SP 4: The Link between Maternal and Placental Health

Research questions, aims

There is a definite correlation between cardiovascular disease, vascular aging and PE and FGR. We are aiming to define causes and consequences of these relations for developing preventive intervention strategies, targeting not only pregnancy complications but also envisaging maternal long-term health.

Scientific background

PE is a multiorgan disorder characterized by a generalized maternal endothelial dysfunction leading to vascular leakage, vasoconstriction and malperfusion of organs. When the placenta is affected, FGR occurs. Affected mothers are at increased risk of cardiovascular disease in adult life (1), while women with pre-existing endothelial dysfunction or altered cardiovascular adaptation in early pregnancy are at higher risk for PE and FGR (2).

Own preceding work

Our research focuses on the effects of the NO-donor Pentaerytrithyltetranitrate (PETN) which enhances HO-1 expression and NO-bioavailability. Besides its vasodilatory effect PETN enhances endothelial function through anti-oxidative mechanisms. In a prospective randomized placebo-controlled pilot-study, we reported the effectiveness of PETN in reducing FGR and prematurity (3). Although the subsequent multicentre trial did not confirm a significant effect of PETN on the primary endpoint development of FGR and/or perinatal death, secondary endpoints like prematurity and pregnancy-induced hypertension were significantly reduced by 30% (4). Three clinician scientist projects (supported by Jena School of Ageing Medicine) have been performed on cardiovascular function in women who developed PE or FGR revealing improvement of long-term cardiac function upon PETN uptake and amelioration of oxidative stress in endothelial (5) and trophoblast cells through PETN, on the influence of PE-like stimuli and PETN on endothelial cell aging, and on expression of senescence markers in placenta of affected pregnancies by using multiplex immunhistochemistry.

Method spectrum, involvement of the Clinician Scientist

The Department of Obstetrics hosts a clinical research unit experienced in clinical trials. This outstanding infrastructure will enable Clinician Scientist projects involving patients. Prof. Groten is specialized in the care of patients with placenta associated pregnancy complications. For clinical assessment of cardiovascular function VCORDER, USCOM, HEPAtonorm analyzer, BIA and echocardiography are established. Future projects will involve patients at risk for PE and FGR in early pregnancy to evaluate mechanisms of adaptation failure of the cardiovascular system. Follow-up studies on mothers and children from the PETN multicenter-trial are scheduled for the 2023 and will include projects on perinatal programming in the context of FGR and long-term consequences of PETN intake. A collection of >1,000 placenta samples from different pathologies including a complete clinical data set is available for immunhistochemical analyses in cooperation with the Institute of Pathology. We are specialized on diabetes and pregnancy evolving a series of retrospective cohort studies (6-8). A databank of more than 1,000 diabetic pregnancies will enable the application of prospective clinical and translational studies involving gestational and preexisting diabetes in pregnancy.

Relevance for CEPRE and for Reproductive Health

This subprogram will focus on translational aspects of CEPRE. The Clinician Scientist will investigate the pathophysiological linkage of maternal conditions and placental function. Results will provide a key for the development of therapeutic strategies to improve reproductive and long-term health of women and offspring.

References

1. Chen SN, Cheng CC, Tsui KH, Tang PL, Chern CU, Huang WC, Lin LT. Hypertensive disorders of pregnancy and future heart failure risk: A nationwide population-based retrospective cohort study. Pregnancy Hypertens. 2018;13:110-5.
2. Brown MC, Best KE, Pearce MS, Waugh J, Robson SC, Bell R. Cardiovascular disease risk in women with pre-eclampsia: systematic review and meta-analysis. Eur J Epidemiol. 2013;28(1):1-19.
3. Schleussner E, Lehmann T, Kahler C, Schneider U, Schlembach D, Groten T. Impact of the nitric oxide-donor pentaerythrityl-tetranitrate on perinatal outcome in risk pregnancies: a prospective, randomized, double-blinded trial. J Perinat Med. 2014;42(4):507-14.
4. Groten T, Lehmann T, Stadtler M, Komar M, Winkler JL, Condic M, Strizek B, Seeger S, Jager Y, Pecks U, Eckmann-Scholz C, Kagan KO, Hoopmann M, von Kaisenberg CS, Brodowski L, Tauscher A, Schrey-Petersen S, Friebe-Hoffmann U, Lato K, Hubener C, Delius M, Verlohren S, Sroka D, Schlembach D, de Vries L, Kraft K, Seliger G, Schleussner E, Group PS. Effect of pentaerythritol tetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at midgestation-a randomized trial. Am J Obstet Gynecol. 2022.
5. Teichert V, Grosse S, Multhaup A, Muller J, Gutierrez-Samudio RN, Morales-Prieto DM, Groten T. PETN-Induced Antioxidative Properties in Endothelial Cells as a Target for Secondary Prevention of Endothelial Dysfunction in Pregnancy. Front Physiol. 2022;13:882544.
6. Weschenfelder F, Lohse K, Lehmann T, Schleussner E, Groten T. Predictors of Treatment Requirements in Women with Gestational Diabetes: A Retrospective Analysis. J Clin Med. 2021;10(19).
7. Weschenfelder F, Herrmann E, Lehmann T, Schleussner E, Kloos C, Battfeld W, Groten T. Predictors of a successful vaginal delivery in women with type 1 diabetes: a retrospective analysis of 20 years. Arch Gynecol Obstet. 2022;305(6):1445-52.
8. Weschenfelder F, Hein F, Lehmann T, Schleussner E, Groten T. Contributing Factors to Perinatal Outcome in Pregnancies with Gestational Diabetes-What Matters Most? A Retrospective Analysis. J Clin Med. 2021;10(2).