Clinical Impact of Differences in Phototherapy and Exchange Transfusion Thresholds Between Turkish Neonatology Society and 2022 AAP Guidelines in Neonates with Indirect Hyperbilirubinemia

Clinical Impact of Differences in Phototherapy and Exchange Transfusion Thresholds Between Turkish Neonatology Society and 2022 AAP Guidelines in Neonates with Indirect Hyperbilirubinemia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical Impact of Differences in Phototherapy and Exchange Transfusion Thresholds Between Turkish Neonatology Society and 2022 AAP Guidelines in Neonates with Indirect Hyperbilirubinemia Deniz Keskindil, Senem Alkan Ozdemir, Şebnem Çalkavur, Tülin Gökmen Yildirim This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8740481/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Clinical management of neonatal indirect hyperbilirubinemia is guided by threshold-based recommendations for initiating phototherapy and exchange transfusion. Differences between national and international guidelines may lead to variability in treatment decisions and hospitalization practices. This retrospective, single-center study compared phototherapy and exchange transfusion thresholds according to the Turkish Neonatology Society (TNS) guideline and the 2022 American Academy of Pediatrics (AAP) guideline in neonates hospitalized for indirect hyperbilirubinemia. Methods This single-center, retrospective cross-sectional study included neonates born at ≥35 weeks of gestation who were admitted to a neonatal intensive care unit solely due to indirect hyperbilirubinemia. Phototherapy and exchange transfusion thresholds were calculated according to both the TNS guideline and the 2022 AAP guideline. Eligibility for treatment and hospitalization according to guideline thresholds was compared between the two guidelines. Statistical analyses were performed using appropriate non-parametric tests. Results A total of 344 neonates were included in the analysis. Mean phototherapy and exchange transfusion thresholds were significantly higher according to the 2022 AAP guideline compared with the TNS guideline (p < 0.001 for both). While 89.2% of admissions met eligibility criteria according to national guideline thresholds, only 36.6% met admission criteria when assessed according to the 2022 AAP guideline. Conclusions Substantial differences exist between national and international guidelines for the management of neonatal indirect hyperbilirubinemia. These differences have a significant impact on treatment thresholds and hospitalization practices in clinical settings. Real-world comparative data may contribute to future evaluations and contextual adaptation of guideline-based management strategies. Neonatal hyperbilirubinemia Phototherapy Exchange transfusion Clinical guidelines Neonatal care Hospital admission Introduction Neonatal jaundice remains one of the most common reasons for hospital admission during the early postnatal period. Although most cases are benign and self-limited, severe indirect hyperbilirubinemia may lead to bilirubin-induced neurological dysfunction (BIND) and kernicterus if not recognized and treated promptly [1]. For this reason, timely identification and appropriate management of hyperbilirubinemia continue to represent a cornerstone of neonatal care. Clinical decision-making in neonatal hyperbilirubinemia relies primarily on guideline-defined thresholds for initiating phototherapy and exchange transfusion. These thresholds are designed to prevent bilirubin neurotoxicity while avoiding unnecessary interventions and hospitalizations [1,2]. Consequently, updates to international guidelines may directly influence daily clinical practice, admission policies, and treatment intensity in neonatal units. In 2022, the American Academy of Pediatrics (AAP) updated its clinical practice guideline for the management of hyperbilirubinemia in infants born at ≥35 weeks of gestation [3]. Compared with previous recommendations, the revised guideline introduced higher thresholds for both phototherapy and exchange transfusion. This update reflects accumulating evidence suggesting that higher bilirubin levels may be safely tolerated in selected neonates without increasing the risk of neurotoxicity [3,4]. The AAP also emphasized individualized risk assessment by incorporating gestational age and specific neurotoxicity risk factors into treatment decisions. In Türkiye, neonatal hyperbilirubinemia is managed according to the national guideline published by the Turkish Neonatology Society (TNS) [5]. Although widely implemented in clinical practice, this guideline differs from the updated AAP recommendations, particularly with respect to treatment thresholds. Such differences may lead to variation in hospital admission practices and therapeutic approaches, especially in neonatal intensive care units (NICUs), where threshold-based decisions often determine the need for hospitalization and intervention. Despite the potential clinical impact of these differences, real-world data directly comparing the practical implications of these guidelines remain limited. In particular, there is a paucity of studies evaluating how variations in treatment thresholds translate into hospital admission patterns among neonates with indirect hyperbilirubinemia [6]. The aim of this study was to compare phototherapy and exchange transfusion thresholds according to the TNS guideline and the 2022 AAP guideline in neonates born at ≥35 weeks of gestation who were admitted to a NICU due to indirect hyperbilirubinemia. By evaluating eligibility according to guideline thresholds and potential differences in admission indications, we sought to clarify the clinical implications of applying national versus updated international recommendations in routine neonatal care. Methods 2.1 Study design and setting This study was designed as a single-center, retrospective cross-sectional analysis. It was conducted in the Neonatal Intensive Care Unit (NICU) of HSU İzmir Dr. Behçet Uz Children’s Diseases and Surgery Training and Research Hospital, a tertiary pediatric referral center. Medical records of neonates hospitalized with a diagnosis of indirect hyperbilirubinemia were reviewed. 2.2 Study population Neonates admitted to the NICU during the study period were identified using relevant ICD-10 diagnostic codes. As our institution is a tertiary pediatric referral hospital without maternity services, all neonates included in this study were born in external maternity hospitals and referred to our center due to indirect hyperbilirubinemia. Infants born at ≥35 weeks of gestation who were hospitalized solely for indirect hyperbilirubinemia were eligible for inclusion. Guideline-based eligibility was evaluated retrospectively for each neonate by considering gestational age, postnatal age at admission, total serum bilirubin (TSB) level, and documented neurotoxicity risk factors. These parameters were individually compared with both the Turkish Neonatology Society (TNS) and the 2022 American Academy of Pediatrics (AAP) guideline thresholds to determine theoretical eligibility for admission and treatment. Thresholds were calculated for each neonate at the time of admission. Inclusion criteria Gestational age ≥ 35 weeks Admission to the NICU due to indirect hyperbilirubinemia Absence of major comorbid conditions Exclusion criteria Presence of additional systemic diseases Incomplete medical records Admission for reasons other than indirect hyperbilirubinemia After applying inclusion and exclusion criteria, 344 neonates were included in the final analysis. 