Assessing Risk for Hemolytic Hyperbilirubinemia in Newborns: Direct Antiglobulin Test versus End-tidal Carbon Monoxide

Assessing Risk for Hemolytic Hyperbilirubinemia in Newborns: Direct Antiglobulin Test versus End-tidal Carbon Monoxide | 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 Article Assessing Risk for Hemolytic Hyperbilirubinemia in Newborns: Direct Antiglobulin Test versus End-tidal Carbon Monoxide Juniper Burch, Ann Cheung, Nora Horick, Leela Sarathy This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9431741/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Objective Compare the direct antiglobulin test (DAT) in the setting of ABO incompatibility versus end-tidal carbon monoxide corrected for ambient carbon monoxide (ETCOc) to predict significant hyperbilirubinemia. Study Design: Prospective review of a convenience sample of 151 newborns admitted to the well newborn nursery who had ETCOc testing in addition to standard of care. Results The optimal ETCOc cutoff to predict a serum bilirubin meeting the neurotoxicity risk phototherapy threshold was 2.1 ppm. DAT had a sensitivity of 13% with specificity of 89% and ETCOc ≥ 2.1 ppm had a sensitivity of 88% with specificity of 68% to predict this outcome. Use of ETCOc ≥ 2.1 ppm rather than DAT to determine neurotoxicity risk increased indications for serum bilirubin testing (25% versus 18%) and phototherapy (8% versus 1%). Conclusion ETCOc ≥2.1 ppm had higher sensitivity but lower specificity than DAT to predict hyperbilirubinemia and resulted in increased indications for serum bilirubin testing and phototherapy. Health sciences/Health care/Diagnosis/Laboratory techniques and procedures Health sciences/Diseases/Haematological diseases Health sciences/Biomarkers/Predictive markers Health sciences/Risk factors Figures Figure 1 Figure 2 Introduction Hemolysis in the newborn, due to isoimmune hemolytic disease or other etiologies, is a primary risk factor for bilirubin induced neurologic dysfunction. 1 – 4 The American Academy of Pediatrics’ (AAP) Clinical Practice Guideline on hyperbilirubinemia gives specific recommendations on using the direct antiglobulin test (DAT) for infants of mothers with unknown or positive antibody screening and for infants receiving phototherapy. 1 Other methods of screening for hemolysis, such as blood typing for infants born to mothers with type O blood with DAT in cases of ABO incompatibility and use of end-tidal carbon monoxide corrected for ambient carbon monoxide (ETCOc) are considered optional and potentially useful, respectively. 1 A survey study found significant practice variation around screening for hemolysis with 63% of centers obtaining a DAT for all newborns. 5 Although widely used, prior studies have found DAT to have a sensitivity of 12–65% for significant hyperbilirubinemia, making it a poor screening test. 6 – 13 ETCOc has demonstrated a sensitivity for detecting hemolytic hyperbilirubinemia of 68–83%, 1415 but there is lack of consensus on which cutoff value should be used to indicate hemolysis with prior studies using values from 1.5–3.0 ppm. 3 , 4 , 14 , 16 , 17 There is also a question of which infants warrant screening with ETCOc; both targeted screening of infants with hyperbilirubinemia and universal screening methods have been tested. 16 – 18 The purpose of this study was threefold: 1) to determine the optimal ETCOc cutoff to predict a serum bilirubin meeting the neurotoxicity risk phototherapy threshold; 2) to compare the performance of DAT versus ETCOc in the prediction of significant hyperbilirubinemia; and 3) to compare rates of indication for serum bilirubin and phototherapy using DAT versus ETCOc to determine neurotoxicity risk. Methods We conducted a prospective feasibility study using a convenience sample of infants admitted to two level 1 newborn nurseries. Recruitment and data collection occurred between April – June 2025 during the birth hospitalization. Hospital guidelines at the time of the study included cord blood typing of infants of mothers with type O or Rh-negative blood or with a positive antibody screen and DAT for infants with ABO incompatibility. All infants were screened with transcutaneous bilirubin (TCB) and/or total serum bilirubin (TSB); late preterm and DAT positive infants were screened at 24 and 36 hours of life (HOL), other infants at 36 HOL or prior to discharge. TCB was recommended for first line screening with TSB per AAP guidelines if the TCB was within 3 mg/dL of the appropriate phototherapy threshold or ≥ 15 mg/dL. 1 Additional TCB and TSB measurements were obtained at provider discretion. All infants admitted to the newborn nurseries were eligible for inclusion. Pre-defined exclusion criteria included infants with a nasal deformity that did not fit the CoSenseⒸ nasal cannula for ETCOc testing. Infants were enrolled when the parent(s) gave verbal consent to ETCOc testing in addition to routine care as described above. Follow up was by electronic medical record review. A receiver operating characteristic curve was used to determine an optimal ETCOc value for the cohort. Two additional values were selected from the literature (≥ 1.7 ppm used by Bao et al. 14 and ≥ 2.5 ppm used by Wells et al. 17 ) for comparison. The primary outcome for sensitivity and specificity analysis was a TSB within 14 days of life that met or exceeded the neurotoxicity risk phototherapy threshold. The secondary outcomes were rates of indication for TSB and for phototherapy using the different methods to determine neurotoxicity risk (positive DAT and ETCOc using three different threshold values). Indication for TSB was determined by distance of the corresponding TCB from the appropriate phototherapy level per AAP guidelines; 1 infants were counted at most once as having an indication for TSB. Indication for phototherapy was based on a TSB during the birth hospitalization that met or exceeded the appropriate phototherapy threshold per the AAP 2022 guideline. 1 ETCOc measurements were obtained between 24–48 HOL or outside of this window if there was clinical concern for hyperbilirubinemia and the infant had not previously been tested. ETCOc testing was done with the CoSenseⒸ monitor and nasal cannulas (Capnia Inc, Foster City, CA) which has FDA 510(k) clearance. ETCOc results and hours of life at measurement were recorded for analysis only; results were not used to guide clinical care. Manual chart review determined gestational age, maternal blood type, infant blood type, DAT result if tested, TCB measurements, TSB measurements, treatment with phototherapy, and readmissions to the same hospital network within 14 days of birth for hyperbilirubinemia. Statistical analysis included generation of a receiver operating characteristic (ROC) curve for ETCOc values predicting the primary outcome and defined the optimal threshold as the value with the minimum Euclidean distance from the (0,1) point on the ROC curve, where both sensitivity and specificity are 100%. McNemar’s test was used to compare sensitivity and specificity between different methods for determining neurotoxicity risk. The Student’s t-test was used to compare continuous data and Chi square test for categorical data. A significance level of p < .05 was used for all analyses without adjustment for multiple comparisons due to the exploratory nature of the study. Statistical analyses were completed using R (Version 2025.05.1 + 513) 19 , Microsoft Excel (version 16.98, Redmond, WA), and SAS (version 9.4, Carey, NC). This study was approved by our Institutional Review Board. Results Ninety-eight percent of families approached consented to ETCOc testing (n = 151/154) and ETCOc results were obtained in all 151 consented infants. Characteristics of the study population are shown in Table 1 . The median gestational age was 39 weeks (IQR 38–40). Seventeen infants (11%) were DAT positive, 21 (14%) were DAT negative, and 113 (75%) did not have a DAT. Of the 38 infants who had a DAT, 33 were tested due to ABO incompatibility and 5 received a DAT although there was no blood type incompatibility. There were no mothers with positive antibody