University of Groningen Paving ways for personalizing drug therapy during pregnancy Daud, Nur IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2017 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Daud, N. (2017). Paving ways for personalizing drug therapy during pregnancy: A focus on the risk of drug teratogenicity. Rijksuniversiteit Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). 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Download date: 23-09-2021 Paving ways for personalizing drug therapy during pregnancy A focus on the risk of drug teratogenicity Nur Aizati Athirah Daud ISBN 978-90-367-9641-5 (printed version) ISBN 978-90-367-9640-8 (electronic version) Author: Nur Aizati Athirah Daud Cover: Nur Aizati Athirah Daud (concept) and Gherasim Florin (graphic design) Lay-out: Nurul ‘Azyyati Sabri Printed by: Ipskamp Printing The publication of this thesis was financially supported by the Research Institute SHARE (Science in Healthy Ageing and healthcaRE), University Medical Center Groningen/University of Groningen and the Ministry of Education, Malaysia. The funding from University Sains Malaysia is gratefully acknowledged. Copyright ©Nur Aizati Athirah Daud, Groningen 2017. All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage or retrieval system, without written permission of the author. The copyright of previously published chapters of this thesis remains with the publisher or journal. Paving ways for personalizing drug therapy during pregnancy A focus on the risk of drug teratogenicity PhD thesis To obtain the degree of PhD at the University of Groningen on the authority of the Rector Magnificus Prof. E. Sterken and in accordance with the decision by the College of Deans. This thesis will be defended in public on Monday 24 April 2017 at 12.45 hours by Nur Aizati Athirah Daud born on 27 December 1985 In Kelantan, Malaysia Supervisor Prof. dr. Bob Wilffert Co-supervisor Dr. Jorieke E.H. Bergman Assessment committee Prof. dr. Eugène P. van Puijenbroek Prof. dr. Toine C.G. Egberts Prof. dr. Régine P.M. Steegers-Theunissen untuk Amir & Natrah.. Paranymphs: Nurul Nadiah Hamidon Heleen van der Meer CONTENTS Chapter 1 General introduction 11 PART A The role of transporter proteins in drug-induced birth defects Chapter 2 P-glycoprotein-mediated drug interactions in pregnancy & the 30 changes on the risk of congenital anomalies: A case-reference study Drug Safety 2015 Chapter 3 Maternal use of drug substrates of placental transporters and 50 the effect of transporter-mediated drug interactions on the risk of congenital anomalies PLOS ONE 2017 Chapter 4 Pharmacogenetics of drug-induced birth defects: the role of 70 polymorphisms of placental transporter proteins Pharmacogenomics 2014 PART B Pharmacogenetic predictors associated with the risk of drug teratogenicity Chapter 5 Knowledge and attitude of formerly pregnant women regarding 98 pharmacogenetics, and their willingness to participate in pharmacogenetic research BMC Pregnancy and Childbirth 2017 Chapter 6 The risk of congenital heart anomalies following prenatal 116 exposure to serotonin reuptake inhibitors- is pharmacogenetics the key? International Journal of Molecular Sciences 2016 Chapter 7 Prenatal exposure to serotonin reuptake inhibitors and congenital 144 heart anomalies: An exploratory gene-environment interaction study Submitted Chapter 8 General discussion 168 Addendum Appendices 184 Summary 215 Samenvatting 218 Acknowledgement 221 List of publications 224 Research Institute SHARE 226 About the author 228 chapter 1 General Introduction 1 Pregnancy is a very important period in women’s life, which notably affects their emotional and physical well-being. Besides these changes, more important from a GENERAL INTRODUCTION pharmacotherapeutic point of view, are the physiological changes that affect the response to drugs consumed by these women (1,2). Drug use during pregnancy has been assessed in many drug utilization studies and it was estimated that between 20 to 90% of pregnant women in developed countries were prescribed at least one drug (3–6). The actual use could be even more prevalent if we take into account the consumption of over-the-counter medicines e.g. analgesics. Some women have clear indications for taking drugs during pregnancy, which are to control their diseases and to avoid fetal complications e.g. antiepileptics, insulin, and antiretrovirals. Other women, usually with minor ailments, may choose whether to take medicines or not. This decision, however, may be affected by the unknown risk of harm to the fetus. Drug risks during pregnancy Some drugs are known to be teratogenic to the human fetus. A teratogenic effect is manifested by developmental toxicity in an embryo/fetus, by the induction or increase in the frequency of structural disorders (7). Drug teratogenicity was not much of a concern until the thalidomide issue came into the picture in the early 1960s. The use of thalidomide, a popular antiemetic for morning sickness, was associated with severe congenital limb anomalies also known as phocomelia. Since this event, the regulation for drug approval has been tightened, and congenital anomaly (CA) registries were set up to monitor the occurrence of CA. These registries were united in several networks, e.g. European Concerted Action on Congenital Anomalies and Twins (EUROCAT), The US National Birth Defects Prevention Network (NBDPN), and the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). These registries are commonly used in observational studies to detect signals of drug-induced teratogenicity. The information on drug use during pregnancy is usually derived from two types of sources, either from self-reports (interviews and questionnaires) or from data linkage with prescription databases. The prevalence of CA is 2-3% of total births, and the highest prevalence is for congenital heart anomalies (CHA), i.e. 8 to 9 cases per 1,000 live births (8). CA can occur due to different reasons including genetic factors, maternal characteristics or environmental exposure during pregnancy (e.g. maternal age, smoking, obesity, and drugs) and also a combination of these factors (9). It is of alarming concern that about 90% of the drugs registered by the US Food and Drug Administration (FDA) between 1980 and 2012 does not have a clear teratogenicity profile in human pregnancy (10–12). There is also a significant lag time, on average 27 years, between drug discovery and the pregnancy safety data to become available (11). A Dutch study 11 1 estimated that a potentially teratogenic drug is taken in approximately five percent of all pregnancies, with doxycycline and paroxetine being the most frequently dispensed (13). Luckily, not all drugs taken during pregnancy are deemed to cause harmful effects to the fetus. Among the determinants of fetal teratogenicity are the dose-effect relationships, the inter- and intraspecies variability in the susceptibility for teratogenic effect, and timing of drug exposure (7). First, the dose-effect relationship is important in toxicological evaluations. Nearly every drug has been tested for the ‘no-effect’ level, GENERAL INTRODUCTION which is the level of exposure that does not promote any biological alterations that might lead to adverse effects (7). Drugs with a wide therapeutic index may provide a safe and effective therapy within a wide range of concentrations in the body (e.g. analgesics), in contrast to drugs with a narrow therapeutic index (e.g. antiepileptics). Next, not all mammalian species are equally susceptible to the teratogenic effect of a given drug. One same drug may induce different developmental disorders in different species. The timing of drug exposure, or window of susceptibility, determines the types of adverse effects on the fetus. Fetal CAs are usually associated with exposure at an early stage of pregnancy, while exposure at a later stage induces functional disorders (7). There are several pregnancy classification systems set up by the authorities to guide clinicians in making a careful choice of drug therapy among pregnant patients, e.g. the Swedish classification, the Australian classification (the Australian Drug Evaluation Committee, ADEC) and the Teratogen Information System (TERIS) risk ratings (14). The risk classifications suggested by these systems are largely based on the data from animal studies, as human data is very limited. The limitation of animal studies is the interspecies variation in drug teratogenicity. For example, thalidomide did not pose much risk of fetal CA in mice, but it was highly teratogenic