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2011-05-28
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Ann Hellström, MD, PhD
Predic'on, preven'on and treatment of Re'nopathy Of Prematurity
Institute of Neuroscience and Physiology, Department of Ophthalmology,
The Sahlgrenska Academy at University of Gothenburg, Sweden
Evidence-based neonatology – today and tomorrow
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Re'nopathy of prematurity (ROP)
Re#nal disease Visual loss
Phase I ROP impaired vessel
growth & vessel loss
Phase II ROP pathological
neovascularization
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ROP -‐ historically (Gilbert, Early Hum Dev 2008, 84:77-82)
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Screening-‐criteria based on GA & BW
GA (weeks) BW (grams)
Sweden < 32 (< 1500g)
USA < 32* < 1500*
UK < 32 < 1501
Turkey < 34 < 1850
Romania < 34 < 2000
China < 34 < 2000
Brazil < 32 or < 35! < 1500
* Sick more mature infants are also screened
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Screening examina'ons are stressful, painful and resource consuming -‐ altera#ons in blood pressure & heart rate -‐ decreased oxygen satura#on -‐ increased cor#sol levels for up to 24h
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Conclusion
• Na#onal guidelines based on GA and BW, although postnatal factors of utmost importance for ROP
• Only 5-‐10% of screened children need treatment • Other selec#on criteria than GA and BW are needed in order to reduce unnecessary examina#ons
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Weight IGF-‐I Neonatal Re#nopathy Of Prematurity
WINROP
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So what does WINROP do?
It calculates and accumulates each week the infants devia#on
from its op#mal growth velocity curve
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WINROP
Model with Weight only
Sensi#vity Specificity
Swedish infants (n=374) 100% 85%
American infants (n=318) 100% 82%
Brazilian infants (n=366) 90% 55%
Swiss infants (n=376) 100% 81%
Published WINROP outcome
Hellström A et al Pediatrics 2009, Wu C et al, Hård A-‐L et al Arch Ophthalmol 2010, Fluckiger S et al Klin Monobl Augenheikld 2011
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Risk for Type 1 ROP aTer alarm in WINROP
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Reduce screening significantly and focus on the right pa'ents
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Hellström A et al Pediatrics 2009
New pathogene'c mechanisms….
Chronological Age (weeks after birth) PMA > 40 weeks
Här skall nyZ ’simplified confusogram’ in
10 9 8 7 6 5 4 3 2 1 0
WINROP iden'fies risk of developing ROP Ophthalmologist applies “destruc've”
treatment
Ophthalmologist diagnosis ROP
Period for ophthalmological screening
Chronological Age (weeks after birth)
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Today’s treatment of ROP
Re#nal disease Visual loss
Phase I ROP impaired vessel growth &
vessel loss
Phase II ROP pathological
neovascularization
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New treatments for ROP
• Avas#n (bevacizumab) –An# VEGF • Propranolol • Inositol • Erythropoie#n
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Bevacizumab (1.25 mg/50µL) intravitreal injec#on one Macaque eye Miyake et al.Invest Ophth Vis Sci 2010
3 male macaques 8-9 years old 3.9-5.5 kg
www.rop.gu.se © The Ophthalmic Communica#ons Society, Inc. Published by Lippincoi Williams & Wilkins, Inc. 2
VITREOUS AND PLASMA CONCENTRATIONS OF APELIN AND VASCULAR ENDOTHELIAL GROWTH FACTOR AFTER INTRAVITREAL BEVACIZUMAB IN EYES WITH PROLIFERATIVE DIABETIC RETINOPATHY. Qian, Jing; Lu, Qiang; Tao, Yong; MD, PhD; Jiang, Yan-‐Rong Re#na. 31(1):161-‐168, January 2011. DOI: 10.1097/IAE.0b013e3181e46ad8
Fig. 2 . Boxplots showing the plasma concentra#ons of VEGF in the bevacizumab study group undergoing pars plana vitrectomy for PDR aqer IVB and a control group undergoing vitrectomy without previous IVB; the difference between both groups was significant (P = 0.003).
1.25 mg bevacizumab was injected into the vitreous of one eye 7 days previously
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Tomorrows treatment of ROP -‐ preven'on?
Phase I ROP impaired vessel growth &
vessel loss
Phase II ROP pathological
neovascularization
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Preven'on -‐ oxygen A majority of studies have shown that a satura#on between 85-‐93% results in reduc#on of severe ROP SUPPORT study
– 85-‐89% oxygen resulted in reduc#on of ROP but increased mortality (one addi#onal death for every two saving severe ROP...)
STOP-‐ROP and BOOST study
-‐ supplemental oxygen at prethreshold decrease non PLUS ROP but increased pulmonary morbidity Compliance poor with lower oxygen levels
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Preven'on -‐ nutri'on Few studies have shown that op#mal nutri#on results in reduc#on of severe ROP Fish-‐oil fat supplementa#on
– reduced risk of laser treatment (Pediatrics Jan 2011) Human milk vs formula
-‐ reduced risk for ROP (J Perinatol 2001) Cochrane database 2005
-‐ not conclusive for recommenda#on
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Preven'on – op'mize growth
IGF-‐I and fetal growth IGF-‐I associated with ini#al weight loss IGF-‐I enhance protein u#lisa#on IGF-‐I improves metabolic control
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Phase II – Study (ROPP-‐2009-‐01)
• Longitudinal infusion 1-‐8 weeks (un#l intrauterine levels reached) • Mul#center study (Lund, Gothenburg & Stockholm)
• 45+45 infants • Study started June 2010 and is ongoing • First sec#on completed June 2011 (n=5)
A Phase II, Open-‐Label, Mul'center, Dose Evalua'on Study to Determine safety and efficacy of rhIGF-‐I/rhIGFBP-‐3 in Premature Infants
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Phase II – Study (ROPP-‐2009-‐01) A Phase II, Open-‐Label, Mul'center, Dose Evalua'on Study to Determine
safety and efficacy of rhIGF-‐I/rhIGFBP-‐3 in Premature Infants
Primary Efficacy Endpoints: Severity of ROP Secondary Efficacy Endpoints: Brain development -‐ MRI at 40 weeks PMA -‐ cogni#ve outcome at 2.5, 6 and 10 years Metabolism Body weight Length Incidence of BPD Days in NICU
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Coworkers Anna-‐Lena Hård
Chatarina Löfqvist David Ley
Ingrid Hansen Pupp Eva Andersson
Gunnel Hellgren Aimon Niklasson
Margareta Hök Wikstrand Carola Pfeiffer-‐Mosesson
Lois Smith