screens except secondary to Rho(D) immune globulin administration during pregnancy. The mean ETCOc was 2.0 (± 0.7) ppm with a median of 1.9 ppm (IQR 1.6–2.3). Median HOL at time of ETCOc testing was 31 (IQR 25–38). Table 1 Characteristics of study participants (n = 151) Rh = Rhesus, RhIG = Rhesus immune globulin Characteristic n % Gestational age 35 weeks 1 1 36 weeks 11 7 37 weeks 17 11 38 weeks 32 21 39 weeks 48 32 40 weeks 28 19 41 weeks 14 9 Maternal blood type O 78 52 A 39 26 B 23 15 AB 11 7 Rh positive 132 87 Rh negative 19 13 Maternal antibody screen Negative 145 96 Positive due to RhIG 6 4 Positive not due to RhIG 0 0 Infant blood type O 46 31 A 27 18 B 10 7 AB 2 1 Not tested 66 43 Rh positive 72 85 Rh negative 13 15 Figure 1 shows the receiver operating curve of ETCOc for predicting a TSB at or above the neurotoxicity risk phototherapy threshold; the optimal ETCOc cutoff was 2.1 ppm. Table 2 shows the ability of DAT and ETCOc thresholds of ≥ 1.7 ppm, ≥ 2.1 ppm, and ≥ 2.5 ppm to predict a TSB meeting the neurotoxicity risk phototherapy threshold. The sensitivity of DAT was significantly lower than ETCOc ≥1.7 ppm ( p < .001), ETCOc ≥ 2.1 ppm ( p = .001), and ETCOc ≥ 2.5 ppm ( p = .01). The specificity of DAT was significantly higher than ETCOc ≥ 1.7 ppm ( p < .001) and ETCOc ≥ 2.1 ppm ( p < .001), but not for ETCOc ≥ 2.5 ppm ( p = .18). There was not a significant association between positive DAT and having a TSB meeting the neurotoxicity risk phototherapy threshold ( p = .75). There was a significant difference in mean ETCOc values for infants who had a TSB reaching the neurotoxicity risk phototherapy threshold (2.8 versus 1.9 ppm, p = .007). Table 2 Ability of DAT and ETCOc to predict a TSB meeting the neurotoxicity risk phototherapy threshold DAT = direct antiglobulin test, ETCOc = end tidal carbon monoxide corrected for ambient carbon monoxide, NPV = negative predictive value, PPV = positive predictive value Cutoff for NT risk (n = 151) Sensitivity Specificity PPV NPV DAT+ 12.5% 88.9% 11.8% 89.6% ETCO ≥ 1.7 ppm 100.0% 37.0% 15.8% 100.0% ETCO ≥ 2.1 ppm 87.5% 68.1% 24.6% 97.9% ETCO ≥ 2.5 ppm 50.0% 84.4% 27.6% 93.4% Figure 2 shows how indication for TSB and phototherapy changed for the full cohort depending on whether positive DAT, ETCOc ≥ 1.7 ppm, ETCOc ≥ 2.1 ppm, or ETCOc ≥ 2.5 ppm was used to determine neurotoxicity risk. Figure 2 also includes the actual number of infants who had one or more TSB measurements (n = 35) and who were treated with phototherapy (n = 14) during the birth hospitalization. For infants who received a TSB during the birth hospitalization there was no significant association with positive DAT ( p = .57) or a significant difference in ETCOc values (1.9 ppm versus 2.0 ppm, p = .20). For the 35 infants who received a TSB, it was indicated when using DAT to determine neurotoxicity risk in 27 (77%) and when using ETCOc ≥ 2.1 ppm in 29 (83%). For infants who received birth hospitalization phototherapy there was a significant association with positive DAT ( p = .002) and a significant difference in mean ETCOc values (2.9 ppm versus 1.9 ppm, p = .01). When using DAT to determine neurotoxicity risk, 12 infants (86%) were starting on phototherapy at a TSB below the AAP recommended threshold. When using ETCOc ≥ 2.1 ppm to determine neurotoxicity risk, four infants (29%) were starting on phototherapy at a TSB below the AAP recommended threshold. Five infants in the full cohort were readmitted for phototherapy within 14 days of birth. None of the readmitted infants were DAT positive. There was no difference in mean ETCOc between patients who were readmitted for phototherapy and those who were not (2.2 ppm versus 2.0 ppm, p = .55). Discussion This study compared the ability of DAT (for infants with ABO incompatibility) versus ETCOc (for any infant) to predict significant hyperbilirubinemia and evaluated the clinical effect of each method of assessing neurotoxicity risk. ETCOc testing was acceptable to parents and feasible to perform in the well newborn nursery. An ETCOc cutoff of ≥ 2.1 ppm was optimal for predicting a TSB meeting or exceeding the neurotoxicity risk phototherapy threshold. ETCOc ≥ 2.1 ppm had higher sensitivity when compared with DAT (87.5% versus 12.5%) but was less specific (68.1% versus 88.9%) and resulted in increased indications for TSB (25% versus 18%) and phototherapy (9% versus 1%). An ETCOc cutoff of ≥ 2.1 ppm is in the middle of the range of ETCOc cutoffs used in prior studies 3 , 4 , 14 , 16 , 17 and balances the benefit of detecting infants at risk (sensitivity 88%) with the potential for overdiagnosis (specificity of 68%). ETCOc ≥ 1.7 ppm overclassified infants as being at risk for hyperbilirubinemia with a sensitivity of 100% and specificity of only 37%, while ETCOc ≥ 2.5 ppm missed detection of infants with hyperbilirubinemia with a sensitivity of 50% but had improved specificity of 84%. All ETCOc thresholds analyzed had improved sensitivity over DAT, though DAT was more specific. Our findings are consistent with prior literature showing that DAT is not an ideal screening test and is of limited utility in predicting significant hyperbilirubinemia in newborns with ABO incompatibility alone, but support use of DAT as diagnostic tool in cases of significant hyperbilirubinemia. 121020 The higher sensitivity of ETCOc should be considered in light of its potential to increase interventions. The specificity of ETCOc ≥ 2.1 ppm of 68.1% suggests that it may over classify some infants as having a neurotoxicity risk factor, resulting in use of lower thresholds for TSB measurement and phototherapy. When analyzed retrospectively, use of ETCOc ≥ 2.1 ppm compared to DAT to determine neurotoxicity risk would have increased the indication for TSB and for phototherapy. In our convenience sample, the percentage of infants who received TSB measurements (23%) was more similar to the percentage indicated by ETCOc ≥ 2.1 ppm (25%) than indicated by DAT (18%). The same was true for phototherapy with 9% of the cohort receiving phototherapy compared to 8% indicated by ETCOc ≥ 2.1 ppm and 1% indicated by DAT. However, not all TSBs measurements that occurred were concordant with AAP guidelines and phototherapy was frequently started at subthreshold levels. A prior study (which included our institution) found that only 30.8% of TSBs were sent according to AAP guidelines and 63% of phototherapy was initiated below the recommended threshold. 21 While subthreshold phototherapy has been shown to decrease readmissions, it also increases length of birth hospital stay and results in overtreatment. 22 Unfortunately, prior studies have not found DAT or ETCOc to be helpful in predicting readmissions for phototherapy. 2324 We similarly found that no DAT positive infants were readmitted and there was no significant difference in mean ETCOc values between infants who were and were not readmitted. While use of ETCOc will likely identify more infants with a potential risk of hemolysis, resulting in more TSB measurements and phototherapy, more study is needed to determine if this identification would prevent escalation of care for or complications of hyperbilirubinemia. Finally, the question remains on which infants to screen for hemolysis. The AAP clinical practice guideline does not recommend universal screening with DAT or with other methods of detecting hemolysis if appropriate bilirubin surveillance and follow up are ensured. 1 Our findings support the lack of utility of routinely obtaining DAT for infants with ABO incompatibility alone given its poor ability to predict hyperbilirubinemia. 12 , 20 , 23 While every infant in our sample received ETCOc testing, we did not find that the ETCOc results would have changed management when the first TCB or TSB was low. This is consistent with prior literature showing that, for example, an infant with a TSB 3–4 mg/dl below the phototherapy threshold has only a 5% chance of ever exceeding the phototherapy threshold. 