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Original research
Neonatal hyperinsulinism: a retrospective study of presentation and management in a tertiary neonatal intensive care unit in the UK
  1. Maria-Sofia Kalogeropoulou1,
  2. Helen Couch2,
  3. Ajay Thankamony3,
  4. Kathy Beardsall4,5
  1. 1 University of Cambridge School of Clinical Medicine, Cambridge, UK
  2. 2 Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
  3. 3 Paediatric Endocrinology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
  4. 4 Neonatal Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
  5. 5 Academic Department of Paediatrics, University of Cambridge, Cambridge, UK
  1. Correspondence to Dr Kathy Beardsall; kb274{at}medschl.cam.ac.uk

Abstract

Objective Reports of hyperinsulinism typically focus on infants managed by highly specialised services. However, neonates with hyperinsulinism are initially managed by neonatologists and often not referred to specialists. This study aimed to characterise the diversity in presentation and management of these infants.

Setting Level 3 neonatal intensive care.

Patients Neonates with hyperinsulinism, defined as blood glucose <2.8 mmol/mL and insulin level >6 pmol/L.

Design 7-year retrospective study (January 2015–December 2021).

Results 99 cases were identified: severe—treated with diazoxide (20%), moderate—clinically concerning hyperinsulinism not treated with diazoxide (30%), mild—biochemical hyperinsulinism (50%). Birth weight z-score was −1.02±2.30 (mean±SD), 42% were preterm, but neither variable correlated with clinical severity. The severe group received a higher concentration of intravenous glucose (27±12%) compared with the moderate (15±7%) and mild (16±10%) groups (p<0.001). At diagnosis, the intravenous glucose intake was similar in the severe (7.43±5.95 mg/kg/min) and moderate (5.09±3.86 mg/kg/min) groups, but higher compared with the mild group (3.05+/2.21 mg/kg/min) (p<0.001). In the severe group, term infants started diazoxide earlier (9.9±4.3 days) compared with preterm (37±26 days) (p=0.002). The national congenital hyperinsulinism service was consulted for 23% of infants, and 3% were transferred.

Conclusions This study highlights the diversity in clinical presentation, severity and prognosis of neonatal hyperinsulinism, irrespective of birth weight and gestational age. More infants were small rather than large for gestational age, and the majority had transient hyperinsulinism and were not referred to the national centre, or treated with diazoxide. Further research is required to understand the breadth of neonatal hyperinsulinism and optimal management.

  • Neonatology
  • Endocrinology
  • Intensive Care Units, Neonatal

Data availability statement

Data are available upon reasonable request. Data available on request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/archdischild-2024-327322

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Hypoglycaemia is a common finding in newborns and may be associated with hyperinsulinism.

    • The clinical course of hyperinsulinism, whether transient or persistent, and the long-term neurodevelopmental outcomes of an affected infant are difficult to predict at presentation.

    • Transient and persistent hyperinsulinism increase the risk of permanent neurological damage.

    WHAT THIS STUDY ADDS

    • This study provides insight into the diverse nature of neonatal hyperinsulinism and provides evidence of the burden of this condition on families and the healthcare system.

    • This study demonstrates the high prevalence of preterm and small for gestational age infants presenting with neonatal hyperinsulinism, despite it being classically associated with infants who are large for gestational age.

    • This study highlights the wide variation in age at which diazoxide is started, depending on the gestational age of the affected infant.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • This study highlights the importance of clinical teams to consider hyperinsulinism early in the management of neonates with hypoglycaemia, irrespective of birth weight or gestational age.

    • This study emphasises the need for further research to better understand the variations in clinical care of neonatal hyperinsulinism across the country.

    • Future prospective studies are essential to understand the impact of different management strategies on long-term neurodevelopmental outcomes in infants with neonatal hyperinsulinism.

