Simulation of the cardiotocogram during labor : towards model-based understanding of fetal physiology Citation for published version (APA): Jongen, G. J. L. M. (2016). Simulation of the cardiotocogram during labor : towards model-based understanding of fetal physiology. Technische Universiteit Eindhoven. Document status and date: Published: 13/09/2016 Document Version: Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers) Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.tue.nl/taverne Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 28. Sep. 2021 Simulation of the cardiotocogram during labor Towards model-based understanding of fetal physiology Germaine Jongen A catalogue record is available from the Eindhoven University of Technology Library. ISBN: 978-90-386-4123-2 Copyright © 2016 by G.J.L.M. Jongen All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronically, mechanically, by print, photo print, recording or any other means, without the prior written permission from the author. Printed by Gildeprint, Enschede, The Netherlands The research described in this thesis was funded by Stichting De Weijerhorst and performed within the IMPULS perinatology framework. Simulation of the cardiotocogram during labor Towards model-based understanding of fetal physiology PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Technische Universiteit Eindhoven, op gezag van de rector magnicus prof.dr.ir. F.P.T. Baaijens, voor een commissie aangewezen door het College voor Promoties, in het openbaar te verdedigen op dinsdag 13 september 2016 om 16:00 uur door Germaine Josefa Lucienne Maria Jongen geboren te Maastricht Dit proefschrift is goedgekeurd door de promotoren en de samenstelling van de promotiecom- missie is als volgt: voorzitter: prof.dr. P.A.J. Hilbers 1e promotor: prof.dr.ir. F.N. van de Vosse 2e promotor: prof.dr. S.G. Oei copromotor: dr.ir. P.H.M. Bovendeerd leden: prof.dr. M. Ursino (Università di Bologna) prof.dr. F.P.H.A. Vandenbussche (RUN) prof.dr.ir. J.W.M. Bergmans adviseur: dr.ir. M.B. van der Hout Het onderzoek of ontwerp dat in dit proefschrift wordt beschreven is uitgevoerd in overeenstem- ming met de TU/e Gedragscode Wetenschapsbeoefening. Contents Summary ix 1 Background and aim of the thesis 1 1.1 General introduction . 2 1.2 Mathematical models in a clinical setting . 3 1.3 The cardiotocogram . 4 1.3.1 Clinical evaluation of the CTG . 4 1.3.2 Physiological background . 5 1.3.3 Mathematical models for CTG simulation . 7 1.4 Outline of the thesis . 8 2 A mathematical model to simulate the cardiotocogram during labor Part A: Model setup and simulation of late decelerations 11 2.1 Introduction . 13 2.2 Material and methods . 14 2.2.1 Feto-maternal hemodynamics . 14 2.2.2 Oxygenation . 18 2.2.3 Regulation . 20 2.2.4 Model simulations . 23 2.3 Results . 24 2.4 Discussion . 27 v Contents 3 A mathematical model to simulate the cardiotocogram during labor Part B: Parameter estimation and simulation of variable decelerations 31 3.1 Introduction . 33 3.2 Material and methods . 33 3.2.1 Model extension . 33 3.2.2 Parameter estimation . 34 3.2.3 Model simulations . 38 3.3 Results . 38 3.4 Discussion . 42 4 Simulation of fetal heart rate variability with a mathematical model 45 4.1 Introduction . 47 4.2 Material and methods . 48 4.2.1 Mathematical model . 48 4.2.2 Model extension with FHRV . 50 4.2.3 Spectral analysis . 51 4.2.4 Model simulations . 51 4.3 Results . 52 4.4 Discussion . 58 5 Hypoxia-induced catecholamine feedback on fetal heart rate: A mathematical model study 63 5.1 Introduction . 65 5.2 Material and methods . 66 5.2.1 Physiological background . 66 5.2.2 Mathematical model . 67 5.2.3 Parameter estimation . 70 5.2.4 Model simulations . 71 5.3 Results . 72 5.4 Discussion . 77 6 General discussion 83 6.1 Introduction . 84 6.2 Main achievements . 84 6.3 Application of the CTG simulation model . 86 6.4 Future perspectives . 88 vi Bibliography 91 Samenvatting 105 Dankwoord 109 About the author 113 vii Contents viii Summary ix Summary Simulation of the cardiotocogram during labor: towards model-based understanding of fetal physiology During labor and delivery, it is important to monitor fetal well-being to enable timely and adequate intervention in case of fetal discomfort. Ideally, fetal monitoring should include assessment of oxygen status, but reliable oxygen measurements can only be performed during labor, after rupture of membranes, and then are only available at a limited number of time points. In current clinical practice, cardiotocography is therefore mainly used to estimate fetal well-being. The cardiotocogram (CTG) represents the simultaneous registration of the fetal heart rate (FHR) and uterine contractions. The underlying physiology, relating uterine contractions to the nal eect on FHR, involves a complex chain of events. This chain includes the baro- and chemoreex, as a response to variations in blood and oxygen pressure. Humoral feedback is also thought to be part of this response. Due to the complexity of this system, assessment of fetal well-being on the basis of the CTG is a challenging task. Mathematical models can be used to gain more insight into the complex chain through which uterine contractions lead to changes in fetal blood and oxygen pressure that nally result into changes in FHR. Previously, a mathematical model for simulation of the CTG was developed. This model describes feto-maternal hemodynamics, oxygenation, fetal regulation and uterine contraction generation, and can be used to simulate early, late and variable decelerations as caused by head compression, uterine blood ow reduction, and umbilical cord compression following uterine contractions. The rst step of this work was to reduce model complexity of the submodels where pa- rameter estimation was complicated or where less detailed model output was sucient. In addition, the physical description of other submodels was improved. In the next step, fetal heart rate variability (FHRV), which is an important indicator of fetal distress, was added to the model. Finally, the contribution of humoral feedback in the cardiovascular response to repetitive severe episodes of hypoxia was investigated with the model. The improved model, resulting from the rst step, was used to investigate the cascade from uterine contractions resulting in decreased uterine and/or umbilical blood ow, to FHR changes. Uterine contractions aect fetal blood and oxygen pressures, which stimulate the baro- and chemoreceptor, and nally change FHR via the sympathetic and parasympathetic nervous system. The faster and more severe FHR decrease during uterine contractions caus- ing combined uterine and umbilical blood ow reduction, compared to contractions leading to uterine ow reduction alone, can be explained by the oxygen buer function of the in- tervillous space. During the latter scenario, this oxygen buer is still available for the fetus, resulting in a delayed and slower drop in fetal oxygen pressure. As a consequence, the chemoreceptor-mediated FHR reduction is also delayed and less severe. If the umbilical cord x becomes occluded, this buer is no longer available for the fetus. During both scenarios, fetal blood ow was redistributed from the peripheral to the cerebral circulation in order to maintain oxygen transport to the brain. The initial FHR increase, observed during umbilical cord occlusions, can be explained by a blood volume shift from the fetus to the fetal placenta. This results in a fetal blood pressure decrease and a baroreceptor-mediated increase in FHR. The volume shift can be attributed to the delay between the closure of the umbilical vein and arteries. The model was evaluated with data from sheep experiments: similar trends in blood pressure, oxygen pressure and FHR were obtained, showing the ability of the model to describe realistic decelerations. Since the exact source of FHRV is not known, in the model we investigated the eect of three possible sources of variability on FHRV: autoregulation of the peripheral blood vessels, inuence of higher brain centers on the processing of the baroreceptor output in the nucleus tractus solitarius of the medulla oblongata, and inuence of aerent systems, such as the heart, lungs and muscles, on the vagal center.