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On the use of antiangiogenetic medications for retinopathy of prematurity.
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PMID:  21517962     Owner:  NLM     Status:  MEDLINE    
CONCLUSION: This viewpoint raises concerns regarding the currently studied antiangiogenetic treatments for ROP and their possible general effects on the developing preterm infant.
Anna-Lena Hård; Ann Hellström
Publication Detail:
Type:  Journal Article     Date:  2011-05-13
Journal Detail:
Title:  Acta paediatrica (Oslo, Norway : 1992)     Volume:  100     ISSN:  1651-2227     ISO Abbreviation:  Acta Paediatr.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-06     Completed Date:  2011-12-07     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  9205968     Medline TA:  Acta Paediatr     Country:  Norway    
Other Details:
Languages:  eng     Pagination:  1063-5     Citation Subset:  IM    
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© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.
Department of Ophthalmology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
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MeSH Terms
Adrenergic beta-1 Receptor Antagonists / therapeutic use
Angiogenesis Inhibitors / therapeutic use*
Antibodies, Monoclonal, Humanized / therapeutic use
Infant, Newborn
Infant, Premature
Propranolol / therapeutic use
Retinopathy of Prematurity / drug therapy*
Vascular Endothelial Growth Factor A / antagonists & inhibitors
Reg. No./Substance:
0/Adrenergic beta-1 Receptor Antagonists; 0/Angiogenesis Inhibitors; 0/Antibodies, Monoclonal, Humanized; 0/Vascular Endothelial Growth Factor A; 2S9ZZM9Q9V/bevacizumab; 525-66-6/Propranolol

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Journal Information
Journal ID (nlm-ta): Acta Paediatr
Journal ID (publisher-id): apa
ISSN: 0803-5253
ISSN: 1651-2227
Publisher: Blackwell Publishing Ltd
Article Information
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Acta Pædiatrica © 2011 Foundation Acta Pædiatrica
Received Day: 03 Month: 4 Year: 2011
Accepted Day: 18 Month: 4 Year: 2011
Print publication date: Month: 8 Year: 2011
Volume: 100 Issue: 8
First Page: 1063 Last Page: 1065
ID: 3206215
PubMed Id: 21517962
DOI: 10.1111/j.1651-2227.2011.02330.x

On the use of antiangiogenetic medications for retinopathy of prematurity
Anna-Lena Hård
Ann Hellström
Department of Ophthalmology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of GothenburgGothenburg, Sweden
Correspondence: Ann Hellström, MD, PhD, Section of Pediatric Ophthalmology, The Queen Silvia Children's Hospital, The Sahlgrenska Academy at University of Gothenburg, S-416 85 Göteborg, Sweden. Tel.: +46 768 979196 | Fax: +46 31 848952 | Email:
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In contrast to the adult, the third-trimester foetus experiences one of the most intense periods of growth and maturation of its lifetime. Early development is characterized by the existence of critical periods when environmental factors effectively produce long-lasting changes. An example is that of the antiangiogenetic substance thalidomide, which during a very limited time period in early pregnancy causes gross malformations. Angiogenesis is important for the alveolarization of the lungs, which in humans mainly takes place after birth in infants born at term (1), and in newborn and infant rats, thalidomide (2) as well as a VEGF-receptor inhibitor (3) reduced lung vascular density and alveolarization. In the central nervous system, maturational processes occur at different times in different brain regions and neural circuits, and therefore, critical periods may be specific for each brain region or neurotransmitter system (4).

The very preterm infant has lost nutrients and other factors supplied by the mother and is exposed to poor nutrition, hyperoxia/hypoxia, infections and other stresses resulting in impaired growth and development. In the eye, reduced physiologic angiogenesis may lead to hypoxia followed by uncontrolled vessel growth. This pathologic angiogenesis is the target for two new treatment modalities for retinopathy of prematurity (ROP), which are being evaluated in ongoing or planned studies. We would like to express our concern about possible adverse effects of these medications on the development of these vulnerable infants.