    Introduction

    Hypoglycaemia is the third most common reason for admission of term infants to neonatal intensive care units (NICUs).1 Hyperinsulinaemic hypoglycaemia presents with a spectrum of severity within the neonatal period: from the physiological phenomenon of transitional hypoglycaemia to persistent hyperinsulinism.2 3 Insulin inhibits lipolysis and ketone body synthesis, and without alternative fuels, neuroglycopaenia can result in neurological damage.4 Both severity and duration of hypoglycaemia correlate with neurodisability.5–7

    Transitional hyperinsulinism is a physiological adaptation to life ex utero due to the persistence of the lower fetal glucose threshold for insulin release and usually resolves within 48 hours.8 Transient hyperinsulinism has a range of aetiologies and can last from days to several months.9 Despite its self-resolving course, transient hyperinsulinism can be severe, with similar risks of neurological damage and developmental delays as persistent hyperinsulinism.5 10–13 Persistent hyperinsulinism is predominately genetic, histologically may be focal or diffuse, and imaging can help delineate further management.14 The clinical course of an affected neonate is difficult to predict; classification as transitional, transient or persistent is commonly retrospective but can be assisted by rapid genetic testing.15 Oral diazoxide is the first-line treatment for hyperinsulinism with unresolving hypoglycaemia.14

    In the USA, the incidence of neonatal hyperinsulinism has been reported to be increasing,16 and there are concerns about diazoxide’s side effects in preterm infants.17 In the UK, previous studies have mainly focused on the characterisation of hyperinsulinism after referral to national specialist services. In this study, we explored the spectrum of disease presentation and its management in a tertiary NICU.

    Methods

    Data collection

    We performed a retrospective study of infants with neonatal hyperinsulinism cared for at Cambridge University Hospital NHS Trust (Level 3 NICU), over 7 years (January 2015–December 2021). Cases were identified from three separate databases: electronic medical records, clinical biochemistry database (all insulin tests ordered by the NICU) and Badgernet(national e-portal for maternity/neonatal records) (online supplemental appendix 1). Hyperinsulinism was defined as blood glucose (BG) <50 mg/dL (<2.8 mmol/mL) and insulin >1 μU/mL (>6 pmol/L).18 Data were collected on maternal health and neonatal care (online supplemental appendix 2).

    Standard clinical practice

    The unit’s standard clinical practice is to routinely monitor BG levels in asymptomatic at-risk infants and in those with clinical concerns. When hypoglycaemia is identified (BG <2.6 mmol/L), infants are initially managed by advancing enteral feeds and intravenous dextrose (5 mg/kg/min). Additional investigations to determine the aetiology (‘hypoglycaemia screen’, online supplemental appendix 3) are indicated in the setting of severe hypoglycaemia (BG <1.5 mmol/L), recurrent BG <2.6 mmol/L or an intravenous glucose requirement >8 mg/kg/min. Clinical practice is to maintain BG levels >2.6 mmol/L unless there is clinical suspicion or biochemical evidence of hyperinsulinaemia. Infants diagnosed with hyperinsulinism are discussed with the national hyperinsulinism service at Great Ormond Street Hospital (GOSH) before diazoxide is started. Before starting diazoxide, infants are fluid restricted (130 mL/kg/day), start chlorothiazide and have a baseline echocardiogram. If diazoxide (≤7 mg/kg/day) achieves a satisfactory glucose response, infants undergo a fasting tolerance test prior to discharge and are followed-up by GOSH. If BG stability is not achieved on this dose, infants are transferred to GOSH for further management.