25 Evaluating for hemolysis only in infants with a clinical concern for hyperbilirubinemia that may require treatment is likely the highest value use of either DAT or ETCOc. This study has several limitations. The cohort was a small, convenience sample from two level 1 newborn nurseries within the same hospital network and results may not be generalizable to other institutions or patient populations. Enrollment was biased towards infants with a positive DAT (11% of the cohort versus a previously published rate of 7.1% 21 ) or hyperbilirubinemia (9% of the cohort received phototherapy versus a previously published rate of 2.1%) 21 Therefore, our cohort is not reflective of universal screening in a well newborn nursery, but rather of a higher-than-average risk sample, and as such may overestimate the predictive ability of ETCOc. Data collection was by retrospective chart review of the infants that underwent ETCOc testing and analysis was based on indication for TSB and phototherapy at threshold, making comparisons to real world practice challenging. Infants who were started on subthreshold phototherapy may have achieved the primary outcome of a TSB meeting the phototherapy threshold if phototherapy had not been started. Follow up was limited to those infants who presented within our hospital network; readmissions to outside hospitals were not captured. In conclusion, in our high-risk convenience sample we found ETCOc to be superior to DAT in predicting hyperbilirubinemia, however its application would have increased indications for TSB and phototherapy. Our findings support the AAP’s position that universal bilirubin screening is sufficient for detecting infants at risk for severe hyperbilirubinemia if appropriate follow up is ensured and as such universal testing for hemolysis is unlikely to provide further clinical benefit. Further study is needed to determine if use of either DAT or ETCOc improves management in infants with known hyperbilirubinemia or if trending bilirubin levels alone is sufficient to prevent the severe, yet rare, complication of bilirubin induced neurologic dysfunction. Abbreviations AAP American Academy of Pediatrics DAT direct antiglobulin test ETCOc end-tidal carbon monoxide corrected for ambient carbon monoxide HOL hours of life IQR interquartile range NPV negative predictive value PPV positive predictive value ROC receiver operating characteristic TCB transcutaneous bilirubin TSB total serum bilirubin Declarations Competing Interests: The authors have no conflicts of interest to disclose. Funding: Data analysis for this study was supported by a Mass General Brigham for Children (MGBfC), Department of Pediatrics micro-grant. Equipment for this study was provided by Capnia, Inc. MGBfC and Capnia Inc. had no role in the design and conduct of the study. Author contributions: Dr. Juniper Burch conceptualized and designed the study, designed the data collection tool, collected data, carried out the initial analyses, drafted the initial manuscript, and critically reviewed and revised the manuscript. Drs. Ann Cheung and Leela Sarathy assisted in study design, collected data, and critically reviewed and revised the manuscript. Ms. Nora Horick carried out final data analyses and critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Acknowledgments: Thank you to Drs. Lowell Fox and Mellory Kaserman for their assistance with study design and data collection. References Kemper AR, Newman TB, Slaughter JL, et al. CLINICAL PRACTICE GUIDELINE Guidance for the Clinician in Rendering Pediatric Care Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation FROM THE AMERICAN ACADEMY OF PEDIATRICS . Vol 150. 2022. http://publications.aap.org/pediatrics/article-pdf/150/3/e2022058859/1561263/peds_2022058859.pdf Alkén J, Håkansson S, Ekéus C, Gustafson P, Norman M. Rates of Extreme Neonatal Hyperbilirubinemia and Kernicterus in Children and Adherence to National Guidelines for Screening, Diagnosis, and Treatment in Sweden. JAMA Netw Open . 2019;2(3):e190858. doi: 10.1001/jamanetworkopen.2019.0858 Bhutani VK, Srinivas S, Castillo Cuadrado ME, Aby JL, Wong RJ, Stevenson DK. Identification of neonatal haemolysis: An approach to predischarge management of neonatal hyperbilirubinemia. Acta Paediatrica, International Journal of Paediatrics . 2016;105(5):e189-e194. doi: 10.1111/apa.13341 Bhutani VK, Maisels MJ, Schutzman DL, et al. Identification of risk for neonatal haemolysis. Acta Paediatrica, International Journal of Paediatrics . 2018;107(8):1350–1356. doi: 10.1111/apa.14316 Leeds H, Gievers L, Tyrrell H, et al. Variability in Screening and Management of Hyperbilirubinemia Across US Hospitals: A BORN Study. Hosp Pediatr . Published online January 8, 2026. doi: 10.1542/hpeds.2025-008553 Alkhater SA, Albalwi RA, Alomar SA, et al. Value of the direct Antiglobulin test in predicting the need for phototherapy in Newborns. J Blood Med . 2021;12:53–61. doi: 10.2147/JBM.S291606 Mehta R, Petrova A. Direct antiglobulin test in the prediction of hyperbilirubinemia and predischarge bilirubin levels in infants with mother-infant blood type incompatibility. Pediatr Neonatol . 2021;62(4):406–411. doi: 10.1016/j.pedneo.2021.04.002 Elsaie AL, Taleb M, Nicosia A, et al. Comparison of end-tidal carbon monoxide measurements with direct antiglobulin tests in the management of neonatal hyperbilirubinemia. Journal of Perinatology . 2020;40(10):1513–1517. doi: 10.1038/s41372-020-0652-y Herschel M, Karrison T, Wen M, Caldarelli L, Baron B. Evaluation of the direct antiglobulin (coombs’) test for identifying newborns at risk for hemolysis as determined by end-tidal carbon monoxide concentration (ETCOc); and comparison of the coombs’ test with ETCOc for detecting significant jaundice. Journal of Perinatology . 2002;22(5):341–347. doi: 10.1038/sj.jp.7210702 Wainer S, Rabi J, Lyon M. Coombs’ testing and neonatal hyperbilirubinemia [5]. CMAJ Canadian Medical Association Journal . Canadian Medical Association . 2007;176(7):972–973. doi: 10.1503/cmaj.1060214 Dinesh D. Review of positive direct antiglobulin tests found on cord blood sampling. J Paediatr Child Health . 2005;41(9–10):504–507. doi: 10.1111/j.1440-1754.2005.00692.x Kumar Krishnegowda V, Ramaswamy VV, Abiramalatha T, Bandyopadhyay T, S AKP, Kannan Loganathan P. Direct antiglobulin test for the prediction of neonatal hyperbilirubinemia needing an intervention: a systematic review and diagnostic test accuracy meta-analysis. Front Pediatr . Frontiers Media SA . 2024;12. doi: 10.3389/fped.2024.1475623 Abbas SA, Dinardo CL, Godinho CH, et al. Direct antiglobulin test in the differential diagnosis of ABO hemolytic disease of the newborn: an important tool with high negative predictive value. Hematol Transfus Cell Ther . 2024;46(4):450–454. doi: 10.1016/j.htct.2024.03.001 Bao Y, Zhu J, Ma L, et al. An End-Tidal Carbon Monoxide Nomogram for Term and Late-Preterm Chinese Newborns. Journal of Pediatrics . 2022;250:16–21.e3. doi: 10.1016/j.jpeds.2022.07.003 Cheng X, Lin B, Yang Y, Yu Y, Fu Y, Yang C. End-tidal carbon monoxide concentrations measured within 48 hours of birth predict hemolytic hyperbilirubinemia. Journal of Perinatology . 2024;44(6):897–901. doi: 10.1038/s41372-024-01967-7 Bahr TM, Shakib JH, Stipelman CH, Kawamoto K, Lauer S, Christensen RD. Improvement Initiative: End-Tidal Carbon Monoxide Measurement in Newborns Receiving Phototherapy. Journal of Pediatrics . 2021;238:168–173.e2. doi: 10.1016/j.jpeds.2021.07.008 Wells S, Balasubramanian R, Nguyen K, Schutzman DL. End-tidal carbon monoxide for routine monitoring of significant hemolysis in the management of newborn hyperbilirubinemia. Journal of Perinatology . Published online 2025. doi: 10.1038/s41372-025-02242-z Yang G, Deng L, Zhang K, et al. End-tidal CO corrected for ambient CO risk adjusted phototherapy threshold for the management of neonatal hyperbilirubinemia: a randomized clinical trial. World Journal of Pediatrics . Published online August 4, 2025. doi: 10.1007/s12519-025-00954-y R Core Team (2024). _R: A Language and Environment for Statistical Computing_. R Foundation for Statistical Computing, Vienna, Austria. < https://www.R-project.org/%3E . Testing C’, Leistikow EA, Collin MF, et al. Wasted Health Care Dollars . Sarathy L, Chou JH, Romano-Clarke G, Darci KA, Lerou PH. Bilirubin Measurement and Phototherapy Use After the AAP 2022 Newborn Hyperbilirubinemia Guideline. Pediatrics . 