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Abstracts of the 19th Annual Meeting of The Perinatal Society of
Australia and New Zealand
,2 Abstracts of the 19th Annual PSANZ Congress
CONCURRENT SESSION 1: MONDAY 20 APRIL MORNING reduced connectivity in a frontal network (p = 0.054). Major brain abnor-
mality at term related to reduced connectivity in the occipital and parietal
lobes, thalamus and putamen (p = 0.013). Impaired IQ was associated with
Neurodevelopment & neuroprotection
reduced connectivity in a diffuse network (p = 0.051). VP children with
A001 motor impairment had reduced connectivity in the right parietal and
temporal lobes (p = 0.052).
FETAL GROWTH RESTRICTION AND PRETERM BIRTH MAY
Conclusions: Adverse perinatal events have a lasting negative impact on
LEAD TO DISTURBED SLEEP IN CHILDHOOD
white matter connectivity. Structural connectivity reveals brain networks
Yiallourou SR1,2, Hollis S1, Odoi A1, Weichert A1, Wallace EM1,2,3,
underlying impairments in VP children.
Horne RSC1,2
1
The Ritchie Centre, MIMR-PHI Institute of Medical Research,
2 A003
Department of Paediatrics, Monash University, Clayton, Australia,
3
Department of Obstetrics and Gynaecology, Monash University, Clayton,
POSITIVE PARENTING BEHAVIOUR AT 2 YEARS PREDICTS
Australia Email: stephanie.yiallourou@monash.edu CHILD SCHOOL-AGE PERFORMANCE AT 7 YEARS IN VERY
PRETERM CHILDREN
Background: Fetal growth restriction (FGR) is associated with increased Treyvaud K1,2, Doyle LW1,2,3, Ure A1, Lee KJ1,2, Inder TE4, Anderson PJ1,2
risk of prematurity and neurodevelopmental impairment. FGR also alters 1
Murdoch Childrens Research Institute, Melbourne, Australia, 2The
sleep state distribution in utero and delays circadian rhythm maturation in University of Melbourne, Melbourne, Australia, 3The Royal Women’s
infancy. Currently, limited data on the long-term effects of FGR on Hospital, Melbourne, Australia, 4Brigham and Women’s Hospital,
childhood sleep exist. Given that sleep is important for neurodevelopment Boston, United States Email: karli.treyvaud@mcri.edu.au
and that poor sleep can lead to impairments in neurocognition, we
assessed the effect of FGR on sleep in children aged between 5 and 12 Background: Parenting influences child development, but it is uncertain
years. whether early parenting can predict school age outcomes in very preterm
Method: 11 children born preterm and FGR (gestation at birth: 30 ± 1 wks, (VPT) children, and whether parenting influences all “at-risk” children
birthweight: 1117 ± 125 g), 6 children born preterm but appropriately equally (differential susceptibility model). This was examined in the
grown (AGA) (gestation at birth: 30 ± 1 wks, birthweight: 1627 ± 331 g) current study.
and 10 term-born, appropriately grown children (controls) were studied Method: Participants were 147 children born <30 weeks’ gestation or birth
using overnight polysomnography. Non-rapid eye movement (NREM) and weight <1250 g and their primary caregiver. At term corrected age (CA),
rapid-eye movement sleep (REM) were scored in the following stages magnetic resonance imaging was used to determine brain abnormality and
NREM1, NREM2 (N2), NREM3 (N3) and REM sleep. There were no differ- medical data collected. High medical risk = at least one of: sepsis,
ences in age or weight at the time of testing between the three groups. necrotising enterocolitis, bronchopulmonary dysplasia, moderate severe
Results: Compared to term and preterm AGA children, FGR children had white matter brain abnormalities, or postnatal corticosteroids. At 2 years
a higher amount of N2 (p < 0.05) and a lower amount of N3 (p < 0.05). CA, parent-child interaction was assessed, and at 7 years CA, child cog-
Preterm AGA children had reduced sleep efficiency compared to IUGR and nitive, language, academic, executive and social-emotional functioning
term children (p < 0.05). were assessed.
