Placenta (1998). 19, 551-555 WORKSHOP REPORT Regulation of Term and Preterm Labour, Castellina, Italy 28 October-l November 1997 J. Challis”, F. Petragliab and K. Chwalisz” a Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada b Department of Obstetrics and Gynaecology, University of Udine, Udine, Italy ’ Research Laboratories of Schering AG, Berlin, Germany This informal workshop was held to discuss recent advances in our understanding of term and preterm parturition. The workshop was sponsored and supported by Schering AG, Berlin, and Schering, Italy. Additional travel support for the attendees was provided by the National Institutes of Health (NICHD), Bethesda, MD, USA. The objective of the meeting was to review and to discuss new information concerned with the control of myometrial activity, placental function, and mechanisms contributing to preterm birth. For the purposes of this report we have provided some highlights of the meeting under three headings: Establishment of Early Pregnancy; Regulation of Myometrial Activity; and Indicators of Preterm Birth and Treatment hlodalities. The list of participants of the workshop is given at the end of this report. This summary reflects the impressions of its authors. Any inaccuracies are our responsibility, the credits and thanks go to our colleagues for their open, frank discussion, and to the sponsors who made the workshop possible. ESTABLISHMENT OF EARLY PREGNANCY The workshop opened with an outstanding discussion of the role of growth factors in the placenta in regulating invasiveness and angiogenesis in normoxaemia and hypoxaemia. Vascular endothelial growth factor (VEGF) is clearly central to these events. VEGF exists as five splice variants. Placental growth factor (PLGF) has 50 per cent homology to VEGF1,,. VEGF-B and VEGF-C have 34 and 30 per cent homology with VEGF,,,, respectively. Receptors for VEGF, PLGF and VEGF-B are flt-1, for VEGF, VECGF-B and VEGF-C are KDR, and for VEGF-C the receptor species is flt-4. There is a unique tissue- and cell-specific localization of receptors and ligands consistent with paracrine control interactions. For example, VEGF is produced in maternal macrophages at the maternal-placental interface in the basal plate region, whereas flt is expressed by trophoblast, including syncytiotrophoblast and extracelluar cytotrophoblast. KDR is only expressed in blood vessels, and not in trophoblast. As VEGF stimulates 01~3~~00~/98/0i0551+05 $12.00/O angiogenesis, it does so by binding to flt and KDR on endothelial cells. The VEGF knockout is lethal; VEGF is massively upregulated in molar pregnancy, but blood vessels are not formed because tissue factor is not present. Other early growth factors include hepatocyte growth factor (HGF) and its receptor CJMET. HGF mediates mesenchymal interactions, and is produced in fetal mesenchyme. cMET is expressed on glands and trophoblast, but as trophoblast moves away from the villous core tissue, it loses &LET. Angiopoetin-1 and -2 (Ang-1, Ang-2) and their receptor Tie 2 are recently described angiogenic factors responsible for nor- mal vascular endothelial growth and development. Ang-2 in fact may be an antagonist for Tie 2, although Ang-1, like basic FGF increases angiogenesis. Further work is clearly required on the regulation, timing of expression, and action of each of these factors in normal development of the placenta, in relation to the impaired trophoblast invasiveness seen in preeclampsia, and as predeterminants of placental and membrane endocrine/ paracrine function in labour-initiated processes. Tissue factor, normally absent from the circulation, is present in decidua, and necessary for thrombin formation and activation of the coagulation cascade. Tissue factor is necessary for post partum coagulation. The possibility was discussed that aberrant expression of tissue factor might predispose to first trimester vaginal bleeding, which is associated in turn with a two-fold increased risk of preterm delivery-. Bleeding later in pregnancy has a higher predictive value for preterm delivery-, even in the absence of other socio-economic indicators. A critical question is whether in fact one should be endeavouring to prevent these cases of preterm delivery, where an acute intrauterine episode could quickly lead to irreversible fetal damage, for example cerebral damage. Twenty per cent of preterm births arc medically indicated for pre-eclampsia and fetal growth retardation. Other obser- vations raise the possibility that these disorders may have a common pathogenesis. In pre-eclampsia, reduced invasion of maternal spiral arteries by trophoblast impacts on the feto- placental unit and generates reduced organ perfusion in the mother. There is abnormal maternal renal function, increased ‘functional’ volume, increased arterial pressure and edema.