Impact of macronutrients intake on glycemic homeostasis of preterm infants : evidence from continuous glucose monitoring

Impact of macronutrients intake on glycemic homeostasis of preterm infants : evidence from continuous glucose monitoring | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of macronutrients intake on glycemic homeostasis of preterm infants : evidence from continuous glucose monitoring Silvia Guiducci, Giulia Res, Luca Bonadies, Federica Savio, Sabrina Brigadoi, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3827863/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Apr, 2024 Read the published version in European Journal of Pediatrics → Version 1 posted 7 You are reading this latest preprint version Abstract Background Nutritional intake could influence blood glucose profile during early life of preterm infants. We investigated the impact of macronutrient’s intake, on glycemic homeostasis using continuous glucose monitoring(CGM). Methods We analyzed macronutrients intake in infants born ≤ 32 weeks gestational age (GA) and/or with birth weight ≤ 1500g enrolled. CGM was started within 48 hours of birth and maintained for 5 days. Hypoglycemia was defined as sensor glucose 8 mmol/L. Results Data from 30 participants were included[age 29.9weeks(29.1; 31.2), birthweight 1230.5g(1040.0; 1458.6)]. A reduced time in hypoglycemia was associated to higher amino acids intake(p = 0.011) while increased exposure to hyperglycemia was observed in presence of higher lipids intake(p = 0.031). The birthweight was the strongest determinant of neonatal glucose profile with an inverse relationship between the time spent in hyperglycemia and birthweight (p = 0.007). Conclusions CGM allowed, for the first time, to describe the relationship between macronutrient’s intake and glycemic homeostasis in preterm infants. Figures Figure 1 Figure 2 Figure 3 Introduction Preterm infants are exposed to large glucose fluctuations that could affect long-term neurodevelopment(1, 2) and short-term clinically relevant outcomes as daily growth during the first weeks of life. Early aggressive parenteral nutrition (3) consists of supplementation of glucose, amino acids and lipids starting the first hours of neonatal life with a progressive increase of the daily intake generally driven by point-of-care glucose measures and weight change. This strategy seems to be effective at reducing the incidence of postnatal growth failure that, in turns, is associated to growth delay and neurodevelopment impairment(4). Nevertheless, preterm infants have low tolerance for parenteral glucose infusion with secondary hyperglycemia(3). This observation oftentimes leads to a more cautious increase of daily nutritional intakes in those receiving parenteral nutrition with a consequent impact on postnatal growth (3). Relying on the availability of CGM technology that allows a safe and accurate estimate of time spent in the hypo and hyperglycemic ranges in preterm infants(5, 6), we investigated the influence of macronutrient’s intake on glucose homeostasis of very low birth weight infants during the first week of life. METHODS Study design. We conducted a secondary analysis on the cohort of the BabyGlucolight Trial (NCT04347590), a monocentric randomized controlled study investigating the role of CGM on long-term neurodevelopment in preterm infants. The trial was approved by the Institutional Ethics Committee of the University Hospital of Padua (Italy) (4773/AO/19 AOP1813 and 5005/AO/21 AOP2216) and conducted according in accordance to the Declaration of Helsinki. Participants were enrolled from March 2020 to June 2023 at the Neonatal Intensive Care Unit (NICU) of the University Hospital of Padua. Participants. Eligible subjects were preterm infants born ≤ 32 weeks gestational age or with birth weight ≤ 1500 g admitted to the NICU. Written informed parental consent was obtained before recruitment. Exclusion criteria were BW < 500 g, congenital malformation, perinatal maternal infections and albinism. The baseline perinatal characteristics we collected include intrauterine growth restriction (IUGR), gestational diabetes and preterm premature rupture of membranes (pPROM); type of delivery (caesarean section or vaginal), Apgar Index, need for endotracheal intubation in delivery room (ET-DR). Postnatal characteristics were GA, sex, birthweight and small for gestational age (SGA) defined as weight percentile < 10% of Intergrowth 21 charts for very preterm infants 16 . We also collected data to describe the course of the first days of life as clinical risk index for babies I score (CRIB I) 17 , surfactant administration during the first day of life 18 , episodes of early onset sepsis (EOS) - within the first 72 hours after birth- patent duct arteriosus (PDA) requiring