Erythropoietin serum levels, versus anaemia as risk factors for severe retinopathy of prematurity

Article metrics

Abstract

Background

Preterm infants with anaemia are treated with recombinant human erythropoietin (rhEPO). It is debated whether rhEPO treatment is a risk factor for retinopathy of prematurity (ROP). We evaluated longitudinal EPO and haemoglobin levels, blood transfusions and neonatal morbidities as risk factors for severe ROP.

Method

This prospective study included 78 Swedish infants, born <28 weeks gestational age (GA), screened for ROP. We tested serum EPO levels on postnatal days 1, 7, 14 and 28 and at postmenstrual ages 32, 36 and 40 weeks. Haemoglobin levels and blood transfusions were recorded during postnatal weeks 1–4. Anaemia was defined as haemoglobin ≤110 g/L.

Results

During postnatal week 1, infants with severe ROP requiring treatment (28%) more frequently developed anaemia (42.9% versus 8.0%, P = 0.003) and had higher mean EPO levels (postnatal day 7: 14.2 versus 10.8 mIU/mL, P = 0.003) compared to infants with no or less severe ROP not requiring treatment. In multivariable analyses, GA and anaemia during week 1 remained significant risk factors, but elevated EPO level postnatal day 7 was no longer significant.

Conclusions

Among infants born <28 weeks GA, anaemia during week 1 was a significant risk factor for severe ROP requiring treatment but not elevated EPO levels.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2

References

  1. 1.

    Jelkmann, W. E., Fandrey, J., Frede, S. & Pagel, H. Inhibition of erythropoietin production by cytokines. Implications for the anemia involved in inflammatory states. Ann. NY Acad. Sci. 718, 300–309 (1994). discussion9–11.

  2. 2.

    Arcasoy, M. O. The non-haematopoietic biological effects of erythropoietin. Br. J. Haematol. 141, 14–31 (2008).

  3. 3.

    Bunn, H. F. Erythropoietin. Cold Spring Harb. Perspect. Med. 3, a011619 (2013).

  4. 4.

    Jopling, J., Henry, E., Wiedmeier, S. E. & Christensen, R. D. Reference ranges for hematocrit and blood hemoglobin concentration during the neonatal period: data from a multihospital health care system. Pediatrics 123, e333–e337 (2009).

  5. 5.

    Bain, A. & Blackburn, S. Issues in transfusing preterm infants in the NICU. J. Perinat. Neonatal Nurs. 18, 170–182 (2004). quiz83-4.

  6. 6.

    Maier, R. F. et al. Changing practices of red blood cell transfusions in infants with birth weights less than 1000 g. J. Pediatr. 136, 220–224 (2000).

  7. 7.

    Bishara, N. & Ohls, R. K. Current controversies in the management of the anemia of prematurity. Semin. Perinatol. 33, 29–34 (2009).

  8. 8.

    Strauss, R. G. Anaemia of prematurity: pathophysiology and treatment. Blood. Rev. 24, 221–225 (2010).

  9. 9.

    Blencowe, H., Lawn, J. E., Vazquez, T., Fielder, A. & Gilbert, C. Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010. Pediatr. Res. 74(Suppl. 1), 35–49 (2013).

  10. 10.

    Aiello, L. P. et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc. Natl. Acad. Sci. USA 92, 10457–10461 (1995).

  11. 11.

    Giannantonio, C. et al. Analysis of risk factors for progression to treatment-requiring ROP in a single neonatal intensive care unit: is the exposure time relevant? J. Matern. Fetal Neonatal Med. 25, 471–477 (2012).

  12. 12.

    Sato, T., Kusaka, S., Shimojo, H. & Fujikado, T. Vitreous levels of erythropoietin and vascular endothelial growth factor in eyes with retinopathy of prematurity. Ophthalmology 116, 1599–1603 (2009).

  13. 13.

    Holm, M. et al. Systemic endogenous erythropoietin and associated disorders in extremely preterm newborns. Arch. Dis. Child Fetal Neonatal Ed. 101, F458–F463 (2016).

  14. 14.

    Holm, M. et al. Systemic inflammation-associated proteins and retinopathy of prematurity in infants born before the 28th week of gestation. Invest. Ophthalmol. Vis. Sci. 58, 6419–6428 (2017).

  15. 15.

    Yang, X., Ze, B., Dai, Y., Zhu, L. & Chen, C. The alteration and significance of erythropoietin serum levels in preterm infants with retinopathy of prematurity. Am. J. Perinatol. 34, 1020–1025 (2017).

  16. 16.

    Suk, K. K. et al. Human recombinant erythropoietin and the incidence of retinopathy of prematurity: a multiple regression model. J. AAPOS 12, 233–238 (2008).

  17. 17.

    Brown, M. S., Baron, A. E., France, E. K. & Hamman, R. F. Association between higher cumulative doses of recombinant erythropoietin and risk for retinopathy of prematurity. J. AAPOS 10, 143–149 (2006).

  18. 18.

    Shah, N. et al. The effect of recombinant human erythropoietin on the development of retinopathy of prematurity. Am. J. Perinatol. 27, 67–71 (2010).