    Data analysis

    The cohort was divided into subgroups based on clinical severity: (1) Severe: treated with diazoxide. (2) Moderate: clinically concerning hyperinsulinism not treated with diazoxide (criteria included coding of hyperinsulinism in clinical records, >1 hypoglycaemia screen, fasting tolerance test prior to discharge). (3) Mild: biochemical evidence of hyperinsulinism not fitting any of the above criteria for persistent clinical concern. Gestational age (GA) subgroups were defined as (1) very preterm: GA <32 weeks, (2) preterm: GA (32, 37 weeks) and (3) term: GA >37 weeks.19 Birth weight z-score subgroups were defined as (1) small for gestational age (SGA): z-score <−1.65 (<5th centile), (2) normal for gestational age (NGA): z-score (−1.65, 1.65) and (3) large for gestational age (LGA): z-score >1.65 (>95th centile).20

    Statistical analyses were performed in Microsoft Excel and R. We used analysis of variance with post hoc Tukey analysis for subgroups of clinical severity, birth weight and GA, χ2 test with Bonferroni correction for ratios of categorical variables, t-tests for subgroups of maternal diabetes and genetic diagnosis.

    Results

    Demographics

    The demographic and clinical details of the cohort (n=99) are summarised in table 1 and figure 1A. In our cohort, 77 (78%) were born locally, 58% of which had a primary diagnosis of hypoglycaemia. Other primary reasons for admission included prematurity <35 weeks of gestation (32%), respiratory distress (13%), high lactate (12%) and jaundice (5%). Regional hospitals transferred 22 (22%) infants, including 7 (32%) primarily due to hypoglycaemia. In terms of GA, 42% infants were preterm (<37 weeks), 29% of which <32 weeks. Mean (±SD) birth weight z-score was −1.02±2.30, 12% were LGA and 35% were SGA (figure 1B). Infants stayed in the hospital for 23.8±26.5 days.

    View this table:
    Table 1

    Demographic and clinical details

    Figure 1
    Figure 1

    Patient demographics. (A) Number of infants who underwent a hypoglycaemia screen per year and the number of infants with hyperinsulinism. Hyperinsulinism is defined as glucose <50 mg/dL / <2.8 mmol/mL and insulin (>1 μU/ml=>6 pmol/L). (B) Density function of the birth weight z-score of our cohort (aqua), mean z-score of −1.02, and SD of 2.30, compared with the expected density distribution of the general population (red). (C) Density function of the birth weight z-score per clinical severity group. Dashed lines indicate the 5th centile (z-score=−1.65), 50th centile (z-score=0) and 95th centile (z-score=+1.65). (D) Stacked bar chart of the percent of term (GA >37 weeks), preterm (GA 32–37 weeks) and very preterm infants (GA <32 weeks) per clinical severity group. (E) Stacked bar chart of the percent of SGA (z-score <−1.65), NGA (z-score (−1.65, +1.65)) and LGA (z-score >1.65) infants, per clinical severity group. GA, gestational age; HI, hyperinsulinism; LGA, large for gestational age; NGA, normal for gestational age; SGA, small for gestational age.

    Characteristics of the clinical severity groups

    Twenty (20%) infants were classified as Severe, 30 (30%) as Moderate and 49 (50%) as Mild. Birth weight z-score, gestational age and presence of maternal diabetes were not statistically different between groups (table 2). Preterm, SGA and LGA infants were equally distributed across clinical severity groups (figure 1D,E). Approximately half the infants in each group were admitted with a primary diagnosis of hypoglycaemia (45%, 63% and 49% of the severe, moderate and mild groups, respectively). Only 23 infants were discussed with the national congenital hyperinsulinism service at GOSH, including 17 (85%) severe and 6 (30%) moderate infants (table 2). Those with severe disease received a higher maximum concentration of dextrose compared with both moderate and mild (p<0.001, figure 2B).

