No abstract

Although much progress is being made in understanding the molecular pathways in the placenta involved in the pathophysiology of pregnancy related disorders, a significant gap exists in utilizing this information for developing new drug therapies to improve pregnancy outcome. On March 5–6, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health sponsored a two day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap. Particular emphasis was given in the identification of important molecular pathways that could serve as drug targets and the advantages and disadvantages of targeting these particular pathways. This article is a summary of the proceedings of this workshop. A broad number of topics were covered ranging from basic placental biology to clinical trials. This included research in the basic biology of placentation, such as trophoblast migration and spiral artery remodeling, and trophoblast sensing and response to infectious and non-infectious agents. Research findings in these areas will be critical for formulating developing future treatments and developing therapies for the prevention of a number of pregnancy disorders of placental origin including preeclampsia, fetal growth restriction, and uterine inflammation. Research was also presented summarizing ongoing clinical efforts in the U.S. and in Europe testing novel interventions for preeclampsia and fetal growth restriction, including agents such as oral arginine supplementation, sildenafil, pravastatin, gene therapy using virally-delivered vascular endothelial growth factor, and oxygen supplementation therapy. Strategies were also proposed to improve fetal growth by enhancing nutrient transport to the fetus by modulating their placental transporters, as well as targeting placental mitochondrial dysfunction and oxidative stress to improve placental health. The roles of microRNAs and placental-derived exosomes, as well as messenger RNAs, were also discussed in the context of their use for diagnostics and as drug targets. The workshop discussed the aspect of safety and pharmacokinetic profiles of potential existing and new therapeutics that will need to be determined especially in the context of the unique pharmacokinetic properties of pregnancy, as well as the hurdles and pitfalls of translating research findings into practice. The workshop also discussed novel methods of drug delivery and targeting during pregnancy using macromolecular carriers, such as nanoparticles and biopolymers, to minimize placental drug transfer and hence fetal drug exposure. In closing, a major theme that developed from the workshop was that the scientific community needs to change their thinking of the pregnant women and her fetus as a vulnerable patient population for which drug development should be avoided, but rather thought of as a deprived population in need of more effective therapeutic interventions.

One of the primary regulators of maternofetal glucose transfer is the density of glucose transporter proteins in the placenta. These transporters, members of the GLUT gene family of facilitated-diffusion transporters, are embedded in the microvillous (maternal-facing) and basal (fetal-facing) membranes of the syncytiotrophoblast, the main placental barrier layer. Eight members of this family have been described in human placental tissue, but only GLUT1 protein has been identified in the syncytium, where its distribution is asymmetric. The microvillous membrane contains markedly more transporter than the basal, and, as a result, the basal membrane acts as the rate-limiting step in transplacental glucose transport; thus, changes in the density of basal membrane GLUT1 will have a significant impact on transplacental glucoseflux. What little is known about syncytial GLUT1 expression is restricted to factors associated with fetoplacental growth and metabolism; GLUT is inversely regulated by glucose concentration and basal membrane GLUT1 is positively regulated by insulin-like growth factor I, placental growth hormone, and hypoxia. In vivo, basal membrane GLUT1 is upregulated over gestation, increased in diabetic pregnancy, and decreased in chronic hypoxia, while microvillous membrane GLUT1 is unaffected. The contrast between in vitro and in vivo regulation and the specific changes in GLUT1 distribution suggest more complex regulatory interactions than those yet described.

Targeted delivery at 34 weeks and team-managed diagnosis, treatment, and care of patients with placenta accreta were associated with improved maternal, but not neonatal outcomes.

Transport of chloride across cell membranes through exchange, cotransport, or conductive pathways is a subject of great biological importance. Current methods of measurement are restricted in their sensitivity, time resolution, and applicability. A new transport measurement technique has been developed on the basis of the fluorescence quenching by chloride of the dye 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ). SPQ fluorescence quenching by chloride is rapid (less than 1 ms) and sensitive, with a greater than 50% decrease in fluorescence at 10 mM chloride. SPQ fluorescence is not altered by other physiological anions or by pH and can be used to measure both neutral and conductive transport processes. The high water solubility and membrane permeability properties of SPQ make it ideal for use in both membrane vesicles and cells. Chloride transport determined with SPQ was validated by measurement of erythrocyte chloride/anion exchange and membrane vesicle chloride conductance.