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The purpose of the study is to assess the prevalence of glucose disturbances (dysglycemia) in very low birth weight (VLBW) infants at 36 weeks postmenstrual age (PMA) using a continuous glucose monitoring (CGM) system and to identify possible risk factors for these disturbances. A prospective observational cohort study (VLBW Infants—Glucose and Hormonal Profiles over Time; LIGHT) included 35 VLBW infants admitted to a single tertiary neonatal intensive care unit during 2016–2019. Perinatal data were registered prospectively. CGM registration was performed at 36 weeks PMA for a period of 48 h. Protracted hyperglycemia and hypoglycemia were defined as > 30 min with glucose concentrations > 8 mmol/L or < 2.6 mmol/L, respectively. A total of 19,907 measurements were retrieved and analyzed. Protracted dysglycemia was found in 68.6% of infants, with 51% of infants experiencing hyperglycemia (4.5% of registration time) and 40% experiencing hypoglycemia (1.2% of registration time). Male sex was associated with longer time spent in hyperglycemia. Insulin treatment prior to 36 weeks PMA was associated with longer time spent in hypoglycemia. CGM values correlated strongly with capillary glucose measurements, and no values fell within clinically dangerous ranges.

Conclusion: Protracted dysglycemia is common in VLBW infants even at 36 weeks PMA. Identification of risk factors for dysglycemia might help delineate certain patients in need of careful monitoring of glucose concentrations even when nearing term age. CGM is a promising tool for glucose monitoring in the neonatal intensive care unit.

Aim: Neonatal hyperglycaemia is associated with a multitude of adverse outcomes, including mortality and impaired neurological development. The aim of this study was to characterise the current management of neonatal hyperglycaemia in Swedish neonatal units.

Methods: A digital survey was sent to 27 Swedish neonatal units providing care to preterm infants born before 32 completed gestational weeks.

Results: Sixty-eight responses were collected from 21 different units. Thirty-two percent (22/68) of clinicians reported having a local treatment guideline for neonatal hyperglycaemia. Hyperglycaemia was defined as a glucose concentration above a value in the range of 8.0–10.0 mmol/L by 62.5% of clinicians, while 16.7% and 21.8% used a definition between 10.1 and 12.0 mmol/L and > 12 mmol/L, respectively. Intravenous glucose reduction was initiated at higher glucose concentrations by clinicians working at university hospital units (p = 0.006). Glucose concentration threshold for initiation of insulin treatment varied between 8 and 30 mmol/L. Three clinicians (3/35 (8.5%)) reported having experienced problems with frequent hypoglycaemia during ongoing insulin treatment.

Conclusions: This study demonstrates extensive differences in clinical practice regarding neonatal hyperglycaemia both within and between neonatal units in Sweden. Randomised controlled trials are needed to provide evidence for clinical guidelines and to improve and standardise the care of these infants.

Aim: To describe glucose homeostasis disturbances (dysglycaemia) in very low-birthweight infants (<1500 g) during the admission period and explore associated risk factors.

Methods: The LIGHT (very low-birthweight infants - glucose and hormonal profile over time) study was a prospective observational cohort study that included 49 very low-birthweight infants admitted to the tertiary neonatal intensive care unit in Umeå, Sweden, during 2016–2019. All glucose concentrations (n = 3515) sampled during the admission period were registered.

Results: Hyperglycaemia >10 mmol/L and hypoglycaemia <2.6 mmol/L were registered in 63% and 55% of the infants, respectively. Onset of dysglycaemia occurred almost exclusively in the first postnatal week. Hyperglycaemia followed 15% of corticosteroid doses given; all were preceded by pre-existing hyperglycaemia. Pre-existing hyperglycaemia was found in 66.7% of hyperglycaemic infants who received inotrope treatment. Upon commencement, 72.5% of antimicrobial treatments given were neither preceded nor followed by hyperglycaemia.

Conclusion: Dysglycaemia was common in very low-birthweight infants. Daily means of glucose concentrations seemed to follow a postmenstrual age-dependent pattern, decreasing towards term age suggesting a postmenstrual age-dependent developmental mechanism. The primary mechanism causing hyperglycaemia was independent of sepsis, and corticosteroid and inotrope treatments. No hypoglycaemia was registered during ongoing insulin treatment.

Background: Bovine colostrum (BC) contains a range of milk bioactive components, and it is unknown how human milk fortification with BC affects glucose-regulatory hormones in very preterm infants (VPIs). This study aimed to investigate the associations between hormone concentrations and fortification type, birth weight (appropriate/small for gestational age, AGA/SGA), milk intake, postnatal age, and body growth.

ethods: 225 VPIs were randomized to fortification with BC or conventional fortifier (CF). Plasma hormones were measured before, one and two weeks after start of fortification. ΔZ-scores from birth to 35 weeks postmenstrual age were calculated.