2.3 Data collection Demographic, clinical, and laboratory data were obtained from electronic medical records and patient files. Recorded variables included gestational age, birth weight, sex, postnatal age at admission, feeding type, duration of hospitalization, and duration of phototherapy. Laboratory parameters included TSB levels at admission, direct Coombs test results, ABO and Rh blood group incompatibilities, reticulocyte count, C-reactive protein (CRP), thyroid function tests (TSH and free T4), glucose-6-phosphate dehydrogenase (G6PD) deficiency status, blood culture results, and the presence of urinary tract infection. 2.4 Guideline-based assessment Phototherapy and exchange transfusion thresholds were determined according to both guidelines. Guideline-based admission, phototherapy, and exchange transfusion thresholds were retrospectively applied to each neonate using recorded clinical and laboratory data. These assessments reflected theoretical eligibility according to guideline criteria and were independent of the actual clinical decisions made at the time of hospitalization. Eligibility was defined as the presence of a TSB level at admission equal to or exceeding the respective phototherapy or exchange transfusion threshold. Guideline-based admission indication rates were compared between the two recommendations. 2.5 Outcomes The primary outcome was the difference in phototherapy and exchange transfusion thresholds between the TNS and AAP 2022 guidelines. Secondary outcomes included differences in guideline-based eligibility rates and potential variations in admission indications according to gestational age. Although subgroup analyses by gestational age may enhance data visualization, the present study focused on overall guideline-based eligibility in order to maintain consistency with its primary objective. Ethics approval and consent to participate: This study was approved by the institutional ethics committee of HSU İzmir Dr. Behçet Uz Children’s Diseases and Surgery Training and Research Hospital (Approval number 2023/901) (26/10/2023). The study was conducted in accordance with the principles of the Declaration of Helsinki. As this was a retrospective study based on medical records, informed consent was waived by the ethics committee. Statistical Analysis Statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). Continuous variables were assessed for normal distribution using the Shapiro–Wilk test. Data were presented as mean ± standard deviation or median (interquartile range), as appropriate. Categorical variables were expressed as numbers and percentages. Paired comparisons of phototherapy and exchange transfusion threshold values between the two guidelines were conducted using the Wilcoxon signed-rank test. Comparisons of hospi-talization and phototherapy durations across gestational age groups were performed us-ing the Kruskal–Wallis test. A p-value < 0.05 was considered statistically significant. Results A total of 510 neonates admitted to the neonatal intensive care unit during the study period were initially screened. Of these, 100 neonates were excluded due to unavailable medical records and 66 did not meet the inclusion criteria. Consequently, 344 neonates born at ≥35 weeks of gestation and hospitalized solely due to indirect hyperbilirubinemia were included in the final analysis. 3.1 Baseline characteristics Baseline demographic and clinical characteristics of the study population are presented in Table 1. The mean gestational age was 37.7 ± 1.43 weeks and the mean birth weight was 3234.6 ± 1372.5 g. Of the infants, 54.4% were male. The median postnatal age at admission for jaundice was 5 days. The mean total serum bilirubin level at initiation of treatment was 17.88 ± 4.92 mg/dL. The mean duration of hospitalization was 4.46 ± 3.21 days, and the mean duration of phototherapy was 17.52 ± 10.87 hours. 3.2 Clinical and laboratory findings Categorical clinical and laboratory characteristics are summarized in Table 2. ABO incompatibility was present in 21.5% of neonates, while Rh incompatibility was observed in 6.1%. Direct Coombs test positivity was detected in 7.3% of cases. Glucose-6-phosphate dehydrogenase (G6PD) deficiency was identified in 9.7% of neonates. Blood culture positivity was detected in 2.6% of cases; these results were interpreted as contamination. Urinary tract infection was identified in 13.4% of infants. Exchange transfusion was performed in 2.0% of the study population. The majority of neonates (89.0%) were exclusively breastfed. 3.3 Comparison of guideline thresholds Phototherapy and exchange transfusion threshold values according to the Turkish Neonatology Society (TNS) and the American Academy of Pediatrics (AAP) 2022 guidelines are presented in Table 3. The mean phototherapy threshold according to the TNS guideline was 15.83 ± 2.46 mg/dL, whereas the mean threshold according to the AAP 2022 guideline was 19.61 ± 2.31 mg/dL. This difference was statistically significant (p < 0.001). Similarly, the mean exchange transfusion threshold was 20.43 ± 2.43 mg/dL according to the TNS guideline and 25.76 ± 1.57 mg/dL according to the AAP 2022 guideline, also showing a statistically significant difference (p < 0.001). These mean threshold values represent the average of guideline-specific phototherapy or exchange transfusion thresholds individually calculated for each neonate at the time of admission, rather than a single uniform threshold applied to the entire cohort. 3.4 Eligibility according to guideline thresholds Among the 344 neonates admitted due to indirect hyperbilirubinemia, 307 infants (89.2%) met admission criteria according to the TNS guideline. In contrast, only 126 infants (36.6%) met admission criteria based on the AAP 2022 guideline. When eligibility was further evaluated according to gestational age, approximately 64.4% of hospitalized neonates did not have an indication for admission according to the AAP 2022 guideline. The distribution of major risk factors associated with bilirubin neurotoxicity is summarized in Table 4. Discussion The present study compared phototherapy and exchange transfusion thresholds defined by the Turkish Neonatology Society (TNS) and the 2022 American Academy of Pediatrics (AAP) guidelines in neonates hospitalized for indirect hyperbilirubinemia. The main finding is the substantial difference between the two guidelines regarding treatment thresholds and admission indications. Both phototherapy and exchange transfusion thresholds were significantly higher when calculated according to the AAP 2022 guideline compared with the TNS guideline. This pattern was consistent across the entire study population and reflects the more conservative approach of the national guideline in comparison with the updated international recommendations [1,2,7]. A particularly notable observation is the marked discrepancy in eligibility according to guideline thresholds. While the majority of neonates