medical treatment, daily weight change, defined as percentage of weight loss respect to BW, and mortality within the first month of life. Glucose monitoring. CGM (Medtronic Guardian 3) was placed on the lateral side of the thigh after adequate disinfection and preceded by containment and analgesia with the use of pacifier and 0.3 ml 24% sucrose 2 minutes before the procedure. Sensor was placed within 48 hours of life and maintained for 5 days. The device was calibrated as per manufacturer’s instructions, with capillary blood glucose values measured by using an Accu-Chek Inform II glucometer (Roche Diabetes Care, Indianapolis, IN). CGM data were analyzed retrospectively to create glucose profile for each subject. Hypoglycemia was defined as sensor glucose value below 4 mmol/L; hyperglycemia was defined if sensor glucose value was above 8 mmol/L. Macronutrient’s intake. Daily macronutrients including glucose, lipids, and amino acids, were titrated based on day of life and following ESPGHAN guidelines 21–23 . We collected both parenteral and enteral intakes during the glucose monitoring. Intravenous macronutrients were given through central venous catheter by personalized parenteral nutrition: glucose share was dextrose, lipid share was a mixed oil lipid emulsion (ClinOleic 20% ®: 80% olive oil, 20% soybean oil); amino acids solution was Primene 10% ®. Nutritional intake by enteral feeding were reported if milk volume was above 24 ml/kg/day, considered the upper limit of minimal enteral feeding 24 . Human milk was preferred to preterm formula. Statistical methods The primary outcome was the relationship between macronutrient’s intake and the frequency of hypoglycemia and hyperglycemia as recorded by the CGM. Data were analyzed using SPSS statistical software v 28.0 for Windows (SPSS, Chicago, IL) and Prism 10.0 (GraphPad Software, San Diego, CA). We excluded from the analysis those with less than 2 days of CGM data. The daily breakdown of glucose patterns was provided by day from CGM start. Macronutrients intakes were reported as g/kg/day. Categorical variables were expressed as number (%). Continuous variables were expressed as median and interquartile range. The relation between macronutrient’s intake, birthweight and time in hypo- and hyperglycemia was analyzed for each variable with a multivariate regression analysis adjusted for GA, sex and IUGR status. The significance level was set to p-value < 0.05. The datasets generated and analysed during the current study are available from the corresponding author on reasonable request. RESULTS We analyzed data from thirty patients. Participants’ neonatal and maternal characteristics are displayed in Table 1 . The total median time of CGM data was 67 hours and 57 minutes (61 h 11 m ; 70 h 23 m ). Glucose profiles are displayed in Fig. 1 A and supplemental Table 1. The median percentage of time in euglycemia was 88.5% (63.7; 97.3) on day 1 without a significant difference across the three days of monitoring. Table 1. Baseline characteristics of the cohort (n=30) expressed as median (IQR) or absolute number (%). Figure 1 B and supplemental Table 1 describe the daily macronutrients intake. As per protocol, glucose intakes were increased by a median of 2.5g/kg/day, from 8.0 g/kg/day (7,1; 9,4) on day 1 to 12.5 g/kg/day (11.0; 13,7) on day 3, while amino acids intakes raised from a median of 1.9 g/kg/day (1.4; 2.1) on day 1 to 3.0 g/kg/day (2.0; 3.7) on day 3, paralleled by the lipids intake [from 1.3g/kg/day (1.1;1.5) on day 1 to 2.6 g/kg/day (1.7;3.8) on day 3]. As displayed in Fig. 2 , the birthweight was the strongest determinant of neonatal glucose profile in this cohort with an inverse relationship between the time spent in hyperglycemia during the first 3 days of monitoring and the birthweight (p = 0.007, r=-0.54), that remained significant when adjusted for gestational age, sex and IUGR (p = 0.023) (Fig. 2 B), while we did not observe a significant relationship between birthweight and the time spent in the hypoglycemic range (p = 0.114) (Fig. 2 A). The influence of macronutrient’s intake on glucose profile is shown in Fig. 3 . The total intake of amino acids during the three days of monitoring was inversely associated with the time in hypoglycemia (p = 0.011, r=-0.460), and lipids had a similar – though non-significant – relationship with the time in hypoglycemia (p = 0.066, r=-0.268). Glucose’s intakes did not significantly affect the time in the hypoglycemic range (p = 0.874) (Fig. 3 A). Conversely, the time in the hyperglycemic range over the first three days was affected by lipids intakes (p = 0.031, r = 0.238) (Fig. 3 B) but not by glucose (p = 0.517, r = 0.122) and amino acids intake (p = 0.357, r = 0.173). Conclusion This study demonstrates the influence of macronutrient’s