    View this table:
    Table 2

    Clinical severity groups

    Figure 2
    Figure 2

    Diagnosis of hyperinsulinism. (A) Scatter plot of intravenous (IV) glucose intake (mg/kg/min) over the birth weight z-score, coloured per clinical severity group. Dashed lines indicate the 5th centile (z-score=−1.65), 50th centile (z-score=0) and 95th centile (z-score=+1.65). (B) Box plot of the highest concentration of dextrose used during their admission (% mass/volume), per clinical severity group. (C) Scatter plot of IV glucose intake (mg/kg/min) on the day of the diagnostic hypoglycaemia screen, plotted over the age on that day. Colours indicate the clinical severity group. (D) Box plot of the glucose intake (mg/kg/min) on diagnostic sampling day, per clinical severity group. Panels (B) and (D) show the results of analysis of variance with post hoc Tukey analysis, with levels of significance: *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

    Diagnosis of hyperinsulinism

    The first diagnostic hypoglycaemia screen was at age 6.5±10 days and the intravenous glucose intake on that day was 4.5±4.0 mg/kg/min (table 2). The maximum concentration of dextrose received was 18%±11%. The mild group had their first diagnostic hypoglycaemia screen earlier in life (4.3±5.1 days) compared with the severe group (10.0±10.5 days, p=0.008) (figure 2C). Glucose intake on the day of diagnostic sampling did not differ between the severe (9.0±5.0 mg/kg/min) and moderate (7.4±3.6 mg/kg/min) groups, but both were higher compared with the mild group (5.3±2.3 mg/kg/min) (p<0.001, figure 2A,D, online supplemental appendix 4). Intravenous glucose intake on diagnostic sampling day was >8 mg/kg/min in 7 (35%) severe, 4 (13%) moderate and 0 (0%) mild infants. Early diagnosis did not correlate with disease severity. A hypoglycaemia screen positive for hyperinsulinism <48 hours of life was noted in 33%; 54% had mild, 33% had moderate and 12% had severe disease.

    Use of diazoxide

    Twenty (20%) infants were treated with diazoxide. The decision to start was at a median (range) of 12.5 (4–85) days (figure 3B), and the infants were discharged after an additional 25.5±16.5 days. Diazoxide was started <7 days of age in six infants, between 7 and 14 days in seven infants and >14 days in seven infants. The interval between diagnostic sampling and the decision to start diazoxide was variable (median (range): 5 (0–31) days). No infant developed pulmonary hypertension, but one preterm and SGA infant developed necrotising enterocolitis. Seventeen (85%) infants were discharged on diazoxide, and 5 (29%) remained on diazoxide at 1 year of age. In 3 (15%) infants, diazoxide was found to be ineffective.

    Figure 3
    Figure 3

    Use of diazoxide. (A) Box plot of the age to achieve full enteral feeds (days), comparing the moderate and severe groups (t-test p<0.0001). (B) Scatter plot of the intravenous (IV) glucose intake (mg/kg/min) on the day of the decision to start diazoxide, plotted over the age on that day (days) in the severe group. Colours highlight the birth weight z-score groups, SGA (z-score <−1.65) (red), NGA (z-score (−1.65, +1.65)) (aqua), LGA (z-score >1.65) (blue). (C) Stacked bar chart showing the IV (purple) and enteral (cyan) glucose intake (mg/kg/min) on diazoxide-decision day for each infant in the severe group (n=20). The infants are ordered on ascending age, as indicated by the number at the base of each bar. GA, gestational age; LGA, large for gestational age; NGA, normal for gestational age; SGA, small for gestational age.

    At the time of starting diazoxide, nutritional support varied: 7(35%) were on parenteral nutrition (PN), 10 (50%) on intravenous dextrose, 1 (5%) on continuous enteral feeds and 2 (10%) on 2-hourly enteral feeds. The glucose intake was 13.2±4.8 mg/kg/min, of which 66%±34% was given intravenously (figure 3C). The fluid intake on the diazoxide-decision day, prior to fluid restriction, was 147±23 mL/kg/day, 72%±23% of which was intravenous.

    Full enteral feeding was achieved at a median (range) of 21 (12–71) days in the severe group, excluding 3 infants (15%) who did not reach full feeds prior to transfer to GOSH. Moderate infants achieved full feeds earlier (p<0.0001), at 8.5 (3–27) days (figure 3A). Three SGA infants were on full feeding and subsequently started diazoxide >14 days of life to advance feeding regimen (figure 3B,C).

