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.

  • Clinical Research Article
  • Published:

Sustained lower bilirubin-binding affinity of albumin in extremely preterm infants

Pediatric Research volume 94, pages 1400–1407 (2023)Cite this article

Abstract

Background

Elevated albumin-free or unbound bilirubin (UB) levels beyond the first week of life have been associated with the development of bilirubin encephalopathy in preterm infants. However, the mechanism(s) that induces this prolonged unbound bilirubinemia has remained unknown. We hypothesized that it may due to a sustained lower bilirubin-binding affinity of albumin in extremely premature infants.

Methods

Twenty-two very preterm infants born at 28–31 weeks’ gestational age (GA) (VPT Group) and 21 extremely preterm infants born at 22–27 weeks’ GA (EPT Group) were retrospectively studied. On days 14, 21, and 28, bilirubin-binding affinity of albumin was assessed by calculating of the UB/total bilirubin ratio, bilirubin-albumin molar ratio (BAMR), and binding affinity (Ka).

Results

On days 14, 21, and 28, significantly higher UB/total bilirubin ratios were found in the EPT than in the VPT Group. Although BAMRs were comparable, significantly lower Ka values on days 14, 21, and 28 were observed in the EPT than those in the VPT Group (56.1 vs. 70.9 L/μmol, p < 0.001; 55.2 vs. 74.7 L/μmol, p < 0.001; 53.0 vs. 86.5 L/μmol, p < 0.001, respectively).

Conclusions

EPT infants have a sustained lower bilirubin-binding affinity of albumin beyond the first week of life.

Impact

  • Bilirubin encephalopathy is still reported in extremely preterm (EPT) infants.

  • EPT infants often have prolonged unbound bilirubinemia beyond the first week of life.

  • Sustained lower bilirubin-binding affinity of albumin, regardless of the bilirubin-albumin molar ratio (BAMR), is observed in EPT infants.

  • BAMRs should not be used as a surrogate marker of unbound bilirubinemia, especially in EPT infants at a later postnatal period.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Changes in serum/plasma total bilirubin (TB), unbound bilirubin (UB), and albumin levels from days 7 to 28 in very preterm infants (VPT Group) and extremely preterm infants (EPT Group).
Fig. 2: Changes in calculated Ka values from days 7 to 28 in very preterm infants (VPT Group) and extremely preterm infants (EPT Group).
Fig. 3: Relationship between unbound bilirubin (UB) levels and bilirubin-albumin molar ratios (BAMRs) on days 14, 21 and 28 in very preterm infants (VPT Group) and extremely preterm infants (EPT Group).

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Watchko, J. F. & Tiribelli, C. Bilirubin-induced neurologic damage-mechanisms and management approaches. N. Engl. J. Med. 369, 2021–2030 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Amin, S. B. Bilirubin binding capacity in the preterm neonate. Clin. Perinatol. 43, 241–257 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Morioka, I. et al. Disorders of bilirubin binding to albumin and bilirubin-induced neurologic dysfunction. Semin. Fetal Neonatal Med. 20, 31–36 (2015).

    Article  PubMed  Google Scholar 

  4. Nakamura, H. et al. Auditory nerve and brainstem responses in newborn infants with hyperbilirubinemia. Pediatrics 75, 703–708 (1985).

    Article  CAS  PubMed  Google Scholar 

  5. Meisel, P., Biebler, K. E., Gens, A. & Jaehrig, K. Albumin binding of photobilirubin II. Biochem J. 213, 25–29 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Abe, S. et al. Bilirubin/albumin (B/A) ratios correlate with unbound bilirubin levels in preterm infants. Pedeatr. Res. 89, 1427–1431 (2021).

    Article  CAS  Google Scholar 

  7. Amin, S. B. & Wang, H. Bilirubin albumin binding and unbound unconjugated hyperbilirubinemia in premature infants. J. Pediatr. 192, 47–52 (2018).

    Article  CAS  PubMed  Google Scholar 

  8. Oh, W. et al. Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants. Pediatrics 112, 773–779 (2003).

    Article  PubMed  Google Scholar 

  9. Okumura, A. et al. A nationwide survey of bilirubin encephalopathy in preterm infants in Japan. Brain Dev. 42, 730–737 (2020).

    Article  PubMed  Google Scholar 

  10. Morioka, I. et al. Current incidence of clinical kernicterus in preterm infants in Japan. Pediatr. Int. 57, 494–497 (2015).

    Article  PubMed  Google Scholar 

  11. Okumura, A. et al. Neonatal jaundice in preterm infants with bilirubin encephalopathy. Neonatology 118, 301–309 (2021).

    Article  CAS  PubMed  Google Scholar 

  12. Morioka, I. et al. Serum unbound bilirubin as a predictor for clinical kernicterus in extremely low birth weight infants at a late age in the neonatal intensive care unit. Brain Dev. 37, 753–757 (2015).

    Article  PubMed  Google Scholar 

  13. Morioka, I. Hyperbilirubinemia in preterm infants in Japan: New treatment criteria. Pediatr. Int. 60, 684–690 (2018).

