Knowledge needed about the exchange physiology of the placenta.

There is now a basic understanding of the driving forces and mechanisms underlying rates of solute exchange across the placenta but there are still major gaps in knowledge. Here we summarise this basic understanding, whilst highlighting gaps in knowledge. We then focus on two particular areas where more knowledge is needed: (1) the electrical potential difference (PD) across the placenta and (2) the paracellular permeability of the placenta to hydrophilic solutes. In many species a PD has been recorded between a catheter in a maternal blood vessel and one in a fetal vessel. However, the key question is whether this PD is the same as that across the placental exchange barrier. We addressed this in the human placenta using microelectrodes to measure the PD in isolated villi in vitro; the transtrophoblast PD so measured had a median value of -3 mV (range 0-15 mV). There have been no subsequent studies to validate this measurement. The syncytiotrophoblast of haemochorial placentas lacks any obvious extracellular water filled paracellular space between the syncytial nuclei. However, in mouse, rat, guinea pig and human there is an inverse relationship between the rate of diffusion of inert hydrophilic solutes across the placenta and their molecular size. The simplest explanation is that a paracellular route exists but its morphological identity is still uncertain. Areas of syncytial denudation could provide a paracellular route but this has not been proven. Answers to these and similar questions are required to fully understand the exchange physiology of the normal placenta and how this is affected in pathology.