{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T20:39:48Z","timestamp":1781383188158,"version":"3.54.1"},"reference-count":47,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T00:00:00Z","timestamp":1715904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>This perspective work by academic neonatal providers is written specifically for the audience of newborn care providers and neonatologists involved in neonatal hypoglycemia screening. Herein, we propose adding a screen for congenital hyperinsulinism (CHI) by measuring glucose and ketone (i.e., \u03b2-hydroxybutyrate (BOHB)) concentrations just prior to newborn hospital discharge and as close to 48 h after birth as possible, at the same time that the mandated state Newborn Dried Blood Spot Screen is obtained. In the proposed protocol, we do not recommend specific metabolite cutoffs, as our primary objective is to simply highlight the concept of screening for CHI in newborns to newborn caregivers. The premise for our proposed screen is based on the known effect of hyperinsulinism in suppressing ketogenesis, thereby limiting ketone production. We will briefly discuss genetic CHI, other forms of neonatal hypoglycemia, and their shared mechanisms; the mechanism of insulin regulation by functional pancreatic islet cell membrane KATP channels; adverse neurodevelopmental sequelae and brain injury due to missing or delaying the CHI diagnosis; the principles of a good screening test; how current neonatal hypoglycemia screening programs do not fulfill the criteria for being effective screening tests; and our proposed algorithm for screening for CHI in newborns.<\/jats:p>","DOI":"10.3390\/jcm13102953","type":"journal-article","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T04:26:29Z","timestamp":1715919989000},"page":"2953","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Proposed Screening for Congenital Hyperinsulinism in Newborns: Perspective from a Neonatal\u2013Perinatal Medicine Group"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8469-3729","authenticated-orcid":false,"given":"Jeffrey R.","family":"Kaiser","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"},{"name":"Department of Obstetrics and Gynecology, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8870-7390","authenticated-orcid":false,"given":"Shaili","family":"Amatya","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca J.","family":"Burke","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy E.","family":"Corr","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2234-3958","authenticated-orcid":false,"given":"Nada","family":"Darwish","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3328-7074","authenticated-orcid":false,"given":"Chintan K.","family":"Gandhi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrienne","family":"Gasda","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen M.","family":"Glass","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell J.","family":"Kresch","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0644-0731","authenticated-orcid":false,"given":"Sarah M.","family":"Mahdally","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria T.","family":"McGarvey","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara J.","family":"Mola","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3124-6129","authenticated-orcid":false,"given":"Yuanyi L.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Nissly","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanyaly M.","family":"Santiago-Aponte","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jazmine C.","family":"Valencia","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy W.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Penn State Health Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1001\/jamapediatrics.2015.1631","article-title":"Association between transient newborn hypoglycemia and fourth-grade achievement test proficiency: A population-based study","volume":"169","author":"Kaiser","year":"2015","journal-title":"JAMA Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.jpeds.2012.05.022","article-title":"Incidence of neonatal hypoglycemia in babies identified as at risk","volume":"161","author":"Harris","year":"2012","journal-title":"J. Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1542\/peds.2010-3851","article-title":"Clinical report\u2014Postnatal glucose homeostasis in late-preterm and term infants","volume":"127","author":"Adamkin","year":"2011","journal-title":"Pediatrics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1001\/jama.2022.0992","article-title":"Association of neonatal hypoglycemia with academic performance in mid-childhood","volume":"327","author":"Shah","year":"2022","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1071206","DOI":"10.3389\/fped.2023.1071206","article-title":"New approaches to screening and management of neonatal hypoglycemia based on improved understanding of the molecular mechanism of hypoglycemia","volume":"11","author":"Stanley","year":"2023","journal-title":"Front. Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"876903","DOI":"10.3389\/fendo.2022.876903","article-title":"Global registries in congenital hyperinsulinism","volume":"13","author":"Pasquini","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1016\/j.jpeds.2015.02.045","article-title":"Re-evaluating \u201ctransitional neonatal hypoglycemia\u201d: Mechanism and implications for management","volume":"166","author":"Stanley","year":"2015","journal-title":"J. Pediatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.jpeds.2015.03.057","article-title":"Recommendations from the Pediatric Endocrine Society for evaluation and management of persistent hypoglycemia in neonates, infants, and children","volume":"167","author":"Thornton","year":"2015","journal-title":"J. Pediatr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1542\/peds.21.6.885","article-title":"Studies of carbohydrate metabolism in the newborn: II. The effect of glucagon on the concentration of sugar in capillary blood of the newborn infant","volume":"21","author":"Cornblath","year":"1958","journal-title":"Pediatrics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1542\/peds.57.5.702","article-title":"Hyperinsulinism in infancy: Diagnosis by demonstration of abnormal response to fasting hypoglycemia","volume":"57","author":"Stanley","year":"1976","journal-title":"Pediatrics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"bqab121","DOI":"10.1210\/endocr\/bqab121","article-title":"Decreased KATP channel activity contributes to the low glucose threshold for insulin secretion of rat neonatal islets","volume":"162","author":"Yang","year":"2021","journal-title":"Endocrinology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.clp.2021.11.007","article-title":"Advances in understanding the mechanism of transitional neonatal hypoglycemia and implications for management","volume":"49","author":"Stanescu","year":"2022","journal-title":"Clin. Perinatol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Yang, J., Hammoud, B., Ridler, A., Won, K.-J., Hoshi, T., Stanley, C.A., Stanescu, D.E., and Ackermann, A.M. (2021). Early postnatal activation of the hypoxia pathway disrupts \u03b2-cell function. bioRxiv.","DOI":"10.1101\/2021.06.09.447705"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1159\/000527715","article-title":"Mid-childhood outcomes after dextrose gel treatment of neonatal hypoglycaemia: Follow-up of the Sugar Babies Randomized Trial","volume":"120","author":"Dai","year":"2023","journal-title":"Neonatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1056\/NEJMoa1905593","article-title":"Lower versus traditional treatment threshold for neonatal hypoglycemia","volume":"382","author":"Eskes","year":"2020","journal-title":"N. Eng. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"999274","DOI":"10.3389\/fped.2022.999274","article-title":"Natural history and neurodevelopmental outcomes in perinatal stress induced hyperinsulinism","volume":"10","author":"Sigal","year":"2022","journal-title":"Front. Pediatr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1515\/jpem-2019-0066","article-title":"Characterization of the duration of treatment with diazoxide in infants with prolonged hyperinsulinism (PHI)","volume":"32","author":"Raisingani","year":"2019","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"60","DOI":"10.3389\/fendo.2013.00060","article-title":"Abnormal neurodevelopmental outcomes are common in children with transient congenital hyperinsulinism","volume":"4","author":"Avatapalle","year":"2013","journal-title":"Front. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1097\/MOP.0000000000001243","article-title":"Bridging the gaps: Recent advances in diagnosis, care, and outcomes in congenital hyperinsulinism","volume":"35","author":"Rosenfeld","year":"2023","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"F98","DOI":"10.1136\/fn.82.2.F98","article-title":"Practical management of hyperinsulinism in infancy","volume":"82","author":"Hussain","year":"2000","journal-title":"Arch. Dis. Child. Fetal. Neonatal. Ed."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1210\/clinem\/dgac604","article-title":"Hyperinsulinemic hypoglycemia diagnosed in childhood can be monogenic","volume":"108","author":"Hopkins","year":"2023","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1231043","DOI":"10.3389\/fendo.2023.1231043","article-title":"Standardised practices in the networked management of congenital hyperinsulinism: A UK national collaborative consensus","volume":"14","author":"Shaikh","year":"2023","journal-title":"Front. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s004310100847","article-title":"Heterogeneity of persistent hyperinsulinaemic hypoglycaemia. A series of 175 cases","volume":"161","author":"Fournet","year":"2002","journal-title":"Eur. J. Pediatr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1530\/eje.0.1490043","article-title":"Long-term follow-up of 114 patients with congenital hyperinsulinism","volume":"149","author":"Meissner","year":"2003","journal-title":"Eur. J. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1111\/pedi.13186","article-title":"Clinical characteristics, outcome, and predictors of neurological sequelae of persistent congenital hyperinsulinism: A single tertiary center experience","volume":"22","author":"Laimon","year":"2021","journal-title":"Pediatr. Diabetes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"580642","DOI":"10.3389\/fendo.2020.580642","article-title":"Risk factors for adverse neurodevelopment in transient or persistent congenital hyperinsulinism","volume":"11","author":"Roeper","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.pedn.2004.12.009","article-title":"Effects of hypoglycemia on developmental outcome in children with congenital hyperinsulinism","volume":"20","author":"Steinkrauss","year":"2005","journal-title":"J. Pediatr. Nurs."