Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Neurodevelopmental outcomes in infants treated with intravitreal bevacizumab versus laser

Abstract

Objective

To compare neurodevelopmental and visual outcomes in preterm infants treated with intravitreal bevacizumab (IVB) to laser ablation at 18ā€“24 months corrected age.

Study design

A retrospective study was performed. The primary outcome was neurodevelopmental impairment (NDI). Secondary neurodevelopmental outcomes were significant NDI (sNDI), cerebral palsy, hearing loss, and composite scores of the Bayley Scales of Infant Development, Third edition. Visual outcomes included structural and refractive outcomes. Adjusted odds ratios (AOR) were calculated controlling for GA, sex, and ROP severity and confounding baseline characteristics using a cutoff of pā€‰<ā€‰0.20.

Results

Thirty-four (60 eyes) infants receiving IVB and 30 (51 eyes) laser were included. No significant differences were identified in NDI (AOR 1.77, 95% CI 0.46, 6.73) or sNDI (AOR 2.31, 95% CI 0.75, 7.14). There were no other differences in outcomes.

Conclusions

Larger randomized trials are required to establish long-term efficacy and safety of IVB in preterm neonates.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Similar content being viewed by others

References

  1. Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003;121:1684ā€“94.

    ArticleĀ  Google ScholarĀ 

  2. Smith LE. Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture. Invest Ophthalmol Vis Sci. 2008;49:5177ā€“82.

    ArticleĀ  Google ScholarĀ 

  3. Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364:603ā€“15.

    ArticleĀ  CASĀ  Google ScholarĀ 

  4. Isaac M, Mireskandari K, Tehrani N. Type I ROP, treatment with bevacizumab versus laser: comparison of visual function, structural outcome and frequency of follow-up. J Am Assoc Pediatr Ophthalmol Strabismus. 2014;18:e5.

    ArticleĀ  Google ScholarĀ 

  5. Lien R, Yu MH, Hsu KH, Liao PJ, Chen YP, Lai CC, et al. Neurodevelopmental outcomes in infants with retinopathy of prematurity and bevacizumab treatment. PLoS ONE. 2016;11:e0148019.

    ArticleĀ  Google ScholarĀ 

  6. Morin J, Luu TM, Superstein R, Ospina LH, Lefebvre F, Simard MN, et al. Neurodevelopmental outcomes following bevacizumab injections for retinopathy of prematurity. Pediatrics. 2016;137:e20153218.

    ArticleĀ  Google ScholarĀ 

  7. Martinez-Castellanos MA, Schwartz S, Hernandez-Rojas ML, Kon-Jara VA, Garcia-Aguirre G, Guerrero-Naranjo JL, et al. Long-term effect of antiangiogenic therapy for retinopathy of prematurity up to 5 years of follow-up. Retina. 2013;33:329ā€“38.

    ArticleĀ  CASĀ  Google ScholarĀ 

  8. Wu WC, Lien R, Liao PJ, Wang NK, Chen YP, Chao AN, et al. Serum levels of vascular endothelial growth factor and related factors after intravitreous bevacizumab injection for retinopathy of prematurity. JAMA Ophthalmol. 2015;133:391ā€“7.

    ArticleĀ  Google ScholarĀ 

  9. Network TCN. The Canadian Neonatal Network Home Page. 2009 Available from: http://www.canadianneonatalnetwork.org/portal/ [cited 16 May 2018].

  10. Network TCNF-u. The Canadian Neonatal Follow-up Network Home Page. 2009. Available from: http://www.cnfun.ca/ [cited 16 May 2018].

  11. Rezai KA, Eliott D, Ferrone PJ, Kim RW. Near confluent laser photocoagulation for the treatment of threshold retinopathy of prematurity. Arch Ophthalmol. 2005;123:621ā€“6.

    ArticleĀ  Google ScholarĀ 

  12. Fallaha N, Lynn MJ, Aaberg TM Jr., Lambert SR. Clinical outcome of confluent laser photoablation for retinopathy of prematurity. J Aapos. 2002;6:81ā€“85.

    ArticleĀ  Google ScholarĀ 

  13. Network TCN. CNN Abstractorā€™s Manual v. 1.3.4. Toronto, Ontario: Canadian Neonatal Network; 2011.

  14. Bassler D, Stoll BJ, Schmidt B, Asztalos EV, Roberts RS, Robertson CM, et al. Using a count of neonatal morbidities to predict poor outcome in extremely low birth weight infants: added role of neonatal infection. Pediatrics. 2009;123:313ā€“8.