admitted with indirect hyperbilirubinemia met admission criteria according to the TNS guideline, less than half fulfilled the criteria based on the AAP 2022 recommendations. Furthermore, when evaluated according to gestational age, approximately two-thirds of hospitalized neonates did not meet admission criteria under the AAP guideline. These findings suggest that guideline selection may significantly influence hospitalization practices in neonatal intensive care units (NICUs) [1,2,8]. Importantly, these differences primarily reflect the inherent structure and philosophy of the respective guidelines rather than evidence of clinical superiority. Thus, the clinical relevance of our findings lies in their potential impact on admission policies and care pathways rather than statistical differences alone. National hyperbilirubinemia guidelines have traditionally adopted a cautious approach, aiming to minimize the risk of bilirubin-induced neurological dysfunction (BIND) and kernicterus [9]. Given the potentially irreversible consequences of severe hyperbilirubinemia, earlier treatment initiation and lower intervention thresholds may be preferred to maximize neuroprotection [10]. However, this strategy may lead to increased phototherapy use and higher NICU admission rates, particularly in healthcare settings where structured outpatient follow-up is limited [11,12]. Some countries continue to use the NICE guideline, which also employs lower thresholds but does not explicitly incorporate neurotoxicity risk stratification [13]. In contrast, the 2022 AAP guideline emphasizes individualized, risk-based decision-making, incorporating gestational age and specific neurotoxicity risk factors. Importantly, meeting treatment thresholds under the AAP guideline does not automatically mandate hospital admission, as close follow-up and clinical judgment are integral components of care. Therefore, our results should be interpreted as a comparison of guideline-based theoretical eligibility rather than an evaluation of real-time clinical decisions. Following publication of the 2022 AAP guideline, several studies have reported real-world practice changes, including reductions in serum bilirubin testing, phototherapy utilization, and hospital admissions for neonatal jaundice [14–17]. These findings support a shift toward more selective treatment approaches while emphasizing the importance of ongoing surveillance of safety outcomes. Our study adds complementary evidence by quantifying how the application of AAP 2022 versus national guideline thresholds would alter theoretical eligibility for treatment and hospitalization in a tertiary pediatric referral hospital. The upward revision of treatment thresholds reflects accumulating data indicating that higher bilirubin levels can be safely tolerated in selected neonates under appropriate monitoring [18]. Available evidence suggests that implementation of higher thresholds has not been associated with increased bilirubin-related neurological complications. Differences between guidelines may also affect healthcare resource utilization. NICU admission is associated with increased healthcare costs, longer hospitalization, and separation of newborns from their families [19–21]. In this context, our finding that a substantial proportion of admitted neonates would not have met AAP 2022 criteria highlights the potential influence of guideline selection on NICU workload and family-centered outcomes. Nevertheless, patient safety remains paramount, and any reduction in hospitalization should be accompanied by reliable monitoring and follow-up systems. Although neurotoxicity risk factors were documented, the present study was not designed for risk-stratified subgroup analyses. Future multicenter studies incorporating standardized follow-up and outcome measures are needed to better clarify the interaction between guideline thresholds and individual risk profiles. From a public health perspective, differences in treatment thresholds may influence admission patterns, NICU capacity, and neonatal care pathways. Real-world comparative data may support the development of risk-adapted admission strategies and optimized resource utilization while maintaining patient safety. This study has several strengths, including a relatively large sample size and the use of real-world clinical data from a tertiary NICU. However, limitations should be acknowledged. The retrospective, single-center design may limit generalizability. Long-term neurological outcomes, post-discharge follow-up, readmission rates, and rebound bilirubin levels were not evaluated. These parameters represent important areas for future prospective research aimed at assessing the real-world safety and effectiveness of guideline-based management strategies [22]. Conclusions This study provides real-world comparative data on phototherapy and exchange transfusion thresholds according to the Turkish Neonatology Society and the 2022 American Academy of Pediatrics guidelines in neonates hospitalized for indirect hyperbilirubinemia. Substantial differences were identified between the two guidelines, with higher treatment thresholds and fewer theoretical admission indications when the updated international recommendations were applied. These findings should not be interpreted as evidence to support changes in clinical practice in the absence of outcome-based data. Rather, they represent real-life observations illustrating how different guideline frameworks may influence hospitalization decisions in pediatric referral centers. Our results suggest that guideline selection may significantly affect hospitalization patterns in centers managing neonatal hyperbilirubinemia. These findings underscore the importance of critically evaluating guideline-based admission criteria within real-world clinical contexts and highlight the need for multicenter studies incorporating post-discharge follow-up and outcome assessment to further optimize neonatal jaundice management. Declarations Author Contributions: Conceptualization, S.A.O.; methodology, S.A.O.; data collection, D.K.; formal analysis, S.A.O. and D.K.; data interpretation, S.A.O., Ş.Ç., and T.G.Y.; writing—original draft preparation, D.K.; writing—review and editing, S.A.O.; supervision, S.A.O. All authors have read and approved the final version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement:. The study was conducted in accordance with the Declaration of Helsinki and has received approval from the T.C. Ministry of Health, İzmir Provincial Health Directorate, H.S.U. İzmir Dr Behçet Uz Children’s Diseases and Surgery Training and Research Hospital Clinical Research Ethics Committee (Approval number 2023/901) (26/10/2023). Clinical Trial Registration: Not applicable. This study is a retrospective observational study based on existing medical records and does not involve prospective intervention or trial registration. Informed Consent Statement: Informed consent was waived by the ethics committee due to the retrospective nature of the study and the use of anonymized data. Data Availability Statement: The data supporting the findings of this study are not publicly available due to ethical and privacy considerations related to patient data. However, anonymized datasets may be made available by the corresponding author upon reasonable request and subject to institutional approval. Acknowledgments: The authors would like to thank the staff of the Neonatal Intensive Care Unit of HSU İzmir Dr. Behçet Uz Children’s Diseases and Surgery Training and Research Hospital for their support during data collection. Conflicts of Interest: The authors declare no conflicts of interest. Consent for publication: Not applicable. References Okulu E, Erdeve Ö, Tuncer O, Ertuğrul S, Özdemir H, Çiftdemir NA, Zenciroğlu A, Atasay B. Exchange transfusion for neonatal hyperbilirubinemia: A multicenter, prospective study of Turkish Neonatal Society. Turk Arch Pediatr. 