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Infantile hemangiomas and retinopathy of prematurity: clues to the regulation of vasculogenesis

Abstract

Retinopathy of prematurity (ROP) and infantile hemangiomas are vascular disorders that may share common mechanisms. This study examined a potential clinical association between these disorders in populations of preterm infants at two hospitals in the USA and Hungary. Clinically collected data from infants with gestational ages less than 32 weeks born between May 1, 2007 and December 31, 2010 seen in the University of Iowa Children’s Hospital or the Department of Obstetrics and Gynecology, University of Pécs, were abstracted from electronic medical records and entered into a study database. Demographic and clinical variables were examined as potential covariates to the disorders of interest. Data were initially analyzed by center and then combined through meta-analysis. Six hundred eighty-four subjects were studied: 236 from Pécs and 448 from Iowa. There were no significant demographic differences between populations. Univariate analysis on each study population yielded covariates to ROP in each population, including infantile hemangioma, which were entered into a logistic regression model. These models were combined through random-effects meta-analysis and demonstrated a significant relationship between infantile hemangioma and ROP (odds ratio = 1.84, 95 % confidence interval 1.08–3.12). Conclusion: Infantile hemangioma and ROP co-occur in premature infant populations. Further studies are needed to investigate the pathogenesis of both disorders.

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Abbreviations

CI:

Confidence interval

IH:

Infantile hemangioma

OR:

Odds ratio

ROP:

Retinopathy of prematurity

References

  1. 1.

    Amir J, Metzker A, Krikler R, Reisner SH (1986) Strawberry hemangioma in preterm infants. Pediatr Dermatol 3(4):331–332

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Ashton N, Ward B, Serpell G (1954) Effect of oxygen on developing retinal vessels with particular reference to the problem of retrolental fibroplasia. Br J Ophthalmol 38(7):397–432

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Boscolo E, Mulliken JB, Bischoff J (2011) VEGFR-1 mediates endothelial differentiation and formation of blood vessels in a murine model of infantile hemangioma. Am J Pathol 179(5):2266–2277

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Boye E, Jinnin M, Olsen BR (2009) Infantile hemangioma: challenges, new insights, and therapeutic promise. J Craniofac Surg 20(1):678–684

    PubMed  Article  Google Scholar 

  5. 5.

    Chen J, Joyal JS, Hatton CJ, Juan AM, Pei DT, Hurst CG, Xu D, Stable A, Hellstrom A, Smith LEH (2012) Propranolol inhibition of β-adrenergic receptor does not suppress pathologic neovascularization in oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 53(6):2968–2977

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Chen TS, Eichenfield LF, Friedlander SF (2013) Infantile hemangiomas: an update on pathogenesis and therapy. Pediatrics 131(1):99–108

    PubMed  Article  Google Scholar 

  7. 7.

    Cringle SJ, Yu DY (2010) Oxygen supply and consumption in the retina: implications for studies of retinopathy of prematurity. Doc Ophthalmol 120(1):99–109

    PubMed  Article  Google Scholar 

  8. 8.

    Crosse VM, Evans PJ (1952) Prevention of retrolental fibroplasia. AMA Arch Ophthalmol 48(1):83–87

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Drolet BA, Esterly NB, Frieden IJ (1999) Hemangiomas in children. N Engl J Med 341(3):173–181

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Drolet BA, Frommelt PC, Chamlin SL, Haggstrom A, Bauman NM, Chiu YE, Chun RH, Garzon MC, Holland KE, Liberman L, MacLellan-Tobert S, Mancini AJ, Metry D, Puttgen KB, Seefeldt M, Sidbury R, Ward KM, Blei F, Baselga E, Cassidy L, Darrow DH, Joachim S, Known EKM, Martin K, Perkins J, Siegel DH, Boucek RJ, Frieden IJ (2013) Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics 131(1):128–140

    PubMed  Article  Google Scholar 

  12. 12.

    Ertl T, Gyarmati J, Gaál V, Szabo I (2006) Relationship between hyperglycemia and retinopathy of prematurity in very low birth weight infants. Biol Neonate 89(1):56–59

    PubMed  Article  Google Scholar 

  13. 13.

    Good WV, Hardy RJ, Dobson V, Palmer EA, Phelps DL, Quintos M, Tung B, Early Treatment for Retinopathy of Prematurity Cooperative Group (2005) The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study. Pediatrics 116(1):15–23

    PubMed  Article  Google Scholar 

  14. 14.

    Greenberger S, Bischoff J (2011) Infantile hemangioma—mechanism(s) of drug action on a vascular tumor. Cold Spring Harb Perspect Med 1(1):a006460

    PubMed  Article  Google Scholar 

  15. 15.

    Greenberger S, Yuan S, Walsh LA, Boscolo E, Kang KT, Matthews B, Mulliken JB, Bischoff J (2011) Rapamycin suppresses self-renewal and vasculogenic potential of stem cells isolated from infantile hemangioma. J Invest Dermatol 131(12):2467–2276

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Gunn TR, Easdown J, Outerbridge EW, Aranda JV (1980) Risk factors in retrolental fibroplasia. Pediatrics 65(6):1096–1100

    PubMed  CAS  Google Scholar 

  17. 17.

    Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA, Lucky AW, Mancini AJ, Metry DW, Newell B, Hopper AJ, Frieden IJ (2006) Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment. Pediatrics 118(3):882–887

    PubMed  Article  Google Scholar 

  18. 18.

    Harris PA, Taylor R, Thieklke R, Payne J, Gonzalez N, Conde JG (2009) Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 42(2):377–381

    PubMed  Article  Google Scholar 

  19. 19.

