HRB Grant Holders Conference

LimerickFebruary 26-27, 2015

Consortium Background• All-Ireland multi-centre consortium focused on

research into maternal and child health• Health Research Board (HRB) funded (€4.9 million)• Additional external funding (€2.8 million)

- Friends of the Rotunda- National Children’s Research Centre- Children’s University Hospital Research Fund- Science Foundation Ireland - Wellcome Trust

• Links seven maternity hospitals and associated academic centers across the island

Network Partners

Maternal Fetal Medicine SupportUniversal National Support

ROTUNDAFionnuala BreathnachSharon CooleyJennifer DonnellyKaren FloodFergal Malone

COOMBEBridgette ByrneSean DalyMairead KennellyCaoimhe LynchAisling MartinCarmen Regan

NMHStephen CarrollMary HigginsShane HigginsRhona MahonyFionnuala McAuliffePeter McParland

CORKRichard GreeneJohn HigginsDan McKennaKeelin O’DonoghueNoirin Russell

GALWAYGeraldine GaffneyJohn Morrison

LIMERICKAmanda CotterJohn Slevin

BELFASTCarolyn BailieSamina DornanAly HunterJohn MandersonStephen Ong

WEXFORDLiz Dunne

Additional Multidisciplinary Support

RADIOLOGYJames Meaney

NEONATOLOGYDavid CorcoranAdrienne ForanJohn KelleherPamela O’ConnorColm O’DonnellDavid Sweet

EPIDEMIOLOGYPatrick DickerRichard Tremblay

CARDIOLOGYOrla FranklinDermot Kenny

MIDWIFERYFiona AlderdiceMary BrosnanEmma DoolinPhyl GarganCecilia MulcahyHilda O’KeeffeMargaret PhilbinAnn Phillips

MASTERS / CD’sSam Coulter SmithRhona MahonySharon SheehanAll clinical directors

PHARMACYBrian Cleary INTERNATIONAL

Zarko AlfirevicTed BarkerMary D’AltonTim LyonsJane NormanMichael PaidasAndrew ShennanIan Young

RADIOGRAPHYFiona CodyEdel Varden

INDUSTRYColin PaulGerald Seifriedsberger

HSEMichael Turner

Personnel StructureChairman – Prof Fergal Malone

Programme Manager – Dr Liz TullyBiostatistician – Dr Pat Dicker

Chairman – Prof Fergal MaloneProgramme Manager – Dr Liz Tully

Biostatistician – Dr Pat Dicker

Personnel StructureChairman – Prof Fergal Malone

Programme Manager – Dr Liz TullyBiostatistician – Dr Pat Dicker

Chairman – Prof Fergal MaloneProgramme Manager – Dr Liz Tully

Biostatistician – Dr Pat Dicker

PI – Prof F McAuliffeRS- Cecelia MulcahyPI – Prof F McAuliffeRS- Cecelia Mulcahy

PI – Prof F BreathnachRS- Fiona Cody

PI – Prof F BreathnachRS- Fiona Cody

PI – Prof S DalyRS- Emma DoolinPI – Prof S Daly

RS- Emma DoolinPI – Prof J Morrison

RS- Edel VardenPI – Prof J Morrison

RS- Edel Varden

PI – Prof J HigginsRS- Ann Phillips

PI – Prof J HigginsRS- Ann Phillips

PI – Dr G. Burke / Prof A Cotter

RS- K Irfah-Ismail

PI – Dr G. Burke / Prof A Cotter

RS- K Irfah-Ismail

PI – Dr Aly Hunter/Dr Samina Dornan

RS- Phyl Gargan

PI – Dr Aly Hunter/Dr Samina Dornan

RS- Phyl Gargan

Management Structure Steering Committee -

comprised of Chairman, Site PIs , Programme Manager,

Biostatistician, Sonographer & Patient representatives

Steering Committee - comprised of Chairman, Site

PIs , Programme Manager, Biostatistician, Sonographer &

Patient representatives

Scientific Advisory

Board

Scientific Advisory

Board

RCSI Research Institute

RCSI Research Institute

Health Research

Board

Health Research

Board

Education & TrainingEducation & Training

FinanceFinancePublicationPublication

ProtocolProtocol

CLINICAL SITES•Rotunda Hospital•Coombe Women and Infants University Hospital•National Maternity Hospital•University College Hospital, Galway•Royal Jubilee Maternity Hospital, Belfast•Mid-Western Regional Maternity Hospital, Limerick•Cork University Maternity Hospital

CLINICAL SITES•Rotunda Hospital•Coombe Women and Infants University Hospital•National Maternity Hospital•University College Hospital, Galway•Royal Jubilee Maternity Hospital, Belfast•Mid-Western Regional Maternity Hospital, Limerick•Cork University Maternity Hospital

Sub-Committees

Research Infrastructure • Unique, world-class research infrastructure comprising :

– state-of-the-art imaging equipment• GE Voluson Ultrasound Equipment & Viewpoint Software

– dedicated research and management personnel • Research Sonographers, Programme Manager, Biostatistician

– central management and governance structure• Steering Committee, Scientific Advisory Board, RCSI Research Institute

– access to associated support services • Pathology, Epidemiology, Range of specialist cross-disciplinary clinical expertise

• Access to large patient populations (55,000+ births pa.):– uniquely positioned to carry-out ground-breaking

clinical research.