  19. 19.

    Schneider, J. K., Gardner, D. K. & Cordero, L. Use of recombinant human erythropoietin and risk of severe retinopathy in extremely low-birth-weight infants. Pharmacotherapy 28, 1335–1340 (2008).

  20. 20.

    Ohlsson, A. & Aher, S. M. Early erythropoiesis-stimulating agents in preterm or low birth weight infants. Cochrane Database Syst. Rev. 11, Cd004863 (2017).

  21. 21.

    Aher, S. M. & Ohlsson, A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst. Rev. 10, Cd004865 (2012).

  22. 22.

    Aher, S. M. & Ohlsson, A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst. Rev. Cd004868 4 (2014).

  23. 23.

    Chou, H. H., Chung, M. Y., Zhou, X. G. & Lin, H. C. Early erythropoietin administration does not increase the risk of retinopathy in preterm infants. Pediatr. Neonatol. 58, 48–56 (2017).

  24. 24.

    Chen, J. & Smith, L. E. A double-edged sword: erythropoietin eyed in retinopathy of prematurity. J. AAPOS 12, 221–222 (2008).

  25. 25.

    Najm, S. et al. Effects of a lipid emulsion containing fish oil on polyunsaturated fatty acid profiles, growth and morbidities in extremely premature infants: a randomized controlled trial. Clin. Nutr. ESPEN 20, 17–23 (2017).

  26. 26.

    Kliegman, R. M. & Walsh, M. C. Neonatal necrotizing enterocolitis: pathogenesis, classification, and spectrum of illness. Curr. Probl. Pediatr. 17, 213–288 (1987).

  27. 27.

    International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch. Ophthalmol. (Chic., Ill: 1960) 123, 991–999 (2005).

  28. 28.

    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. (Chic., Ill: 1960) 121, 1684–1694 (2003).

  29. 29.

    Altman, D. G., Vergouwe, Y., Royston, P. & Moons, K. G. Prognosis and prognostic research: validating a prognostic model. BMJ (Clin. Res. Ed.) 338, b605 (2009).

  30. 30.

    Lundgren, P. et al. Duration of anaemia during the first week of life is an independent risk factor for retinopathy of prematurity. Acta Paediatr. (Oslo, Nor.: 1992) 107, 759–766 (2017).

  31. 31.

    Banerjee, J. et al. Haemoglobin level at birth is associated with short term outcomes and mortality in preterm infants. BMC Med. 13, 16 (2015).

  32. 32.

    Shannon, K. M. et al. Recombinant human erythropoietin in the anemia of prematurity: results of a placebo-controlled pilot study. J. Pediatr. 118, 949–955 (1991).

  33. 33.

    Gumy-Pause, F. et al. Stepping up versus standard doses of erythropoietin in preterm infants: a randomized controlled trial. Pediatr. Hematol. Oncol. 22, 667–678 (2005).

  34. 34.

    Chen, J., Connor, K. M., Aderman, C. M. & Smith, L. E. Erythropoietin deficiency decreases vascular stability in mice. J. Clin. Invest. 118, 526–533 (2008).

  35. 35.

    Mowat, F. M. et al. Endogenous erythropoietin protects neuroretinal function in ischemic retinopathy. Am. J. Pathol. 180, 1726–1739 (2012).

  36. 36.

    Stutchfield, C. J., Jain, A., Odd, D., Williams, C. & Markham, R. Foetal haemoglobin, blood transfusion, and retinopathy of prematurity in very preterm infants: a pilot prospective cohort study. Eye 31, 1451–1455 (2017).

Download references

Acknowledgements

We thank all participants, the study team led by Carola Pfeiffer-Mosesson, Anne Rosenqvist, Mary Gustafsson, Svetlana Najm, Clara Mannheimer and Anna Thurfjell for very valuable help with retrieving data for the study. This study was supported by grants provided by the Swedish Research Council (DNR# 2011-2432), Gothenburg County Council (ALFGBG-426531), De Blindas Vänner, Kronprinsessan Margaretas Arbetsnämnd för synskadade, Stiftelsen Handlanden Herman Svenssons fond för blinda och synsvaga, Carmen och Bertil Regnérs Stiftelse, Cronqvists stiftelse, NIH EY024864, EY017017, P01 HD18655, Lowy Medical Research Institute.

Authors contribution

P.L. and A.H. designed the study, participated in the acquisition, analyses and interpretation of data, drafted the article and critically revised and approved the final draft. A.P. participated in the analyses and interpretation of data, and critically revised and approved the final draft. G.H., K.S. and L.E.H.S. critically revised and approved the final draft.

Author information

Correspondence to Pia Lundgren.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics statement:

This study was approved by the Regional Ethics Board, Gothenburg (Dnr 303-11) (Clinical trial NCT02760472).

Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lundgren, P., Hellgren, G., Pivodic, A. et al. Erythropoietin serum levels, versus anaemia as risk factors for severe retinopathy of prematurity. Pediatr Res 86, 276–282 (2019) doi:10.1038/s41390-018-0186-6

Download citation

Further reading