Severe neonatal hyperbilirubinaemia in European and Indian subcontinent descendent newborns: a retrospective cohort study

Severe neonatal hyperbilirubinaemia in European and Indian subcontinent descendent newborns: a retrospective cohort study | 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 Severe neonatal hyperbilirubinaemia in European and Indian subcontinent descendent newborns: a retrospective cohort study João Ferreira Simões, Margarida Simão, Paula Rocha, Sara Ferreira, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5133532/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Nov, 2024 Read the published version in European Journal of Pediatrics → Version 1 posted 8 You are reading this latest preprint version Abstract Purpose Neonatal hyperbilirubinaemia is more common in Asian-descendent populations but differences in disease severity are poorly reported. Our study aimed to compare neonatal hyperbilirubinaemia severity between European and Indian subcontinent descendent newborns. Methods We conducted a single-centre retrospective cohort study including newborns admitted with unconjugated hyperbilirubinaemia (January 2016 to December 2021). Patients were followed during admission, comparing those with European ancestry (control group) and Indian subcontinent ancestry (India, Pakistan, Bangladesh and Nepal) (study group). Primary outcome was severe hyperbilirubinemia (TSB > 25 mg/dL, phototherapy > 6 hours or need for exchange transfusion [ET]) and secondary was TSB levels. Adjusted analysis for potential confounding factors was performed using binary logistic regression models. Results Of 110 newborns included, 27 (24.5%) had Indian subcontinent ancestry. Occurrence of TSB > 25 mg/dL was significantly higher in the study group (22.2% vs 4.8%, p = 0.006), while no differences were noted in exposure to phototherapy > 6 hours and ET therapy. Logistic regression models for confounding factors adjustment showed Indian subcontinent ancestry as an independent risk factor for TSB > 25 mg/dL (OR 7.49, CI 95% [1.23–45.50]). The study group revealed also higher absolute values of TSB both at admission (22.0 mg/dL vs 19.6 mg/dL, p = 0.013) and discharge (13.6 mg/dL vs 11.4 mg/dL, p = 0.005). Conclusion Our findings suggest that newborns with Indian subcontinent ancestry might show higher risk for development of severe hyperbilirubinemia compared to European ancestry newborns. Implementing earlier treatment thresholds in this subset of patients may help prevent severe hyperbilirubinemia. Neonatal Hyperbilirubinemia Disease Severity Risk Factors Figures Figure 1 Figure 2 INTRODUCTION Neonatal unconjugated hyperbilirubinaemia is one of the most common reasons for hospitalization in the neonatal period, with reported incidences of 60% and 80% in term and preterm newborns, respectively [ 1 , 2 ]. Bilirubin high levels in newborns may result from increased haemoglobin production (hemolysis, polycythemia, sepsis), defects in conjugation (Crigler-Najjar syndrome, Gilbert syndrome, 5’-diphosphate-glucuronosyltransferase [UGT] polymorphisms), enterohepatic recirculation increase (breastfeeding, constipation) or decreased clearance (galactosaemia, hypothyroidism) [ 3 – 5 ]. Although, in most cases, it is a benign clinical picture, protein-unbound unconjugated bilirubin can cross the blood-brain barrier, where its deposition may lead to acute and/or chronic neurotoxicity. Bilirubin-induced neurologic dysfunction (BIND) spectrum encompasses a multitude of neurodevelopmental disorders, from mild to severe, including auditory deficits, language disorders, attention deficit hyperactivity disorder, specific learning disorder and cognitive delay [ 6 – 8 ]. Long-term neurological dysfunction may occur in the absence of acute encephalopathy, with higher levels of total serum bilirubin (TSB) (> 20–25 mg/dL) and/or prolonged exposure [ 2 , 9 ]. The American Academy of Pediatrics (AAP) published new guidelines in 2022 for management of neonatal hyperbilirubinaemia, defining new nomograms for hyperbilirubinaemia management and higher thresholds for phototherapy and exchange-transfusion (ET) therapy [ 10 ]. Neonatal unconjugated hyperbilirubinaemia incidence varies geographically, estimating 12% incidence among African ancestry newborns, 20% in European ancestry newborns and 49% in Asian ancestry newborns [ 11 , 12 ]. Several different genetic backgrounds have been linked to these asymmetric incidences, particularly involving UGT1A1 gene [ 1 , 13 – 15 ]. High-risk populations for hyperbilirubinaemia refer mainly to children from China, Japan and Phillipines, but data regarding newborns from the indian subcontinent (India, Pakistan, Bangladesh and Nepal) are scarce [ 11 , 16 ]. Moreover, studies largely address higher incidence but few describe differences in clinical severity [ 17 ]. This study aims to analyse the clinical outcomes of inpatients with neonatal unconjugated hyperbilirubinaemia comparing newborns from European and Indian subcontinent ancestry, including its severity. MATERIALS AND METHODS Design, setting and participants We conducted a retrospective, longitudinal, single-centre cohort study evaluating neonatal hyperbilirubinaemia severity in Lisbon, Portugal. Potentially eligible patients included newborns admitted due to indirect hyperbilirubinaemia (codified main diagnosis), while all patients with direct hyperbilirubinaemia (direct bilirubin > 1 mg/dL) were excluded. We compared clinical and laboratorial data from newborns of Indian subcontinent countries' ancestry (India, Nepal, Pakistan, and Bangladesh) (study group) with those of European ancestry (control group). Ancestry was assumed only by maternal nationality. Individuals considered were inpatients in the general paediatrics ward in a tertiary paediatric hospital in Lisbon, Portugal. Enrolled patients were selected during a six-year period, from January 2016 to December 2021. We used a consecutive sampling method. The total number of inpatients determined the sample size. Patients were followed since admission until discharge. Data collection occurred for 6 months, from January 2022 to June 2022. The study protocol was approved by the institutional review board and the ethics committee prior to data collection. Informed consent was waived by the ethical review board. We followed Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines for reporting. Outcomes and variables The primary outcome was a composite of severe hyperbilirubinaemia (defined by total bilirubin > 25 mg/dL or phototherapy > 6 hours or ET). As a secondary outcome, differences in total and direct bilirubin values at each moment of evaluation (admission and discharge) were