    Prematurity

    Very preterm infants had their first hypoglycaemia screen later in life (14.25±10.28 days), compared with term babies (3.81±4.14, p<0.0001) and started diazoxide later (37±26 days compared with term babies (9.9±4.3 days) p=0.002). Disease severity did not correlate with GA (online supplemental appendix 5).

    Birth weight

    There were 35 (35%) SGA and 12 (12%) LGA infants. There was no association between z-score grouping and disease severity (online supplemental appendix 6), although infants with extremely low z-score <−5 had either severe or moderate disease (figure 1C). LGA infants were more likely to have diabetic mothers (58%), compared with SGA (3%) and NGA (17%) infants (p<0.001). Prematurity was concurrent in 26 (74%) SGA infants.

    Maternal diabetes

    There were 17 infants of mothers with diabetes (including 9 mothers on insulin): 5 (29%) type 1, 4 (23%) type 2 and 8 (47%) with gestational diabetes (table 1). Of these, 3 (18%) had severe disease, 7 (41%) were LGA and 1 (6%) was SGA (online supplemental appendix 7).

    Genetic testing

    Genetic testing was undertaken in 35 infants: 17 (49%) severe, 7 (20%) moderate and 11 (31%) mild. A genetic diagnosis was identified in 12 (34%): 7 (58%) severe, 5 (42%) mild. The severe group had a higher proportion of genetic diagnoses (p<0.001). Indications for genetic testing included dysmorphic features, congenital abnormalities and/or persistent hypoglycaemia. Genetic syndromes identified included Beckwith-Wideman (n=3), DiGeorge, mandibulofacial dysostosis, variant galactosemia, Cri-du-Chat, Patau, Schuurs-Hoeijmakers, Arboleda-Tham and copy number gain of Xp22.12 of unclear clinical significance. One case of HNF4A-related macrosomia and neonatal hyperinsulinism was identified.

    Longer term follow-up

    Four (4%) infants died from unrelated causes during the admission, all of which were in the mild group. Follow-up after discharge was arranged by GOSH in 15 (15%), 14 of which were in the severe group and 1 in the moderate group with severe comorbidities. The local endocrine team followed up 3 (3%), the local neonatal clinic 8 (8%), other local specialist teams 6 (6%) and the repatriation hospitals 5 (5%). Readmission rates in the first year of life were higher for the severe group (20%) compared with the moderate (3%) and mild (6%) groups (p=0.083, table 2). Reasons for readmission included controlled fasting, acute illness on the background of HI or related to other comorbidities.

    Discussion

    This study is unique in characterising the diversity of a cohort of neonates presenting with hyperinsulinism after delivery. Most infants did not conform to the classical phenotype of being LGA, with a high prevalence of preterm and SGA infants likely as a result of perinatal-stress hyperinsulinism. Most infants were not discussed with the national congenital hyperinsulinism service (77%), and only 15% were followed up by this highly specialised service. High glucose intake and high maximum concentration of glucose infusion were associated with more prolonged, complicated course of hyperinsulinism. However, there was considerable overlap of the initial presentation of infants, with similar glucose intake, but higher maximum intravenous glucose concentration in those started on diazoxide.

    Maternal diabetes is classically associated with self-resolving transient hyperinsulinism.21 However, 45% were classified as moderate or severe, reflecting the potential for persistent challenges of glucose control with maternal diabetes. This highlights the importance of not presuming a mild, transient course of hyperinsulinism in infants of diabetic mothers.12 22 23 There was a wide variation in age of hyperinsulinism diagnosis, and early diagnosis did not predict clinical course. Evidence of hyperinsulinaemia <48 hours cannot distinguish between transitional hyperinsulinism from transient or persistent hyperinsulinism.2 24 Our data would support the paediatric endocrine society guidelines, which advise treating early hypoglycaemia and deferring diagnostic testing >48 hours.24

    The clinical presentation and demographics of the severe and moderate groups were not distinctly separate at diagnosis. Intravenous glucose intake was similar between these two groups, and for the majority, it was below the expected threshold indicative of hyperinsulinism (<8 mg/kg/min).14 This highlights the importance of considering hyperinsulinism in any infant with recurrent hypoglycaemia. The severe group received higher maximum concentration of intravenous glucose infusion, which may have influenced the decision to start diazoxide. In addition, the severe group had a higher proportion of genetic diagnoses; however, these were not all directly associated with hyperinsulinism.