intake on glycemic homeostasis during the first week of life of very low birth weight infants wearing a CGM. Higher amino acids intake is associated with reduced time spent in the hypoglycemic range, whilst greater lipids intake increases the exposure to hyperglycemia. Birthweight remains a main determinant of neonatal hyperglycemia during the first week of life, confirming the increased risk for hyperglycemia in those with the lowest birthweights( 7 ). Glucose intake did not have a major effect on glycemic homeostasis per se : although the relationship between daily glucose intake and neonatal glycemia remains controversial( 7 ), herein we proved that glucose instability during PN in preterm infants is not exclusively related to parenteral glucose intake. Our results were aligned with most studies describing a reduction of the hypoglycemic events with higher amino acids intake - between 2.5 g/kg/day and 4 g/kg/day( 8 , 9 ). main mechanism to support the effect of parenteral lipids infusion on hyperglycemic risk seems to be the stimulation of gluconeogenesis through two components of the lipids infusion, glycerol and free-fatty acid (FFA)( 10 ). The major novelty of our study stands in the use of CGM technology that provides a comprehensive load of data on the actual exposure to hypo- and hyper-glycemia rather than point-of-care measures of blood glucose. Previous studies investigating the influence of nutritional intakes on glycemic homeostasis, used intermittent glucose tests, while the use of continuous glucose measures unveiled that clinically silent hypo- and hyper-glycemia are associated with worse developmental outcomes in childhood ( 11 , 12 ). The main limit of the study is the small sample size and the monocentric design. Even if CGM data were prospectively collected, they were retrospectively analyzed, therefore we cannot infer a causative relationship between the nutritional intakes and glucose control. Moreover, we assessed total macronutrients intake without considering the route of administration that may influence the impact on glucose homeostasis. However, parenteral amount was more than 60% of total intake for the entire cohort, thus making unlikely that the enteral intakes may have a major effect on glucose homeostasis. CGM appears as a promising tool to individualize nutritional strategies in preterm infants during the first weeks of birth. Declarations ACKNOWLEDEMENTS We are grateful to the patients’ families for participating to the study and to the medical and nursing staff of the NICU of the University Hospital of Padua. AUTHOR CONTRIBUTIONS AG, SB, DT and EB were involved in the study design, methodology, data variable creation, data acquisition design and reviewed the final version of the manuscript. SG, GR, FS, LB and EP contributed to the recruitment of participants and obtained consent. SG and AG analyzed and interpreted data. SG wrote the first draft. AG and SB obtained funding support. All the authors approved the final manuscript and agree to be accountable for all aspects of the work. COMPETING INTERESTS The authors declare no conflict of interest. FUNDING This work was supported by the Institute for Pediatric Research (IRP, Padova, Italy) Starting Grant 2020, University of Padova Star Grant and the Italian Ministry of Health Call for Proposals GR-RF 2019-12368539. References Shah R, Harding J, Brown J, McKinlay C. Neonatal Glycaemia and Neurodevelopmental Outcomes: A Systematic Review and Meta-Analysis. Neonatology. 2019;115(2):116-26. Paulsen ME, Brown SJ, Satrom KM, Scheurer JM, Ramel SE, Rao RB. Long-Term Outcomes after Early Neonatal Hyperglycemia in VLBW Infants: A Systematic Review. Neonatology. 2021;118(5):509-21. Stensvold HJ, Strommen K, Lang AM, Abrahamsen TG, Steen EK, Pripp AH, Ronnestad AE. Early Enhanced Parenteral Nutrition, Hyperglycemia, and Death Among Extremely Low-Birth-Weight Infants. JAMA Pediatr. 2015;169(11):1003-10. Cormack BE, Harding JE, Miller SP, Bloomfield FH. The Influence of Early Nutrition on Brain Growth and Neurodevelopment in Extremely Preterm Babies: A Narrative Review. Nutrients. 2019;11(9). Galderisi A, Facchinetti A, Steil GM, Ortiz-Rubio P, Cavallin F, Tamborlane WV, et al. Continuous Glucose Monitoring In Very Preterm Infants: A Randomized Controlled Trial. Pediatrics [Internet]. 2017. Beardsall K, Thomson L, Guy C, Iglesias-Platas I, van Weissenbruch M, Bond S, et al. Real-time continuous glucose monitoring in preterm infants (REACT): an international, open-label, randomised controlled trial. The Lancet Child & adolescent health. 2021;5(4). Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, Palmer CR, Ong K, et al. Prevalence and determinants of hyperglycemia in very low birth weight infants: cohort analyses of the NIRTURE study. J Pediatr. 