Introduction

Advances in technologies like imaging, non-invaisve measurement of bloodflow and molecular biology have led to an enormous expansion of our knowledge and understanding of the developmental changes of structure and function of the placenta throughout gestation. Undisturbed progression of growth and differentiation is directly linked to normal pregnancy outcome, whereas disturbances of development are reflected in various pregnancy pathologies. It is therefore quite appropriate, that advances in basic research on the placenta and their relevance for clinical obstetrics was chosen as a main topic of the 13. Kongress der Deutschen Gesellschaft für Pränatal- und Geburtsmedizin, 24.–26. April 2008, Bonn.

The contribution of Irene Cetin and Patrizio Antonazzo is based on the presentation given by Irene Cetin. According to present day understanding of placental pathophysiology reduced supply of nutrients by the placenta can result from a decrease in utero-placental blood flows as well as a reduced placental transport capacity. The human placenta simulates a venous equilibrator, which is a relatively inefficient system for gas exchange and in IUGR pregnancies uterine venous pO2 levels and uterine-umbilical venous gradients are significantly increased when compared to normal pregnancies of comparable gestational age. In the presence of reduction in uterine oxygen supply placental oxygen consumption, which accounts for approximately 40% of the total utero-placental uptake, seems to remain constant leading to a further decrease in oxygen delivery to the fetus. In IUGR placentas the activity of mammalian target of rapamycin (mTOR), which is an important regulator of placental amino acid transport, is reduced. The mTOR system seems to be the molecular basis for the function of the placenta as a sensor for maternal supply of nutrients, regulating fetal growth by adjusting placental transport capacity to the availability of nutrients. Mouse and human models suggest that epigenetic regulation of fetal growth may also play a significant role, through placental imprinted genes.

The contribution of Magnus Centlow, Katja Junus, Helena Nyström, Karen May, Irene Larsson, Magnus G. Olsson, Bo Åkerström, Ruth Sager, Henning Schneider, and Stefan R. Hansson is based on the presentation given by Stefan Hansson. The dual placental perfusion model was used to evaluate the damaging effects of oxidative stress induced by xanthine/xanthine oxidase and free hemoglobin. Ex vivo perfusion of placental tissue from normal pregnancies with xanthine/xanthine oxidase as well as its exposure to free hemoglobin induce changes in gene expression similar to what has been described for the preeclamptic placenta. This is the first report on gene expression in ex vivo perfused human placental tissue. The group from Lund had previously shown production and accumulation of free fetal Hb (Hb-F) in the placental vascular lumen from women with PE. Furthermore, free Hb-F is eight times increased in plasma from women with PE. Free hemoglobin and its toxic metabolite heme can cause oxidative stress and have pro-inflammatory, tissue damaging as well as vasoconstrictive properties. In placentae perfused with xanthine/xanthine oxidase as an inducer of oxidative stress all hemoglobin chains with the exception of Hbβ showed an increased expression as compared to placenta perfused with medium only. In experiments with medium containing erythrocytes, oxygen consumption reached a mean value of 8.32±1.33 ml/kg/min as compared to 1.49±0.41 ml/kg/min in the control group. Furthermore, production of hPL and progesterone were significantly higher. In these experiments all perfusate samples showed high levels of free adult hemoglobin (HbA) indicating lysis of the added red cells. Interestingly HbA levels were highest at the beginning of each experimental phase and decreased as the experiment continued suggesting that the placenta has a hemoglobin buffering capacity. Gene alterations were prominent in categories such as iron ion binding, response to wounding, complement activation and acute phase response. Taken together these result suggest that the dual placenta perfusion may be a suitable model to study pathophysiological mechanisms in the PE placenta.