    The decision to start diazoxide was based on the combination of biochemical evidence and clinical phenotype. Infants with higher glucose intake started diazoxide earlier, and in cases where diazoxide was started relatively late, it was due to a failure to tolerate a reduction in the frequency of intermittent feeds, to allow infants to be discharged home safely. Preterm infants started diazoxide later than term, probably to prioritise growth and nutrition, which may be compromised by the fluid restriction required for diazoxide or due to concerns about side effects. Although diazoxide reduces the time to full enteral feeding in SGA infants,25 treatment needs to be balanced with potential risks of drug toxicity.26 27 SGA and preterm infants are more likely to experience complications, such as respiratory deterioration17 and necrotising enterocolitis.28 29 In our cohort, there was one case of necrotising enterocolitis in a preterm, SGA infant. Length of discharge after diazoxide was longer than expected, likely reflecting management of other comorbidities.

    Very preterm infants were diagnosed significantly later than term infants, potentially due to the presumption of hypoglycaemia being related to prematurity and lack of alternative fuels but may be related to the pathophysiology of hyperinsulinism. Hyperinsulinism may be an additional driver for persistent hypoglycaemia in preterm infants, possibly driven by perinatal stress or prenatal steroid use.12 30 Hence, a higher degree of suspicion is required to ensure timely diagnosis and optimal management to minimise neurological sequalae.

    This study’s findings are limited by the retrospective nature of data collection, rendering it difficult to fully characterise the trajectory of disease progression and drivers in clinical decision-making. The cohort is from a single tertiary neonatal unit and does not encapsulate the presentation of hyperinsulinism in the general population, as some infants will be managed in their local units. The subgroups of ‘clinical severity’ were based on use of diazoxide and not on any externally validated criteria, hence the classification is likely influenced by clinician bias. This is partially mitigated, as prescription of diazoxide was usually undertaken after consultation with the national specialist centre. Reporting of side effects of diazoxide was reliant on clinical documentation and may have therefore missed common side effects if not clearly recorded.

    Conclusion

    This study highlights the diversity of presentation of neonatal hyperinsulinism and the importance of considering it irrespective of birth weight or GA. We highlighted some of the challenges in diagnosis and management, especially in SGA and preterm infants. Treatment of neonatal hyperinsulinism requires a personalised approach, especially in preterm and growth-restricted infants with multiple morbidities. Further research is needed into larger cohorts to better characterise the clinical course and long-term impact of neonatal hyperinsulinism and to determine the optimal treatment strategies for this diverse group of infants.

    Data availability statement

    Data are available upon reasonable request. Data available on request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    No requirement for ethics approval as this study is a retrospective service evaluation of the clinical management of hyperinsulinism in the department of neonatal intensive care. Data collection was performed retrospectively, for a service evaluation. Consent was not required. Patient details fully anonymised. No identifiable information included.

    Acknowledgments

    We would like to thank the staff in the NICU of the Rosie Hospital and the families of the infants included in this study.

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    Footnotes

    • Contributors The idea was conceived by KB. The protocol was designed by KB, AT and M-SK. Data collection, statistical analysis and data presentation were performed by M-SK, under the guidance of KB, AT and HC. The manuscript was written by M-SK, and edited by all authors. All authors have reviewed and approved the final content and act as guarantors. Artificial intelligence was not used for this manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; internally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.