetal lung-derived mesenchymal stem cells (MSC) promote the engraftment of umbilical cord blood (UCB)-derived CD34((+)) cells. The high frequency of MSC in fetal lung allowed us to study whether this represented a biological feature of these cells or a property that was acquired during expansion in culture. MATERIALS AND METHODS Irradiated NOD/SCID mice (n=80) were transplanted with 0.1x10(6) UCB CD34(+) cells in the presence or absence of 10(6) primary nonexpanded or culture-expanded fetal lung, liver, or BM CD45(-) cells, or with nonexpanded fetal lung liver or BM CD45(-) cells only. RESULTS In comparison with transplantation of UCB CD34(+) cells only, cotransplantation of UCB CD34(+) cells and primary fetal lung or BM CD45(-) cells resulted in a significantly higher level of engraftment (% hCD45(+) cells) in BM, PB, and spleen. In addition, primary mesenchymal cells derived from adult BM had a similar promoting effect. The engraftment-enhancing effect was similar to that of culture-expanded fetal lung and BM MSC. Primary mesenchymal cells, but not culture-expanded MSC, were detected in recipient mice, suggesting that the primary cells were able to home and that this capacity was lost after expansion. CONCLUSIONS These results show that primary mesenchymal cells from fetal lung and BM promote the engraftment of UCB-derived CD34(+) cells to a similar degree as culture-expanded MSC, indicating that it reflects a biological property of primary MSC that is preserved during expansion in culture.

Human Decidual Tissue Contains Differentiated CD8+ Effector-Memory T Cells with Unique Properties

During pregnancy, maternal lymphocytes at the fetal–maternal interface play a key role in the immune acceptance of the allogeneic fetus. Recently, CD4+CD25bright regulatory T cells have been shown to be concentrated in decidual tissue, where they are able to suppress fetus-specific and nonspecific immune responses. Decidual CD8+ T cells are the main candidates to recognize and respond to fetal HLA-C at the fetal–maternal interface, but data on the characteristics of these cells are limited. In this study we examined the decidual and peripheral CD8+ T cell pool for CD45RA, CCR7, CD28, and CD27 expression, using nine-color flow cytometry. Our data demonstrate that decidual CD8+ T cells mainly consist of differentiated CD45RA−CCR7− effector-memory (EM) cells, whereas unprimed CD45RA+CCR7+ naive cells are almost absent. Compared with peripheral blood EM CD8+ T cells, the decidual EM CD8+ T cells display a significantly reduced expression of perforin and granzyme B, which was confirmed by immunohistochemistry of decidual tissue sections. Interestingly, quantitative PCR analysis demonstrates an increased perforin and granzyme B mRNA content in decidual EM CD8+ T cells in comparison with peripheral blood EM CD8+ T cells. The presence of high levels of perforin and granzyme B mRNA in decidual EM T cells suggests that decidual CD8+ T cells pursue alternative means of EM cell differentiation that may include a blockade of perforin and granzyme B mRNA translation into functional perforin and granzyme B proteins. Regulation of decidual CD8+ T cell differentiation may play a crucial role in maternal immune tolerance to the allogeneic fetus.

Differential distribution of NK cells in decidua basalis compared with decidua parietalis after uncomplicated human term pregnancy

As pregnancy progresses, a characteristic decline in the percentage of CD56bright CD16- uterine natural killer (NK) cells occurs. Studies of term decidua, however, have focused only on leukocytes derived from decidua basalis, the site of implantation. The decidua parietalis, lining the remainder of the uterine cavity is another important region of the maternal-fetal interface that forms contact with fetal tissue at the end of the first trimester. The aim of this study was to evaluate possible differences in expression of CD16 and CD56 on leukocytes from normal term decidua basalis and decidua parietalis. Decidua basalis and parietalis samples were obtained from 30 placentas collected after elective cesarean section. Percentages of leukocyte subpopulations and NK cell subsets within the CD45+ cell fraction were determined by flow cytometry. In six decidual samples, concurrent immunohistochemical staining was performed. Higher percentages of CD56dim CD16+ NK cells and CD56- CD16+ cells were found in decidua basalis in comparison to decidua parietalis. In contrast, the percentage of CD56bright CD16- uterine NK cells was significantly higher in decidua parietalis. Immunohistochemical quantification supported flow cytometric results. We conclude that significant differences exist with respect to the distribution of NK cells in term decidua basalis and parietalis. Future functional studies may improve our understanding of their role at the maternal-fetal interface.

Intra‐observer and inter‐observer reliability of the pulsatility index calculated from pulsed Doppler flow velocity waveforms in three fetal vessels

Objective Study of the intra observer and inter observer reliability of the pulsatility index, calculated from pulsed Doppler recordings of three fetal vessels.

Fetal brain sparing is associated with accelerated shortening of visual evoked potential latencies during early infancy

OBJECTIVE Our purpose was to assess the effects that fetal growth restriction exerts on the myelination of the developing brain. STUDY DESIGN Fetal haemodynamic centralization, an adaptive strategy to growth restriction caused by placental insufficiency, was determined by Doppler ultrasonography. Infants with a raised ratio between umbilical artery pulsatility index and cerebral artery pulsatility index are severely growth restricted. Visual evoked potentials give information on the degree of brain myelination. Shortening of visual evoked potential latencies is a normal feature of myelination. In a consecutive series of 105 Neonates, visual evoked potentials were recorded at the corrected ages of 6 months and 1 years. Correction for possible confounders, such as cranial ultrasonographic findings, gestational age, and head circumference, was performed. RESULTS At 6 months, infants with a raised umbilical artery/cerebral artery pulsatility index ratio have shorter visual evoked potential latencies. Opposite of neonates with a normal umbilical artery/cerebral artery ratio, they show no postnatal maturational shortening of visual evoked potential latencies. CONCLUSION Accelerated neurophysiologic maturation, found in infants with a high umbilical artery/cerebral artery ratio, might be the result of a beneficial adaptive process to severe fetal growth restriction.