compared between both groups. Relevant demographic, laboratorial and clinical variables were obtained through individual digital files consultation. Demographic variables considered were age at admission and at discharge, sex, maternal age and maternal nationality. In cases where mother’s nationality was not registered in the clinical record, the patient was excluded, in order to reduce bias induced by intuitive name interpretation. Laboratorial variables studied were TSB and direct bilirubin values at admission, peak values recorded during admission and discharge values, all considered as continuous variables. Data on intervention were also collected, both phototherapy (and its cumulative duration in hours) and/or ET. Clinical variables collected considered as potential confounding factors included gestational age (preterm, term or post term), birth route, birth weight (and its percentile for gestational age), simultaneous relevant diagnosis (sepsis, Rh and/or AB0 isoimunization and glucose 6-phosphate dehydrogenase deficiency), number of siblings (0, 1, 2 and 3 or more), feeding regimen (exclusive breastfeeding, exclusive formula or mixed regimen), maternal smoking habits, gestational diabetes and other familiar risk factors for hyperbilirubinaemia (siblings and/or parents with history of neonatal jaundice phototherapy during neonatal period, haemolytic anaemia or Gilbert’s syndrome). If suitable, genetic test results for UGT1A1 related mutations were also reported. Statistical analysis Categorical variables were reported using frequencies and percentages and continuous variables using means and standard deviation (SD), or median and interquartile range (IQR), when skewly distributed. Normality was tested using Kolmogorov-Smirnov and Shapiro-Wilk tests. Comparison across groups was performed using Chi-square tests for categorical data (Fishers’ when applicable) and T-tests or Mann-Whitney U for continuous data, whether normally or non-normally distributed. Missing data were handled using pairwise deletion method. Adjusted analysis was conducted using binary multivariate logistic regression, and the independent variables included in the model were previously chosen based on biological and clinical plausibility. Odds ratio (OR) and 95% confidence intervals (CI) for independent risk factors to develop severe hyperbilirubinaemia were reported. Statistical analysis was made using SPSS 28.0.1.0 for iOS (IBM SPSS Statistics) and STATA 14.1 IC for Windows (StataCorp LLC). We considered p value < 0.05 as statistically significant. RESULTS Demographic and clinical characteristics of the population From January 2016 to December 2021, a total of 126 newborns were admitted due to unconjugated hyperbilirubinaemia (Fig. 1 ). Of these, 16 were excluded due to non-European and non-Indian subcontinent ancestry, conjugated hyperbilirubinaemia or insufficient data. Of the remaining 110 patients included, 27 were in the study group (24.5%) and 83 in the control group (75.5%). Demographic and clinical variables of the total sample and both groups are detailed in Table 1 . Apart from patients’ age and gestational diabetes history, the remainder of the collected characteristics were not found to be statistically different between groups. The age at admission was found to be higher in the study group (8 days, IQR 6–14) than the control group (6 days, IQR 5–8) (p = 0.004). It was also found that the study group had a higher occurrence of gestational diabetes, with 22.2% (6/27) of the cases compared to 7.2% (6/83) in the control group (p = 0.03). Primary and secondary outcomes Severe hyperbilirubinaemia occurred in 20 of 27 (74.1%) patients in the study group and in 62 of 83 (74.7%) patients in the control group (p = 0.948) (Table 2 ). Considering each component of the composite outcome, there were no significant differences in exposure to phototherapy for more than 6 hours and ET therapy, but the occurrence of TSB > 25 mg/dL was significantly higher in the study group (6/27, 22.2%) comparing to the control group (4/83, 4.8%) (p = 0.006). After adjustment for confounding factors, Indian subcontinent ancestry predicted occurrence of TSB > 25 mg/dL (OR 7.49, CI 95% [1.23–45.50], p = 0.029) (Panel 1). Potential confounding factors considered were age at admission, sex, small for gestational age, prematurity, sepsis and family history of neonatal jaundice. Gestational diabetes was excluded from the model due to high risk of relation with TSB > 25 mg/dL, contributing to model multicollinearity. All cases with gestational diabetes in both groups had TSB < 25 mg/dL. In respect to secondary outcomes, the study group revealed significantly higher absolute values of TSB both at admission (22.0 mg/dL, IQR [18.7–24.0] vs. 19.6 mg/dL, IQR [18.0–21.4], p = 0.013) and discharge (13.6 mg/dL, IQR [10.9–14.6] vs. 11.4 mg/dL, IQR [10.0–12.6], p = 0.005). No significant differences were observed between groups irrespective of phototherapy exposure or absolute duration. Genetic study In our sample, 10 patients (9.1%) had genetic study performed regarding UGT1A1 gene (promotor and coding region), with 4 of them revealing alterations (Table 3 ). All those patients were in the study group and mutations identified were: TA6/7 heterozygotic allele (1 patient) and UGT1A1*6 variant (c.211 G > A) homozygotic variation (3 patients). These samples had enzymatic activity tested, with 1 patient (patient 2, UGT1A1*6 variant) showing decreased UGT activity. DISCUSSION In the present study, indian subcontinent maternal ancestry was associated with significantly higher risk of developing neonatal hyperbilirubinaemia with TSB > 25 mg/dL compared to European ancestry, maintained after adjustment for confounding factors (OR 6.97, CI 95% [1.15–42.24], p = 0.026). Our data suggests that these infants have increased risk for severe hyperbilirubinaemia. To our knowledge, this is the first study regarding hyperbilirubinaemia severity comparing neonates from European and Indian ancestry. Although clinical practice guidelines have been evolving towards a less interventive approach in neonatal hyperbilirubinaemia, levels of TSB > 25 mg/dL (427 mmol/L) are close to ET threshold in term-newborns older than 72 hours [ 10 ]. Whether a less interventive approach apply adequately to this subset of patients is still to answer. As mentioned earlier, severe hyperbilirubinaemia may contribute to long-term neurodevelopment impairment, with or without acute bilirubin encephalopathy [ 2 ]. In our sample, newborns from Indian subcontinent ancestry were older at admission, had longer hospital stay and higher levels of TSB (both at admission and discharge). We conjecture that