Conclusions: Prematurity and FGR have long-lasting effects on childhood Results: Higher levels of parent-child synchrony, and parent facilitation,
sleep. N3 sleep is important for brain maturation and memory consolida- sensitivity and positive affect were associated with better outcomes for
tion. Sleep disturbance and its impact on neurodevelopment in FGR and children, while higher levels of intrusiveness and negative affect were
preterm children warrants further investigation as a means of mitigating associated with poorer outcomes. Parenting explained an additional
neurodevelopmental impairment in preterm children, whether born FGR or 6–17% of variance in child outcomes on top of that explained by medical
not. and social risk factors. Interactions between child medical risk category
(higher/lower) and parenting were limited to child reading, maths and
A002 executive functioning outcomes, with stronger relationships for lower
REDUCED CONNECTIVITY IN 7-YEAR-OLD PRETERM BRAIN medical risk children.
Conclusions: The contribution of early parenting to VPT children’s
NETWORKS RELATES TO ADVERSE PERINATAL EVENTS,
school-age performance is significant, with possibly stronger effects for
COGNITIVE AND MOTOR IMPAIRMENT
lower medical risk children in some outcome domains.
Thompson DK1,2,3, Chen J1, Beare R1, Adamson C1, Ahmadzai ZM1,
Kelly CE1, Inder TE4, Doyle LW1,5, Seal M1, Anderson PJ1,3
1
Murdoch Childrens Research Institute, Melbourne, Australia, 2Florey
Institute of Neuroscience & Mental Health, Melbourne, Australia,
3
Paediatrics, University of Melbourne, Australia, 4Brigham & Women’s
Hospital, Boston, United States, 5Royal Women’s Hospital, Melbourne,
Australia Email: deanne.thompson@mcri.edu.au
Background: Very preterm (VP) infants often suffer brain abnormalities
related to adverse perinatal events and are at risk of cognitive and motor
impairments. The aim of this study was to use Network Based Statistics
(NBS) to identify brain networks (1) associated with perinatal insults, and
(2) that differ between VP children with or without cognitive and motor
impairments at 7 years of age.
Method: At 7 years’ corrected age, 107 VP [<30 weeks’ gestational age
(GA) and/or <1250 g birthweight] children underwent MRI, and were
assessed on the Wechsler Abbreviated Scale of Intelligence (WASI) and
Movement Assessment Battery for Children (MABC2). Connectivity graphs
were created using Freesurfer regions as nodes, and white matter fibre
tracts as edges. NBS identified sub-networks whose connectivity strength
differed between groups.
Results: Connectivity within a left temporal, cingulate and putamen
network increased with GA (p = 0.096). Those with perinatal infection had
Journal of Paediatrics and Child Health 51 (Suppl. 1) (2015), 1–138
© 2015 The Authors. Paediatrics and Child Health Division (Royal Australasian College of Physicians)
, Neurodevelopment & neuroprotection 3
A004 A006
DIMINISHED NEUROSTEROID EXPOSURE IN UTERO AFFECTS MOLECULAR MECHANISMS OF IMPAIRED MYELINATION IN
ANXIETY-LIKE PHENOTYPE IN JUVENILE GUINEA PIGS THE IUGR OFFSPRING: RELEVANCE TO CEREBRAL PALSY
Cumberland AL1,2, Palliser HK1,2, Hirst JJ1,2 Azhan A, Hale N, Li A, Zahra V, Lu H, Moss TJ, Walker DW, Tolcos M
1
School of Biomedical Sciences and Pharmacy, University of Newcastle, The Ritchie Centre, MIMR-PHI Institute of Medical Research,
Callaghan, Australia, 2Hunter Medical Research Institute, Newcastle, Melbourne, Australia Email: aminath.azhan@monash.edu
Australia Email: angela.cumberland@uon.edu.au
Background: Intrauterine growth restriction (IUGR) increases the risk of
Background: Pregnancy compromises are associated with alterations in cerebral palsy (CP). In animal models of IUGR, oligodendrocyte (OL)
behavioural outcomes in the offspring. Female offspring are more likely to development is delayed, but the molecular mechanisms causing this are
develop mood disorders including depression and anxiety than males. not completely understood. We hypothesize that thyroid hormone (TH)
Neurosteroids, particularly allopregnanolone, are critical for fetal brain signalling is decreased, leading to increased expression in the inhibitory
development. Deregulation of allopregnanolone synthesis is associated Wnt/Notch pathways, resulting in delayed OL maturation and reduced
with mood disorders during adolescence and adulthood. We hypothesised myelination in the IUGR brain.