2021;56:121–6. Schwarts HP, Haberman BE, Rudy MR, Hyperbilirubinemia. Current guidelines and emerging therapies. Pediatr Emerg Care. 2011;27:884–9. Kemper AR, Newman TB, Slaughter JL, Maisels MBMJ, Watchko JF, Downs SM, Grout RW, Bundy DG, Stark AR, Bogen DL, et al. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2022;150:e2022058859. https://doi.org/10.1542/peds.2022-058859 . American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297–316. Çoban A, Kaynak Türkmen M, Gürsoy T. Yenidoğan Sarılıklarında Yaklaşım, Izlem ve Tedavi Rehberi; Türk Neonatoloji Derneği Rehberleri: Ankara, Türkiye, 2022; ISBN: 978-605-68344-0-0. Bhutani VK, Johnson LH, Keren R. Diagnosis and management of hyperbilirubinemia in the term neonate: For a safer first week. Pediatr Clin N Am. 2004;51:843–61. https://doi.org/10.1016/j.pcl.2004.03.011 . Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin nomogram for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 1999, 103, 6–14. https://doi.org/10.1542/peds.103.1.6 Maisels MJ, Phototherapy—Traditional, Perinatol nontraditionalJ. 2001, 21, S93–S97. https://doi.org/10.1038/sj.jp.7210642 Shapiro SM. Chronic bilirubin encephalopathy: Diagnosis and outcome. Semin. Fetal Neonatal Med. 2010;15:157–63. https://doi.org/10.1016/j.siny.2009.12.004 . Maisels MJ, Bhutani VK. Revised thresholds for neonatal hyperbilirubinemia. Pediatrics. 2022;150:e2022058858. https://doi.org/10.1542/peds.2022-058858 . Newman TB, Liljestrand P, Jeremy RJ, Ferriero DM, Wu YW, Hudes ES, Escobar GJ. Outcomes among newborns with total serum bilirubin levels of 25 mg per deciliter or more. N Engl J Med. 2006;354:1889–900. https://doi.org/10.1056/NEJMoa054244 . Kuzniewicz MW, Wickremasinghe AC, Wu YW, McCulloch CE, Walsh EM, Wi S, Newman TB. Incidence, etiology, and outcomes of hazardous hyperbilirubinemia in newborns. Pediatr 2014, 134 , 504–9. https://doi.org/10.1542/peds.2014-0987 National Institute for Health and Care Excellence (NICE). Jaundice in Newborn Babies Under 28 Days ; Clinical Guideline CG98; NICE: London, UK, 2023. Available online: https://www.nice.org.uk/guidance/cg98 (accessed on). Sarathy L, Chou JH, Giuseppina RC, Darci AK, Lerou PH. Bilirubin measurement and phototherapy use after the AAP 2022 Newborn Hyperbilirubinemia Guideline. Pediatrics 2024, 153, e2023063323. https://doi.org/10.1542/peds.2023-063323 Jameel A, Richardson T, Slaughter JL. Impact of the 2022 AAP Guidelines on Neonatal Hyperbilirubinemia Admissions: A PHIS Study. Hosp Pediatr. 2025;15:537–44. https://doi.org/10.1542/hpeds.2024-008205 . Dani C, Fusco M, Andreini M, Pepe G, Pratesi S. Implementation of the 2022 AAP guidelines for neonatal hyperbilirubinemia could reduce the need for phototherapy in Italy. Ital J Pediatr. 2025;51:162. https://doi.org/10.1186/s13052-025-02002-x . Nguyen EL, Joshi NS. Rapid Implementation of Updated Guidelines for Neonatal Hyperbilirubinemia. Hosp Pediatr. 2025;15:e309–11. https://doi.org/10.1542/hpeds.2024-008283 . Profit J, Gould JB, Zupancic JAF et al. Formal assessment of family-centered outcomes in neonatal intensive care. Pediatr 2017, 139, e20163475. https://doi.org/10.1542/peds.2016-3475 Maisels MJ. Managing the jaundiced newborn: A persistent challenge. Can Med Assoc J. 2015, 187, 335–43. Johnson L, Bhutani VK. The clinical syndrome of bilirubin-induced neurologic dysfunction. Semin Perinatol. 2011;35:101–13. O’Brien K, Robson K, Bracht M, Cruz M, Lui K, Alvaro R, da Silva O, Monterrosa L, Narvey M, Ng E, et al. Effectiveness of family integrated care in neonatal intensive care units on infant and parent outcomes: A multicentre, multinational, cluster-randomised controlled trial. Lancet Child Adolesc Health. 2018;2:245–54. Roșca I, Constantin AT, Popescu DE, Jura AMC, Miu A, Turenschi A. Are We Able to Prevent Neonatal Readmission? A Retrospective Analysis from a Pediatrics Department in Ploiești. Romania Med. 2024;60:705. https://doi.org/10.3390/medicina60050705 . Tables Table 1 to 4 are available in the Supplementary Files section. Supplementary Files TablesIJP.docx Table2.docx Table3.docx Table4.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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jaundice remains one of the most common reasons for hospital admission during the early postnatal period. Although most cases are benign and self-limited, severe indirect hyperbilirubinemia may lead to bilirubin-induced neurological dysfunction (BIND) and kernicterus if not recognized and treated promptly [1]. For this reason, timely identification and appropriate management of hyperbilirubinemia continue to represent a cornerstone of neonatal care.\u003c/p\u003e\n\u003cp\u003eClinical decision-making in neonatal hyperbilirubinemia relies primarily on guideline-defined thresholds for initiating phototherapy and exchange transfusion. These thresholds are designed to prevent bilirubin neurotoxicity while avoiding unnecessary interventions and hospitalizations [1,2]. Consequently, updates to international guidelines may directly influence daily clinical practice, admission policies, and treatment intensity in neonatal units.\u003c/p\u003e\n\u003cp\u003eIn 2022, the American Academy of Pediatrics (AAP) updated its clinical practice guideline for the management of hyperbilirubinemia in infants born at \u0026ge;35 weeks of gestation [3]. Compared with previous recommendations, the revised guideline introduced higher thresholds for both phototherapy and exchange transfusion. This update reflects accumulating evidence suggesting that higher bilirubin levels may be safely tolerated in selected neonates without increasing the risk of neurotoxicity [3,4]. The AAP also emphasized individualized risk assessment by incorporating gestational age and specific neurotoxicity risk factors into treatment decisions.\u003c/p\u003e\n\u003cp\u003eIn T\u0026uuml;rkiye, neonatal hyperbilirubinemia is managed according to the national guideline published by the Turkish Neonatology Society (TNS) [5]. Although widely implemented in clinical practice, this guideline differs from the updated AAP recommendations, particularly with respect to treatment thresholds. Such differences may lead to variation in hospital admission practices and therapeutic approaches, especially in neonatal intensive care units (NICUs), where threshold-based decisions often determine the need for hospitalization and intervention.\u003c/p\u003e\n\u003cp\u003eDespite the potential clinical impact of these differences, real-world data directly comparing the practical implications of these guidelines remain limited. In particular, there is a paucity of studies evaluating how variations in treatment thresholds translate into hospital admission patterns among neonates with indirect hyperbilirubinemia [6].