    ArticleĀ  Google ScholarĀ 

  15. Schlapbach LJ, Adams M, Proietti E, Aebischer M, Grunt S, Borradori-Tolsa C, et al. Outcome at two years of age in a Swiss national cohort of extremely preterm infants born between 2000 and 2008. BMC Pediatr. 2012;12:198.

    ArticleĀ  Google ScholarĀ 

  16. Tyson JE, Parikh NA, Langer J, Green C, Higgins RD. Intensive care for extreme prematurityā€“moving beyond gestational age. N Engl J Med. 2008;358:1672ā€“81.

    ArticleĀ  CASĀ  Google ScholarĀ 

  17. Amer R, Moddemann D, Seshia M, Alvaro R, Synnes A, Lee KS, et al. Neurodevelopmental outcomes of infants born at <29 weeks of gestation admitted to canadian neonatal intensive care units based on location of birth. J Pediatr. 2018;196:31.e31ā€“37.e31.

    ArticleĀ  Google ScholarĀ 

  18. Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128:e1053ā€“61.

    ArticleĀ  Google ScholarĀ 

  19. Sprung J, Flick RP, Katusic SK, Colligan RC, Barbaresi WJ, Bojanic K, et al. Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia. Mayo Clin Proc. 2012;87:120ā€“9.

    ArticleĀ  Google ScholarĀ 

  20. Ing C, DiMaggio C, Whitehouse A, Hegarty MK, Brady J, von Ungern-Sternberg BS, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130:e476ā€“85.

    ArticleĀ  Google ScholarĀ 

  21. Bayley N. Bayley Scales of Infant and Toddler Development, 3rd edn. San Antonio, TX: Psychocorp; 2005.

  22. Squires J, Bricker D. Ages & Stages QuestionnairesĀ®, Third Edition (ASQ- 3ā„¢). A parent-completed child-monitoring system. Baltimore, MD: Paul H. Brookes Publishing Co; 2009.

    Google ScholarĀ 

  23. Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med child Neurol. 1997;39:214ā€“23.

    ArticleĀ  CASĀ  Google ScholarĀ 

  24. Sharp M, DeMauro SB. Counterbalanced comparison of the BSID-II and Bayley-III at eighteen to twenty-two months corrected age. J Dev Behav Pediatr. 2017;38:322ā€“9.

    ArticleĀ  Google ScholarĀ 

  25. Schonhaut L, Armijo I, Schƶnstedt M, Alvarez J, Cordero M. Validity of the ages and stages questionnaires in term and preterm infants. Pediatrics. 2013;131:e1468ā€“74.

    ArticleĀ  Google ScholarĀ 

  26. Lowe JR, Erickson SJ, Schrader R, Duncan AF. Comparison of the Bayley II Mental Developmental Index and the Bayley III Cognitive Scale: are we measuring the same thing? Acta Paediatr. 2012;101:e55ā€“8.

    ArticleĀ  Google ScholarĀ 

  27. Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D, et al. A report: the definition and classification of cerebral palsy. Dev Med Child Neurol Suppl. 2007;109:8ā€“14.

    PubMedĀ  Google ScholarĀ 

  28. Weisz DE, Mirea L, Rosenberg E, Jang M, Ly L, Church PT, et al. Association of patent ductus arteriosus ligation with death or neurodevelopmental impairment among extremely preterm infants. JAMA Pediatr. 2017;171:443ā€“9.

    ArticleĀ  Google ScholarĀ 

  29. Glass TJA, Chau V, Gardiner J, Foong J, Vinall J, Zwicker JG, et al. Severe retinopathy of prematurity predicts delayed white matter maturation and poorer neurodevelopment. Arch Dis Child Fetal Neonatal Ed. 2017;102:F532ā€“7.

    ArticleĀ  Google ScholarĀ 

  30. Kennedy KA, Mintz-Hittner HA, Group B-RC. Medical and developmental outcomes of bevacizumab versus laser for retinopathy of prematurity. J AAPOS. 2018;22:61.e1ā€“5.e1.

    PubMedĀ  Google ScholarĀ 

  31. Chen TA, Schachar IH, Moshfeghi DM. Outcomes of intravitreal bevacizumab and diode laser photocoagulation for treatment-warranted retinopathy of prematurity. Ophthalmic Surg Lasers Imaging Retin. 2018;49:126ā€“31.

    ArticleĀ  Google ScholarĀ 

  32. Haigh JJ. Role of VEGF in organogenesis. Organogenesis. 2008;4:247ā€“56.

    ArticleĀ  Google ScholarĀ 

  33. Khalili S, Shifrin Y, Pan J, Belik J, Mireskandari K. The effect of a single anti-vascular endothelial growth factor injection on neonatal growth and organ development: in-vivo study. Exp Eye Res. 2018;169:54ā€“59.