Results: Compared with CF, infants fortified with BC had higher plasma GLP-1, GIP, glucagon, and leptin concentrations after start of fortification. Prior to fortification, leptin concentrations were negatively associated with growth, while IGF-1 concentrations associated positively with growth during fortification. In AGA infants, hormone concentrations generally increased after one week of fortification. Relative to AGA infants, SGA infants showed reduced IGF-1 and leptin concentrations.

Conclusion: Fortification with BC increased the plasma concentrations of several glucose-regulatory hormones. Concentrations of IGF-1 were positively, and leptin negatively, associated with growth. Glucose-regulatory hormone levels were affected by birth weight, milk intake and postnatal age, but not closely associated with growth in VPIs.

Impact:

• Little is known about the variation in glucose-regulatory hormones in the early life of very preterm infants (VPIs).
• This study shows that the levels of glucose-regulatory hormones in plasma of VPIs are highly variable and modified by birth weight (appropriate or small for gestational age, AGA or SGA), the type of fortifier, enteral nutritional intake, and advancing postnatal age.
• The results confirm that IGF-1 levels are positively associated with early postnatal growth in VPIs, yet the levels of both IGF-1 and other glucose-regulatory hormones appeared to explain only a small part of the overall variation in growth rates.

Objective: To evaluate whether implementing a nutritional care bundle is associated with growth and morbidity in very preterm (VPT) infants.

Study design: This study compared 87 VPT infants (<32 gestational weeks) born 2018 (Before group) with 75 infants born 2020 (After group), treated at a single center in the Czech Republic. A nutritional care bundle was implemented during 2019.

Results: Median gestational age (weeks) was 30.0 [IQR 27.6-31.1] for the Before group and 29.9 [IQR 27.9-30.6] for the After group. During postnatal days 1-14, parenteral fluid intake was significantly lower in the After group compared to the Before group and conversely for enteral fluid intake. Infants in the After group achieved full enteral feeds by postnatal day 14 (72.9 % vs. Before group 51.9 %). Weight z-scores decreased significantly less from birth to 36 weeks postmenstrual age in the After group (-0.8 [IQR -1.3 to -0.5]) compared to the Before group (-1.5 [IQR -2.0 to -1.2]). Head circumference z-scores decreased significantly less in the After group (-0.8±0.9) than the Before group (-1.6±1.1). Decreased rate of patent ductus arteriosus (PDA) requiring treatment was observed in the After group (P < 0.001).

Conclusions: Implementation of a nutritional care bundle in VPT infants was associated with improved postnatal growth and may reduce treatment-requiring PDA.

Objective: To explore the glucose-related hormone profile of very low birthweight (VLBW) infants and assess the association between neonatal hyperglycaemia and insulin resistance during the admission period.

Design: A prospective observational study—the Very Low Birth Weight Infants, Glucose and Hormonal Profiles over Time study.

Setting: A tertiary neonatal intensive care unit and four neonatal units in county hospitals in Sweden.

Patients: 48 infants born <1500 g (VLBW) during 2016–2019.

Outcome measures: Plasma concentrations of glucose-related hormones and proteins (C-peptide, insulin, ghrelin, glucagon-like peptide 1 (GLP-1), glucagon, leptin, resistin and proinsulin), insulin:C-peptide and proinsulin:insulin ratios, Homoeostatic Model Assessment 2 (HOMA2) and Quantitative Insulin Sensitivity Check (QUICKI) indices, measured on day of life (DOL) 7 and at postmenstrual age 36 weeks.

Results: Lower gestational age was significantly associated with higher glucose, C-peptide, insulin, proinsulin, leptin, ghrelin, resistin and GLP-1 concentrations, increased HOMA2 index, and decreased QUICKI index and proinsulin:insulin ratio. Hyperglycaemic infants had significantly higher glucose, C-peptide, insulin, leptin and proinsulin concentrations, and lower QUICKI index, than normoglycaemic infants. Higher glucose and proinsulin concentrations and insulin:C-peptide ratio, and lower QUICKI index on DOL 7 were significantly associated with longer duration of hyperglycaemia during the admission period.

Conclusions: VLBW infants seem to have a hormone profile consistent with insulin resistance. Lower gestational age and hyperglycaemia are associated with higher concentrations of insulin resistance markers.

