The influence of thyroid disorders on adverse pregnancy outcomes rs s

192 Pages·2016·6.16 MB·English

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13407_Vissenberg_OM.indd 1 10-02-16 13:17

THE INFLUENCE OF THYROID DISORDERS ON
ADVERSE PREGNANCY OUTCOMES
Rosa Vissenberg
Financial support for printing of this thesis was kindly provided by Stichting Gynaecologische Endocrinologie
en Kunstmatige Humane Voortplanting, Schildklier Organisatie Nederland, Stichting Fertiliteitsfonds
(www.fertiliteitsfonds.nl), Toshiba Medical Systems Nederland, Nutricia Early life Nutrition and by SBOH.
Met dank aan: Saskia’s huiskamerrestaurant
ISBN: 978-94-6299-306-8
Printed by: Ridderprint BV – www.ridderprint.nl
Layout: Ridderprint BV – www.ridderprint.nl
Cover design: Lyanne Tonk, www.persoonlijkproefschrift.nl
© All rights reserved. Save exceptions stated by the law, no part of this publication may be reproduced, stored in a
retrieval system of any nature, or transmitted in any form or by any means, electronic, mechanical, photocopying,
recording or otherwise, included a complete or partial transcription, without the prior written permission of the
publishers, application for which should be addressed to the author.
THE INFLUENCE OF THYROID DISORDERS ON ADVERSE
PREGNANCY OUTCOMES
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctor
aan de Universiteit van Amsterdam
op gezag van de Rector Magnificus
prof. dr. D.C. van den Boom
ten overstaan van een door het College voor Promoties ingestelde commissie,
in het openbaar te verdedigen in de Agnietenkapel
op vrijdag 29 april 2016, te 12.00 uur
door Rosa Vissenberg
geboren te Eindhoven
PROMOTIECOMMISSIE
Promotores: Prof. dr. J.A.M. van der Post Universiteit van Amsterdam
Prof. dr. E. Fliers Universiteit van Amsterdam
Co-promotores: Dr. M. Goddijn Universiteit van Amsterdam
Dr. P.H.L.T. Bisschop Universiteit van Amsterdam
Overige leden: Prof. dr. J.H. Kok Universiteit van Amsterdam
Prof. dr. F. van der Veen Universiteit van Amsterdam
Prof. dr. C.B. Lambalk Vrije Universiteit Amsterdam
Prof. dr. E.A.P. Steegers Erasmus Universiteit Rotterdam
Dr. R.P. Peeters Erasmus Universiteit Rotterdam
Dr. C. Ris-Stalpers Universiteit van Amsterdam
Faculteit der Geneeskunde
CONTENTS
Chapter 1 General introduction and outline of the thesis 7
Chapter 2 Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity 17
before conception and in early pregnancy: a systematic review
Human Reproduction Update 2011;17:605-19
Chapter 3 Increased Thyroid Stimulating Hormone in early pregnancy is associated with 49
breech presentation at term: a nested cohort study
Accepted in adapted form in European Journal of Obstetrics and Gynecology and
Reproductive Biology
Chapter 4 Is subclinical hypothyroidism associated with lower live birth rates in women 65
with unexplained recurrent miscarriage?
Submitted
Chapter 5 Pathophysiological aspects of thyroid hormone disorders/ thyroid peroxidase 79
autoantibodies and reproduction
Human Reproduction Update 2015;21:378-87
Chapter 6 Treatment of thyroid disorders before conception and in early pregnancy: 105
a systematic review
Human Reproduction Update 2012;18:360-73

Chapter 7 Live-birth rate in euthyroid women with recurrent miscarriage and thyroid 131
peroxidase antibodies
Gynecological Endocrinology 2015;2:1-4
Chapter 8 Effect of levothyroxine on live birth rate in euthyroid women with recurrent 141
miscarriage and TPO antibodies (T4-LIFE study)
Contemporary Clinical Trials 2015;44:134–138
Chapter 9 General discussion 159
Chapter 10 Summary 167
Nederlandse samenvatting 172
Addendum 177
List of co-authors and their contribution 178
List of publications 182
Portfolio 184
Dankwoord 186
Curriculum Vitae 188

1 |
General introduction and outline of the thesis
8 | Chapter 1
THYROID DISORDERS AND PREGNANCY
Thyroid hormone physiology
Circulating thyroid hormone concentrations are regulated via a negative feedback system at
the level of the hypothalamus and the pituitary. The production of thyroid hormone by the
thyroid gland is regulated by thyroid-stimulating hormone (TSH) produced by the anterior
pituitary, which itself is regulated by thyrotropin-releasing hormone (TRH) produced by the
hypothalamus. Iodide is a rate-limiting element that is needed for the production of thyroid
hormone. TSH stimulates expression of the enzyme thyroid peroxidase (TPO) in the thyroid
gland, which oxidises iodide to iodine. Subsequently iodine is incorporated in the glycoprotein
thyroglobulin (Tg) to form thyroid hormones, the majority in the form of the prohormone
thyroxine (T4) and also limited amounts of the biologically active triiodothyronine (T3).
Thyroxine-binding globulin (TBG) is a protein that binds T4 and T3 in the circulation. Only
the free, unbound T4 and T3 can enter target cells by virtue of specific thyroid hormone
transporters (MCT8, MCT10 and Oatp1c1). In target cells, thyroid hormone can be activated (T4
to T3) or inactivated (T4 to rT3 or T3 to T2) depending on the local activity of specific selenium-
containing enzymes, known as deiodinases (D1, D2 and D3). Subsequently, T3 can bind to the
nuclear thyroid hormone receptors (TR-alpha and TR-beta) and modulate transcription(1).
Thyroid physiology in pregnancy
Thyroid hormone is critical for the development of the foetal and neonatal brain, as well
as for many other aspects of pregnancy including placentation and foetal growth. As soon
as pregnancy is established, various physiological changes occur to ensure optimal thyroid
function to maintain a normal pregnancy and foetal development. During the first trimester,
human chorionic gonadotropin (hCG) stimulates the thyroid gland because of its structural
resemblance to thyroid stimulating hormone (TSH) (Figure 1). This may temporarily (typically
in the first trimester of pregnancy) result in higher free thyroxine (FT4) concentrations and
lower TSH concentrations(2;3) than outside pregnancy. Following this period, serum FT4
concentrations decrease by approximately 10 to 15%, and serum TSH values steadily return to
normal. Also starting in early gestation, oestrogen concentrations increase, which stimulates
production of thyroxine-binding globulin (TBG) by the liver. During pregnancy, serum TBG
concentrations increase, peaking around mid-gestation to be maintained thereafter(4). This
results in a significant rise in total T4 and T3. There is an increase in renal blood flow and
glomerular filtration rate, which leads to increased iodide clearance from plasma and loss of
iodine(5). The net effect is an increased demand for the production of thyroid hormones by the
thyroid gland in pregnancy. Foetuses are completely dependent on maternal thyroid hormone
production in the first trimester. T4 can be detected in foetal serum from approximately 10-12