those findings might have played a role in hyperbilirubinaemia severity. A study from Boo et al. also reports later diagnosis and age at admission as a risk factor for severe hyperbilirubinaemia [ 18 ]. Prior to the study, we conjectured that higher levels of bilirubin in one group would result in longer periods of phototherapy and higher rates of ET. Surprisingly, no differences were verified considering phototherapy duration and ET performance (Table 2 ). Concerning phototherapy, we found multiple electronic records to be incomplete. On the other hand, 6 of our patients reached ET threshold (like patient 4 from Table 3 ) but none had escalation of care. ET is a complex, expensive and resource-consuming technique, recommended by the AAP in cases of extreme hyperbilirubinaemia [ 10 ]. We think that factors like need for neonatal intensive care unit, inherent risks (like infection and haemorrhage) and high costs of ET might interfere with escalation of care. In fact, one study reported non-inferiority of intensive phototherapy compared to ET in treatment of extreme hyperbilirubinaemia [ 12 ]. Although it had a 3-year period follow-up after treatment, it was a retrospective cohort and not a randomized-controlled trial, enlightening many limitations that should not be ignored. To this date, AAP recommends ET as first-line therapy in extreme hyperbilirubinaemia and we found insufficient data supporting intensive phototherapy preference over ET in those cases [ 10 ]. Regarding the cause, many studies point out genetic polymorphisms as a base of higher incidence of hyperbilirubinaemia in Asian-descendent communities, particularly in countries like China, Japan and Philippines [ 11 , 18 ]. Most studies highlight genetic polymorphisms as the cause to hyperbilirubinaemia, mostly with mutations involving UGT1A1 and SLCO1B1 [ 1 ]. In our study, only a small subset of patients underwent genetic testing, four of them revealing genetic mutations (Table 3 ). One had promoter gene mutation (TA7/TA6 heterozygotic allele mutation) of uncertain clinical significance, and three others had c.211 G > A mutations (known for causing jaundice). Boo et al. mentioned previous reports mentioning a correlation between severe hyperbilirubinaemia and variations in UGT1A1, SLCO1B1 and glucose-6-phosphate dehydrogenase genes [ 18 ]. One case-control study from Yang et al. identified higher rate of c.211 G > A in UGT1A1 gene in neonates with severe hyperbilirubinaemia compared to controls without hyperbilirubinaemia, supporting our findings [ 15 ]. We acknowledge that genetic polymorphisms regarding bilirubin conjugation might play a significant role in hyperbilirubinaemia development. However, in our sample only one patient had a mutation with identified lower enzymatic activity (Table 3 ). Aside from better genetic characterization, other factors like maternal dietary habits, delayed healthcare admission or underrecognized clinical jaundice should be addressed in the future as they might influence severe hyperbilirubinaemia. Gestational diabetes was more frequent in the study group than the control group, although none presented TSB > 25 mg/dL. Higher incidence of both type 2 diabetes mellitus and gestational diabetes in the Indian population has already been reported [ 19 ]. As gestational diabetes is a known risk factor for neonatal hyperbilirubinaemia, in our sample it did not translate to increased clinical severity. Further research should address gestational diabetes role in hyperbilirubinaemia severity. Long-term follow-up data was unfortunately unavailable for most patients. We believe that prospective long-term follow-up data should help to clarify if newborns from Indian subcontinent ancestry are more susceptible to long-term neurodevelopmental compromise comparing to European ancestry newborns. Consequently, we propose two opposite research pathways in the future. If the study group reveals higher neurodevelopmental compromise, investigation should address more precocious treatment, careful pre and after-birth vigilance and neurodevelopmental intervention. However, if these higher TSB levels do not reflect in neurodevelopmental co-morbidity, overtreatment and over admission should be avoided, guiding research towards population-based adjusted thresholds for phototherapy and ET in this subset of patients. LIMITATIONS There are several limitations to report in the present study. First, the retrospective design led to incomplete information in health records. Although most data was available, certain records were missing details, including past personal and family history and phototherapy duration/modality. Furthermore, paternal nationality was not available in most records, making it impossible to include in the analysis and undermining both parent vs one parent ancestry impact on hyperbilirubinaemia. We believe that implementation of standardized daily registration including these data could help overcome those limitations. Secondly, the sample size was medium with uneven distribution between study and control groups (ratio approximately 1:3), possibly compromising data generalizability. Multicentric studies could allow more patients to be enrolled and produce more robust evidence. Finally, the absence of standardized follow-up data compromised long-term evaluation of neurological complications, which could be obtained by prospective studies. CONCLUSIONS In our retrospective cohort of patients, newborns from Indian subcontinent mothers were at higher risk of developing hyperbilirubinaemia > 25 mg/dL than European ancestry newborns (adjusted OR 7.49, CI 95% [1.23–45.50]). Severe hyperbilirubinaemia might lead to long-term neurological consequences, which if confirmed in this subset of patients in prospective studies, should lead to better pre and post-natal vigilance. If no long-term consequences are verified, more suitable phototherapy and ET thresholds should take place for this subset of patients, avoiding overtreatment and over admission. Abbreviations AAP American Academy of Pediatrics BIND Bilirubin–induced neurologic dysfunction CI confidence interval ET exchange transfusion IQR interquartile range OR odds ratio SD standard deviation STROBE Strengthening the Reporting of Observational studies in Epidemiology TSB total serum bilirubin UGT 5’–diphosphate–glucuronosyltransferase Declarations ACKNOWLEDGMENTS We additionally thank to Dr. Rute Baeta Baptista who contributed greatly for study planning and statistical analysis. CONTRIBUTORS STATEMENT João Ferreira Simões and Margarida Simão conceptualized the study design and conducted data collection, statistical analysis and interpretation. Paula Rocha, Sara Ferreira, Rosário Perry, Diana Amaral, Beatriz Costa and Mário Coelho provided advice to study design and contributed to data acquisition. All authors critically reviewed and revised the manuscript. All authors approved the final manuscript and agree to be accountable for all aspects of the work. AVAILABILITY OF DATA AND MATERIALS The data that support the findings of this study are available from the corresponding author upon reasonable request. COMPETING INTERESTS All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. FUNDING No funding was received for conducting this study. ETHICS APPROVAL This retrospective study was conducted on already available data and was previously approved by the Institutional Review Board and the Ethics Committee of Saint Joseph Health Local Unit ( Unidade Local de Saúde de São José ). 