Introduction: Neonatal hypoglycemia is a common complication associated with gestational diabetes and therefore relevant to consider in evaluations of maternal treatment. We aimed to investigate the risk of neonatal hypoglycemia in offspring exposed to metformin treatment alone (MT) or combined with insulin (MIT) in comparison with nutrition therapy alone (NT), and insulin treatment alone (IT). In addition, we investigated MT in comparison with MIT. Secondary outcomes included neonatal anthropometrics, respiratory morbidity, hyperbilirubinemia, 5-min Apgar score, and preterm birth.

Material and methods: This Swedish population-based cohort included 16 181 women diagnosed with gestational diabetes, and their singleton offspring born in 2019–2021. We estimated risk as adjusted odds ratio (aOR) with 95% confidence interval (CI), using individual-level, linkage register-data in multivariable logistic regression models.

Results: In the main analysis, MT was associated with a lower risk of neonatal hypoglycemia versus NT (aOR 0.85, 95% CI: 0.74–0.96), versus MIT (0.74 [0.64–0.87]), and versus IT (0.47 [0.40–0.55]), whereas MIT was associated with a similar risk of neonatal hypoglycemia versus NT (1.14 [0.99–1.30]) and with lower risk versus IT (0.63 [0.53–0.75]). However, supplemental feeding rates were lower for NT versus pharmacological treatments (p < 0.001). In post hoc subgroup analyses including only exclusively breastfed offspring, the risk of neonatal hypoglycemia was modified and similar among MT and NT, and higher in MIT versus NT. Insulin exposure, alone or combined with metformin, was associated with increased risk of being large for gestational age. Compared with NT, exposure to any pharmacological treatment was associated with significantly lower risk of 5-min Apgar score < 4. All other secondary outcomes were comparable among the treatment categories.

Conclusions: The risk of neonatal hypoglycemia appears to be comparable among offspring exposed to single metformin treatment and nutrition therapy alone, and the lower risk that we observed in favor of metformin is probably explained by a difference in supplemental feeding practices rather than metformin per se. By contrast, the lower risk favoring metformin exposure over insulin exposure was not explained by supplemental feeding. However, further investigations are required to determine whether the difference is an effect of metformin per se or mediated by other external factors.

Survivors of extremely preterm birth (gestational age < 27 weeks) have been reported to exhibit an altered cardiovascular phenotype in childhood. The mechanisms are unknown. We investigated associations between postnatal nutritional intakes and hyperglycemia, and left heart and aortic dimensions in children born extremely preterm. Postnatal nutritional data and echocardiographic dimensions at 6.5 years of age were extracted from a sub-cohort of the Extremely Preterm Infants in Sweden Study (EXPRESS; children born extremely preterm between 2004–2007, n = 171, mean (SD) birth weight = 784 (165) grams). Associations between macronutrient intakes or number of days with hyperglycemia (blood glucose > 8 mmol/L) in the neonatal period (exposure) and left heart and aortic dimensions at follow-up (outcome) were investigated. Neonatal protein intake was not associated with the outcomes, whereas higher lipid intake was significantly associated with larger aortic root diameter (B = 0.040, p = 0.009). Higher neonatal carbohydrate intake was associated with smaller aorta annulus diameter (B = −0.016, p = 0.008). Longer exposure to neonatal hyperglycemia was associated with increased thickness of the left ventricular posterior wall (B = 0.004, p = 0.008) and interventricular septum (B = 0.004, p = 0.010). The findings in this study indicate that postnatal nutrition and hyperglycemia may play a role in some but not all long-lasting developmental adaptations of the cardiovascular system in children born extremely preterm.

Objective: To assess the associations between neonatal hyperglycaemia and insulin treatment, versus long-Term neurodevelopmental outcomes in children born extremely preterm.

Design and setting: Observational national cohort study (Extremely Preterm Infants in Sweden Study) using prospectively and retrospectively collected data. Neurodevelopmental assessment was performed at 6.5 years of age.

Patients: 533 infants born <27 gestational weeks during 2004-2007; 436 survivors were assessed at 6.5 years.

Outcome measures: Neurodevelopmental disability (NDD), survival without moderate to severe NDD, Wechsler Intelligence Scale for Children IV Full scale intelligence quotient (WISC-IV FSIQ) and Movement Assessment Battery for Children 2 (MABC-2) total score.

Results: Duration of neonatal hyperglycaemia >8 mmol/L was associated with WISC-IV scores-for each day with hyperglycaemia there was a decrease of 0.33 points (95% CI 0.03 to 0.62) in FSIQ. Neonatal hyperglycaemia >8 mmol/L occurring on 3 consecutive days was associated with lower MABC-2 scores (adjusted mean difference:-4.90; 95% CI-8.90 to-0.89). For each day with hyperglycaemia >8 mmol/L, there was a decrease of 0.55 points (95% CI 0.17 to 0.93) in MABC-2 total score. Insulin treatment was not associated with any of the outcome measures.