    Hatton DD, Schwietz E, Boyer B, Rychwalski P (2007) Babies count: the national registry for children with visual impairments, birth to 3 years. J AAPOS 11(4):351–355

    PubMed  Article  Google Scholar 

  20. 20.

    Hellstrom A, Perruzzi C, Ju M, Engstrom E, Hard AL, Liu JL, Albertsson-Wikland K, Carlsson B, Niklasson A, Sjodell L, LeRoith D, Senger DR, Smith LE (2001) Low IGF-1 suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity. Proc Natl Acad Sci U S A 98(10):5804–5808

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Hemangioma Investigator Group, Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA, Lucky AW, Mancini AJ, Metry DW, Newell B, Nopper AJ, Frieden IJ (2007) Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics. J Pediatr 150(3):291–294

    PubMed  Article  Google Scholar 

  22. 22.

    Holland KE, Drolet BA (2010) Infantile hemangioma. Pediatr Clin North Am 57(5):1069–1083

    PubMed  Article  Google Scholar 

  23. 23.

    Hussain N, Clive J, Bhandari V (1999) Current incidence of retinopathy of prematurity, 1989–1997. Pediatrics 104(3):e26

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Hylander MA, Strobino DM, Pezzullo JC, Dhanireddy R (2001) Association of human milk feedings with a reduction in retinopathy of prematurity among very low birthweight infants. J Perinatol 21(6):356–362

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    International Committee for the Classification of Retinopathy of Prematurity (2005) The international classification of retinopathy of prematurity revisited. Arch Ophthalmol 123(7):991–999

    Article  Google Scholar 

  26. 26.

    Jinnin M, Medici D, Park L, Limaye N, Liu Y, Boscolo E, Bischoff J, Vikkula M, Boye E, Olsen BR (2008) Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med 14(11):1236–1246

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Kaempf JW, Kaempf AJ, Wu Y, Stawarz M, Niemeyer J, Grunkemeier G (2011) Hyperglycemia, insulin and slower growth velocity may increase the risk of retinopathy of prematurity. J Perinatol 31(4):251–257

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Khan ZA, Boscolo E, Picard A, Psutka S, Melero-Martin JM, Bartch TC, Mulliken JB, Bischoff J (2008) Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J Clin Invest 118(7):2592–2599

    PubMed  CAS  Google Scholar 

  29. 29.

    Kilcline C, Frieden IJ (2008) Infantile hemangiomas: how common are they? A systematic review of the medical literature. Pediatr Dermatol 25(2):168–173

    PubMed  Article  Google Scholar 

  30. 30.

    Kinsey VE (1956) Retrolental fibroplasia: cooperative study of retrolental fibroplasia and the use of oxygen. AMA Arch Ophthalmol 56(4):481–543

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Kleinman ME, Greives MR, Churgin SS, Blechman KM, Chang EI, Ceradini DJ, Tepper OM, Gurtner GC (2007) Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with hemangioma. Arterioscler Thromb Vasc Biol 27(12):2664–2670

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Madan A, Jan JE, Good WV (2005) Visual development in preterm infants. Dev Med Child Neurol 47(4):276–280

    PubMed  Article  Google Scholar 

  33. 33.

    Penn JS, Henry MM, Tolman BL (1994) Exposure to alternating hypoxia and hyperoxia causes severe proliferative retinopathy in the newborn rat. Pediatr Res 36(6):724–731

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Pierce EA, Foley ED, Smith LE (1996) Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol 114(10):1210–1228

    Article  Google Scholar 

  35. 35.

    Praveen V, Vidavalur R, Rosenkrantz TS, Hussain N (2009) Infantile hemangiomas and retinopathy of prematurity: possible association. Pediatrics 123(3):e484–489

    PubMed  Article  Google Scholar 

  36. 36.

    Raghuveer TS, Bloom BT (2011) A paradigm shift in the prevention of retinopathy of prematurity. Neonatology 100(2):116–129

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Ristori C, Filippi L, Dal Monte M, Martini D, Cammalleri M, Fortunato P, la Marca G, Fiorini P, Bagnoli P (2011) Role of the adrenergic system in a mouse model of oxygen-induced retinopathy: antiangiogenic effects of β-adrenoreceptor blockade. Invest Ophthalmol Vis Sci 52(1):155–170

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Romagnoli C, Tesfagabir MG, Giannantonio C, Papacci P (2011) Erythropoietin and retinopathy of prematurity. Early Hum Dev 87(Suppl 1):S39–42

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Sapieha P, Joyal JS, Rivera JC, Kermorvant-Duchemin E, Sennlaub F, Hardy P, Lachapelle P, Chemtob S (2010) Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life. J Clin Invest 120(9):3022–3032

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Yu Y, Flint AF, Mulliken JB, Wu JK, Bischoff J (2004) Endothelial progenitor cells in infantile hemangioma. Blood 103(4):1373–1375

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

This research was supported by grant UL1 RR024979 from the National Institutes of Health and grant OTKA 78480 from the Országos Tudományos Kutatási Alapprogramok (Hungarian Scientific Research Fund). We thank Gretchen A. Cress, RN, BSN, Erin M. Reynolds, PhD, MPH, and Heather A. Davis, MLIS for advice on setting up the database used for this study.

Conflict of interest

The authors declare that they have no financial relationships and no conflict of interest relevant to this article to disclose.

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Correspondence to Edward F. Bell.

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Hyland, R.M., Komlósi, K., Alleman, B.W. et al. Infantile hemangiomas and retinopathy of prematurity: clues to the regulation of vasculogenesis. Eur J Pediatr 172, 803–809 (2013). https://doi.org/10.1007/s00431-013-1966-y

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Keywords

  • Angiogenesis
  • Hemangioma
  • Preterm infants
  • Retinopathy of prematurity
  • Vascular endothelial growth factor
  • Vasculogenesis