\u003c/p\u003e\n\u003cp\u003eThe aim of this study was to compare phototherapy and exchange transfusion thresholds according to the TNS guideline and the 2022 AAP guideline in neonates born at \u0026ge;35 weeks of gestation who were admitted to a NICU due to indirect hyperbilirubinemia. By evaluating eligibility according to guideline thresholds and potential differences in admission indications, we sought to clarify the clinical implications of applying national versus updated international recommendations in routine neonatal care.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1 Study design and setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was designed as a single-center, retrospective cross-sectional analysis. It was conducted in the Neonatal Intensive Care Unit (NICU) of HSU İzmir Dr. Beh\u0026ccedil;et Uz Children\u0026rsquo;s Diseases and Surgery Training and Research Hospital, a tertiary pediatric referral center. Medical records of neonates hospitalized with a diagnosis of indirect hyperbilirubinemia were reviewed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Study population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNeonates admitted to the NICU during the study period were identified using relevant ICD-10 diagnostic codes. As our institution is a tertiary pediatric referral hospital without maternity services, all neonates included in this study were born in external maternity hospitals and referred to our center due to indirect hyperbilirubinemia.\u003c/p\u003e\n\u003cp\u003eInfants born at \u0026ge;35 weeks of gestation who were hospitalized solely for indirect hyperbilirubinemia were eligible for inclusion. Guideline-based eligibility was evaluated retrospectively for each neonate by considering gestational age, postnatal age at admission, total serum bilirubin (TSB) level, and documented neurotoxicity risk factors. These parameters were individually compared with both the Turkish Neonatology Society (TNS) and the 2022 American Academy of Pediatrics (AAP) guideline thresholds to determine theoretical eligibility for admission and treatment. Thresholds were calculated for each neonate at the time of admission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eGestational age \u0026ge; 35 weeks\u003c/li\u003e\n \u003cli\u003eAdmission to the NICU due to indirect hyperbilirubinemia\u003c/li\u003e\n \u003cli\u003eAbsence of major comorbid conditions\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003ePresence of additional systemic diseases\u003c/li\u003e\n \u003cli\u003eIncomplete medical records\u003c/li\u003e\n \u003cli\u003eAdmission for reasons other than indirect hyperbilirubinemia\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eAfter applying inclusion and exclusion criteria, 344 neonates were included in the final analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Data collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDemographic, clinical, and laboratory data were obtained from electronic medical records and patient files. Recorded variables included gestational age, birth weight, sex, postnatal age at admission, feeding type, duration of hospitalization, and duration of phototherapy.\u003c/p\u003e\n\u003cp\u003eLaboratory parameters included TSB levels at admission, direct Coombs test results, ABO and Rh blood group incompatibilities, reticulocyte count, C-reactive protein (CRP), thyroid function tests (TSH and free T4), glucose-6-phosphate dehydrogenase (G6PD) deficiency status, blood culture results, and the presence of urinary tract infection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Guideline-based assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePhototherapy and exchange transfusion thresholds were determined according to both guidelines. Guideline-based admission, phototherapy, and exchange transfusion thresholds were retrospectively applied to each neonate using recorded clinical and laboratory data. These assessments reflected theoretical eligibility according to guideline criteria and were independent of the actual clinical decisions made at the time of hospitalization.\u003c/p\u003e\n\u003cp\u003eEligibility was defined as the presence of a TSB level at admission equal to or exceeding the respective phototherapy or exchange transfusion threshold. Guideline-based admission indication rates were compared between the two recommendations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.5 Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome was the difference in phototherapy and exchange transfusion thresholds between the TNS and AAP 2022 guidelines. Secondary outcomes included differences in guideline-based eligibility rates and potential variations in admission indications according to gestational age.\u003c/p\u003e\n\u003cp\u003eAlthough subgroup analyses by gestational age may enhance data visualization, the present study focused on overall guideline-based eligibility in order to maintain consistency with its primary objective.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e This study was approved by the institutional ethics committee of HSU İzmir Dr. Beh\u0026ccedil;et Uz Children\u0026rsquo;s Diseases and Surgery Training and Research Hospital (Approval number 2023/901) (26/10/2023).\u0026nbsp;The study was conducted in accordance with the principles of the Declaration of Helsinki. As this was a retrospective study based on medical records, informed consent was waived by the ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). Continuous variables were assessed for normal distribution using the Shapiro\u0026ndash;Wilk test. Data were presented as mean \u0026plusmn; standard deviation or median (interquartile range), as appropriate. Categorical variables were expressed as numbers and percentages. Paired comparisons of phototherapy and exchange transfusion threshold values between the two guidelines were conducted using the Wilcoxon signed-rank test. Comparisons of hospi-talization and phototherapy durations across gestational age groups were performed us-ing the Kruskal\u0026ndash;Wallis test. A p-value \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 510 neonates admitted to the neonatal intensive care unit during the study period were initially screened. Of these, 100 neonates were excluded due to unavailable medical records and 66 did not meet the inclusion criteria. Consequently, 344 neonates born at \u0026ge;35 weeks of gestation and hospitalized solely due to indirect hyperbilirubinemia were included in the final analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.1 Baseline characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline demographic and clinical characteristics of the study population are presented in Table 1. The mean gestational age was 37.7 \u0026plusmn; 1.43 weeks and the mean birth weight was 3234.6 \u0026plusmn; 1372.5 g. Of the infants, 54.4% were male. The median postnatal age at admission for jaundice was 5 days. The mean total serum bilirubin level at initiation of treatment was 17.88 \u0026plusmn; 4.92 mg/dL. The mean duration of hospitalization was 4.46 \u0026plusmn; 3.21 days, and the mean duration of phototherapy was 17.52 \u0026plusmn; 10.87 hours.