Network AimsPerinatal Ireland was established with the mission of improving the standard of healthcare for women and children in Ireland.

Key goals and objectives•to establish a centre of excellence in perinatal medicine research, performing world-class clinical research •to build a national dedicated research capacity to conduct high-quality patient-oriented clinical research •to translate research findings into clinical practice for the benefit of women and children’s health •to develop collaborative, cross-disciplinary programmes to generate national research networks •to develop human capital through high-quality education and training programmes

Research to date ESPRiT – National Twin Study

– Two year Programme to Jan 2010– Recruited over 1000 twin pregnancies– Multiple high profile publications– Multiple oral presentations at Society for Maternal Fetal Medicine Annual Clinical

Meeting– Long term paediatric follow-up ongoing– Long term epigenetic studies ongoing– Published new national guidelines on the management of twin pregnancies

Research StudiesPORTO - investigation of multi-vessel Doppler in the management of growth restricted fetuses:

• Two year programme to June 2012• Recruited over 1200 patients

PORTO 1:The Optimal Definition of Intrauterine Growth Restriction Based on Perinatal Morbidity and MortalityJ. Unterscheider on behalf of Perinatal IrelandOral Presentations at SMFM, San Francisco, Feb 2013

PORTO 1:Methods

•1,200 consecutive singleton pregnancies 24 0/7 – 36 6/7 wks•EFW < 10th centile•Followed with twice weekly ultrasound / advanced Doppler:

– Biometry / amniotic fluid– Uterine artery– Umbilical artery– Ductus venosus– Middle cerebral artery– Aortic isthmus– Myocardial performance index

PORTO 1:Methods

•Detailed obstetric and pediatric outcome•Neonatal US and MR Imaging•2 year Bayley’s assessments•Adverse outcome:

– Perinatal mortality– NICU admission– IVH / PVL– HIE– NEC– BPD– Sepsis

PORTO 1:Methods

•Various definitions of significant IUGR:– EFW < 10th, < 5th, < 3rd centiles– AC < 10th, <5th, < 3rd centiles– All with or without oligohydramnios– All with or without abnormal umbilical artery Doppler (AEDF / PI

>95%)

PORTO 1:Results

•Perinatal Mortality 1.4% (17)•Composite Adverse Perinatal Outcome 6.2% (74)•NICU Admission 31% (372)

PORTO 1: ResultsPredictor n Adverse outcome (n=60) Normal outcome (n=1058) P-value

EFW<3rd 828 53 (88.3%) 775 (73.3%) 0.0095

EFW<5th 1049 57 (95.0%) 992 (93.8%) 0.6982

EFW<10th 1118 60 (100%) 1058 (100%) N/A

AC<3rd 911 54 (90.0%) 857 (81.0%) 0.0809

AC<5th 1000 55 (91.7%) 945 (89.3%) 0.5649

AC<10th 1082 58 (96.7%) 1024 (96.8%) 0.9592

EFW<3rd + oligo 128 14 (23.3%) 114 (10.8%) 0.0030

EFW<5th + oligo 190 14 (23.3%) 176 (16.6%) 0.1790

EFW<10th + oligo 232 16 (26.7%) 216 (20.4%) 0.2454

EFW<3rd + abnormal UA 251 42 (70.0%) 209 (19.8%) <0.0001*

EFW<5th + abnormal UA 346 45 (75.0%) 301 (28.4%) <0.0001*

EFW<10th + abnormal UA 413 47 (78.3%) 366 (34.6%) <0.0001*

PORTO 1:Conclusions:

•EFW or AC < 10th or 5th centiles should no longer be used to define pregnancies at high risk adverse outcome•EFW < 3rd centile is reasonable cut-off to define high risk group•Abnormal UA Doppler is strongest predictor of adverse outcome whenever EFW < 10th centile•These data will allow more focussed use of obstetric resources whenever EFW < 10th centile

PORTO 2:Sequential Doppler Changes in IUGR: Is There a Benefit of Advanced Multi-Vessel Doppler Assessment?

J. Unterscheider on behalf of Perinatal IrelandOral Presentation at SMFM, San Francisco, Feb 2013

PORTO 2: Results

PORTO 2:Results

UA MCA DV AoI MPI

GA at first abnormal Doppler 32 6/7 32 5/7 32 4/7 30 6/7 33 1/7

Median time to delivery 23 d 21 d 17 d 21 d 29 d

GA at delivery 37 3/7 37 2/7 34 5/7 38 1/7 38 4/7

PORTO 2:Conclusions:

•Umbilical artery and MCA Doppler are most predictable in demonstrating progressive temporal changes for IUGR•Ductus venosus and cardiac indices demonstrated no added benefit in surveillance for IUGR•Surveillance for IUGR should be simplified and should rely primarily on finding of AEDF or REDF in umbilical artery•New HSE National Guideline published

Current Studies• GENESIS – Prospective observational study to assess the use of fetal head circumference (FHC),

measured using ultrasound in the late third trimester, and other markers as predictive tools for labour dystocia and intrapartum caesarean section.