2010;157(5):715-9.e1-3. Burattini I, Bellagamba MP, Spagnoli C, D'Ascenzo R, Mazzoni N, Peretti A, et al. Targeting 2.5 versus 4 g/kg/day of amino acids for extremely low birth weight infants: a randomized clinical trial. J Pediatr. 2013;163(5):1278-82 e1. te Braake FW, van den Akker CH, Wattimena DJ, Huijmans JG, van Goudoever JB. Amino acid administration to premature infants directly after birth. J Pediatr. 2005;147(4):457-61. van Kempen AA, van der Crabben SN, Ackermans MT, Endert E, Kok JH, Sauerwein HP. Stimulation of gluconeogenesis by intravenous lipids in preterm infants: response depends on fatty acid profile. Am J Physiol Endocrinol Metab. 2006;290(4):E723-30. Tottman AC, Alsweiler JM, Bloomfield FH, Pan M, Harding JE. Relationship between Measures of Neonatal Glycemia, Neonatal Illness, and 2-Year Outcomes in Very Preterm Infants. J Pediatr. 2017;188:115-21. Tottman AC, Bloomfield FH, Cormack BE, Harding JE, Mohd Slim MA, Weston AF, Alsweiler JM. Relationships Between Early Nutrition and Blood Glucose Concentrations in Very Preterm Infants. J Pediatr Gastroenterol Nutr. 2018;66(6):960-6. Supplemental Table 1 Supplemental Table 1 is not available with this version Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 18 Apr, 2024 Read the published version in European Journal of Pediatrics → Version 1 posted Editorial decision: Revision requested 31 Jan, 2024 Reviews received at journal 18 Jan, 2024 Reviewers agreed at journal 09 Jan, 2024 Reviewers invited by journal 08 Jan, 2024 Editor assigned by journal 04 Jan, 2024 Submission checks completed at journal 04 Jan, 2024 First submitted to journal 01 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-3827863","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":265334841,"identity":"7cdc3719-df2d-4320-89c1-4f1b536ff302","order_by":0,"name":"Silvia Guiducci","email":"","orcid":"","institution":"University of Padova","correspondingAuthor":false,"prefix":"","firstName":"Silvia","middleName":"","lastName":"Guiducci","suffix":""},{"id":265334842,"identity":"ea81c359-dc6e-4698-82f7-3b21267d9867","order_by":1,"name":"Giulia Res","email":"","orcid":"","institution":"University of 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17:14:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3827863/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3827863/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00431-024-05532-4","type":"published","date":"2024-04-18T23:53:32+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49433449,"identity":"cb3218b9-2b4c-42d0-a433-0a5ed83d0bb9","added_by":"auto","created_at":"2024-01-10 19:10:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":35648,"visible":true,"origin":"","legend":"\u003cp\u003eBox plot of the percentage of time spent in hypoglycemia (\u0026lt;72mg/dL [\u0026lt;4 mmol/L]), hyperglycemia (\u0026gt;144mg/dL [\u0026gt;8 mmol/L]) and euglycemia (A) and daily nutrients’ intakes (g/kg) (B).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3827863/v1/449a440a7f8bf0fed01f5f5d.png"},{"id":49433450,"identity":"cd5d6b62-5878-4d71-8c49-026555ca5bcc","added_by":"auto","created_at":"2024-01-10 19:10:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":40970,"visible":true,"origin":"","legend":"\u003cp\u003eTime spent in hypo (\u0026lt;72 mg/dL [\u0026lt;4 mmol/L]) and hyperglycemia (\u0026gt;144 mg/dL[\u0026gt;8 mmol/L]) and birthweight\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3827863/v1/3d29aa117fb6bede83591a68.png"},{"id":49433451,"identity":"6fa95618-bcef-481c-90a6-0e863240f7c3","added_by":"auto","created_at":"2024-01-10 19:10:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":94044,"visible":true,"origin":"","legend":"\u003cp\u003eTime spent in hypo (\u0026lt;72 mg/dL [\u0026lt;4 mmol/L]) and hyperglycemia (\u0026gt;144 mg/dL, [ \u0026gt;8 mmol/L]) and macronutrient’s intakes over the three days of monitoring.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3827863/v1/eedde71051accc690cdc2c8d.png"},{"id":55696733,"identity":"ac4e83c2-d220-4343-a14e-f496d003a60e","added_by":"auto","created_at":"2024-05-02 01:54:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":493455,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3827863/v1/3533376c-433c-4bae-a6f9-f94b13697646.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of macronutrients intake on glycemic homeostasis of preterm infants : evidence from continuous glucose monitoring","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePreterm infants are exposed to large glucose fluctuations that could affect long-term neurodevelopment(1, 2)\u0026nbsp;and short-term clinically relevant outcomes as daily growth during the first weeks of life.