that reduced allopregnanolone exposure during late gestation would alter Method: At embryonic day 18 (term = 22 d), pregnant WKY rats under-
behavioural outcomes in juvenile guinea pigs. went bilateral uterine vessel ligation to generate IUGR pups at postnatal (P)
Method: Time-mated, outbred pregnant guinea pig dams received oral days, 2 (n = 8), 7 (n = 5) and 35 (n = 5); controls were from sham surgeries.
administration of vehicle (45% β-cyclodextrin) or finasteride Brains were fixed and immunostained to identify pre-myelinating (NG2-
(allopregnanolone synthesis inhibitor, 25 mg/kg) daily1, commencing at positive) and myelinating (myelin basic protein; MBP-positive) OLs (P7
GA60 until delivery (term ∼71 days). At postnatal day (PND) 20 all only). Pathways that promote [TH, Sox10, myelin regulatory factor (MyRF)]
pups underwent open field (OF) and novel object recognition testing or inhibit (Wnt, Notch) OL development were assessed via qPCR in pre-
(NORT). dominantly white matter brain regions.
Results: In OF, finasteride exposed females travelled significantly less Results: In IUGR vs. control, there was a significant: (i) decrease in NG2-
distance in the arena compared to vehicle females (p = 0.026). They also and MBP-positive cell density; (ii) decrease in MBP mRNA (P7, P35);
spent less time investigating novel objects (p = 0.050) and this translated (iii) decrease in TH monocarboxylate transporter 8 (MCT8), TH receptor α
to a lower % function of novel object recognition (p = 0.05). A low (TRα), Sox10, MyRF mRNA and increase in Axin2, Notch1/2, Jagged1 and
neurosteroid environment in pregnancy did not affect these parameters in Hes5 mRNA (P7). There were no differences (i) MCT8 or TRα mRNA at P2
male neonates. or (ii) deiodinase 2/3,(TH enzymes) mRNA (P7, P35).
Conclusions: This study shows that reduced neurosteroid exposure during Conclusions: TH signalling and pathways that promote OL maturation and
late gestation affects the later development of anxiety-like phenotypes and myelination are down-regulated while those that inhibit OL maturation are
poorer memory function in female juvenile guinea pigs. This may impli- up-regulated. Understanding these mechanisms could identify targets for
cate neurosteroid loss during pregnancy in the development of mood therapies to restore myelination in infants born IUGR and affected by CP.
disorders later in life.
1. Kelleher MA, Palliser HK, Walker DW, Hirst JJ. J Endocrinol.
A007
2011;208(3):301–309. CELLULAR AND MORPHOLOGICAL CHANGES IN THE FETAL
SHEEP BRAIN DURING GYRIFICATION – AN
A005
IMMUNOHISTOCHEMICAL STUDY
CHRONIC HIGH-DOSE CAFFEINE INCREASES THE DENSITY OF
Boomgardt M1, Britto J2, Tolcos M1, Walker D1
NEURONS IN THE DEVELOPING CEREBRAL CORTEX OF THE 1
The Ritchie Centre, MIMR-PHI Institute of Medical Research, Monash
VERY IMMATURE OVINE FETUS Medical Centre, Clayton VIC., 3168, 2The Florey Institute of
De Matteo R1, Sutherland A1, Cheong J2, Rees S3, Harding R1, Tolcos M4 Neurosciences and Mental Health, Parkville, 3052 Email:
1
Monash University, Melbourne, Australia, 2Royal Women’s Hospital, meg.boomgardt@monash.edu
Melbourne, Australia, 3University of Melbourne, Melbourne, Australia,
4
MIMR-PHI Institute of Medical Research, Melbourne, Australia Email: Background: In some species (incl. humans) the formation of cortical gyri
robert.dematteo@monash.edu and sulci is largely accomplished by the time of birth; however, the
fundamental mechanisms driving this process are poorly understood.
