Perinatal glucocorticoid treatment and perspectives for antioxidant therapy

208 Pages·2013·8.68 MB·English

Perinatal glucocorticoid treatment and
perspectives for antioxidant therapy
Deodata Tijsseling
Perinatal glucocorticoid treatment and perspectives for antioxidant therapy
Thesis, Utrecht University, the Netherlands, with a summary in Dutch
ISBN: 978-90-393-6091-0
Author: Deodata Tijsseling
Cover design: Pieter van Hagen, Mariëlle Slotemaker
Layout & print: Gildeprint, Enschede, The Netherlands
Printed on: FSC certified paper
The studies in this thesis were supported by ‘Het Internationaliseringsfonds van de Universiteit
Utrecht’, ‘Stichting de Drie Lichten’ and ‘De Catharijnestichting’.
The author gratefully acknowledges financial support for printing this thesis by:
Division Woman and Baby, University Medical Center Utrecht; BMA BV (Mosos); Origio Benelux
BV, the Gilles Hondius Foundation, Medical Dynamics.
© D. Tijsseling, Utrecht, 2014
Perinatal glucocorticoid treatment and
perspectives for antioxidant therapy
Perinatale glucocorticoïd behandeling en perspectieven voor antioxidanten therapie
(met een samenvatting in het Nederlands)
Proefschrift
ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de
rector magnificus, prof. dr. G.J. van der Zwaan, ingevolge het besluit van het
college voor promoties in het openbaar te verdedigen op donderdag 30 januari
2014 des middags te 2.30 uur
door
Deodata Tijsseling
geboren op 1 maart 1983 te Leeuwarden
Promotoren: Prof. dr. G.H.A. Visser
Prof. dr. F. van Bel
Co-promotoren: Dr. J.B. Derks
Dr. W.B. de Vries
Contents
Chapter 1 General introduction 7
Part I Antenatal glucocorticoids
Chapter 2 Antenatal glucocorticoid treatment affects hippocampal 21
development in mice
Chapter 3 Effects of antenatal glucocorticoid therapy on hippocampal 39
histology of preterm Infants
Part II Postnatal glucocorticoids
Chapter 4 Oxidative stress in the developing brain: effects of postnatal 59
glucocorticoid therapy and antioxidants in the rat

Chapter 5 Statins prevent adverse effects of postnatal glucocorticoid 79
therapy on the developing brain in rats
Chapter 6 Statin therapy prevents the detrimental effects of postnatal 95
dexamethasone on the cardiovascular system
Chapter 7 Neonatal glucocorticoid therapy affects growth patterns 123
in early infancy

Part III Chronic fetal hypoxia
Chapter 8 Allopurinol prevents object recognition memory impairment in 145
adult offspring following chronic fetal hypoxia

Chapter 9 Summary and general discussion 163
Chapter 10 Samenvatting in het Nederlands 183
Chapter 11 Contributing authors 195
List of publications 199
Curriculum Vitae 201
Dankwoord 203