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEarly aggressive parenteral nutrition\u0026nbsp;(3)\u0026nbsp;consists of supplementation of glucose, amino acids and lipids starting the first hours of neonatal life with a progressive increase of the daily intake generally driven by point-of-care glucose measures and weight change. This strategy seems to be effective at reducing the incidence of postnatal growth failure that, in turns, is associated to growth delay and neurodevelopment impairment(4). Nevertheless, preterm infants have low tolerance for parenteral glucose infusion with secondary hyperglycemia(3). This observation oftentimes leads to a more cautious increase of daily nutritional intakes in those receiving parenteral nutrition with a consequent impact on postnatal growth\u0026nbsp;(3).\u003c/p\u003e\n\u003cp\u003eRelying on the availability of CGM technology that allows a safe and accurate estimate of time spent in the hypo and hyperglycemic ranges in preterm infants(5, 6), we investigated the influence of macronutrient\u0026rsquo;s intake on glucose homeostasis of very low birth weight infants during the first week of life.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cb\u003eStudy design.\u003c/b\u003e We conducted a secondary analysis on the cohort of the BabyGlucolight Trial (NCT04347590), a monocentric randomized controlled study investigating the role of CGM on long-term neurodevelopment in preterm infants. The trial was approved by the Institutional Ethics Committee of the University Hospital of Padua (Italy) (4773/AO/19 AOP1813 and 5005/AO/21 AOP2216) and conducted according in accordance to the Declaration of Helsinki. Participants were enrolled from March 2020 to June 2023 at the Neonatal Intensive Care Unit (NICU) of the University Hospital of Padua.\u003c/p\u003e \u003cp\u003e\u003cb\u003eParticipants.\u003c/b\u003e Eligible subjects were preterm infants born\u0026thinsp;\u0026le;\u0026thinsp;32 weeks gestational age or with birth weight\u0026thinsp;\u0026le;\u0026thinsp;1500 g admitted to the NICU. Written informed parental consent was obtained before recruitment. Exclusion criteria were BW\u0026thinsp;\u0026lt;\u0026thinsp;500 g, congenital malformation, perinatal maternal infections and albinism. The baseline perinatal characteristics we collected include intrauterine growth restriction (IUGR), gestational diabetes and preterm premature rupture of membranes (pPROM); type of delivery (caesarean section or vaginal), Apgar Index, need for endotracheal intubation in delivery room (ET-DR). Postnatal characteristics were GA, sex, birthweight and small for gestational age (SGA) defined as weight percentile\u0026thinsp;\u0026lt;\u0026thinsp;10% of Intergrowth 21 charts for very preterm infants \u003csup\u003e16\u003c/sup\u003e. We also collected data to describe the course of the first days of life as clinical risk index for babies I score (CRIB I) \u003csup\u003e17\u003c/sup\u003e, surfactant administration during the first day of life \u003csup\u003e18\u003c/sup\u003e, episodes of early onset sepsis (EOS) - within the first 72 hours after birth- patent duct arteriosus (PDA) requiring medical treatment, daily weight change, defined as percentage of weight loss respect to BW, and mortality within the first month of life.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGlucose monitoring.\u003c/b\u003e CGM (Medtronic Guardian 3) was placed on the lateral side of the thigh after adequate disinfection and preceded by containment and analgesia with the use of pacifier and 0.3 ml 24% sucrose 2 minutes before the procedure. Sensor was placed within 48 hours of life and maintained for 5 days. The device was calibrated as per manufacturer\u0026rsquo;s instructions, with capillary blood glucose values measured by using an Accu-Chek Inform II glucometer (Roche Diabetes Care, Indianapolis, IN). CGM data were analyzed retrospectively to create glucose profile for each subject. Hypoglycemia was defined as sensor glucose value below 4 mmol/L; hyperglycemia was defined if sensor glucose value was above 8 mmol/L.\u003c/p\u003e \u003cp\u003e\u003cb\u003eMacronutrient\u0026rsquo;s intake.\u003c/b\u003e Daily macronutrients including glucose, lipids, and amino acids, were titrated based on day of life and following ESPGHAN guidelines \u003csup\u003e21\u0026ndash;23\u003c/sup\u003e. We collected both parenteral and enteral intakes during the glucose monitoring. Intravenous macronutrients were given through central venous catheter by personalized parenteral nutrition: glucose share was dextrose, lipid share was a mixed oil lipid emulsion (ClinOleic 20% \u0026reg;: 80% olive oil, 20% soybean oil); amino acids solution was Primene 10% \u0026reg;. Nutritional intake by enteral feeding were reported if milk volume was above 24 ml/kg/day, considered the upper limit of minimal enteral feeding \u003csup\u003e24\u003c/sup\u003e. Human milk was preferred to preterm formula.