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Clinical and laboratory findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCategorical clinical and laboratory characteristics are summarized in Table 2. ABO incompatibility was present in 21.5% of neonates, while Rh incompatibility was observed in 6.1%. Direct Coombs test positivity was detected in 7.3% of cases. Glucose-6-phosphate dehydrogenase (G6PD) deficiency was identified in 9.7% of neonates. Blood culture positivity was detected in 2.6% of cases; these results were interpreted as contamination. Urinary tract infection was identified in 13.4% of infants. Exchange transfusion was performed in 2.0% of the study population. The majority of neonates (89.0%) were exclusively breastfed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Comparison of guideline thresholds\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePhototherapy and exchange transfusion threshold values according to the Turkish Neonatology Society (TNS) and the American Academy of Pediatrics (AAP) 2022 guidelines are presented in Table 3. The mean phototherapy threshold according to the TNS guideline was 15.83 \u0026plusmn; 2.46 mg/dL, whereas the mean threshold according to the AAP 2022 guideline was 19.61 \u0026plusmn; 2.31 mg/dL. This difference was statistically significant (p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003eSimilarly, the mean exchange transfusion threshold was 20.43 \u0026plusmn; 2.43 mg/dL according to the TNS guideline and 25.76 \u0026plusmn; 1.57 mg/dL according to the AAP 2022 guideline, also showing a statistically significant difference (p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003eThese mean threshold values represent the average of guideline-specific phototherapy or exchange transfusion thresholds individually calculated for each neonate at the time of admission, rather than a single uniform threshold applied to the entire cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Eligibility according to guideline thresholds\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 344 neonates admitted due to indirect hyperbilirubinemia, 307 infants (89.2%) met admission criteria according to the TNS guideline. In contrast, only 126 infants (36.6%) met admission criteria based on the AAP 2022 guideline. When eligibility was further evaluated according to gestational age, approximately 64.4% of hospitalized neonates did not have an indication for admission according to the AAP 2022 guideline.\u003c/p\u003e\n\u003cp\u003eThe distribution of major risk factors associated with bilirubin neurotoxicity is summarized in Table 4.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study compared phototherapy and exchange transfusion thresholds defined by the Turkish Neonatology Society (TNS) and the 2022 American Academy of Pediatrics (AAP) guidelines in neonates hospitalized for indirect hyperbilirubinemia. The main finding is the substantial difference between the two guidelines regarding treatment thresholds and admission indications. Both phototherapy and exchange transfusion thresholds were significantly higher when calculated according to the AAP 2022 guideline compared with the TNS guideline. This pattern was consistent across the entire study population and reflects the more conservative approach of the national guideline in comparison with the updated international recommendations [1,2,7].\u003c/p\u003e\n\u003cp\u003eA particularly notable observation is the marked discrepancy in eligibility according to guideline thresholds. While the majority of neonates admitted with indirect hyperbilirubinemia met admission criteria according to the TNS guideline, less than half fulfilled the criteria based on the AAP 2022 recommendations. Furthermore, when evaluated according to gestational age, approximately two-thirds of hospitalized neonates did not meet admission criteria under the AAP guideline. These findings suggest that guideline selection may significantly influence hospitalization practices in neonatal intensive care units (NICUs) [1,2,8]. Importantly, these differences primarily reflect the inherent structure and philosophy of the respective guidelines rather than evidence of clinical superiority. Thus, the clinical relevance of our findings lies in their potential impact on admission policies and care pathways rather than statistical differences alone.\u003c/p\u003e\n\u003cp\u003eNational hyperbilirubinemia guidelines have traditionally adopted a cautious approach, aiming to minimize the risk of bilirubin-induced neurological dysfunction (BIND) and kernicterus [9]. Given the potentially irreversible consequences of severe hyperbilirubinemia, earlier treatment initiation and lower intervention thresholds may be preferred to maximize neuroprotection [10]. However, this strategy may lead to increased phototherapy use and higher NICU admission rates, particularly in healthcare settings where structured outpatient follow-up is limited [11,12]. Some countries continue to use the NICE guideline, which also employs lower thresholds but does not explicitly incorporate neurotoxicity risk stratification [13].\u003c/p\u003e\n\u003cp\u003eIn contrast, the 2022 AAP guideline emphasizes individualized, risk-based decision-making, incorporating gestational age and specific neurotoxicity risk factors. Importantly, meeting treatment thresholds under the AAP guideline does not automatically mandate hospital admission, as close follow-up and clinical judgment are integral components of care. Therefore, our results should be interpreted as a comparison of guideline-based theoretical eligibility rather than an evaluation of real-time clinical decisions.\u003c/p\u003e\n\u003cp\u003eFollowing publication of the 2022 AAP guideline, several studies have reported real-world practice changes, including reductions in serum bilirubin testing, phototherapy utilization, and hospital admissions for neonatal jaundice [14\u0026ndash;17]. These findings support a shift toward more selective treatment approaches while emphasizing the importance of ongoing surveillance of safety outcomes.\u003c/p\u003e\n\u003cp\u003eOur study adds complementary evidence by quantifying how the application of AAP 2022 versus national guideline thresholds would alter theoretical eligibility for treatment and hospitalization in a tertiary pediatric referral hospital. The upward revision of treatment thresholds reflects accumulating data indicating that higher bilirubin levels can be safely tolerated in selected neonates under appropriate monitoring [18]. Available evidence suggests that implementation of higher thresholds has not been associated with increased bilirubin-related neurological complications.\u003c/p\u003e\n\u003cp\u003eDifferences between guidelines may also affect healthcare resource utilization. NICU admission is associated with increased healthcare costs, longer hospitalization, and separation of newborns from their families [19\u0026ndash;21]. In this context, our finding that a substantial proportion of admitted neonates would not have met AAP 2022 criteria highlights the potential influence of guideline selection on NICU workload and family-centered outcomes. Nevertheless, patient safety remains paramount, and any reduction in hospitalization should be accompanied by reliable monitoring and follow-up systems.