Conclusion: Neonatal hyperglycaemia >8 mmol/L was associated with lower intelligence scores and worse motor outcomes at 6.5 years of age. Insulin treatment was not associated with either worsened or improved neurodevelopmental outcomes. Randomised controlled trials are needed to clarify the role of insulin in treating hyperglycaemia in extremely preterm infants.

Background

Survival among very low birth weight (VLBW) and extremely preterm (EPT) infants has increased markedly during the last decades. Neonatal hyperglycemia is common in these infants and is known to be associated with adverse outcomes. However, much about neonatal hyperglycemia is still unknown: which mechanisms are responsible for it, its long-term risk profile, how to treat it and even how to define it. This thesis focuses on neonatal hyperglycemia in preterm-born infants - its prevalence, possible causes (including postnatal nutrition and its possible programming effect of later outcomes), consequences and treatment.

Methods

Two cohorts were studied in this thesis. The EXtremely PREterm infants in Sweden Study (EXPRESS) – a national population-based cohort - included all infants born before completed 27 gestational weeks during the years 2004-2007 in Sweden. Nutritional data as well as glucose measurements (n=9850) and insulin treatment data for the first 28 days of life were obtained for 580 infants. In a sub-cohort of 171 children, blood pressure measurements were obtained at a follow-up visit at 6.5 years of age. Neurodevelopment was assessed at 6.5 years of age in 436 children. Intellectual ability was assessed using Wechsler Intelligence Scale for Children IV (WISC-IV; n=355). Gross and fine motor function were assessed using Movement Assessment Battery for Children 2 (MABC-2; n=345).

The very Low birth weight Infants - Glucose and Hormonal profiles over Time (LIGHT) study was a prospective cohort study that included 50 VLBW infants born in Umeå, Sweden, between 2016-2019. Infants were placed on continuous glucose monitoring (CGM) for a 48-hour period when a postmenstrual age (PMA) of 36 gestational weeks was reached (n=35).

Results

Daily prevalence of hyperglycemia > 10 mmol/L in EPT infants was high during the first two weeks of life (up to 30%), followed by a slow decrease thereafter. Protracted hyperglycemia > 8 mmol/L was detected in more than half of VLBW infants at PMA 36 weeks.

In EPT infants, glucose concentrations during the first 28 days of life were increased by 1.6% on the day following an increase of 1 g/kg/day in parenteral carbohydrate intake. Male sex, amnionitis and prior hypoglycemia and hyperglycemia episodes were risk factors for hyperglycemia at PMA 36 weeks in VLBW infants.

In EPT infants, neonatal hyperglycemia > 10 mmol/L was associated with increased 28-day mortality. Neonatal hyperglycemia, its severity and duration were associated with increased diastolic blood pressure (DBP) and lower MABC-2 scores at 6.5 years of age. Insulin treatment was associated with improved 28- and 70-day survival but not with BP or neurodevelopmental outcomes at 6.5 years of age.

Higher protein intake during the first eight weeks of life was associated with higher DBP at 6.5 years of age. An increase of the carbohydrate intake by 1 g/kg/day during this period was associated with an increase of 0.18 SDS in systolic (SBP) and 0.14 SDS in DBP at 6.5 years. Growth during the same period was not associated with BP at 6.5 years.

Conclusions

Neonatal hyperglycemia during the first four weeks of life was more common in EPT infants than has previously been described. Remaining glucose disturbances were common at PMA 36 weeks in VLBW infants. Parenteral glucose intakes within the range given seems to have had low contribution to glucose concentration variability. Neonatal hyperglycemia was associated with increased 28-day mortality as well as with increased blood pressure and reduced motor skills at 6.5 years of age. Carbohydrate intake in the immediate postnatal period was indepentently associated with increased blood pressure at 6.5 years of age. The results add to the knowledge regarding important risk factors and health effects of neonatal hyperglycemia. Different treatment options for neonatal hyperglycemia should be evaluated in animal models and in randomized controlled clinical trials in premature infants.