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cp\u003eThe primary outcome was the relationship between macronutrient\u0026rsquo;s intake and the frequency of hypoglycemia and hyperglycemia as recorded by the CGM.\u003c/p\u003e \u003cp\u003eData were analyzed using SPSS statistical software v 28.0 for Windows (SPSS, Chicago, IL) and Prism 10.0 (GraphPad Software, San Diego, CA). We excluded from the analysis those with less than 2 days of CGM data. The daily breakdown of glucose patterns was provided by day from CGM start. Macronutrients intakes were reported as g/kg/day. Categorical variables were expressed as number (%). Continuous variables were expressed as median and interquartile range. The relation between macronutrient\u0026rsquo;s intake, birthweight and time in hypo- and hyperglycemia was analyzed for each variable with a multivariate regression analysis adjusted for GA, sex and IUGR status. The significance level was set to p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003cp\u003eThe datasets generated and analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eWe analyzed data from thirty patients. Participants\u0026rsquo; neonatal and maternal characteristics are displayed in Table \u003cspan\u003e1\u003c/span\u003e. The total median time of CGM data was 67 hours and 57 minutes (61\u003csup\u003eh\u003c/sup\u003e11\u003csup\u003em\u003c/sup\u003e; 70\u003csup\u003eh\u003c/sup\u003e23\u003csup\u003em\u003c/sup\u003e). Glucose profiles are displayed in Fig. \u003cspan\u003e1\u003c/span\u003eA and supplemental Table\u0026nbsp;1. The median percentage of time in euglycemia was 88.5% (63.7; 97.3) on day 1 without a significant difference across the three days of monitoring.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Baseline characteristics of the cohort (n=30) expressed as median (IQR) or absolute number (%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/122228_c8a1650c59388082/122228_custom_files/img1704695100.png\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eFigure \u003cspan\u003e1\u003c/span\u003eB and supplemental Table\u0026nbsp;1 describe the daily macronutrients intake. As per protocol, glucose intakes were increased by a median of 2.5g/kg/day, from 8.0 g/kg/day (7,1; 9,4) on day 1 to 12.5 g/kg/day (11.0; 13,7) on day 3, while amino acids intakes raised from a median of 1.9 g/kg/day (1.4; 2.1) on day 1 to 3.0 g/kg/day (2.0; 3.7) on day 3, paralleled by the lipids intake [from 1.3g/kg/day (1.1;1.5) on day 1 to 2.6 g/kg/day (1.7;3.8) on day 3].\u003c/p\u003e\n\u003cp\u003eAs displayed in Fig. \u003cspan\u003e2\u003c/span\u003e, the birthweight was the strongest determinant of neonatal glucose profile in this cohort with an inverse relationship between the time spent in hyperglycemia during the first 3 days of monitoring and the birthweight (p\u0026thinsp;=\u0026thinsp;0.007, r=-0.54), that remained significant when adjusted for gestational age, sex and IUGR (p\u0026thinsp;=\u0026thinsp;0.023) (Fig. \u003cspan\u003e2\u003c/span\u003eB), while we did not observe a significant relationship between birthweight and the time spent in the hypoglycemic range (p\u0026thinsp;=\u0026thinsp;0.114) (Fig. \u003cspan\u003e2\u003c/span\u003eA). The influence of macronutrient\u0026rsquo;s intake on glucose profile is shown in Fig. \u003cspan\u003e3\u003c/span\u003e. The total intake of amino acids during the three days of monitoring was inversely associated with the time in hypoglycemia (p\u0026thinsp;=\u0026thinsp;0.011, r=-0.460), and lipids had a similar \u0026ndash; though non-significant \u0026ndash; relationship with the time in hypoglycemia (p\u0026thinsp;=\u0026thinsp;0.066, r=-0.268). Glucose\u0026rsquo;s intakes did not significantly affect the time in the hypoglycemic range (p\u0026thinsp;=\u0026thinsp;0.874) (Fig. \u003cspan\u003e3\u003c/span\u003eA). Conversely, the time in the hyperglycemic range over the first three days was affected by lipids intakes (p\u0026thinsp;=\u0026thinsp;0.031, r\u0026thinsp;=\u0026thinsp;0.238) (Fig. \u003cspan\u003e3\u003c/span\u003eB) but not by glucose (p\u0026thinsp;=\u0026thinsp;0.517, r\u0026thinsp;=\u0026thinsp;0.122) and amino acids intake (p\u0026thinsp;=\u0026thinsp;0.357, r\u0026thinsp;=\u0026thinsp;0.173).