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Nat Rev Endocrinol 12:357–370. https://doi.org/10.1038/nrendo.2016.53 Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Published Journal Publication published 29 Nov, 2024 Read the published version in European Journal of Pediatrics → Version 1 posted Editorial decision: Revision requested 16 Oct, 2024 Reviews received at journal 15 Oct, 2024 Reviewers agreed at journal 06 Oct, 2024 Reviewers agreed at journal 03 Oct, 2024 Reviewers invited by journal 03 Oct, 2024 Editor assigned by journal 24 Sep, 2024 Submission checks completed at journal 24 Sep, 2024 First submitted to journal 22 Sep, 2024 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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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5133532","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":366844690,"identity":"74038e8e-ce97-4778-b9fa-a650ee35dff2","order_by":0,"name":"João Ferreira Simões","email":"data:image/png;base64,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","orcid":"","institution":"Unidade Local de Saúde São José","correspondingAuthor":true,"prefix":"","firstName":"João","middleName":"Ferreira","lastName":"Simões","suffix":""},{"id":366844691,"identity":"33c30aad-b59e-4c29-b2f8-f2122d8a3339","order_by":1,"name":"Margarida Simão","email":"","orcid":"","institution":"Unidade Local de Saúde São José","correspondingAuthor":false,"prefix":"","firstName":"Margarida","middleName":"","lastName":"Simão","suffix":""},{"id":366844692,"identity":"c124f294-2d2b-4041-a6ae-9418efcbfbbe","order_by":2,"name":"Paula Rocha","email":"","orcid":"","institution":"Unidade Local de Saúde São José","correspondingAuthor":false,"prefix":"","firstName":"Paula","middleName":"","lastName":"Rocha","suffix":""},{"id":366844693,"identity":"a91edcff-ae83-4e46-8876-1881d9d82002","order_by":3,"name":"Sara Ferreira","email":"","orcid":"","institution":"Unidade Local de Saúde São José","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Ferreira","suffix":""},{"id":366844694,"identity":"a2901bbe-1f8b-465d-9019-db2e4837e3d5","order_by":4,"name":"Rosário Perry","email":"","orcid":"","institution":"Unidade Local de Saúde São José","correspondingAuthor":false,"prefix":"","firstName":"Rosário","middleName":"","lastName":"Perry","suffix":""},{"id":366844695,"identity":"c6e3c8d4-d054-485e-99b3-f32a7d854946","order_by":5,"name":"Diana Amaral","email":"","orcid":"","institution":"Unidade Local de Saúde São José","correspondingAuthor":false,"prefix":"","firstName":"Diana","middleName":"","lastName":"Amaral","suffix":""},{"id":366844696,"identity":"3fb20613-ffde-44ad-b361-b8fa241eb223","order_by":6,"name":"Beatriz Costa","email":"","orcid":"","institution":"Unidade Local de Saúde São José","correspondingAuthor":false,"prefix":"","firstName":"Beatriz","middleName":"","lastName":"Costa","suffix":""},{"id":366844697,"identity":"98973dc9-337d-4003-a638-e2498389a511","order_by":7,"name":"Mário Coelho","email":"","orcid":"","institution":"Unidade Local de Saúde São José","correspondingAuthor":false,"prefix":"","firstName":"Mário","middleName":"","lastName":"Coelho","suffix":""}],"badges":[],"createdAt":"2024-09-22 17:45:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5133532/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5133532/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00431-024-05892-x","type":"published","date":"2024-11-29T15:57:19+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":68868788,"identity":"dc887d00-7185-4aa9-94ae-b5670bef439f","added_by":"auto","created_at":"2024-11-13 02:33:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":14538,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of inclusion and exclusion process.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePanel 1 – \u003c/strong\u003eLogistic regression models for hyperbilirubinaemia \u0026gt; 25 mg/dL, according to maternal descent.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5133532/v1/df6a607daf96b3222cc00385.png"},{"id":68868483,"identity":"5ac70d8c-4f52-4c45-bd9f-4ea1aae4b9ad","added_by":"auto","created_at":"2024-11-13 02:25:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":33350,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePanel 1\u003c/strong\u003e Logistic regression model for adjustment for confounding factors. In figure 2-A, it is represented crude and adjusted OR for TSB \u0026gt; 25 mg/dL according to Indian subcontinent ancestry. In figure 2-B, there is a graphic representation of each variable included in the final regression model, with respective OR and Confidence Intervals 95%.\u003c/p\u003e\n\u003cp\u003eCI 95%, confidence interval 95%; OR, odds ratio; SGA, small for gestational age.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5133532/v1/a3f198f1e9dbebbd3aa9e0af.png"},{"id":70382328,"identity":"4aaa2eac-383d-4025-892a-85d0b64e2994","added_by":"auto","created_at":"2024-12-02 16:25:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":411292,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5133532/v1/fa4b328e-15fd-4eef-ba10-da494e3b339a.pdf"},{"id":68868484,"identity":"46923f81-f7f3-4fab-aaa2-cc0d17c6dbe2","added_by":"auto","created_at":"2024-11-13 02:25:38","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":32894,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5133532/v1/e2808fa54d8bf28ce3c094a3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Severe neonatal hyperbilirubinaemia in European and Indian subcontinent descendent newborns: a retrospective cohort study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eNeonatal unconjugated hyperbilirubinaemia is one of the most common reasons for hospitalization in the neonatal period, with reported incidences of 60% and 80% in term and preterm newborns, respectively [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBilirubin high levels in newborns may result from increased haemoglobin production (hemolysis, polycythemia, sepsis), defects in conjugation (Crigler-Najjar syndrome, Gilbert syndrome, 5\u0026rsquo;-diphosphate-glucuronosyltransferase [UGT] polymorphisms), enterohepatic recirculation increase (breastfeeding, constipation) or decreased clearance (galactosaemia, hypothyroidism) [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Although, in most cases, it is a benign clinical picture, protein-unbound unconjugated bilirubin can cross the blood-brain barrier, where its deposition may lead to acute and/or chronic neurotoxicity. Bilirubin-induced neurologic dysfunction (BIND) spectrum encompasses a multitude of neurodevelopmental disorders, from mild to severe, including auditory deficits, language disorders, attention deficit hyperactivity disorder, specific learning disorder and cognitive delay [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Long-term neurological dysfunction may occur in the absence of acute encephalopathy, with higher levels of total serum bilirubin (TSB) (\u0026gt;\u0026thinsp;20\u0026ndash;25 mg/dL) and/or prolonged exposure [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The American Academy of Pediatrics (AAP) published new guidelines in 2022 for management of neonatal hyperbilirubinaemia, defining new nomograms for hyperbilirubinaemia management and higher thresholds for phototherapy and exchange-transfusion (ET) therapy [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNeonatal unconjugated hyperbilirubinaemia incidence varies geographically, estimating 12% incidence among African ancestry newborns, 20% in European ancestry newborns and 49% in Asian ancestry newborns [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Several different genetic backgrounds have been linked to these asymmetric incidences, particularly involving UGT1A1 gene [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. High-risk populations for hyperbilirubinaemia refer mainly to children from China, Japan and Phillipines, but data regarding newborns from the indian subcontinent (India, Pakistan, Bangladesh and Nepal) are scarce [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Moreover, studies largely address higher incidence but few describe differences in clinical severity [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study aims to analyse the clinical outcomes of inpatients with neonatal unconjugated hyperbilirubinaemia comparing newborns from European and Indian subcontinent ancestry, including its severity.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign, setting and participants\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective, longitudinal, single-centre cohort study evaluating neonatal hyperbilirubinaemia severity in Lisbon, Portugal. Potentially eligible patients included newborns admitted due to indirect hyperbilirubinaemia (codified main diagnosis), while all patients with direct hyperbilirubinaemia (direct bilirubin\u0026thinsp;\u0026gt;\u0026thinsp;1 mg/dL) were excluded. We compared clinical and laboratorial data from newborns of Indian subcontinent countries' ancestry (India, Nepal, Pakistan, and Bangladesh) (study group) with those of European ancestry (control group). Ancestry was assumed only by maternal nationality.\u003c/p\u003e \u003cp\u003eIndividuals considered were inpatients in the general paediatrics ward in a tertiary paediatric hospital in Lisbon, Portugal. Enrolled patients were selected during a six-year period, from January 2016 to December 2021. We used a consecutive sampling method. The total number of inpatients determined the sample size. Patients were followed since admission until discharge. Data collection occurred for 6 months, from January 2022 to June 2022.\u003c/p\u003e \u003cp\u003e The study protocol was approved by the institutional review board and the ethics committee prior to data collection. Informed consent was waived by the ethical review board. We followed Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines for reporting.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcomes and variables\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was a composite of severe hyperbilirubinaemia (defined by total bilirubin\u0026thinsp;\u0026gt;\u0026thinsp;25 mg/dL or phototherapy\u0026thinsp;\u0026gt;\u0026thinsp;6 hours or ET). As a secondary outcome, differences in total and direct bilirubin values at each moment of evaluation (admission and discharge) were compared between both groups.\u003c/p\u003e \u003cp\u003eRelevant demographic, laboratorial and clinical variables were obtained through individual digital files consultation. Demographic variables considered were age at admission and at discharge, sex, maternal age and maternal nationality. In cases where mother\u0026rsquo;s nationality was not registered in the clinical record, the patient was excluded, in order to reduce bias induced by intuitive name interpretation. Laboratorial variables studied were TSB and direct bilirubin values at admission, peak values recorded during admission and discharge values, all considered as continuous variables. Data on intervention were also collected, both phototherapy (and its cumulative duration in hours) and/or ET. Clinical variables collected considered as potential confounding factors included gestational age (preterm, term or post term), birth route, birth weight (and its percentile for gestational age), simultaneous relevant diagnosis (sepsis, Rh and/or AB0 isoimunization and glucose 6-phosphate dehydrogenase deficiency), number of siblings (0, 1, 2 and 3 or more), feeding regimen (exclusive breastfeeding, exclusive formula or mixed regimen), maternal smoking habits, gestational diabetes and other familiar risk factors for hyperbilirubinaemia (siblings and/or parents with history of neonatal jaundice phototherapy during neonatal period, haemolytic anaemia or Gilbert\u0026rsquo;s syndrome). If suitable, genetic test results for UGT1A1 related mutations were also reported.