    ArticleĀ  CASĀ  Google ScholarĀ 

  34. Jo DH, Park SW, Cho CS, Powner MB, Kim JH, Fruttiger M. Intravitreally injected anti-VEGF antibody reduces brown fat in neonatal mice. PLoS ONE. 2015;10:e0134308.

    ArticleĀ  Google ScholarĀ 

  35. Chen YH, Chen SN, Lien RI, Shih CP, Chao AN, Chen KJ, et al. Refractive errors after the use of bevacizumab for the treatment of retinopathy of prematurity: 2-year outcomes. Eye (Lond). 2014;28:1080ā€“6.

    ArticleĀ  CASĀ  Google ScholarĀ 

  36. Geloneck MM, Chuang AZ, Clark WL, Hunt MG, Norman AA, Packwood EA, et al. Refractive outcomes at age 2Ā½ years in the bevacizumab eliminates the angiogenic threat for retinopathy of prematurity trial: a randomized clinical trial. J Am Assoc Pediatr Ophthalmol Strabismus. 2013;17:e1ā€“7.

    ArticleĀ  Google ScholarĀ 

  37. Sankar MJ, Sankar J, Chandra P. Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity. Cochrane Database Syst Rev. 2018;1:CD009734.

    PubMedĀ  Google ScholarĀ 

  38. VanderVeen DK, Melia M, Yang MB, Hutchinson AK, Wilson LB, Lambert SR. Anti-vascular endothelial growth factor therapy for primary treatment of type 1 retinopathy of prematurity: a report by the American Academy of Ophthalmology. Ophthalmology. 2017;124:619ā€“33.

    ArticleĀ  Google ScholarĀ 

  39. Zhang G, Yang M, Zeng J, Vakros G, Su K, Chen M, et al. Comparison of intravitreal injection of ranibizumab versus laser therapy for zone II treatment-requiring retinopathy of prematurity. Retina. 2017;37:710ā€“7.

    ArticleĀ  CASĀ  Google ScholarĀ 

  40. Lepore D, Quinn GE, Molle F, Orazi L, Baldascino A, Ji MH, et al. Follow-up to age 4 years of treatment of type 1 retinopathy of prematurity intravitreal bevacizumab injection versus laser: fluorescein angiographic findings. Ophthalmology. 2018;125:218ā€“26.

    ArticleĀ  Google ScholarĀ 

Download references

Acknowledgements

The authors gratefully acknowledge all site investigators of the Canadian Neonatal Network (CNN) and Canadian Neonatal Follow-Up Network (CNFUN). We would also like to extend our thanks to the data abstractors of the CNN and CNFUN at three participating hospitals, as well as the staff at the Maternal-Infant Care Research Centre at Mount Sinai Hospital, Toronto, ON for providing organizational support for this project.

Funding source

Although no specific funding has been received for this study, organizational support for the Canadian Neonatal Network was provided by the Maternal-Infant Care Research Centre (MiCare) at Mount Sinai Hospital in Toronto. MiCare and the Canadian Neonatal Follow-Up Network are supported by a Canadian Institutes of Health Research (CIHR) Team Grant (FRN87518) and in-kind support from Mount Sinai Hospital. PSS holds an Applied Research Chair in Reproductive and Child Health Services and Policy Research awarded by the CIHR (APR-126340). The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author information

Authors and Affiliations

Authors

Contributions

MI and KR contributed to conceptualizing the study and designed the study, drafted the initial manuscript, and approved the final manuscript as submitted. JY carried out the initial analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. AAA contributed to data collected, aided in formulating the study proposal, reviewed and revised the manuscript, and approved the final manuscript as submitted. KM contributed to the concept, design and interpretation of data, critically reviewed and revised the draft manuscript for intellectual content, and approved the final submitted version of the article. LGL, EK, and RB oversaw and interpreted all the developmental assessments at their respective institutions, reviewed and critically revised the manuscript, and approved the final manuscript as submitted. PSS reviewed the initial study proposal and research ethics application, contributed to the concept of the study, acquisition, analysis and interpretation of data, reviewed and critically revised the manuscript, and approved the final manuscript as submitted. NT proposed the research question, conceptualized the study, reviewed the initial study proposal and research ethics application, contributed to the acquisition, analysis and interpretation of data, reviewed and critically revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Nasrin Tehrani.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisherā€™s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Raghuram, K., Isaac, M., Yang, J. et al. Neurodevelopmental outcomes in infants treated with intravitreal bevacizumab versus laser. J Perinatol 39, 1300ā€“1308 (2019). https://doi.org/10.1038/s41372-019-0420-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-019-0420-z

This article is cited by

Search

Quick links