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study demonstrates the influence of macronutrient\u0026rsquo;s intake on glycemic homeostasis during the first week of life of very low birth weight infants wearing a CGM. Higher amino acids intake is associated with reduced time spent in the hypoglycemic range, whilst greater lipids intake increases the exposure to hyperglycemia. Birthweight remains a main determinant of neonatal hyperglycemia during the first week of life, confirming the increased risk for hyperglycemia in those with the lowest birthweights(\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eGlucose intake did not have a major effect on glycemic homeostasis \u003cem\u003eper se\u003c/em\u003e: although the relationship between daily glucose intake and neonatal glycemia remains controversial(\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e), herein we proved that glucose instability during PN in preterm infants is not exclusively related to parenteral glucose intake.\u003c/p\u003e\n\u003cp\u003eOur results were aligned with most studies describing a reduction of the hypoglycemic events with higher amino acids intake - between 2.5 g/kg/day and 4 g/kg/day(\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003emain mechanism to support the effect of parenteral lipids infusion on hyperglycemic risk seems to be the stimulation of gluconeogenesis through two components of the lipids infusion, glycerol and free-fatty acid (FFA)(\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe major novelty of our study stands in the use of CGM technology that provides a comprehensive load of data on the actual exposure to hypo- and hyper-glycemia rather than point-of-care measures of blood glucose. Previous studies investigating the influence of nutritional intakes on glycemic homeostasis, used intermittent glucose tests, while the use of continuous glucose measures unveiled that clinically silent hypo- and hyper-glycemia are associated with worse developmental outcomes in childhood (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe main limit of the study is the small sample size and the monocentric design. Even if CGM data were prospectively collected, they were retrospectively analyzed, therefore we cannot infer a causative relationship between the nutritional intakes and glucose control. Moreover, we assessed total macronutrients intake without considering the route of administration that may influence the impact on glucose homeostasis. However, parenteral amount was more than 60% of total intake for the entire cohort, thus making unlikely that the enteral intakes may have a major effect on glucose homeostasis.\u003c/p\u003e\n\u003cp\u003eCGM appears as a promising tool to individualize nutritional strategies in preterm infants during the first weeks of birth.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to the patients\u0026rsquo; families for participating to the study and to the medical and nursing staff of the NICU of the University Hospital of Padua.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAG, SB, DT and EB were involved in the study design, methodology, data variable creation, data acquisition design and reviewed the final version of the manuscript. SG, GR, FS, LB and EP contributed to the recruitment of participants and obtained consent. SG and AG analyzed and interpreted data. SG wrote the first draft. AG and SB obtained funding support. All the authors approved the final manuscript and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by\u0026nbsp;the Institute for Pediatric Research (IRP, Padova, Italy) Starting Grant 2020, University of Padova Star Grant and the Italian Ministry of Health Call for Proposals GR-RF 2019-12368539.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShah R, Harding J, Brown J, McKinlay C. Neonatal Glycaemia and Neurodevelopmental Outcomes: A Systematic Review and Meta-Analysis. Neonatology. 2019;115(2):116-26.\u003c/li\u003e\n\u003cli\u003ePaulsen ME, Brown SJ, Satrom KM, Scheurer JM, Ramel SE, Rao RB. Long-Term Outcomes after Early Neonatal Hyperglycemia in VLBW Infants: A Systematic Review. Neonatology. 2021;118(5):509-21.\u003c/li\u003e\n\u003cli\u003eStensvold HJ, Strommen K, Lang AM, Abrahamsen TG, Steen EK, Pripp AH, Ronnestad AE. Early Enhanced Parenteral Nutrition, Hyperglycemia, and Death Among Extremely Low-Birth-Weight Infants. JAMA Pediatr. 2015;169(11):1003-10.\u003c/li\u003e\n\u003cli\u003eCormack BE, Harding JE, Miller SP, Bloomfield FH. The Influence of Early Nutrition on Brain Growth and Neurodevelopment in Extremely Preterm Babies: A Narrative Review. Nutrients. 2019;11(9).\u003c/li\u003e\n\u003cli\u003eGalderisi A, Facchinetti A, Steil GM, Ortiz-Rubio P, Cavallin F, Tamborlane WV, et al. Continuous Glucose Monitoring In Very Preterm Infants: A Randomized Controlled Trial. Pediatrics [Internet]. 2017.\u003c/li\u003e\n\u003cli\u003eBeardsall K, Thomson L, Guy C, Iglesias-Platas I, van Weissenbruch M, Bond S, et al. Real-time continuous glucose monitoring in preterm infants (REACT): an international, open-label, randomised controlled trial. The Lancet Child \u0026amp; adolescent health. 2021;5(4).