The contribution of Friederike Herr, Nelli Baal and Marek Zygmunt is based on the presentation given by Marek Zygmunt. Several steps of vascular adaptation both on fetal and maternal side are necessary and involve uterine vasodilation and remodelling by extravillous trophoblast as well as vasculo- and angiogenesis within the placenta. Ubiquitous (e. g. VEGF, bFGF) as well as pregnancy specific (PlGF, hCG, IGF-II, AFP) angiogenic factors are involved. Consequences of abnormal vascular development have been associated with different pregnancy-related pathologies ranging from miscarriage to intrauterine growth restriction or preeclampsia. Pregnancy-associated exposure to bacterial and viral infections or toxic agents (e. g. alcohol, nicotine or drugs) may also influence vascular development of the placenta and often lead to preterm labour and delivery. The group from Greifswald has developed a complex three-dimensional, three-component coculture model of developing vessels in the human placenta and utilized it for in vitro placental vasculogenesis- and trophoblast invasion studies in physiological relevant oxygen environment. The recently established three-dimensional endothelial spheroid models of vascular differentiation showed its positive influence on cellular apoptosis, cell-cell- signalling and expression of vasoactive cytokines and growth factors. Aggregates of three major placental derived cell types including endothelial precursor cells from umbilical cord blood, cytotrophoblasts and villous stromal cells were generated. The aggregates developed spontaneously in nonadherent culture plates and resulted in stable spheroids. In this model, both, early placental tissue and placental spheroids revealed comparative structure and differentiation pattern. Similar to isolated placental villi, differentiation antigens are expressed on cytotrophoblasts, villous stromal cells and endothelial progenitor cells in the new spheroidal model. Cytokeratin-7, a specific marker for cytotrophoblast cells, stains around the spheroidal core and resembles the villous architecture in vivo. It was further demonstrated that spheroids incorporated CD34+ cells similar to the chorionic villous stroma from early placental tissue and become relevant for testing the influence of toxins or viral exposure on vascular development.

The contribution of Holger Stepan und Alexander Jank is based on the presentation given by Holger Stepan. A dysbalance between angiogenic factors like placental growth factor (PlGF) and anti-angiogenic factors like soluble fms-like tyrosine kinase 1 (sFlt1) and soluble Endoglin (sENG) is a central feature of the pathogenesis of preclampsia. Antiangiogenic factors like sFlt1 und sENG have been shown to be significantly elevated in maternal serum weeks before clinical signs of preclampsia appear and maternal serum concentration correlates well with the later clinical course of the disease. Previous studies in pregnant women from a high risk population showed, that a disturbed uterine bloodflow as shown by Doppler in the 2^nd trimester alone predicted a later development of complications like preeclampsia together with intrauterine growth restriction with a specificity of only 60% and a positive predictive value of 58%. The group in Leipzig showed an improvement of the diagnostic precision for predicting early-onset preclampsia (<34 weeks) by measuring in parallel sFlt1 and PlGF, achieving a sensitivity of 83% and a specificity of 95% with a positive predictive value of 71%. A combined analysis of uterine Doppler, sEng and sFlt1 predicted early-onset PE even with a sensitivity of 99% and a specificity of 93%. Future clinical trials must test, whether an early use of a theoretically possible therapeutic intervention with correction of the dysbalance of angiogenic-antiangiogenic factors will have a positive effect on the development of the disease.

The final article comes from Katharina Seck and Thorsten Fischer, who present the new guidelines of the German Society of Obstetrics and Gynecology (DGGG) for the treatment of hypertensive disorders in pregnancy. The changes in these guidelines were compared with the recently revised guidelines of Australia and Canada and important points as they were discussed by representatives of the different societies at a conference in Washington are outlined. As is appropriate for our interdisciplinary journal issues relevant for the neonatologist are specially addressed.

Prof. Dr. Henning Schneider

Guest Editor

PS:

This issue is composed of a series of articles, which come from contributions presented at the Seminar „Placental Pathophysiology and its Relevance for Pregnancy Complications”, which took place at the 13. Kongress der Deutschen Gesellschaft für Pränatal- und Geburtsmedizin, 24.–26. April 2008, Bonn.

Correspondence