2024;153(4). doi: 10.1542/peds.2023-063323 Wickremasinghe AC, Kuzniewicz MW, McCulloch CE, Newman TB. Efficacy of subthreshold newborn phototherapy during the birth hospitalization in preventing readmission for phototherapy. JAMA Pediatr . 2018;172(4):378–385. doi: 10.1001/jamapediatrics.2017.5630 Madan A, Huntsinger K, Burgos A, Benitz WE. Readmission for newborn jaundice: the value of the Coombs’ test in predicting the need for phototherapy. Clin Pediatr (Phila) . 2004;43(1):63–68. doi: 10.1177/000992280404300108 Maisels MJ, Kring EA, Coffey MP. Heme Catabolism and Bilirubin Production in Readmitted Jaundiced Newborns. Journal of Pediatrics . 2020;226:285–288. doi: 10.1016/j.jpeds.2020.06.012 Kuzniewicz MW, Park J, Niki H, Walsh EM, McCulloch CE, Newman TB. Predicting the need for phototherapy after discharge. Pediatrics . 2021;147(5). doi: 10.1542/peds.2020-019778 Additional Declarations There is NO conflict of interest to disclose. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 01 May, 2026 Review # 1 received at journal 27 Apr, 2026 Review # 2 received at journal 20 Apr, 2026 Reviewer # 2 agreed at journal 20 Apr, 2026 Reviewer # 1 agreed at journal 19 Apr, 2026 Reviewers invited by journal 19 Apr, 2026 Submission checks completed at journal 16 Apr, 2026 Editor assigned by journal 15 Apr, 2026 First submitted to journal 15 Apr, 2026 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-9431741","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":625749948,"identity":"9f45cdf1-0751-4cd3-aed3-2e5e5161da9e","order_by":0,"name":"Juniper 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Horick","email":"","orcid":"https://orcid.org/0000-0002-4355-5853","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Nora","middleName":"","lastName":"Horick","suffix":""},{"id":625749951,"identity":"81100181-1721-4ab8-a7a6-002074a557ab","order_by":3,"name":"Leela Sarathy","email":"","orcid":"https://orcid.org/0009-0001-0934-1376","institution":"Mass General Brigham for Children","correspondingAuthor":false,"prefix":"","firstName":"Leela","middleName":"","lastName":"Sarathy","suffix":""}],"badges":[],"createdAt":"2026-04-16 01:10:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9431741/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9431741/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107932681,"identity":"9d00d3dc-ee7a-430b-83a7-a4f75db9dc3d","added_by":"auto","created_at":"2026-04-27 16:55:25","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":241757,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eReceiver operating characteristic curve with the optimal threshold for ETCOc to predict a serum bilirubin meeting the neurotoxicity risk phototherapy threshold\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eETCOc = end-tidal carbon monoxide corrected for ambient carbon monoxide\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9431741/v1/10522dea3d2f750d233f1a02.jpg"},{"id":107932716,"identity":"0f0ca02c-fa9a-46b4-a620-72666c4f96b5","added_by":"auto","created_at":"2026-04-27 16:55:41","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":344358,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRates of indication for and receipt of serum bilirubin and phototherapy during the birth hospitalization using different methods of determining neurotoxicity risk (N = 151)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDAT = direct antiglobulin test, ETCOc = end-tidal carbon monoxide corrected for ambient carbon monoxide, PTX = phototherapy, TSB = total serum bilirubin\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9431741/v1/bf4d6505937eb80697ad58b5.jpg"},{"id":107932751,"identity":"4d6c8007-b02d-4b95-9cc9-9298df8ad1a4","added_by":"auto","created_at":"2026-04-27 16:55:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":864755,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9431741/v1/fdea6d91-dcf1-4afc-a792-5b94467cad4a.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Assessing Risk for Hemolytic Hyperbilirubinemia in Newborns: Direct Antiglobulin Test versus End-tidal Carbon Monoxide","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHemolysis in the newborn, due to isoimmune hemolytic disease or other etiologies, is a primary risk factor for bilirubin induced neurologic dysfunction.\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The American Academy of Pediatrics\u0026rsquo; (AAP) Clinical Practice Guideline on hyperbilirubinemia gives specific recommendations on using the direct antiglobulin test (DAT) for infants of mothers with unknown or positive antibody screening and for infants receiving phototherapy.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Other methods of screening for hemolysis, such as blood typing for infants born to mothers with type O blood with DAT in cases of ABO incompatibility and use of end-tidal carbon monoxide corrected for ambient carbon monoxide (ETCOc) are considered optional and potentially useful, respectively.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e A survey study found significant practice variation around screening for hemolysis with 63% of centers obtaining a DAT for all newborns.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAlthough widely used, prior studies have found DAT to have a sensitivity of 12\u0026ndash;65% for significant hyperbilirubinemia, making it a poor screening test.\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e ETCOc has demonstrated a sensitivity for detecting hemolytic hyperbilirubinemia of 68\u0026ndash;83%,\u003csup\u003e1415\u003c/sup\u003e but there is lack of consensus on which cutoff value should be used to indicate hemolysis with prior studies using values from 1.5\u0026ndash;3.0 ppm.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e There is also a question of which infants warrant screening with ETCOc; both targeted screening of infants with hyperbilirubinemia and universal screening methods have been tested.\u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe purpose of this study was threefold: 1) to determine the optimal ETCOc cutoff to predict a serum bilirubin meeting the neurotoxicity risk phototherapy threshold; 2) to compare the performance of DAT versus ETCOc in the prediction of significant hyperbilirubinemia; and 3) to compare rates of indication for serum bilirubin and phototherapy using DAT versus ETCOc to determine neurotoxicity risk.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe conducted a prospective feasibility study using a convenience sample of infants admitted to two level 1 newborn nurseries. Recruitment and data collection occurred between April \u0026ndash; June 2025 during the birth hospitalization. Hospital guidelines at the time of the study included cord blood typing of infants of mothers with type O or Rh-negative blood or with a positive antibody screen and DAT for infants with ABO incompatibility. All infants were screened with transcutaneous bilirubin (TCB) and/or total serum bilirubin (TSB); late preterm and DAT positive infants were screened at 24 and 36 hours of life (HOL), other infants at 36 HOL or prior to discharge. TCB was recommended for first line screening with TSB per AAP guidelines if the TCB was within 3 mg/dL of the appropriate phototherapy threshold or \u0026ge; 15 mg/dL.\u003csup\u003e1\u003c/sup\u003e Additional TCB and TSB measurements were obtained at provider discretion.\u003c/p\u003e \u003cp\u003eAll infants admitted to the newborn nurseries were eligible for inclusion. Pre-defined exclusion criteria included infants with a nasal deformity that did not fit the CoSenseⒸ nasal cannula for ETCOc testing. Infants were enrolled when the parent(s) gave verbal consent to ETCOc testing in addition to routine care as described above. Follow up was by electronic medical record review.\u003c/p\u003e \u003cp\u003eA receiver operating characteristic curve was used to determine an optimal ETCOc value for the cohort. Two additional values were selected from the literature (\u0026ge; 1.7 ppm used by Bao et al.