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1542\/peds.107.3.476","article-title":"Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia","volume":"107","author":"Menni","year":"2001","journal-title":"Pediatrics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1053\/j.semperi.2015.11.002","article-title":"What is prenatal screening and why to do it?","volume":"40","author":"Temming","year":"2016","journal-title":"Sem. Perinatol."},{"key":"ref_30","unstructured":"Wilson, J., and Jungner, G. (1968). Principles and Practice of Screening for Disease, World Health Organization."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"811","DOI":"10.3109\/08958378.2014.955932","article-title":"Screening tests: A review with examples","volume":"26","author":"Maxim","year":"2014","journal-title":"Inhal. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1001\/jamapediatrics.2023.3957","article-title":"Infants eligible for neonatal hypoglycemia screening: A systematic review","volume":"177","author":"Gilchrist","year":"2023","journal-title":"JAMA Pediatr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.jpeds.2009.06.044","article-title":"Knowledge gaps and research needs for understanding and treating neonatal hypoglycemia: Workshop report from Eunice Kennedy Shriver National Institute of Child Health and Human Development","volume":"155","author":"Hay","year":"2009","journal-title":"J. Pediatr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"933508","DOI":"10.3389\/fped.2022.933508","article-title":"Different glucose analyzers report different glucose concentration values in term newborns","volume":"10","author":"Duke","year":"2022","journal-title":"Front Pediatr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1048897","DOI":"10.3389\/fped.2022.1048897","article-title":"Application of the screening test principles to screening for neonatal hypoglycemia","volume":"10","author":"Alsweiler","year":"2022","journal-title":"Front. Pediatr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E381","DOI":"10.9778\/cmajo.20210324","article-title":"Association between newborn hypoglycemia screening and breastfeeding success in an Ottawa, Ontario, hospital: A retrospective cohort study","volume":"11","author":"Saginur","year":"2023","journal-title":"CMAJ Open"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.earlhumdev.2016.12.009","article-title":"An emerging evidence base for the management of neonatal hypoglycaemia","volume":"104","author":"Harding","year":"2017","journal-title":"Early Hum. Dev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/S2352-4642(20)30387-4","article-title":"Strategies to improve neurodevelopmental outcomes in babies at risk of neonatal hypoglycaemia","volume":"5","author":"Alsweiler","year":"2021","journal-title":"Lancet Child Adolesc. Health"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1542\/peds.32.3.338","article-title":"A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants","volume":"32","author":"Guthrie","year":"1963","journal-title":"Pediatrics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e2114336","DOI":"10.1001\/jamanetworkopen.2021.14336","article-title":"Principles of genomic newborn screening programs","volume":"4","author":"Downie","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jpeds.2020.12.063","article-title":"Alternative cerebral fuels in the first five days in healthy term infants: The Glucose in Well Babies (GLOW) Study","volume":"231","author":"Harris","year":"2021","journal-title":"J. Pediatr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.jpeds.2020.02.079","article-title":"Glucose profiles in healthy term infants in the first 5 days: The Glucose in Well Babies (GLOW) Study","volume":"223","author":"Harris","year":"2020","journal-title":"J. Pediatr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1159\/000239968","article-title":"Changes in the blood levels of acetoacetate and ketone bodies in newborn infants","volume":"8","author":"Melichar","year":"1965","journal-title":"Biol. Neonat."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1147659","DOI":"10.3389\/fped.2023.1147659","article-title":"Relationships between feeding and glucose concentrations in healthy term infants during the first five days after birth\u2014The Glucose in Well Babies Study (GLOW)","volume":"11","author":"Harris","year":"2023","journal-title":"Front. Pediatr."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Stanley, C.A., Weston, P.J., Harris, D.L., De Le\u00f3n, D.D., and Harding, J.E. (2024). Role of beta-hydroxybutyrate measurement in the evaluation of plasma glucose concentrations in newborn infants. Arch. Dis. Child. Fetal Neonatal. Ed.","DOI":"10.1136\/archdischild-2024-326865"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1136\/adc.67.4_Spec_No.357","article-title":"Patterns of metabolic adaptation for preterm and term infants in the first neonatal week","volume":"67","author":"Hawdon","year":"1992","journal-title":"Arch. Dis. Child."},{"key":"ref_47","unstructured":"(2024, February 25). Breastfeeding Report Card: United States, Available online: https:\/\/www.cdc.gov\/breastfeeding\/data\/reportcard.htm."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/10\/2953\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:43:43Z","timestamp":1760107423000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/10\/2953"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,17]]},"references-count":47,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["jcm13102953"],"URL":"https:\/\/doi.org\/10.3390\/jcm13102953","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,17]]}}}