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were reported using frequencies and percentages and continuous variables using means and standard deviation (SD), or median and interquartile range (IQR), when skewly distributed. Normality was tested using Kolmogorov-Smirnov and Shapiro-Wilk tests. Comparison across groups was performed using Chi-square tests for categorical data (Fishers\u0026rsquo; when applicable) and T-tests or Mann-Whitney U for continuous data, whether normally or non-normally distributed. Missing data were handled using pairwise deletion method. Adjusted analysis was conducted using binary multivariate logistic regression, and the independent variables included in the model were previously chosen based on biological and clinical plausibility. Odds ratio (OR) and 95% confidence intervals (CI) for independent risk factors to develop severe hyperbilirubinaemia were reported. Statistical analysis was made using SPSS 28.0.1.0 for iOS (IBM SPSS Statistics) and STATA 14.1 IC for Windows (StataCorp LLC). We considered p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 as statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eDemographic and clinical characteristics of the population\u003c/h2\u003e\n \u003cp\u003eFrom January 2016 to December 2021, a total of 126 newborns were admitted due to unconjugated hyperbilirubinaemia (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Of these, 16 were excluded due to non-European and non-Indian subcontinent ancestry, conjugated hyperbilirubinaemia or insufficient data. Of the remaining 110 patients included, 27 were in the study group (24.5%) and 83 in the control group (75.5%).\u003c/p\u003e\n \u003cp\u003eDemographic and clinical variables of the total sample and both groups are detailed in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Apart from patients\u0026rsquo; age and gestational diabetes history, the remainder of the collected characteristics were not found to be statistically different between groups. The age at admission was found to be higher in the study group (8 days, IQR 6\u0026ndash;14) than the control group (6 days, IQR 5\u0026ndash;8) (p\u0026thinsp;=\u0026thinsp;0.004). It was also found that the study group had a higher occurrence of gestational diabetes, with 22.2% (6/27) of the cases compared to 7.2% (6/83) in the control group (p\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e\n \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003ePrimary and secondary outcomes\u003c/h2\u003e\n \u003cp\u003eSevere hyperbilirubinaemia occurred in 20 of 27 (74.1%) patients in the study group and in 62 of 83 (74.7%) patients in the control group (p\u0026thinsp;=\u0026thinsp;0.948) (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Considering each component of the composite outcome, there were no significant differences in exposure to phototherapy for more than 6 hours and ET therapy, but the occurrence of TSB\u0026thinsp;\u0026gt;\u0026thinsp;25 mg/dL was significantly higher in the study group (6/27, 22.2%) comparing to the control group (4/83, 4.8%) (p\u0026thinsp;=\u0026thinsp;0.006). After adjustment for confounding factors, Indian subcontinent ancestry predicted occurrence of TSB\u0026thinsp;\u0026gt;\u0026thinsp;25 mg/dL (OR 7.49, CI 95% [1.23\u0026ndash;45.50], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029) (Panel 1). Potential confounding factors considered were age at admission, sex, small for gestational age, prematurity, sepsis and family history of neonatal jaundice. Gestational diabetes was excluded from the model due to high risk of relation with TSB\u0026thinsp;\u0026gt;\u0026thinsp;25 mg/dL, contributing to model multicollinearity. All cases with gestational diabetes in both groups had TSB\u0026thinsp;\u0026lt;\u0026thinsp;25 mg/dL.\u003c/p\u003e\n \u003cp\u003eIn respect to secondary outcomes, the study group revealed significantly higher absolute values of TSB both at admission (22.0 mg/dL, IQR [18.7\u0026ndash;24.0] \u003cem\u003evs.\u003c/em\u003e 19.6 mg/dL, IQR [18.0\u0026ndash;21.4], p\u0026thinsp;=\u0026thinsp;0.013) and discharge (13.6 mg/dL, IQR [10.9\u0026ndash;14.6] \u003cem\u003evs.\u003c/em\u003e 11.4 mg/dL, IQR [10.0\u0026ndash;12.6], p\u0026thinsp;=\u0026thinsp;0.005). No significant differences were observed between groups irrespective of phototherapy exposure or absolute duration.\u003c/p\u003e\n \u003c/div\u003e\n \u003ch3\u003eGenetic study\u003c/h3\u003e\n \u003cp\u003eIn our sample, 10 patients (9.1%) had genetic study performed regarding UGT1A1 gene (promotor and coding region), with 4 of them revealing alterations (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). All those patients were in the study group and mutations identified were: TA6/7 heterozygotic allele (1 patient) and UGT1A1*6 variant (c.211 G\u0026thinsp;\u0026gt;\u0026thinsp;A) homozygotic variation (3 patients). These samples had enzymatic activity tested, with 1 patient (patient 2, UGT1A1*6 variant) showing decreased UGT activity.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn the present study, indian subcontinent maternal ancestry was associated with significantly higher risk of developing neonatal hyperbilirubinaemia with TSB\u0026thinsp;\u0026gt;\u0026thinsp;25 mg/dL compared to European ancestry, maintained after adjustment for confounding factors (OR 6.97, CI 95% [1.15\u0026ndash;42.24], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026). Our data suggests that these infants have increased risk for severe hyperbilirubinaemia. To our knowledge, this is the first study regarding hyperbilirubinaemia severity comparing neonates from European and Indian ancestry. Although clinical practice guidelines have been evolving towards a less interventive approach in neonatal hyperbilirubinaemia, levels of TSB\u0026thinsp;\u0026gt;\u0026thinsp;25 mg/dL (427 mmol/L) are close to ET threshold in term-newborns older than 72 hours [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Whether a less interventive approach apply adequately to this subset of patients is still to answer.\u003c/p\u003e \u003cp\u003eAs mentioned earlier, severe hyperbilirubinaemia may contribute to long-term neurodevelopment impairment, with or without acute bilirubin encephalopathy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In our sample, newborns from Indian subcontinent ancestry were older at admission, had longer hospital stay and higher levels of TSB (both at admission and discharge). We conjecture that those findings might have played a role in hyperbilirubinaemia severity. A study from Boo \u003cem\u003eet al.