Chapter 1
General introduction
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8 | Chapter 1
Preterm delivery occurs in approximately 7-10% of all pregnancies in western countries and is R1
the most important cause of infant morbidity and mortality [1]. Due to improvements in both 1 R2
obstetric and, especially, neonatal care, survival of preterm infants has increased substantially R3
over the last decades. The introduction of ante- and neonatal glucocorticoids (GCs) has been an R4
important factor in increasing survival rates and quality of survival of preterm infants. R5
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Antenatal glucocorticoid treatment
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Since the pioneering work of Liggins and Howie [2] in the early seventies, synthetic GCs, like
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betamethasone and dexamethasone, are used worldwide antenatally to treat fetuses at risk for
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preterm delivery in order to reduce the risk of life-threatening complications of preterm birth
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including respiratory distress syndrome, necrotizing enterocolitis and intraventricular haemorrhage.
Moreover, by decreasing morbidity, antenatal therapy shortens the duration and thereby reduces R13
the costs of neonatal hospitalization. Since the National Institute of Health consensus statement in R14
1994, a single course of antenatal GC treatment has been recommended for all pregnant women R15
of gestation between 24 and 34 weeks, at risk of delivering within seven days [3]. Antenatal R16
GC treatment involves two maternal intramuscular (i.m.) injections of 12 mg betamethasone 24 R17
hours apart or four i.m. injections of 6 mg dexamethasone 12 hours apart. After crossing the R18
placenta and entering the fetal circulation GC treatment influences the development of the fetus
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[4]. To exert their effects, GCs bind to the intracellular GC receptor and/or the mineralocorticoid
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receptor, expressed in almost every organ. In the lungs, GCs stimulate surfactant production,
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increase lung compliance and maximal volume, promote structural and functional maturation,
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and regulate pulmonary fluid absorption [5]. Besides beneficial effects, undesirable effects of
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GCs on other tissues can be expected. In the brain GC receptors are abundantly expressed in
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the hippocampus [6], an important brain region involved in cognition, behaviour, many memory
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formation processes, coordination of autonomic functions, regulation of endocrine systems
and feedback regulation of the hypothalamic-pituitary-adrenal (HPA)-axis [7,8]. It is therefore R26
likely that among various brain regions the hippocampus appears to be the most vulnerable R27
to antenatal GC treatment and the area of interest of many studies exploring possible adverse R28
effects on brain development. Coe and others [9] have shown that elevated GC levels, caused by R29
prenatal stress, decrease neurogenesis in the dentate gyrus (DG) of juvenile rhesus monkeys and R30
that GCs may suppress cell proliferation. Moreover, dexamethasone administration in adult rats R31
results in death of pyramidal neurons in the cornu ammonal (CA) subfields and granule cells in
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the DG of the hippocampus [10,11]. Disturbance in development of the hippocampus may have
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effects later in life. So far in human, the use of a single course of antenatal GCs has not been
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associated with any significant maternal or fetal adverse effects on the long term [12]. However,
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data of human follow up studies are only complete up to 30 years of age.
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General introduction | 9
R1 Subgroup analysis of randomized trials, suggested decreased clinical benefit of antenatal GC
R2 treatment if birth was delayed more than 7 days after treatment [12]. Furthermore, laboratory
R3 evidence showed that fetal surfactant production could be repetitively induced [13], and sheep
R4 studies showed that fetal lung maturation was maximal when GCs were administered consecutive
R5 over several weeks [14,15]. Therefore, during the nineties, the use of repeated courses of antenatal
GCs among pregnant women with prolonged risk of preterm delivery became common clinical
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practice in many centers. However, since the effects of glucocorticoids are dose dependent, it
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is likely that adverse effects are more severe when multiple courses are administered. In animal
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models, an association was found between repeat or high-dose antenatal GCs and reduced
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fetal growth, long-term adverse effects on brain development, neuroendocrine function, glucose
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homeostasis and blood pressure [16]. Weekly antenatal GC courses in human do seem to have
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adverse effects. Although not consistent, several studies found decreased birth weight and
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head circumference using repeated courses [17-25]. The relative risk of cerebral palsy in infants
R13 exposed to repeated courses of antenatal GCs (relative risk, 5.7; 95% confidence interval, 0.7-
R14 46.7; P=0.12) in the study of Wapner and co-workers [26] is a serious concern and warrants
R15 further study. Because of insufficient scientific evidence and possible harmful effects, the NIH
R16 panel recommended that repeat GC courses, including the so-called “rescue therapy,” should
R17 not be used routinely, but reserved for women enrolled in clinical trials [27]. Because numerous
R18 preterm born children received high doses of antenatal GCs, knowledge of expected adverse
effects remains important.
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Neonatal glucocorticoid treatment
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Survivors of preterm delivery may require prolonged mechanical ventilation and may develop
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chronic lung disease (CLD). CLD is usually defined as oxygen dependency at 36 weeks post
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menstrual age or 28 days postnatal age, together with persistent clinical respiratory symptoms
R26 and concomitant abnormalities on chest radiographs [28,29]. In the eighties Mammel [30] and
R27 Avery [31] reported that neonatal/postnatal dexamethasone treatment of preterm neonates
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R29 infants at risk for developing CLD.
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R31 Although far less research has been conducted on neonatal compared to antenatal GC therapy,
a number of studies have highlighted the beneficial effects of neonatal use of GCs, at two
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key time points after delivery: early (<8 days), and late (>7 days). Given early, GCs facilitate
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extubation and decrease the risk of CLD and patent ductus arteriosus [32]. If GC therapy was
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initiated late, treatment was associated with a reduction in neonatal mortality [33]. Late GC
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treatment also facilitates extubation, it decreases the risk of CLD, and it helps wean infants
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from mechanical ventilation [33]. Neonatally, dexamethasone has been the GC of choice and
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commonly administered as a tapering course beginning at 0.5mg/kg. However, the duration of
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treatment varies from 3 to 42 days [34], and also the timepoint at which treatment is initiated
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10 | Chapter 1