Potential use of autologous umbilical cord blood red blood cells for early transfusion needs of premature infants.

BACKGROUND:  This prospective study investigated whether the odds of receiving a red blood cell (RBC) transfusion in premature infants can be predicted at birth and for whom of these infants harvesting of umbilical cord blood (UCB) for autologous transfusion within 30 days after birth would be worthwhile.

Placental anatomy, fetal demise and therapeutic intervention in monochorionic twins and the transfusion syndrome: New hypotheses

OBJECTIVE Monochorionic twins with circulatory sharing have an incompletely understood response to acute hemodynamic events. We relate placental vascular anatomy with, first, the response to (a) acute fetal demise and (b) laser interrupted placental anastomoses and, second, the efficacy of current and possibly future therapeutic interventions in twin-twin transfusion syndrome. DESIGN Hemodynamic response to acute fetal demise and laser interrupted anastomoses is analysed using the model previously developed for monochorionic twins. Efficacy of therapeutic interventions in twin-twin transfusion syndrome is analysed by combining the estimated incidence of placental anastomotic patterns with three previously proposed pathophysiologic mechanisms. RESULTS Fetal demise may cause sequelae for the co-twin in all anastomotic patterns except unidirectional arteriovenous and single venovenous anastomoses which are predicted to be hemodynamically harmless. In twin-twin transfusion syndrome, laser interruption of all anastomoses mitigates further transfusion. This is of benefit for the twins in equally but not in unequally shared placentas. Analysis predicts that approximately 75% fetal survival could be achieved interrupting only arteriovenous anastomoses. Amniocentesis may only prolong pregnancies that lack progressively increasing discordance, assuming that placental anastomoses remain patent following polyhydramnios. This proposed mechanism of action predicts current therapeutic efficacy accurately and could explain the significantly higher reported serious morbidity compared with laser (15/81 = 19+/-5% versus 4/146=3%, P=0.00004). However, if therapeutic interventions could match the syndromes individual placental anatomy, the analysis suggests approximately 10-15% laser related mortality (premature rupture of membranes) and <3% severe morbidity could possibly become achievable goals. CONCLUSION Our predictions allow clinical testing. This information may contribute to an improved management of monochorionic twins.

Monitoring human growth and development: a continuum from the womb to the classroom

A comprehensive set of fully integrated anthropometric measures is needed to evaluate human growth from conception to infancy so that consistent judgments can be made about the appropriateness of fetal and infant growth. At present, there are 2 barriers to this strategy. First, descriptive reference charts, which are derived from local, unselected samples with inadequate methods and poor characterization of their putatively healthy populations, commonly are used rather than prescriptive standards. The use of prescriptive standards is justified by the extensive biologic, genetic, and epidemiologic evidence that skeletal growth is similar from conception to childhood across geographic populations, when health, nutrition, environmental, and health care needs are met. Second, clinicians currently screen fetuses, newborn infants, and infants at all levels of care with a wide range of charts and cutoff points, often with limited appreciation of the underlying population or quality of the study that generated the charts. Adding to the confusion, infants are evaluated after birth with a single prescriptive tool: the World Health Organization Child Growth Standards, which were derived from healthy, breastfed newborn infants, infants, and young children from populations that have been exposed to few growth-restricting factors. The International Fetal and Newborn Growth Consortium for the 21st Century Project addressed these issues by providing international standards for gestational age estimation, first-trimester fetal size, fetal growth, newborn size for gestational age, and postnatal growth of preterm infants, all of which complement the World Health Organization Child Growth Standards conceptually, methodologically, and analytically. Hence, growth and development can now, for the first time, be monitored globally across the vital first 1000 days and all the way to 5 years of age. It is clear that an integrative approach to monitoring growth and development from pregnancy to school age is desirable, scientifically supported, and likely to improve care, referral patterns, and reporting systems. Such integration can be achieved only through the use of international growth standards, especially in increasingly diverse, mixed ancestry populations. Resistance to new scientific developments has been hugely problematic in medicine; however, we are confident that the obstetric and neonatal communities will join their pediatric colleagues worldwide in the adoption of this integrative strategy.

A clinical study on the feasibility of autologous cord blood transfusion for anemia of prematurity.

BACKGROUND: The objective was to investigate the use of autologous red blood cells (RBCs) derived from umbilical cord blood (UCB), as an alternative for allogeneic transfusions in premature infants admitted to a tertiary neonatal center.

Effect of fetal brainsparing on the early neonatal cerebral circulation.

The effect of antenatal brainsparing on subsequent neonatal cerebral blood flow velocity (CBFV) was studied in very preterm infants. CBFV was determined, using a pulsed Doppler technique, both in the fetal and neonatal period. Neonatally, blood pressure and transcutaneous carbon dioxide tension (TcPCO2) was monitored simultaneously; daily cranial ultrasound examinations were performed. In infants with evidence of brainsparing a higher mean value of CBFV and a different pattern of changes of CBFV during the first week of life was demonstrated compared with infants with normal fetal cerebral haemodynamics. No differences were found in blood pressure and TcPCO2. The incidence of intracranial haemorrhages and of ischaemic echo-dense lesions was also the same for both groups. In a multivariate statistical model gestational age, antepartum brainsparing, and TcPCO2 all contributed significantly in explanation of variation in CBFV. It is speculated that a different setting of cerebral autoregulation related to differences in gestational age or to brainsparing might explain the difference in changes found in neonatal CBFV.