\u003csup\u003e14\u003c/sup\u003e and \u0026ge; 2.5 ppm used by Wells et al.\u003csup\u003e17\u003c/sup\u003e) for comparison. The primary outcome for sensitivity and specificity analysis was a TSB within 14 days of life that met or exceeded the neurotoxicity risk phototherapy threshold. The secondary outcomes were rates of indication for TSB and for phototherapy using the different methods to determine neurotoxicity risk (positive DAT and ETCOc using three different threshold values). Indication for TSB was determined by distance of the corresponding TCB from the appropriate phototherapy level per AAP guidelines;\u003csup\u003e1\u003c/sup\u003e infants were counted at most once as having an indication for TSB. Indication for phototherapy was based on a TSB during the birth hospitalization that met or exceeded the appropriate phototherapy threshold per the AAP 2022 guideline.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eETCOc measurements were obtained between 24\u0026ndash;48 HOL or outside of this window if there was clinical concern for hyperbilirubinemia and the infant had not previously been tested. ETCOc testing was done with the CoSenseⒸ monitor and nasal cannulas (Capnia Inc, Foster City, CA) which has FDA 510(k) clearance. ETCOc results and hours of life at measurement were recorded for analysis only; results were not used to guide clinical care. Manual chart review determined gestational age, maternal blood type, infant blood type, DAT result if tested, TCB measurements, TSB measurements, treatment with phototherapy, and readmissions to the same hospital network within 14 days of birth for hyperbilirubinemia.\u003c/p\u003e \u003cp\u003eStatistical analysis included generation of a receiver operating characteristic (ROC) curve for ETCOc values predicting the primary outcome and defined the optimal threshold as the value with the minimum Euclidean distance from the (0,1) point on the ROC curve, where both sensitivity and specificity are 100%. McNemar\u0026rsquo;s test was used to compare sensitivity and specificity between different methods for determining neurotoxicity risk. The Student\u0026rsquo;s t-test was used to compare continuous data and Chi square test for categorical data. A significance level of \u003cem\u003ep\u003c/em\u003e \u0026lt; .05 was used for all analyses without adjustment for multiple comparisons due to the exploratory nature of the study. Statistical analyses were completed using R (Version 2025.05.1\u0026thinsp;+\u0026thinsp;513)\u003csup\u003e19\u003c/sup\u003e, Microsoft Excel (version 16.98, Redmond, WA), and SAS (version 9.4, Carey, NC). This study was approved by our Institutional Review Board.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eNinety-eight percent of families approached consented to ETCOc testing (n\u0026thinsp;=\u0026thinsp;151/154) and ETCOc results were obtained in all 151 consented infants. Characteristics of the study population are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median gestational age was 39 weeks (IQR 38\u0026ndash;40). Seventeen infants (11%) were DAT positive, 21 (14%) were DAT negative, and 113 (75%) did not have a DAT. Of the 38 infants who had a DAT, 33 were tested due to ABO incompatibility and 5 received a DAT although there was no blood type incompatibility. There were no mothers with positive antibody screens except secondary to Rho(D) immune globulin administration during pregnancy. The mean ETCOc was 2.0 (\u0026plusmn; 0.7) ppm with a median of 1.9 ppm (IQR 1.6\u0026ndash;2.3). Median HOL at time of ETCOc testing was 31 (IQR 25\u0026ndash;38).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eCharacteristics of study participants (n\u0026thinsp;=\u0026thinsp;151)\u003c/b\u003e Rh\u0026thinsp;=\u0026thinsp;Rhesus, RhIG\u0026thinsp;=\u0026thinsp;Rhesus immune globulin\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e35 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e36 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e37 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e38 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e39 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e41 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal blood type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRh positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRh negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal antibody screen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive due to RhIG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive not due to RhIG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfant blood type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot tested\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRh positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRh negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the receiver operating curve of ETCOc for predicting a TSB at or above the neurotoxicity risk phototherapy threshold; the optimal ETCOc cutoff was 2.1 ppm. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the ability of DAT and ETCOc thresholds of \u0026ge; 1.7 ppm, \u0026ge; 2.1 ppm, and \u0026ge; 2.5 ppm to predict a TSB meeting the neurotoxicity risk phototherapy threshold. The sensitivity of DAT was significantly lower than ETCOc \u0026ge;1.7 ppm (\u003cem\u003ep\u003c/em\u003e \u0026lt; .001), ETCOc \u0026ge; 2.1 ppm (\u003cem\u003ep\u003c/em\u003e = .001), and ETCOc \u0026ge; 2.5 ppm (\u003cem\u003ep\u003c/em\u003e = .01). The specificity of DAT was significantly higher than ETCOc \u0026ge; 1.7 ppm (\u003cem\u003ep\u003c/em\u003e \u0026lt; .001) and ETCOc \u0026ge; 2.1 ppm (\u003cem\u003ep\u003c/em\u003e \u0026lt; .001), but not for ETCOc \u0026ge; 2.5 ppm (\u003cem\u003ep\u003c/em\u003e = .18). There was not a significant association between positive DAT and having a TSB meeting the neurotoxicity risk phototherapy threshold (\u003cem\u003ep = .75).\u003c/em\u003e There was a significant difference in mean ETCOc values for infants who had a TSB reaching the neurotoxicity risk phototherapy threshold (2.8 versus 1.9 ppm, \u003cem\u003ep\u003c/em\u003e = .007).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eAbility of DAT and ETCOc to predict a TSB meeting the neurotoxicity risk phototherapy threshold\u003c/b\u003e DAT\u0026thinsp;=\u0026thinsp;direct antiglobulin test, ETCOc\u0026thinsp;=\u0026thinsp;end tidal carbon monoxide corrected for ambient carbon monoxide, NPV\u0026thinsp;=\u0026thinsp;negative predictive value, PPV\u0026thinsp;=\u0026thinsp;positive predictive value\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCutoff for NT risk\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;151)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSensitivity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSpecificity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePPV\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNPV\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDAT+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e88.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e89.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eETCO\u0026thinsp;\u0026ge;\u0026thinsp;1.7 ppm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e100.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e100.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eETCO\u0026thinsp;\u0026ge;\u0026thinsp;2.1 ppm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e87.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e68.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e97.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eETCO\u0026thinsp;\u0026ge;\u0026thinsp;2.5 ppm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e84.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e93.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows how indication for TSB and phototherapy changed for the full cohort depending on whether positive DAT, ETCOc \u0026ge; 1.7 ppm, ETCOc \u0026ge; 2.1 ppm, or ETCOc \u0026ge; 2.5 ppm was used to determine neurotoxicity risk. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e also includes the actual number of infants who had one or more TSB measurements (n\u0026thinsp;=\u0026thinsp;35) and who were treated with phototherapy (n\u0026thinsp;=\u0026thinsp;14) during the birth hospitalization. For infants who received a TSB during the birth hospitalization there was no significant association with positive DAT (\u003cem\u003ep\u003c/em\u003e = .57) or a significant difference in ETCOc values (1.9 ppm versus 2.0 ppm, \u003cem\u003ep\u003c/em\u003e = .20). For the 35 infants who received a TSB, it was indicated when using DAT to determine neurotoxicity risk in 27 (77%) and when using ETCOc \u0026ge; 2.1 ppm in 29 (83%). For infants who received birth hospitalization phototherapy there was a significant association with positive DAT (\u003cem\u003ep\u003c/em\u003e = .002) and a significant difference in mean ETCOc values (2.9 ppm versus 1.9 ppm, \u003cem\u003ep\u003c/em\u003e = .01). When using DAT to determine neurotoxicity risk, 12 infants (86%) were starting on phototherapy at a TSB below the AAP recommended threshold. When using ETCOc \u0026ge; 2.1 ppm to determine neurotoxicity risk, four infants (29%) were starting on phototherapy at a TSB below the AAP recommended threshold.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFive infants in the full cohort were readmitted for phototherapy within 14 days of birth. None of the readmitted infants were DAT positive. There was no difference in mean ETCOc between patients who were readmitted for phototherapy and those who were not (2.2 ppm versus 2.0 ppm, \u003cem\u003ep\u003c/em\u003e = .55).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study compared the ability of DAT (for infants with ABO incompatibility) versus ETCOc (for any infant) to predict significant hyperbilirubinemia and evaluated the clinical effect of each method of assessing neurotoxicity risk. ETCOc testing was acceptable to parents and feasible to perform in the well newborn nursery. An ETCOc cutoff of \u0026ge; 2.1 ppm was optimal for predicting a TSB meeting or exceeding the neurotoxicity risk phototherapy threshold. ETCOc \u0026ge; 2.1 ppm had higher sensitivity when compared with DAT (87.5% versus 12.5%) but was less specific (68.1% versus 88.9%) and resulted in increased indications for TSB (25% versus 18%) and phototherapy (9% versus 1%).\u003c/p\u003e \u003cp\u003eAn ETCOc cutoff of \u0026ge; 2.1 ppm is in the middle of the range of ETCOc cutoffs used in prior studies\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e and balances the benefit of detecting infants at risk (sensitivity 88%) with the potential for overdiagnosis (specificity of 68%). ETCOc \u0026ge; 1.7 ppm overclassified infants as being at risk for hyperbilirubinemia with a sensitivity of 100% and specificity of only 37%, while ETCOc \u0026ge; 2.5 ppm missed detection of infants with hyperbilirubinemia with a sensitivity of 50% but had improved specificity of 84%. All ETCOc thresholds analyzed had improved sensitivity over DAT, though DAT was more specific. Our findings are consistent with prior literature showing that DAT is not an ideal screening test and is of limited utility in predicting significant hyperbilirubinemia in newborns with ABO incompatibility alone, but support use of DAT as diagnostic tool in cases of significant hyperbilirubinemia.\u003csup\u003e121020\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe higher sensitivity of ETCOc should be considered in light of its potential to increase interventions. The specificity of ETCOc \u0026ge; 2.1 ppm of 68.1% suggests that it may over classify some infants as having a neurotoxicity risk factor, resulting in use of lower thresholds for TSB measurement and phototherapy. When analyzed retrospectively, use of ETCOc \u0026ge; 2.1 ppm compared to DAT to determine neurotoxicity risk would have increased the indication for TSB and for phototherapy.\u003c/p\u003e \u003cp\u003eIn our convenience sample, the percentage of infants who received TSB measurements (23%) was more similar to the percentage indicated by ETCOc \u0026ge; 2.1 ppm (25%) than indicated by DAT (18%). The same was true for phototherapy with 9% of the cohort receiving phototherapy compared to 8% indicated by ETCOc \u0026ge; 2.1 ppm and 1% indicated by DAT. However, not all TSBs measurements that occurred were concordant with AAP guidelines and phototherapy was frequently started at subthreshold levels. A prior study (which included our institution) found that only 30.8% of TSBs were sent according to AAP guidelines and 63% of phototherapy was initiated below the recommended threshold.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e While subthreshold phototherapy has been shown to decrease readmissions, it also increases length of birth hospital stay and results in overtreatment.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Unfortunately, prior studies have not found DAT or ETCOc to be helpful in predicting readmissions for phototherapy.\u003csup\u003e2324\u003c/sup\u003e We similarly found that no DAT positive infants were readmitted and there was no significant difference in mean ETCOc values between infants who were and were not readmitted. While use of ETCOc will likely identify more infants with a potential risk of hemolysis, resulting in more TSB measurements and phototherapy, more study is needed to determine if this identification would prevent escalation of care for or complications of hyperbilirubinemia.\u003c/p\u003e \u003cp\u003eFinally, the question remains on which infants to screen for hemolysis. The AAP clinical practice guideline does not recommend universal screening with DAT or with other methods of detecting hemolysis if appropriate bilirubin surveillance and follow up are ensured.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Our findings support the lack of utility of routinely obtaining DAT for infants with ABO incompatibility alone given its poor ability to predict hyperbilirubinemia.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e While every infant in our sample received ETCOc testing, we did not find that the ETCOc results would have changed management when the first TCB or TSB was low. This is consistent with prior literature showing that, for example, an infant with a TSB 3\u0026ndash;4 mg/dl below the phototherapy threshold has only a 5% chance of ever exceeding the phototherapy threshold.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e Evaluating for hemolysis only in infants with a clinical concern for hyperbilirubinemia that may require treatment is likely the highest value use of either DAT or ETCOc.\u003c/p\u003e \u003cp\u003eThis study has several limitations. The cohort was a small, convenience sample from two level 1 newborn nurseries within the same hospital network and results may not be generalizable to other institutions or patient populations. Enrollment was biased towards infants with a positive DAT (11% of the cohort versus a previously published rate of 7.1%\u003csup\u003e21\u003c/sup\u003e) or hyperbilirubinemia (9% of the cohort received phototherapy versus a previously published rate of 2.1%)\u003csup\u003e21\u003c/sup\u003e Therefore, our cohort is not reflective of universal screening in a well newborn nursery, but rather of a higher-than-average risk sample, and as such may overestimate the predictive ability of ETCOc. Data collection was by retrospective chart review of the infants that underwent ETCOc testing and analysis was based on indication for TSB and phototherapy at threshold, making comparisons to real world practice challenging. Infants who were started on subthreshold phototherapy may have achieved the primary outcome of a TSB meeting the phototherapy threshold if phototherapy had not been started. Follow up was limited to those infants who presented within our hospital network; readmissions to outside hospitals were not captured.