Bakgrund

Överlevnaden hos för tidigt födda barn har förbättrats markant under de senaste decennierna. Hos dessa barn är förhöjda blodsockernivåer under de första 28 dagarna av livet (neonatal hyperglykemi) vanligt förekommande och är förknippat med sämre kortsiktiga hälsoutfall. Mycket kvarstår som inte är känt kring neonatal hyperglykemi: vilka mekanismer som orsakar det, vad de långsiktiga hälsoutfallen blir, hur hyperglykemi bör behandlas samt hur den bör definieras. Denna avhandling fokuserar på neonatal hyperglykemi hos för tidigt födda barn, dess förekomst, eventuella riskfaktorer, konsekvenser och behandling. Gällande riskfaktorer undersöktes bland annat den näring som tillförs spädbarnet i början av livet och dess möjliga påverkan på hälsoutfall senare i livet.

Metoder

Delarbeten I-III är baserade på data från EXtremely PREterm infants in Sweden Study (EXPRESS) – en nationell populationsbaserad studie som inkluderade alla barn som föddes i Sverige före 27 graviditetsveckor under åren 2004–2007. Data kring nutrition, blodsockernivåer (totalt 9850 värden) samt insulinbehandling registrerades dagligen för de första 28 dagarna av livet hos 580 barn. Hos en grupp som inkluderade 171 av dessa barn mättes blodtryck vid en uppföljning vid 6,5-års ålder. Neurologisk utveckling utvärderades hos 436 barn vid 6,5-års ålder. Kognitiv utveckling utvärderades med hjälp av Wechsler Intelligence Scale for Children IV (WISC-IV) hos 355 barn. Grov- och finmotorisk funktion utvärderades med hjälp av Movement Assessment Battery for Children 2 (MABC-2) hos 345 barn.

Delarbete IV är baserat på the very Low birth weight Infants - Glucose and Hormonal profiles over Time (LIGHT) studien, en prospektiv studie som inkluderade 50 barn med mycket låg födelsevikt (< 1500 g) som föddes i Umeå under åren 2016-2019. En kontinuerlig blodsockermätare sattes på 35 av barnen för en 48-timmars period vid en ålder motsvarande 36 graviditetsveckor.

Resultat

Förekomsten av neonatal hyperglykemi hos extremt för tidigt födda barn ökade under de första två veckorna av livet och sjönk därefter långsamt under efterföljande veckor. Hyperglykemi förekom hos mer än hälften av barnen med mycket låg födelsevikt, kontrollerat vid ålder motsvarande 36 graviditetsveckor.

Blodsockernivåerna hos extremt för tidigt födda barn ökade med 1,6% dagen efter en ökning av glukos (socker i näringslösning) med 1 g/kg/dag. Hos barn med mycket låg födelsevikt hade pojkar större risk än flickor att få hyperglykemi vid en ålder motsvarande 36 graviditetsveckor. Även infektion i fostervattnet och tidigare blodsockerrubbningar under vårdperioden var riskfaktorer för hyperglykemi.

Neonatal hyperglykemi var förknippat med ökad dödlighet före 28 dagars ålder hos extremt för tidigt födda barn. Insulinbehandling var förknippad med bättre överlevnad vid både 28- och 70 dagars ålder. Förekomsten, svårighetsgraden och durationen av neonatal hyperglykemi visade samband med högre diastoliskt blodtryck och lägre MABC-2 score vid 6,5-års ålder. Insulinbehandling hade inget statistiskt samband med dessa utfall.

Högre proteinintag under de första åtta veckorna av livet visade samband med högre diastoliskt blodtryck vid 6,5-års ålder. Ökning i kolhydratintaget under denna period var förknippad med ökat systoliskt och diastoliskt blodtryck vid 6,5-års ålder. Tillväxten under samma period var inte statistiskt kopplad till senare blodtrycksnivå.

Slutsatser

Neonatal hyperglykemi visades vara vanligare hos extremt för tidigt födda barn än man tidigare trott. Resultaten tyder på att blodsockerrubbningar verkar vara vanliga även vid en ålder motsvarande 36 graviditetsveckor hos barn med mycket låg födelsevikt. Tillförsel av glukos (sockerdropp) verkar vara associerad med enbart ringa påverkan på blodsockernivåerna. Neonatal hyperglykemi var förknippat med ökad dödlighet före 28 dagars ålder samt med förhöjt blodtryck och sämre motorisk utveckling vid 6,5-års ålder. Ökat kolhydratintag under de första åtta veckorna i livet visade statistiskt samband med förhöjt blodtryck vid 6,5-års ålder. Resultaten bidrar med kunskap kring viktiga riskfaktorer för neonatal hyperglykemi och dess påverkan på hälsoutfall upp till 6,5-års ålder. Olika behandlingsalternativ för neonatal hyperglykemi bör utvärderas i djurmodeller samt i randomiserade kontrollerade kliniska studier hos för tidigt födda barn.