Background: Caffeine is widely used to treat apnea of prematurity (AOP). Using fetal sheep, we have used immunohistochemistry to identify struc-
As the standard dosing regimen is not always sufficient to abolish AOP, tural and cellular changes that occur between 56 and 113 days gestation,
higher doses may be used. Our objective was to determine the impact of a time that precedes and accompanies cortical folding in this species. The
chronic, high-dose caffeine on the developing cerebral cortex. effects of permanent restriction of feto-placental blood flow were assessed
Method: We administered a caffeine loading dose (50 mg/kg; maternal to determine the impact of growth processes on normal development.
i.v.) followed 2 h later by a constant infusion (3.8 mg/kg/h, maternal i.v.) Method: Fetal brains were collected at 56, 70, 78, 90 and 113 days
to ovine fetuses (n = 9) from 104 to 118 days of gestation (DG; term = 147 gestation (term∼147 days) to assess ontogeny. In 5 fetuses, feto-placental
DG); control fetuses (n = 8) received saline. At 119 DG, cell death (TUNEL), blood flow was restricted by single umbilical artery ligation (SUAL) (n = 5)
microglia (Iba-1), astrocytes (GFAP), oligodendrocytes (Olig2) and neurons at 65–70 days gestation and brains collected at 90 days; controls were
(NeuN) were assessed in the cerebral cortex. sham surgery (n = 7). All tissue was examined by diffusion-tensor MRI,
Results: Compared with control fetuses, caffeine-exposed fetuses had a and subsequently paraffin-embedded to assess gross histology and cellular
33% increase in the density of neurons in the marginal zone (167 ± 6 vs architecture with specfic markers for neurons, microglia, astrocytes,
228 ± 12 cells/mm2, p < 0.05). There were no significant differences in oligodendrocytes, interneurons and blood vessels.
other parameters measured. Results: The first primary sulci appear after 70 days gestation, and the
Conclusions: Chronic high dose caffeine exposure does cause overt injury secondary folds are present within a 20-day period. This rapid growth phase
in the very immature cerebral cortex but increases the density of neurons is associated reorientation of glial-fibre tracts and migration of projection
in the marginal zone. Further studies are needed to determine the immedi- neurons, interneurons and oligodendrocytes into the expanding gyri. The
ate and long-term consequences of this finding. SUAL perturbation did not change absolute or relative brain weight, but
reduced the rate of gyri expansion and resulted in shallow sulci.
Conclusion: Gyral formation involves changes in cell positioning within
the entire cortical depth and depends on spatially distinct growth/
specification factors.
Journal of Paediatrics and Child Health 51 (Suppl. 1) (2015), 1–138
© 2015 The Authors. Paediatrics and Child Health Division (Royal Australasian College of Physicians)
, 4 Abstracts of the 19th Annual PSANZ Congress
A008 A010
HIGH-DOSE CAFFEINE INCREASES NEURONAL AND GLIAL ERYTHROPOIETIN (EPO) PROTECTS AGAINST
DENSITY IN THE FETAL SHEEP CEREBRAL CORTEX LIPOPOLYSACCHARIDE (LPS)-INDUCED INJURY IN THE FETAL
Atik A1, De Matteo R1, Cheong J2, Harding R1, Rees S3, Tolcos M4 CEREBELLUM, BUT ALTERS CEREBELLAR DEVELOPMENT
1
Monash University, Melbourne, Australia, 2Royal Woman’s Hospital, McDougall ARA1, Hale N1, Rees S2, Harding R3, De Matteo R3,
Melbourne, Australia, 3University of Melbourne, Melbourne, Australia, Hooper SB1, Tolcos M1
4
MIMR-PHI Institute of Medical Research, Melbourne, Australia Email: 1
The Ritchie Centre, MIMR-PHI Institute of Medical Research, 2Dept of
mary.tolcos@mimr-phi.org Anatomy and Cell Biology, University of Melbourne, 3Dept of Anatomy
Background: Standard doses of caffeine are often insufficient to treat and Developmental Biology, Monash University, Melbourne, Australia
apnea of prematurity, potentially resulting in the need for higher doses. Email: annie.mcdougall@monash.edu
However, the effects of high doses of caffeine on the very immature brain Background: Intrauterine inflammation is an antecedent for preterm birth
have not been thoroughly investigated. Our aim was to determine whether and cerebral palsy (CP). EPO is neuroprotective clinically and in animal
high-dose caffeine affects the developing cerebral cortex. studies. Our aim was to determine i) whether LPS-induced intrauterine
Method: Caffeine (50 mg/kg loading; 40 mg/kg daily maintenance; n = 9) inflammation causes injury to, and impairs development of the fetal ovine
or saline (n = 9) was administered to ovine fetuses via the maternal cerebellum and ii) whether recombinant human EPO (rhEPO) would miti-
circulation (104–118 days of gestation (DG); term = 147 DG). At 119 DG, gate these changes.