    Article  CAS  PubMed  Google Scholar 

  14. Nakamura, H. et al. Determination of serum unbound bilirubin for prediction of kernicterus in low birthweight infants. Acta Paediatr. Jpn. 34, 642–647 (1992).

    Article  CAS  PubMed  Google Scholar 

  15. Morioka, I. et al. Clinical kernicterus in preterm infants in Japan. NeoReviews 17, e124 (2016).

    Article  Google Scholar 

  16. Miwa, A. et al. Correlation and precision of serum free bilirubin concentrations determined by single and two peroxidase concentration methods in term or late-preterm newborn infants using a FDA-approved analyzer. Clin. Lab. 58, 507–514 (2012).

    CAS  PubMed  Google Scholar 

  17. Sato, Y. et al. Is bilirubin/albumin ratio correlated with unbound bilirubin concentration? Pediatr. Int. 54, 81–85 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Miwa, A. et al. Hypoalbuminemia following abdominal surgery leads to high serum unbound bilirubin concentrations in newborns soon after birth. Neonatology 99, 202–207 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Ichinomiya, K. et al. Problems with using total serum bilirubin as a criterion for phototherapy in extremely low-birthweight infants. Pediatr. Int. 56, 731–734 (2014).

    Article  PubMed  Google Scholar 

  20. Kono, Y. et al. Developmental assessment of VLBW infants at 18 months of age: a comparison study between KSPD and Bayley III. Brain Dev. 38, 377–385 (2016).

    Article  PubMed  Google Scholar 

  21. Hulzebos, C. V. & Dijk, P. H. Bilirubin-albumin binding, bilirubin/albumin ratios, and free bilirubin levels: where do we stand? Semin. Perinatol. 38, 412–421 (2014).

    Article  PubMed  Google Scholar 

  22. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 114, 297–316 (2004).

    Article  Google Scholar 

  23. Hulzebos, C. V. et al. The bilirubin albumin ratio in the management of hyperbilirubinemia in preterm infants to improve neurodevelopmental outcome: a randomized controlled trial–BARTrial. PLos One 9, e99466 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Brodersen, R. & Ebbesen, F. Bilirubin-displacing effect of ampicillin, indomethacin, chlorpromazine, gentamicin, and parabens in vitro and in newborn infants. J. Pharm. Sci. 72, 248–253 (1983).

    Article  CAS  PubMed  Google Scholar 

  25. Amin, S. B. et al. Intravenous lipid and bilirubin-alubumin binding variables in premature infants. Pediatrics 124, 211–217 (2009).

    Article  PubMed  Google Scholar 

  26. Hegyi, T. et al. Effects of soybean lipid infusion on unbound free fatty acids and unbound bilirubin in preterm infants. J. Pediatr. 184, 45–50 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr Ronald J. Wong from the Department of Pediatrics at Stanford University School of Medicine for critical review and valuable suggestions for the improvement of this manuscript. We thank Drs Takao Kobayashi, Shohei Ohyama, Toshihiko Ikuta, Emiko Takeoka, Shoko Tamaki, and Hitomi Mimura at Hyogo Prefectural Kobe Children’s Hospital for their assistance with the manuscript.

Funding

This study was partially supported by a Research Grant from the Ministry of Health, Labour, and Welfare of Japan, grant number 21FC1001 (to S.I.).

Author information

Author notes

  1. These authors contributed equally: Kentaro Hirayama, Sota Iwatani.

Authors and Affiliations

  1. Department of Neonatology, Hyogo Prefectural Kobe Children’s Hospital, 1-6-7 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan

    Kentaro Hirayama, Sota Iwatani, Shinji Hagimoto, Ayako Izumi, Dai Kataoka, Sachiko Matsui & Seiji Yoshimoto

  2. Department of Pediatrics, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama, 641-0012, Japan

    Kentaro Hirayama

  3. Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Hajime Nakamura

  4. Department of Pediatrics, Tottori Prefectural Central Hospital, 730, Ezu, Tottori, Tottori, 680-0901, Japan

    Shinji Hagimoto

Authors
  1. Kentaro Hirayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sota Iwatani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hajime Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shinji Hagimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ayako Izumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dai Kataoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sachiko Matsui
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Seiji Yoshimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.H. and S.I. drafted the initial manuscript. K.H., S.I., and H.N. designed and performed the study. K.H., S.I., S.H., A.I., D.K., S.M, and S.Y. collected the clinical data. H.N. and S.Y. supervised the manuscript. All authors approved the final manuscript.

Corresponding author

Correspondence to Sota Iwatani.

Ethics declarations

Competing interests

The authors declare no competing interests.

Consent for publication

Written informed consent was received from the parents regarding the use of clinical data for research purposes.

Additional information

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

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hirayama, K., Iwatani, S., Nakamura, H. et al. Sustained lower bilirubin-binding affinity of albumin in extremely preterm infants. Pediatr Res 94, 1400–1407 (2023). https://doi.org/10.1038/s41390-022-02418-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41390-022-02418-9

Search

Advanced search

Quick links