\u003c/p\u003e \u003cp\u003eIn conclusion, in our high-risk convenience sample we found ETCOc to be superior to DAT in predicting hyperbilirubinemia, however its application would have increased indications for TSB and phototherapy. Our findings support the AAP\u0026rsquo;s position that universal bilirubin screening is sufficient for detecting infants at risk for severe hyperbilirubinemia if appropriate follow up is ensured and as such universal testing for hemolysis is unlikely to provide further clinical benefit. Further study is needed to determine if use of either DAT or ETCOc improves management in infants with known hyperbilirubinemia or if trending bilirubin levels alone is sufficient to prevent the severe, yet rare, complication of bilirubin induced neurologic dysfunction.\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\"\u003eDAT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edirect antiglobulin test\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eETCOc\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eend-tidal carbon monoxide corrected for ambient carbon monoxide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHOL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehours of life\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\"\u003eNPV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enegative predictive value\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePPV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epositive predictive value\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ereceiver operating characteristic\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTCB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etranscutaneous bilirubin\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 \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eThe authors have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eData analysis for this study was supported by a Mass General Brigham for Children (MGBfC), Department of Pediatrics micro-grant. Equipment for this study was provided by Capnia, Inc. MGBfC and Capnia Inc. had no role in the design and conduct of the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Juniper Burch conceptualized and designed the study, designed the data collection tool, collected data, carried out the initial analyses, drafted the initial manuscript, and critically reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eDrs. Ann Cheung and Leela Sarathy assisted in study design, collected data, and critically reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eMs. Nora Horick carried out final data analyses and critically reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eThank you to Drs. Lowell Fox and Mellory Kaserman for their assistance with study design and data collection.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKemper AR, Newman TB, Slaughter JL, et al. \u003cem\u003eCLINICAL PRACTICE GUIDELINE Guidance for the Clinician in Rendering Pediatric Care Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation FROM THE AMERICAN ACADEMY OF PEDIATRICS\u003c/em\u003e. Vol 150. 2022. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://publications.aap.org/pediatrics/article-pdf/150/3/e2022058859/1561263/peds_2022058859.pdf\u003c/span\u003e\u003cspan address=\"http://publications.aap.org/pediatrics/article-pdf/150/3/e2022058859/1561263/peds_2022058859.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlk\u0026eacute;n J, H\u0026aring;kansson S, Ek\u0026eacute;us C, Gustafson P, Norman M. Rates of Extreme Neonatal Hyperbilirubinemia and Kernicterus in Children and Adherence to National Guidelines for Screening, Diagnosis, and Treatment in Sweden. \u003cem\u003eJAMA Netw Open\u003c/em\u003e. 2019;2(3):e190858. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamanetworkopen.2019.0858\u003c/span\u003e\u003cspan address=\"10.1001/jamanetworkopen.2019.0858\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhutani VK, Srinivas S, Castillo Cuadrado ME, Aby JL, Wong RJ, Stevenson DK. Identification of neonatal haemolysis: An approach to predischarge management of neonatal hyperbilirubinemia. \u003cem\u003eActa Paediatrica, International Journal of Paediatrics\u003c/em\u003e. 2016;105(5):e189-e194. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/apa.13341\u003c/span\u003e\u003cspan address=\"10.1111/apa.13341\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhutani VK, Maisels MJ, Schutzman DL, et al. Identification of risk for neonatal haemolysis. \u003cem\u003eActa Paediatrica, International Journal of Paediatrics\u003c/em\u003e. 2018;107(8):1350\u0026ndash;1356. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/apa.14316\u003c/span\u003e\u003cspan address=\"10.1111/apa.14316\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeeds H, Gievers L, Tyrrell H, et al. Variability in Screening and Management of Hyperbilirubinemia Across US Hospitals: A BORN Study. \u003cem\u003eHosp Pediatr\u003c/em\u003e. Published online January 8, 2026. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1542/hpeds.2025-008553\u003c/span\u003e\u003cspan address=\"10.1542/hpeds.2025-008553\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlkhater SA, Albalwi RA, Alomar SA, et al. Value of the direct Antiglobulin test in predicting the need for phototherapy in Newborns. \u003cem\u003eJ Blood Med\u003c/em\u003e. 2021;12:53\u0026ndash;61. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/JBM.S291606\u003c/span\u003e\u003cspan address=\"10.2147/JBM.S291606\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMehta R, Petrova A. Direct antiglobulin test in the prediction of hyperbilirubinemia and predischarge bilirubin levels in infants with mother-infant blood type incompatibility. \u003cem\u003ePediatr Neonatol\u003c/em\u003e. 2021;62(4):406\u0026ndash;411. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.pedneo.2021.04.002\u003c/span\u003e\u003cspan address=\"10.1016/j.pedneo.2021.04.002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElsaie AL, Taleb M, Nicosia A, et al. Comparison of end-tidal carbon monoxide measurements with direct antiglobulin tests in the management of neonatal hyperbilirubinemia. \u003cem\u003eJournal of Perinatology\u003c/em\u003e. 2020;40(10):1513\u0026ndash;1517. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41372-020-0652-y\u003c/span\u003e\u003cspan address=\"10.1038/s41372-020-0652-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHerschel M, Karrison T, Wen M, Caldarelli L, Baron B. Evaluation of the direct antiglobulin (coombs\u0026rsquo;) test for identifying newborns at risk for hemolysis as determined by end-tidal carbon monoxide concentration (ETCOc); and comparison of the coombs\u0026rsquo; test with ETCOc for detecting significant jaundice. \u003cem\u003eJournal of Perinatology\u003c/em\u003e. 2002;22(5):341\u0026ndash;347. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/sj.jp.7210702\u003c/span\u003e\u003cspan address=\"10.1038/sj.jp.7210702\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWainer S, Rabi J, Lyon M. Coombs\u0026rsquo; testing and neonatal hyperbilirubinemia [5]. \u003cem\u003eCMAJ Canadian Medical Association Journal\u003c/em\u003e. \u003cem\u003eCanadian Medical Association\u003c/em\u003e. 2007;176(7):972\u0026ndash;973. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1503/cmaj.1060214\u003c/span\u003e\u003cspan address=\"10.1503/cmaj.1060214\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDinesh D. Review of positive direct antiglobulin tests found on cord blood sampling. \u003cem\u003eJ Paediatr Child Health\u003c/em\u003e. 2005;41(9\u0026ndash;10):504\u0026ndash;507. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1440-1754.2005.00692.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1440-1754.2005.00692.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKumar Krishnegowda V, Ramaswamy VV, Abiramalatha T, Bandyopadhyay T, S AKP, Kannan Loganathan P. Direct antiglobulin test for the prediction of neonatal hyperbilirubinemia needing an intervention: a systematic review and diagnostic test accuracy meta-analysis. \u003cem\u003eFront Pediatr\u003c/em\u003e. \u003cem\u003eFrontiers Media SA\u003c/em\u003e. 2024;12. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fped.2024.1475623\u003c/span\u003e\u003cspan address=\"10.3389/fped.2024.1475623\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbbas SA, Dinardo CL, Godinho CH, et al. Direct antiglobulin test in the differential diagnosis of ABO hemolytic disease of the newborn: an important tool with high negative predictive value. \u003cem\u003eHematol Transfus Cell Ther\u003c/em\u003e. 2024;46(4):450\u0026ndash;454. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.htct.2024.03.001\u003c/span\u003e\u003cspan address=\"10.1016/j.htct.2024.03.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBao Y, Zhu J, Ma L, et al. An End-Tidal Carbon Monoxide Nomogram for Term and Late-Preterm Chinese Newborns. \u003cem\u003eJournal of Pediatrics\u003c/em\u003e. 2022;250:16\u0026ndash;21.e3. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jpeds.2022.07.003\u003c/span\u003e\u003cspan address=\"10.1016/j.jpeds.2022.07.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng X, Lin B, Yang Y, Yu Y, Fu Y, Yang C. End-tidal carbon monoxide concentrations measured within 48 hours of birth predict hemolytic hyperbilirubinemia. \u003cem\u003eJournal of Perinatology\u003c/em\u003e. 2024;44(6):897\u0026ndash;901. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41372-024-01967-7\u003c/span\u003e\u003cspan address=\"10.1038/s41372-024-01967-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBahr TM, Shakib JH, Stipelman CH, Kawamoto K, Lauer S, Christensen RD. Improvement Initiative: End-Tidal Carbon Monoxide Measurement in Newborns Receiving Phototherapy. \u003cem\u003eJournal of Pediatrics\u003c/em\u003e. 2021;238:168\u0026ndash;173.e2. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jpeds.2021.07.008\u003c/span\u003e\u003cspan address=\"10.1016/j.jpeds.2021.07.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWells S, Balasubramanian R, Nguyen K, Schutzman DL. End-tidal carbon monoxide for routine monitoring of significant hemolysis in the management of newborn hyperbilirubinemia. \u003cem\u003eJournal of Perinatology\u003c/em\u003e. Published online 2025. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41372-025-02242-z\u003c/span\u003e\u003cspan address=\"10.1038/s41372-025-02242-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang G, Deng L, Zhang K, et al. End-tidal CO corrected for ambient CO risk adjusted phototherapy threshold for the management of neonatal hyperbilirubinemia: a randomized clinical trial. \u003cem\u003eWorld Journal of Pediatrics\u003c/em\u003e. Published online August 4, 2025. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12519-025-00954-y\u003c/span\u003e\u003cspan address=\"10.1007/s12519-025-00954-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eR Core Team (2024). _R: A Language and Environment for Statistical Computing_. R Foundation for Statistical Computing, Vienna, Austria. \u0026lt;\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.R-project.org/%3E\u003c/span\u003e\u003cspan address=\"https://www.R-project.org/%3E\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTesting C\u0026rsquo;, Leistikow EA, Collin MF, et al. \u003cem\u003eWasted Health Care Dollars\u003c/em\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSarathy L, Chou JH, Romano-Clarke G, Darci KA, Lerou PH. Bilirubin Measurement and Phototherapy Use After the AAP 2022 Newborn Hyperbilirubinemia Guideline. \u003cem\u003ePediatrics\u003c/em\u003e. 2024;153(4). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1542/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\u003eWickremasinghe AC, Kuzniewicz MW, McCulloch CE, Newman TB. Efficacy of subthreshold newborn phototherapy during the birth hospitalization in preventing readmission for phototherapy. \u003cem\u003eJAMA Pediatr\u003c/em\u003e. 2018;172(4):378\u0026ndash;385. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamapediatrics.2017.5630\u003c/span\u003e\u003cspan address=\"10.1001/jamapediatrics.2017.5630\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMadan A, Huntsinger K, Burgos A, Benitz WE. Readmission for newborn jaundice: the value of the Coombs\u0026rsquo; test in predicting the need for phototherapy. \u003cem\u003eClin Pediatr (Phila)\u003c/em\u003e. 2004;43(1):63\u0026ndash;68. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/000992280404300108\u003c/span\u003e\u003cspan address=\"10.1177/000992280404300108\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaisels MJ, Kring EA, Coffey MP. Heme Catabolism and Bilirubin Production in Readmitted Jaundiced Newborns. \u003cem\u003eJournal of Pediatrics\u003c/em\u003e. 2020;226:285\u0026ndash;288. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jpeds.2020.06.012\u003c/span\u003e\u003cspan address=\"10.1016/j.jpeds.2020.06.012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuzniewicz MW, Park J, Niki H, Walsh EM, McCulloch CE, Newman TB. Predicting the need for phototherapy after discharge. \u003cem\u003ePediatrics\u003c/em\u003e. 2021;147(5). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1542/peds.2020-019778\u003c/span\u003e\u003cspan address=\"10.1542/peds.2020-019778\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9431741/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9431741/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eCompare the direct antiglobulin test (DAT) in the setting of ABO incompatibility versus end-tidal carbon monoxide corrected for ambient carbon monoxide (ETCOc) to predict significant hyperbilirubinemia.\u003c/p\u003e\u003ch2\u003eStudy Design:\u003c/h2\u003e \u003cp\u003eProspective review of a convenience sample of 151 newborns admitted to the well newborn nursery who had ETCOc testing in addition to standard of care.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe optimal ETCOc cutoff to predict a serum bilirubin meeting the neurotoxicity risk phototherapy threshold was 2.1 ppm. DAT had a sensitivity of 13% with specificity of 89% and ETCOc \u0026ge; 2.1 ppm had a sensitivity of 88% with specificity of 68% to predict this outcome. Use of ETCOc \u0026ge; 2.1 ppm rather than DAT to determine neurotoxicity risk increased indications for serum bilirubin testing (25% versus 18%) and phototherapy (8% versus 1%).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eETCOc \u0026ge;2.1 ppm had higher sensitivity but lower specificity than DAT to predict hyperbilirubinemia and resulted in increased indications for serum bilirubin testing and phototherapy.\u003c/p\u003e","manuscriptTitle":"Assessing Risk for Hemolytic Hyperbilirubinemia in Newborns: Direct Antiglobulin Test versus End-tidal Carbon Monoxide","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-27 16:55:08","doi":"10.21203/rs.3.rs-9431741/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-05-01T12:54:23+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-04-27T14:03:49+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-04-20T19:39:07+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-20T13:39:07+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-20T01:49:08+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-04-19T15:12:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-16T12:20:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-16T01:06:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Perinatology","date":"2026-04-16T01:06:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d0c017bc-cd4d-494b-b056-093c7fb12836","owner":[],"postedDate":"April 27th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"revise","date":"2026-05-01T12:54:23+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":66600590,"name":"Health sciences/Health care/Diagnosis/Laboratory techniques and procedures"},{"id":66600591,"name":"Health sciences/Diseases/Haematological diseases"},{"id":66600592,"name":"Health sciences/Biomarkers/Predictive markers"},{"id":66600593,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2026-05-07T21:06:05+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-27 16:55:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9431741","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9431741","identity":"rs-9431741","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}