– Recruitment target : 2500 (achieved Dec 2014)– Study duration : 36 months (outcomes ongoing)

Current Studies• GENESIS – Prospective observational study to assess the use of fetal head circumference (FHC), measured using

ultrasound in the late third trimester, and other markers as predictive tools for labour dystocia and intrapartum caesarean section.

– Recruitment target : 2500 (achieved Dec 2014)– Study duration : 36 months (outcomes ongoing)

• AFFIRM – Fetal Movement study - Can promoting awareness of fetal movements and focussing interventions reduce fetal mortality - a stepped wedge cluster randomised trial?

– Hospital education and intervention programme– Study duration : 24 months

Current Studies• GENESIS – Prospective observational study to assess the use of fetal head circumference (FHC), measured using ultrasound in the late third

trimester, and other markers as predictive tools for labour dystocia and intrapartum caesarean section.– Recruitment target : 2500 (achieved Dec 2014)– Study duration : 36 months (outcomes ongoing)

• AFFIRM – Fetal Movement study - Can promoting awareness of fetal movements and focussing interventions reduce fetal mortality - a stepped wedge cluster randomised trial?

– Hospital education and intervention programme– Study duration : 24 months

• TEST – Randomised trial of aspirin therapy and early screening tests for pre-eclampsia and fetal growth restriction, during pregnancy in low-risk first-time mothers

– Recruitment target : 5,700 – Pilot study target: 500 (250 recruited to date)

Future Direction?

HRB Ireland Perinatal Clinical Trial Network: Mission

• To improve health outcomesfor women and children, both in Ireland and globally

HRB Ireland Perinatal Clinical Trial Network:

• Bringing together two highly successful, existing, clinical research networks in the perinatal arena

Overwhelming need

• More than 1 in 10 babies are born preterm

• Over 1 million children die each year due to complications of preterm birth

• Many survivors face a lifetime of disability, including learning disabilities and visual and hearing problems

Economic need• Perinatal disease accounts

for 10% of the global health burden1

• R&D investment in perinatal health remains small and non-strategic

• The number of registered pipeline drugs is only 1-5% that for other major disease areas

1. Fisk, N.M. and R. Atun, Market failure and the poverty of new drugs in

maternal health. PLoS Med, 2008. 5(1): p. e22.

HRB Ireland Perinatal Clinical Trial Network: Vision

HRB Ireland Perinatal Clinical Trial Network: International Collaborations

Trials MethodologyTrials Methodology

Maternal Fetal Medicine

Maternal Fetal Medicine

NeonatologyNeonatology

General PracticeGeneral Practice

EpidemiologyEpidemiology

Developmental Psychology

Developmental Psychology

PathologyPathology

BiochemistryBiochemistryCardiologyCardiology

HaematologyHaematology

EndocrinologyEndocrinology

Neonatal PhysiologyNeonatal

Physiology

Masters & Clinical Directors

Masters & Clinical Directors

Directors Nursing & Midwifery

Directors Nursing & Midwifery

HRB Ireland Perinatal Clinical Trial Network: Expertise

HRB Ireland Perinatal Clinical Trial Network: Governance Structure

Executive Management

Committee

Executive Management

Committee

External Scientific

Advisory Board

External Scientific

Advisory Board

Clinical Research Facilities

Clinical Research Facilities

Health Research

Board

Health Research

Board

CLINICAL SITES

•Rotunda Hospital•Coombe Women’s Hospital•National Maternity Hospital•University Hospital, Galway•Royal Maternity, Belfast•MW Regional Hospital, Limerick•Cork University Maternity Hospital

CLINICAL SITES

•Rotunda Hospital•Coombe Women’s Hospital•National Maternity Hospital•University Hospital, Galway•Royal Maternity, Belfast•MW Regional Hospital, Limerick•Cork University Maternity Hospital

Management Sub-Committees

Education & TrainingEducation & Training

FinanceFinancePublicationPublicationProtocolProtocol

Industrial Liaison Business

Development

Industrial Liaison Business

Development

HRB Ireland Perinatal Clinical Trial Network: Portfolio of Trials - New

• Implement two Definitive Intervention studies Parrot DIParrot DI Strider DIStrider DI

TESTTEST MINTMINT IRELANDIRELAND

• Pilot & Feasibility Work

• Launch network programme of bespoke, clinical assessment of longer term paediatric outcomes

Paediatric Follow upPaediatric Follow up

Core Outcome SetCore Outcome Set

• Launch research programme in Clinical Trials Methodology