\u003c/p\u003e\n\u003cp\u003eAlthough neurotoxicity risk factors were documented, the present study was not designed for risk-stratified subgroup analyses. Future multicenter studies incorporating standardized follow-up and outcome measures are needed to better clarify the interaction between guideline thresholds and individual risk profiles.\u003c/p\u003e\n\u003cp\u003eFrom a public health perspective, differences in treatment thresholds may influence admission patterns, NICU capacity, and neonatal care pathways. Real-world comparative data may support the development of risk-adapted admission strategies and optimized resource utilization while maintaining patient safety.\u003c/p\u003e\n\u003cp\u003eThis study has several strengths, including a relatively large sample size and the use of real-world clinical data from a tertiary NICU. However, limitations should be acknowledged. The retrospective, single-center design may limit generalizability. Long-term neurological outcomes, post-discharge follow-up, readmission rates, and rebound bilirubin levels were not evaluated. These parameters represent important areas for future prospective research aimed at assessing the real-world safety and effectiveness of guideline-based management strategies [22].\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study provides real-world comparative data on phototherapy and exchange transfusion thresholds according to the Turkish Neonatology Society and the 2022 American Academy of Pediatrics guidelines in neonates hospitalized for indirect hyperbilirubinemia. Substantial differences were identified between the two guidelines, with higher treatment thresholds and fewer theoretical admission indications when the updated international recommendations were applied. These findings should not be interpreted as evidence to support changes in clinical practice in the absence of outcome-based data. Rather, they represent real-life observations illustrating how different guideline frameworks may influence hospitalization decisions in pediatric referral centers.\u003c/p\u003e\n\u003cp\u003eOur results suggest that guideline selection may significantly affect hospitalization patterns in centers managing neonatal hyperbilirubinemia. These findings underscore the importance of critically evaluating guideline-based admission criteria within real-world clinical contexts and highlight the need for multicenter studies incorporating post-discharge follow-up and outcome assessment to further optimize neonatal jaundice management.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eConceptualization, S.A.O.; methodology, S.A.O.; data collection, D.K.; formal analysis, S.A.O. and D.K.; data interpretation, S.A.O., Ş.\u0026Ccedil;., and T.G.Y.; writing\u0026mdash;original draft preparation, D.K.; writing\u0026mdash;review and editing, S.A.O.; supervision, S.A.O. All authors have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement:.\u003c/strong\u003e The study was conducted in accordance with the Declaration of Helsinki and has received approval from the T.C. Ministry of Health, İzmir Provincial Health Directorate, H.S.U. İzmir Dr Beh\u0026ccedil;et Uz Children\u0026rsquo;s Diseases and Surgery Training and Research Hospital Clinical Research Ethics Committee (Approval number 2023/901) (26/10/2023).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration:\u003c/strong\u003eNot applicable. This study is a retrospective observational study based on existing medical records and does not involve prospective intervention or trial registration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u0026nbsp;\u003c/strong\u003eInformed consent was waived by the ethics committee due to the retrospective nature of the study and the use of anonymized data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003eThe data supporting the findings of this study are not publicly available due to ethical and privacy considerations related to patient data. However, anonymized datasets may be made available by the corresponding author upon reasonable request and subject to institutional approval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e The authors would like to thank the staff of the Neonatal Intensive Care Unit of HSU İzmir Dr. Beh\u0026ccedil;et Uz Children\u0026rsquo;s Diseases and Surgery Training and Research Hospital for their support during data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOkulu E, Erdeve \u0026Ouml;, Tuncer O, Ertuğrul S, \u0026Ouml;zdemir H, \u0026Ccedil;iftdemir NA, Zenciroğlu A, Atasay B. Exchange transfusion for neonatal hyperbilirubinemia: A multicenter, prospective study of Turkish Neonatal Society. Turk Arch Pediatr. 2021;56:121\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchwarts HP, Haberman BE, Rudy MR, Hyperbilirubinemia. Current guidelines and emerging therapies. Pediatr Emerg Care. 2011;27:884\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKemper AR, Newman TB, Slaughter JL, Maisels MBMJ, Watchko JF, Downs SM, Grout RW, Bundy DG, Stark AR, Bogen DL, et al. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2022;150:e2022058859. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1542/peds.2022-058859\u003c/span\u003e\u003cspan address=\"10.1542/peds.2022-058859\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297\u0026ndash;316.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u0026Ccedil;oban A, Kaynak T\u0026uuml;rkmen M, G\u0026uuml;rsoy T. Yenidoğan Sarılıklarında Yaklaşım, Izlem ve Tedavi Rehberi; T\u0026uuml;rk Neonatoloji Derneği Rehberleri: Ankara, T\u0026uuml;rkiye, 2022; ISBN: 978-605-68344-0-0.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhutani VK, Johnson LH, Keren R. Diagnosis and management of hyperbilirubinemia in the term neonate: For a safer first week. Pediatr Clin N Am. 2004;51:843\u0026ndash;61. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.pcl.2004.03.011\u003c/span\u003e\u003cspan address=\"10.1016/j.pcl.2004.03.011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin nomogram for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics \u003cem\u003e1999, 103, 6\u0026ndash;14.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1542/peds.103.1.6\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1542/peds.103.1.6\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaisels MJ, Phototherapy\u0026mdash;Traditional, Perinatol nontraditionalJ. 2001, \u003cem\u003e21, S93\u0026ndash;S97.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/sj.jp.7210642\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1038/sj.jp.7210642\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShapiro SM. Chronic bilirubin encephalopathy: Diagnosis and outcome. Semin. Fetal Neonatal Med. 2010;15:157\u0026ndash;63. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.siny.2009.12.004\u003c/span\u003e\u003cspan address=\"10.1016/j.siny.2009.12.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaisels MJ, Bhutani VK. Revised thresholds for neonatal hyperbilirubinemia. Pediatrics. 2022;150:e2022058858. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1542/peds.2022-058858\u003c/span\u003e\u003cspan address=\"10.1542/peds.2022-058858\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNewman TB, Liljestrand P, Jeremy RJ, Ferriero DM, Wu YW, Hudes ES, Escobar GJ. Outcomes among newborns with total serum bilirubin levels of 25 mg per deciliter or more. N Engl J Med. 2006;354:1889\u0026ndash;900. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMoa054244\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa054244\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuzniewicz MW, Wickremasinghe AC, Wu YW, McCulloch CE, Walsh EM, Wi S, Newman TB. Incidence, etiology, and outcomes of hazardous hyperbilirubinemia in newborns. Pediatr 2014, \u003cem\u003e134\u003c/em\u003e, 504\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1542/peds.2014-0987\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1542/peds.2014-0987\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNational Institute for Health and Care Excellence (NICE). \u003cem\u003eJaundice in Newborn Babies Under 28 Days\u003c/em\u003e; Clinical Guideline CG98; NICE: London, UK, 2023. Available online: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nice.org.uk/guidance/cg98\u003c/span\u003e\u003cspan address=\"https://www.nice.org.uk/guidance/cg98\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed on).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSarathy L, Chou JH, Giuseppina RC, Darci AK, Lerou PH. Bilirubin measurement and phototherapy use after the AAP 2022 Newborn Hyperbilirubinemia Guideline. Pediatrics 2024, 153, e2023063323. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1542/peds.2023-063323\u003c/span\u003e\u003cspan address=\"10.1542/peds.2023-063323\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJameel A, Richardson T, Slaughter JL. Impact of the 2022 AAP Guidelines on Neonatal Hyperbilirubinemia Admissions: A PHIS Study. Hosp Pediatr. 2025;15:537\u0026ndash;44. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1542/hpeds.2024-008205\u003c/span\u003e\u003cspan address=\"10.1542/hpeds.2024-008205\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDani C, Fusco M, Andreini M, Pepe G, Pratesi S. Implementation of the 2022 AAP guidelines for neonatal hyperbilirubinemia could reduce the need for phototherapy in Italy. Ital J Pediatr. 2025;51:162. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s13052-025-02002-x\u003c/span\u003e\u003cspan address=\"10.1186/s13052-025-02002-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNguyen EL, Joshi NS. Rapid Implementation of Updated Guidelines for Neonatal Hyperbilirubinemia. Hosp Pediatr. 2025;15:e309\u0026ndash;11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1542/hpeds.2024-008283\u003c/span\u003e\u003cspan address=\"10.1542/hpeds.2024-008283\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eProfit J, Gould JB, Zupancic JAF et al. Formal assessment of family-centered outcomes in neonatal intensive care. Pediatr 2017, 139, e20163475. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1542/peds.2016-3475\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1542/peds.2016-3475\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaisels MJ. Managing the jaundiced newborn: A persistent challenge. Can Med Assoc J. 2015, 187, 335\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohnson L, Bhutani VK. The clinical syndrome of bilirubin-induced neurologic dysfunction. Semin Perinatol. 2011;35:101\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO\u0026rsquo;Brien K, Robson K, Bracht M, Cruz M, Lui K, Alvaro R, da Silva O, Monterrosa L, Narvey M, Ng E, et al. Effectiveness of family integrated care in neonatal intensive care units on infant and parent outcomes: A multicentre, multinational, cluster-randomised controlled trial. Lancet Child Adolesc Health. 2018;2:245\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoșca I, Constantin AT, Popescu DE, Jura AMC, Miu A, Turenschi A. Are We Able to Prevent Neonatal Readmission? A Retrospective Analysis from a Pediatrics Department in Ploiești. Romania Med. 2024;60:705. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/medicina60050705\u003c/span\u003e\u003cspan address=\"10.3390/medicina60050705\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Neonatal hyperbilirubinemia, Phototherapy, Exchange transfusion, Clinical guidelines, Neonatal care, Hospital admission","lastPublishedDoi":"10.21203/rs.3.rs-8740481/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8740481/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background\n\nClinical management of neonatal indirect hyperbilirubinemia is guided by threshold-based recommendations for initiating phototherapy and exchange transfusion. Differences between national and international guidelines may lead to variability in treatment decisions and hospitalization practices. This retrospective, single-center study compared phototherapy and exchange transfusion thresholds according to the Turkish Neonatology Society (TNS) guideline and the 2022 American Academy of Pediatrics (AAP) guideline in neonates hospitalized for indirect hyperbilirubinemia.\n\nMethods\n\nThis single-center, retrospective cross-sectional study included neonates born at ≥35 weeks of gestation who were admitted to a neonatal intensive care unit solely due to indirect hyperbilirubinemia. Phototherapy and exchange transfusion thresholds were calculated according to both the TNS guideline and the 2022 AAP guideline. Eligibility for treatment and hospitalization according to guideline thresholds was compared between the two guidelines. Statistical analyses were performed using appropriate non-parametric tests.\n\nResults\n\nA total of 344 neonates were included in the analysis. Mean phototherapy and exchange transfusion thresholds were significantly higher according to the 2022 AAP guideline compared with the TNS guideline (p \u0026lt; 0.001 for both). While 89.2% of admissions met eligibility criteria according to national guideline thresholds, only 36.6% met admission criteria when assessed according to the 2022 AAP guideline.\n\nConclusions\n\nSubstantial differences exist between national and international guidelines for the management of neonatal indirect hyperbilirubinemia. These differences have a significant impact on treatment thresholds and hospitalization practices in clinical settings. Real-world comparative data may contribute to future evaluations and contextual adaptation of guideline-based management strategies.","manuscriptTitle":"Clinical Impact of Differences in Phototherapy and Exchange Transfusion Thresholds Between Turkish Neonatology Society and 2022 AAP Guidelines in Neonates with Indirect Hyperbilirubinemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-16 09:20:36","doi":"10.21203/rs.3.rs-8740481/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b20d33d1-1670-4693-907c-75d37891cce9","owner":[],"postedDate":"February 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-13T11:05:24+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-16 09:20:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8740481","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8740481","identity":"rs-8740481","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}