In the Pan-VEGF Blockade for the Treatment of Retinopathy of Prematurity (BLOCK-ROP) study ( Identifier: NCT01232777), intravitreal injection of 0.625 or 0.75 bevacizumab (Avastin®), an anti-VEGF antibody, will be compared with standard of care laser for type 1 prethreshold ROP diagnosed at 30–36 postmenstrual weeks. In the Safety and Efficacy of propranolol in newborns with retinopathy of prematurity (PROP-ROP) study ( Identifier: NCT01079715) (5), preterm infants with stage 2 ROP in zone II or III without plus-disease will receive systemic propranolol, a nonselective beta blocker, up to 90 days in addition to standard care in comparison with standard treatment only.

Avastin for ROP

VEGF promotes both normal and pathologic angiogenesis, and it is a neuronal survival factor. The blockage of VEGF with Avastin® may thus influence other processes than pathologic angiogenesis in the eye. Bevacizumab is a large molecule, and an advantage put forward is its inability to escape the eye unless in very small amounts (6). However, one intravitreal injection of 1.25 mg/50 μL in three adult cynomolgus macaques weighing 3.9–5.5 kg resulted in a maximum serum concentration of 1430 ± 186 ng/mL 1 week after injection and concentration declined more slowly than in the eye, with little change after 4 weeks, and was 67 ± 24.3 ng/mL after 8 weeks (7).

In a recent study (BEAT-ROP, Identifier: NCT01232777) (n = 150), infants with stage 3+ ROP were given bilateral intravitreal injections of 0.625 mg of Avastin® bilaterally (6) resulting in a dose equal to that given to the adult macaques. As the blood retinal barrier is compromised in eyes with pathologic neovascularization, one may fear higher serum concentrations in these infants than in the monkeys. Regarding safety, the authors of this study concluded that 2800 infants were needed to assess mortality and an even larger sample for local or systemic toxicity and that the study was too small to address the question of whether intravitreal bevacizumab is safe. Thus, no attempts to monitor adverse effects were made, and serum concentrations of bevacizumab were not reported.

Propranolol for ROP

Propranolol has been found to be efficient in reducing the growth of infantile hemangiomas in a number of patients (8,9), although no controlled trials of safety and efficacy have been reported yet. In a mouse model of ROP, propranolol was protective against retinal angiogenesis and ameliorated blood–retina barrier dysfunction in oxygen-induced retinopathy (OIR) (10).

The hypothesis of the PROP-ROP study is that in preterm infants with ROP, VEGF overexpression could be induced by beta2-adrenoreceptor stimulation and that propranolol, administered when ROP stage 2 is detected in zone II or III, could reduce the progression of the disease. As mentioned by the authors, most cases of ROP stage 2 regress spontaneously, which means that most of the infants treated with propranolol never risked blindness anyway.

Propranolol is reported to be well tolerated in most cases. However, hemodynamic effects such as bradycardia and hypotension as well as metabolic effects such as hypoglycemia may be serious (1113). In addition, beta blockers may cause masking of hypoglycemia, insulin resistance and dyslipidemia (14). It is well known that very preterm infants already have an increased risk of hypotension (15) and deranged glucose metabolism including insulin resistance (16).

Less is known about the roles of the adrenergic system and the beta-adrenergic receptors on the development of the premature infant's brain. In rats, OIR is induced by exposure to increased oxygen concentrations from birth to postnatal day 11 followed by room air for 7 days after which proliferative retinopathy, similar to human stage 3 ROP, is found (17). In the rat brain, the timing of noradrenergic cortical innervations coincides with neurogenesis, neuronal migration, sprouting of cellular processes and the formation of synaptic contacts and occurs mainly during the first 3 weeks of postnatal life (18), just like the development of OIR and the transition to proliferative disease. Noradrenalin is a neurotransmitter that is essential for the modulation of memory (19) and for the plasticity of visual (20,21) and olfactory systems (19). Propranolol passes the blood–brain barrier and causes memory loss in chicks (19) and blocks early olfactory learning in rats (22).

It is likely that during the period when pathologic angiogenesis is a threat to the eye, windows of susceptibility occur in other parts of the central nervous system, where adequate angiogenesis and development of neural and other tissues are essential for later normal function. Administering potent blockers of VEGF and of the adrenergic system during these periods may be deleterious. As long as we lack methods to explore how the growth and modulation of neuronal networks are orchestrated, medications that possibly alter these processes for the rest of life should be avoided. In preterm infants prone to abnormal brain development, it will be impossible to sort out adverse effects of these drugs. Laser ablation of the retina is not ideal, but its effects are restricted to the eye and it usually works well. Antiangiogenetic treatment might be indicated in serious cases when laser treatment has failed, but that is different from it being an alternative to laser. There might be a place for propranolol for pathologic vessels just like for severe hemangiomas, but its use as prophylaxis to prevent proliferative ROP during stage 2 like in the PROP-ROP study should be questioned. If Avastin® is further used in infants, monitoring of serum bevacizumab and exploration of its pharmacokinetics and effects on premature babies are needed.

