HRB Grant Holders Conference Limerick February 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 Support Universal National Support COOMBE Bridgette Byrne Sean Daly Mairead Kennelly Caoimhe Lynch Aisling Martin Carmen Regan CORK Richard Greene John Higgins Dan McKenna Keelin O’Donoghue Noirin Russell NMH Stephen Carroll Mary Higgins Shane Higgins Rhona Mahony Fionnuala McAuliffe Peter McParland ROTUNDA Fionnuala Breathnach Sharon Cooley Jennifer Donnelly Karen Flood Fergal Malone BELFAST Carolyn Bailie Samina Dornan Aly Hunter John Manderson Stephen Ong GALWAY Geraldine Gaffney John Morrison LIMERICK Amanda Cotter John Slevin WEXFORD Liz Dunne

Additional Multidisciplinary Support NEONATOLOGY David Corcoran Adrienne Foran John Kelleher Pamela O’Connor Colm O’Donnell David Sweet CARDIOLOGY Orla Franklin Dermot Kenny EPIDEMIOLOGY Patrick Dicker Richard Tremblay INDUSTRY Colin Paul Gerald Seifriedsberger PHARMACY Brian Cleary MIDWIFERY Fiona Alderdice Mary Brosnan Emma Doolin Phyl Gargan Cecilia Mulcahy Hilda O’Keeffe Margaret Philbin Ann Phillips INTERNATIONAL Zarko Alfirevic Ted Barker Mary D’Alton Tim Lyons Jane Norman Michael Paidas Andrew Shennan Ian Young MASTERS / CD’s Sam Coulter Smith Rhona Mahony Sharon Sheehan All clinical directors RADIOGRAPHY Fiona Cody Edel Varden RADIOLOGY James Meaney HSE Michael Turner

Personnel Structure Chairman – Prof Fergal Malone Programme Manager – Dr Liz Tully Biostatistician – Dr Pat Dicker

Personnel Structure Chairman – Prof Fergal Malone Programme Manager – Dr Liz Tully Biostatistician – Dr Pat Dicker PI – Prof F McAuliffe RS- Cecelia Mulcahy PI – Prof F Breathnach RS- Fiona Cody PI – Prof J Higgins RS- Ann Phillips PI – Dr G. Burke / Prof A Cotter RS- K Irfah-Ismail PI – Prof J Morrison RS- Edel Varden PI – Prof S Daly RS- Emma Doolin PI – Dr Aly Hunter/ Dr Samina Dornan RS- Phyl Gargan

Scientific Advisory Board RCSI Research Institute Management Structure Steering Committee - comprised of Chairman, Site PIs , Programme Manager, Biostatistician, Sonographer & Patient representatives Scientific Advisory Board RCSI Research Institute Health Research Board Education & Training Finance Publication Protocol 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 SCM – RCSI Administrative Hub, support in activities such financial/grant award administration, technology transfer/IP protection, education and outreach activities in conjunction with the Programme Manager. SAB - Mary D’Alton, Mark Kilby, Pran Pandya, Mike Clarke, Michael Turner, and Nadine Farah. - provides support and guidance on the scientific and clinical aspects of the consortium’s activities, including reviewing proposed studies and highlighting areas of clinical and scientific importance that should be addressed by the Consortium’s research studies. Sub-committees - with responsibility for issues such as preparation and conduct of research studies, publications arising from the studies, finance, ethics and training, industrial relations, technology transfer and intellectual property. Last official communication with SAB at Fetoscopy meeting in Carton House last year

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 Aims Perinatal 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 Studies PORTO - 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 Mortality J. Unterscheider on behalf of Perinatal Ireland Oral 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: Perinatal Mortality 1.4% (17) Results Perinatal Mortality 1.4% (17) Composite Adverse Perinatal Outcome 6.2% (74) NICU Admission 31% (372)

PORTO 1: Results Predictor EFW<3rd 828 53 (88.3%) 775 (73.3%)  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 190 176 (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%) EFW<10th + abnormal UA 413 47 (78.3%) 366 (34.6%)

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 Ireland Oral 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   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 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 Pilot study target: 500 (250 recruited to date) 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 outcomes for 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 Born too soon, the global action report on preterm birth was published this year, This is the current situation today around the world then read headlines….

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. It is…as long as the message is (and I know it will be) that these are the implications of not investing in research in this area…but also AND I SUSPECT THIS MIGHT NOT BE IN THE MESSAGE…if Ireland now takes the opportunity to invest in this research thru Capture, and thus provides our industry partners with access to world-leading (please say it Louise) research leading to innovative technologies, and in turn leading to massive commercial opportunities in this vast market, a market that is untapped due to the unmet needs presented in the perinatal setting.

HRB Ireland Perinatal Clinical Trial Network: Vision To establish a world-class centre of excellence in perinatal medicine research To build an all-Ireland dedicated research capacity to conduct high-quality, patient-oriented clinical research To translate research findings into clinical practice to improve the health of women and children To develop collaborative, cross-disciplinary programmes to generate a self-sustaining national and international research infrastructure

HRB Ireland Perinatal Clinical Trial Network: International Collaborations

HRB Ireland Perinatal Clinical Trial Network: Expertise General Practice Epidemiology Developmental Psychology Pathology Biochemistry Cardiology Haematology Endocrinology Neonatal Physiology Masters & Clinical Directors Directors Nursing & Midwifery Trials Methodology Maternal Fetal Medicine Neonatology Not sure what this adds

HRB Ireland Perinatal Clinical Trial Network: Governance Structure 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 Executive Management Committee External Scientific Advisory Board Clinical Research Facilities Health Research Board Management Sub-Committees Education & Training Finance Publication Protocol Industrial Liaison Business Development Updated graphic

HRB Ireland Perinatal Clinical Trial Network: Portfolio of Trials - New Implement two Definitive Intervention studies Parrot DI Strider DI TEST MINT IRELAND Pilot & Feasibility Work Launch network programme of bespoke, clinical assessment of longer term paediatric outcomes Paediatric Follow up Core Outcome Set Launch research programme in Clinical Trials Methodology