title: Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
abstract: Although much progress is being made in understanding the molecular pathways in the placenta that are involved in the pathophysiology of pregnancy-related disorders, a significant gap exists in the utilization of this information for the development of 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 2-day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap. Particular emphasis was given to 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 that workshop. A broad number of topics were covered that ranged 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 noninfectious agents. Research findings in these areas will be critical for the formulation of the development of future treatments and the development of therapies for the prevention of a number of pregnancy disorders of placental origin that include preeclampsia, fetal growth restriction, and uterine inflammation. Research was also presented that summarized ongoing clinical efforts in the United States and in Europe that has tested novel interventions for preeclampsia and fetal growth restriction, including agents such as oral arginine supplementation, sildenafil, pravastatin, gene therapy with virally delivered vascular endothelial growth factor, and oxygen supplementation therapy. Strategies were also proposed to improve fetal growth by the enhancement of nutrient transport to the fetus by modulation of their placental transporters and the targeting of 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 and the hurdles and pitfalls of the translation of research findings into practice. The workshop also discussed novel methods of drug delivery and targeting during pregnancy with the use of 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 must change their thinking of the pregnant woman and her fetus as a vulnerable patient population for which drug development should be avoided, but rather be thought of as a deprived population in need of more effective therapeutic interventions.
authors.affiliation: Pregnancy and Perinatology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Department of Health and Human Services, Bethesda, MD. Electronic address: ilekisj@mail.nih.gov.
authors.forename: John V
authors.initials: JV
authors.lastname: Ilekis
authors.affiliation: Obstetric and Pediatric Pharmacology and Therapeutics Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Department of Health and Human Services, Bethesda, MD. Electronic address: tsiloue@mail.nih.gov.
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Tsilou
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Francisco, San Francisco, CA.
authors.forename: Susan
authors.initials: S
authors.lastname: Fisher
authors.affiliation: Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine; New Haven, CT.
authors.forename: Vikki M
authors.initials: VM
authors.lastname: Abrahams
authors.affiliation: Institute of Reproductive Health and Regenerative Medicine and Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Soares
authors.affiliation: Comparative Biology and Experimental Medicine, University of Calgary Health Sciences Centre, Calgary, Alberta, Canada.
authors.forename: James C
authors.initials: JC
authors.lastname: Cross
authors.affiliation: Department of Obstetrics and Gynecology, Hackensack University Medical Center, Hackensack, NJ.
authors.forename: Stacy
authors.initials: S
authors.lastname: Zamudio
authors.affiliation: Department of Obstetrics and Gynecology, Hackensack University Medical Center, Hackensack, NJ.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Illsley
authors.affiliation: Center for Pregnancy and Newborn Research, University of Texas Health Science Center, San Antonio, TX.
authors.forename: Leslie
authors.initials: L
authors.lastname: Myatt
authors.affiliation: Therapeutics Discovery Program, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD.
authors.forename: Christine
authors.initials: C
authors.lastname: Colvis
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
authors.forename: Maged M
authors.initials: MM
authors.lastname: Costantine
authors.affiliation: Department of Obstetrics and Gynecology Indiana University, Indianapolis, IN.
authors.forename: David M
authors.initials: DM
authors.lastname: Haas
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, PA.
authors.forename: Yoel
authors.initials: Y
authors.lastname: Sadovsky
authors.affiliation: University of Kansas Medical Center, Kansas City, KS.
authors.forename: Carl
authors.initials: C
authors.lastname: Weiner
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
authors.forename: Erik
authors.initials: E
authors.lastname: Rytting
authors.affiliation: Department of Neurology, University of Mississippi Medical Center, Jackson, MS.
authors.forename: Gene
authors.initials: G
authors.lastname: Bidwell
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016503:Drug Delivery Systems; D055808:Drug Discovery; D005260:Female; D005819:Genetic Markers; D006801:Humans; D051379:Mice; D023421:Models, Animal; D058990:Molecular Targeted Therapy; D054582:National Institute of Child Health and Human Development (U.S.); D010920:Placenta / Q000196:embryology / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D010922:Placenta Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D011256:Pregnancy Outcome; D051381:Rats; D057170:Translational Research, Biomedical; D014481:United States
chemical_list: D015415:Biomarkers; D005819:Genetic Markers
keywords: drugs; placenta; pregnancy; therapeutics; trial