cell death (TUNEL), microglia (Iba-1), astrocytes (GFAP), oligodendrocytes Method: At 107 ± 1 days gestational age (GA) fetal sheep received either
(Olig2, MBP), neurons (NeuN), layer V/VI subcortical projection neurons i) an intravenous bolus dose of LPS (∼0.9 μg/kg; n = 6), ii) a bolus dose of
(Ctip2), GABAergic interneurons (somatostatin), cell proliferation (Ki67) LPS followed at 1 h by 5000 U/kg rhEPO (EPO + LPS; n = 8), iii) rhEPO
and pyramidal cell dendritic spine (Golgi-cox) density were assessed in the alone (EPO; n = 4) or iv) saline (n = 8). At 116 ± 1 GA cerebellar sections
cerebral cortex. were collected and examined histologically.
Results: In caffeine-exposed vs. control fetuses there was an increased Results: Microglial density increased (p = 0.003) in cerebellar white matter
density in cells positive for Ctip2 (22% increase; p < 0.05), GFAP (43% in LPS fetuses compared to controls; EPO returned microglial density to
increase; p < 0.05) and Olig2 (12% increase, p < 0.05). There was no control levels. External granule layer (EGL) thickness was decreased
difference (p > 0.05) between treatment groups in any of the other (p = 0.002) in EPO and EPO + LPS groups, compared to control and LPS
parameters. groups. In EPO, LPS and EPO + LPS fetuses compared to controls, there was
Conclusions: High-dose caffeine does not appear to cause overt injury, an increase (p = 0.04) in the proportion of the EGL occupied by the
but does result in an increased density of layer V/VI subcortical projection proliferative zone; this was due to a decrease (p = 0.03) in the thickness of
neurons, oligodendrocytes and astrocytes that cannot be accounted for by the post-mitotic zone in EPO and EPO + LPS groups compared to controls.
an increase in cell proliferation at this time point. There was no change between groups in area of the cerebellum, molecular
layer (ML) or internal granule layer, the density of granule cells in the ML
A009 or the linear density of Bergmann glial fibres.
A NEW PROMISE FOR THE TREATMENT OF NEONATAL Conclusions: Intrauterine inflammation injures and alters the develop-
SEIZURES ment of the cerebellum. EPO protects against LPS-induced injury, but may
Yawno T1, Aridas J2, Jenkin G, Miller S, Walker DW1, Fahey M3 alter normal cerebellar development.
1
MIMR-PHI Institute of Medical Research, Clayton, Melbourne,
Australia, 2Monash Medical Centre, Clayton, Melbourne, Australia
Email: tamara.yawno@monash.edu
Background: Seizures in neonates are relatively common; they are pow-
erful predictors of long-term cognitive and developmental impairment.
There is also a significant concern about current anti-seizure therapies,
which can cause brain injury as they have the potential to be neurotoxic.
We will investigate the effects of the synthetic GABAA agonist ganaxolone,
or phenobarbitone given at the onset of seizure in term fetal sheep caused
by hypoxia ischemia.
Method: Hypoxia ischemia was induced via umbilical cord occlusion
(UCO) at caesarean delivery in near-term lambs (∼141 days gestation). UCO
or control lambs were resuscitated using standard resuscitation guidelines.
UCO lambs with seizures were treated with phenobarbitone (20 mg/kg over
30 min). At 72 hours, lambs were euthanased for brain collection and
analysis.
Results: At the time of birth, asphyxiated lambs had a pH < 7.0
(6.92 ± 0.02) and a base excess >12 mmol/L (−14.2 ± 1.1), indicating severe
birth asphyxia. Brain histology at 72 hr showed an increase in the number
of inflammatory cells and cell death in phenobarbitone treated-lambs
compared to control lambs. We are now investigating the outcome effects
of ganaxolone treatment.
Conclusions: Phenobarbitone suppresses seizure activity but is associated
with the presence of a high incidence of microglial activation and cell
death. Ganaxolone, known to have a high margin of safety and lack of
tolerance with repeated administration, is proposed to decrease both
seizure activity and indices of cerebral inflammation and cell death.
Ganaxolone may therefore be a therapy that avoids the side-effects and
poor efficacy associated with the current recommended treatments.
Journal of Paediatrics and Child Health 51 (Suppl. 1) (2015), 1–138
© 2015 The Authors. Paediatrics and Child Health Division (Royal Australasian College of Physicians)