\u003c/em\u003e also reports later diagnosis and age at admission as a risk factor for severe hyperbilirubinaemia [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrior to the study, we conjectured that higher levels of bilirubin in one group would result in longer periods of phototherapy and higher rates of ET. Surprisingly, no differences were verified considering phototherapy duration and ET performance (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Concerning phototherapy, we found multiple electronic records to be incomplete. On the other hand, 6 of our patients reached ET threshold (like patient 4 from Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) but none had escalation of care. ET is a complex, expensive and resource-consuming technique, recommended by the AAP in cases of extreme hyperbilirubinaemia [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. We think that factors like need for neonatal intensive care unit, inherent risks (like infection and haemorrhage) and high costs of ET might interfere with escalation of care. In fact, one study reported non-inferiority of intensive phototherapy compared to ET in treatment of extreme hyperbilirubinaemia [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Although it had a 3-year period follow-up after treatment, it was a retrospective cohort and not a randomized-controlled trial, enlightening many limitations that should not be ignored. To this date, AAP recommends ET as first-line therapy in extreme hyperbilirubinaemia and we found insufficient data supporting intensive phototherapy preference over ET in those cases [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRegarding the cause, many studies point out genetic polymorphisms as a base of higher incidence of hyperbilirubinaemia in Asian-descendent communities, particularly in countries like China, Japan and Philippines [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Most studies highlight genetic polymorphisms as the cause to hyperbilirubinaemia, mostly with mutations involving UGT1A1 and SLCO1B1 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In our study, only a small subset of patients underwent genetic testing, four of them revealing genetic mutations (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). One had promoter gene mutation (TA7/TA6 heterozygotic allele mutation) of uncertain clinical significance, and three others had c.211 G\u0026thinsp;\u0026gt;\u0026thinsp;A mutations (known for causing jaundice). Boo \u003cem\u003eet al.\u003c/em\u003e mentioned previous reports mentioning a correlation between severe hyperbilirubinaemia and variations in UGT1A1, SLCO1B1 and glucose-6-phosphate dehydrogenase genes [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. One case-control study from Yang \u003cem\u003eet al.\u003c/em\u003e identified higher rate of c.211 G\u0026thinsp;\u0026gt;\u0026thinsp;A in UGT1A1 gene in neonates with severe hyperbilirubinaemia compared to controls without hyperbilirubinaemia, supporting our findings [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. We acknowledge that genetic polymorphisms regarding bilirubin conjugation might play a significant role in hyperbilirubinaemia development. However, in our sample only one patient had a mutation with identified lower enzymatic activity (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Aside from better genetic characterization, other factors like maternal dietary habits, delayed healthcare admission or underrecognized clinical jaundice should be addressed in the future as they might influence severe hyperbilirubinaemia. Gestational diabetes was more frequent in the study group than the control group, although none presented TSB\u0026thinsp;\u0026gt;\u0026thinsp;25 mg/dL. Higher incidence of both type 2 diabetes mellitus and gestational diabetes in the Indian population has already been reported [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. As gestational diabetes is a known risk factor for neonatal hyperbilirubinaemia, in our sample it did not translate to increased clinical severity. Further research should address gestational diabetes role in hyperbilirubinaemia severity.\u003c/p\u003e \u003cp\u003eLong-term follow-up data was unfortunately unavailable for most patients. We believe that prospective long-term follow-up data should help to clarify if newborns from Indian subcontinent ancestry are more susceptible to long-term neurodevelopmental compromise comparing to European ancestry newborns. Consequently, we propose two opposite research pathways in the future. If the study group reveals higher neurodevelopmental compromise, investigation should address more precocious treatment, careful pre and after-birth vigilance and neurodevelopmental intervention. However, if these higher TSB levels do not reflect in neurodevelopmental co-morbidity, overtreatment and over admission should be avoided, guiding research towards population-based adjusted thresholds for phototherapy and ET in this subset of patients.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eLIMITATIONS\u003c/h2\u003e \u003cp\u003eThere are several limitations to report in the present study. First, the retrospective design led to incomplete information in health records. Although most data was available, certain records were missing details, including past personal and family history and phototherapy duration/modality. Furthermore, paternal nationality was not available in most records, making it impossible to include in the analysis and undermining both parent vs one parent ancestry impact on hyperbilirubinaemia. We believe that implementation of standardized daily registration including these data could help overcome those limitations. Secondly, the sample size was medium with uneven distribution between study and control groups (ratio approximately 1:3), possibly compromising data generalizability. Multicentric studies could allow more patients to be enrolled and produce more robust evidence. Finally, the absence of standardized follow-up data compromised long-term evaluation of neurological complications, which could be obtained by prospective studies.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eIn our retrospective cohort of patients, newborns from Indian subcontinent mothers were at higher risk of developing hyperbilirubinaemia\u0026thinsp;\u0026gt;\u0026thinsp;25 mg/dL than European ancestry newborns (adjusted OR 7.49, CI 95% [1.23\u0026ndash;45.50]). Severe hyperbilirubinaemia might lead to long-term neurological consequences, which if confirmed in this subset of patients in prospective studies, should lead to better pre and post-natal vigilance. If no long-term consequences are verified, more suitable phototherapy and ET thresholds should take place for this subset of patients, avoiding overtreatment and over admission.