\u003c/li\u003e\n\u003cli\u003eBeardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, Palmer CR, Ong K, et al. Prevalence and determinants of hyperglycemia in very low birth weight infants: cohort analyses of the NIRTURE study. J Pediatr. 2010;157(5):715-9.e1-3.\u003c/li\u003e\n\u003cli\u003eBurattini I, Bellagamba MP, Spagnoli C, D\u0026apos;Ascenzo R, Mazzoni N, Peretti A, et al. Targeting 2.5 versus 4 g/kg/day of amino acids for extremely low birth weight infants: a randomized clinical trial. J Pediatr. 2013;163(5):1278-82 e1.\u003c/li\u003e\n\u003cli\u003ete Braake FW, van den Akker CH, Wattimena DJ, Huijmans JG, van Goudoever JB. Amino acid administration to premature infants directly after birth. J Pediatr. 2005;147(4):457-61.\u003c/li\u003e\n\u003cli\u003evan Kempen AA, van der Crabben SN, Ackermans MT, Endert E, Kok JH, Sauerwein HP. Stimulation of gluconeogenesis by intravenous lipids in preterm infants: response depends on fatty acid profile. Am J Physiol Endocrinol Metab. 2006;290(4):E723-30.\u003c/li\u003e\n\u003cli\u003eTottman AC, Alsweiler JM, Bloomfield FH, Pan M, Harding JE. Relationship between Measures of Neonatal Glycemia, Neonatal Illness, and 2-Year Outcomes in Very Preterm Infants. J Pediatr. 2017;188:115-21.\u003c/li\u003e\n\u003cli\u003eTottman AC, Bloomfield FH, Cormack BE, Harding JE, Mohd Slim MA, Weston AF, Alsweiler JM. Relationships Between Early Nutrition and Blood Glucose Concentrations in Very Preterm Infants. J Pediatr Gastroenterol Nutr. 2018;66(6):960-6.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Supplemental Table 1","content":"\u003cp\u003eSupplemental Table 1 is not available with this version\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3827863/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3827863/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eNutritional intake could influence blood glucose profile during early life of preterm infants. We investigated the impact of macronutrient\u0026rsquo;s intake, on glycemic homeostasis using continuous glucose monitoring(CGM).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe analyzed macronutrients intake in infants born\u0026thinsp;\u0026le;\u0026thinsp;32 weeks gestational age (GA) and/or with birth weight\u0026thinsp;\u0026le;\u0026thinsp;1500g enrolled. CGM was started within 48 hours of birth and maintained for 5 days. Hypoglycemia was defined as sensor glucose\u0026thinsp;\u0026lt;\u0026thinsp;4mmol/L, hyperglycemia\u0026thinsp;\u0026gt;\u0026thinsp;8 mmol/L.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eData from 30 participants were included[age 29.9weeks(29.1; 31.2), birthweight 1230.5g(1040.0; 1458.6)]. A reduced time in hypoglycemia was associated to higher amino acids intake(p\u0026thinsp;=\u0026thinsp;0.011) while increased exposure to hyperglycemia was observed in presence of higher lipids intake(p\u0026thinsp;=\u0026thinsp;0.031). The birthweight was the strongest determinant of neonatal glucose profile with an inverse relationship between the time spent in hyperglycemia and birthweight (p\u0026thinsp;=\u0026thinsp;0.007).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCGM allowed, for the first time, to describe the relationship between macronutrient\u0026rsquo;s intake and glycemic homeostasis in preterm infants.\u003c/p\u003e","manuscriptTitle":"Impact of macronutrients intake on glycemic homeostasis of preterm infants : evidence from continuous glucose monitoring","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-10 19:10:14","doi":"10.21203/rs.3.rs-3827863/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-01-31T18:13:08+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-01-19T02:11:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"c8a91e6b-fe98-438e-b371-1bef94bc19c0","date":"2024-01-09T09:30:26+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-08T16:23:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-05T04:02:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-05T04:02:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2024-01-01T17:02:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4c9d2da1-ac03-42cb-954c-a8e85084f2cd","owner":[],"postedDate":"January 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-05-01T23:53:32+00:00","versionOfRecord":{"articleIdentity":"rs-3827863","link":"https://doi.org/10.1007/s00431-024-05532-4","journal":{"identity":"european-journal-of-pediatrics","isVorOnly":false,"title":"European Journal of Pediatrics"},"publishedOn":"2024-04-18 23:53:32","publishedOnDateReadable":"April 18th, 2024"},"versionCreatedAt":"2024-01-10 19:10:14","video":"","vorDoi":"10.1007/s00431-024-05532-4","vorDoiUrl":"https://doi.org/10.1007/s00431-024-05532-4","workflowStages":[]},"version":"v1","identity":"rs-3827863","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3827863","identity":"rs-3827863","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}