1. Stenmark KR,Abman SH. Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasiaAnnu Rev PhysiolYear: 2005676236115709973
2. Jakkula M,et al. Inhibition of angiogenesis decreases alveolarization in the developing rat lungAm J Physiol Lung Cell Mol PhysiolYear: 20002796007
3. Le Cras TD,et al. Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structureAm J Physiol Lung Cell Mol PhysiolYear: 200228355562
4. Rice D,Barone S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal modelsEnviron Health PerspectYear: 2000108Suppl 35113310852851
5. Filippi L,et al. Study protocol: safety and efficacy of propranolol in newborns with Retinopathy of Prematurity (PROP-ROP): ISRCTN18523491BMC PediatrYear: 2010108321087499
6. Mintz-Hittner HA,Kennedy KA,Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurityN Engl J MedYear: 20113646031521323540
7. Miyake T,et al. Pharmacokinetics of bevacizumab and its effect on vascular endothelial growth factor after intravitreal injection of bevacizumab in macaque eyesInvest Ophthalmol Vis SciYear: 2010511606819875666
8. Leaute-Labreze C,et al. Propranolol for severe hemangiomas of infancyN Engl J MedYear: 200835826495118550886
9. Manunza F,et al. Propranolol for complicated infantile haemangiomas: a case series of 30 infantsBr J DermatolYear: 2010162466820055816
10. Ristori C,et al. Role of the adrenergic system in a mouse model of oxygen-induced retinopathy: antiangiogenic effects of beta-adrenoreceptor blockadeInvest Ophthalmol Vis SciYear: 2011521557020739470
11. Lawley LP,Siegfried E,Todd JL. Propranolol treatment for hemangioma of infancy: risks and recommendationsPediatr DermatolYear: 200926610419840322
12. Breur JM,et al. Hypoglycemia as a result of propranolol during treatment of infantile hemangioma: a case reportPediatr DermatolYear: 2010281697120738795
13. Bonifazi E,et al. Severe hypoglycemia during successful treatment of diffuse hemangiomatosis with propranololPediatr DermatolYear: 201027195620537072
14. Fonseca VA. Effects of beta-blockers on glucose and lipid metabolismCurr Med Res OpinYear: 2010266152920067434
15. Dempsey EM,Barrington KJ. Evaluation and treatment of hypotension in the preterm infantClin PerinatolYear: 200936758519161866
16. Mitanchez-Mokhtari D,et al. Both relative insulin resistance and defective islet beta-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infantsPediatricsYear: 20041135374114993546
17. Sarlos S,et al. Retinal angiogenesis is mediated by an interaction between the angiotensin type 2 receptor, VEGF, and angiopoietinAm J PatholYear: 20031638798712937129
18. Murrin LC,Sanders JD,Bylund DB. Comparison of the maturation of the adrenergic and serotonergic neurotransmitter systems in the brain: implications for differential drug effects on juveniles and adultsBiochem PharmacolYear: 20077312253617316571
19. Gibbs ME,Hutchinson DS,Summers RJ. Noradrenaline release in the locus coeruleus modulates memory formation and consolidation; roles for alpha- and beta-adrenergic receptorsNeuroscienceYear: 201017012092220709158
20. Inaba M,et al. Facilitation of low-frequency stimulation-induced long-term potentiation by endogenous noradrenaline and serotonin in developing rat visual cortexNeurosci ResYear: 200964191819428700
21. Kasamatsu T,Shirokawa T. Involvement of beta-adrenoreceptors in the shift of ocular dominance after monocular deprivationExp Brain ResYear: 198559507142993012
22. Wilson DA,Sullivan RM. Olfactory associative conditioning in infant rats with brain stimulation as reward: II. Norepinephrine mediates a specific component of the bulb response to rewardBehav NeurosciYear: 199110584391663758

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Keywords: Antiangiogenetic treatment, Anti-VEGF, Propranolol, Retinopathy of prematurity.

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