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAAP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican Academy of Pediatrics\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBIND\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBilirubin\u0026ndash;induced neurologic dysfunction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eET\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eexchange transfusion\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eodds ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estandard deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSTROBE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStrengthening the Reporting of Observational studies in Epidemiology\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTSB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etotal serum bilirubin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUGT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e5\u0026rsquo;\u0026ndash;diphosphate\u0026ndash;glucuronosyltransferase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe additionally thank to Dr. Rute Baeta Baptista who contributed greatly for study planning and statistical analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONTRIBUTORS STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJo\u0026atilde;o Ferreira Sim\u0026otilde;es and Margarida Sim\u0026atilde;o conceptualized the study design and conducted data collection, statistical analysis and interpretation. Paula Rocha, Sara Ferreira, Ros\u0026aacute;rio Perry, Diana Amaral, Beatriz Costa and M\u0026aacute;rio Coelho provided advice to study design and contributed to data acquisition. All authors critically reviewed and revised the manuscript. All authors approved the final manuscript and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAVAILABILITY OF DATA AND MATERIALS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for conducting this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICS APPROVAL\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study was conducted on already available data and was previously approved by the Institutional Review Board and the Ethics Committee of Saint Joseph Health Local Unit (\u003cem\u003eUnidade Local de Sa\u0026uacute;de de S\u0026atilde;o Jos\u0026eacute;\u003c/em\u003e).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBentz MG, Carmona N, Bhagwat MM et al (2018) Beyond Asian: Specific East and Southeast Asian Races or Ethnicities Associated With Jaundice Readmission. 8:. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1542/hpeds.2017-0234\u003c/span\u003e\u003cspan address=\"10.1542/hpeds.2017-0234\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDas S, van Landeghem FKH (2019) Clinicopathological spectrum of bilirubin encephalopathy/kernicterus. 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Nat Rev Endocrinol 12:357\u0026ndash;370. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/nrendo.2016.53\u003c/span\u003e\u003cspan address=\"10.1038/nrendo.2016.53\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Neonatal Hyperbilirubinemia, Disease Severity, Risk Factors","lastPublishedDoi":"10.21203/rs.3.rs-5133532/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5133532/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eNeonatal hyperbilirubinaemia is more common in Asian-descendent populations but differences in disease severity are poorly reported. Our study aimed to compare neonatal hyperbilirubinaemia severity between European and Indian subcontinent descendent newborns.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a single-centre retrospective cohort study including newborns admitted with unconjugated hyperbilirubinaemia (January 2016 to December 2021). Patients were followed during admission, comparing those with European ancestry (control group) and Indian subcontinent ancestry (India, Pakistan, Bangladesh and Nepal) (study group). Primary outcome was severe hyperbilirubinemia (TSB\u0026thinsp;\u0026gt;\u0026thinsp;25 mg/dL, phototherapy\u0026thinsp;\u0026gt;\u0026thinsp;6 hours or need for exchange transfusion [ET]) and secondary was TSB levels. Adjusted analysis for potential confounding factors was performed using binary logistic regression models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf 110 newborns included, 27 (24.5%) had Indian subcontinent ancestry. Occurrence of TSB\u0026thinsp;\u0026gt;\u0026thinsp;25 mg/dL was significantly higher in the study group (22.2% \u003cem\u003evs\u003c/em\u003e 4.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006), while no differences were noted in exposure to phototherapy\u0026thinsp;\u0026gt;\u0026thinsp;6 hours and ET therapy. Logistic regression models for confounding factors adjustment showed Indian subcontinent ancestry as an independent risk factor for TSB\u0026thinsp;\u0026gt;\u0026thinsp;25 mg/dL (OR 7.49, CI 95% [1.23\u0026ndash;45.50]). The study group revealed also higher absolute values of TSB both at admission (22.0 mg/dL \u003cem\u003evs\u003c/em\u003e 19.6 mg/dL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013) and discharge (13.6 mg/dL \u003cem\u003evs\u003c/em\u003e 11.4 mg/dL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur findings suggest that newborns with Indian subcontinent ancestry might show higher risk for development of severe hyperbilirubinemia compared to European ancestry newborns. Implementing earlier treatment thresholds in this subset of patients may help prevent severe hyperbilirubinemia.\u003c/p\u003e","manuscriptTitle":"Severe neonatal hyperbilirubinaemia in European and Indian subcontinent descendent newborns: a retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-13 02:25:33","doi":"10.21203/rs.3.rs-5133532/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-16T15:06:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-15T20:29:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"260254762649163687848180005476744666743","date":"2024-10-06T06:29:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"145894143263242420891140781864275054630","date":"2024-10-03T11:20:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-03T07:43:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-24T23:59:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-24T23:56:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2024-09-22T17:43:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6a1d1619-9526-4b3a-9a92-dffc7ad657be","owner":[],"postedDate":"November 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-02T16:01:12+00:00","versionOfRecord":{"articleIdentity":"rs-5133532","link":"https://doi.org/10.1007/s00431-024-05892-x","journal":{"identity":"european-journal-of-pediatrics","isVorOnly":false,"title":"European Journal of Pediatrics"},"publishedOn":"2024-11-29 15:57:19","publishedOnDateReadable":"November 29th, 2024"},"versionCreatedAt":"2024-11-13 02:25:33","video":"","vorDoi":"10.1007/s00431-024-05892-x","vorDoiUrl":"https://doi.org/10.1007/s00431-024-05892-x","workflowStages":[]},"version":"v1","identity":"rs-5133532","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5133532","identity":"rs-5133532","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}