Neonatal hypoglycaemia

Neonatal hypoglycaemia is defined as blood glucose levels < 2.6mmol/L.

It’s a common problem in the first days of life, affecting up to 15% of neonates. It can be due to a variety of reasons, stemming from factors such as maternal diabetes, preterm birth, congenital hyperinsulinism or transient hypoglycaemia of the newborn.

Recognising the condition early is vital as left unaddressed, hypoglycaemia can lead to serious consequences for the newborn including neurological impairment and seizures.

Neonatal physiology

Within the first few hours of life, blood glucose levels fall rapidly since the continuous glucose supply from the placenta in intrauterine life is removed. Glucose levels steadily begin to rise again over the first few days and return the normal range (3.9-5.6mmol/L). Some infants fail to make this adaptation to extrauterine life, and so are at a greater risk of symptomatic hypoglycaemia, therefore at-risk infants must have their blood glucose levels monitored regularly post-delivery.

The level of blood glucose at which hypoglycaemia leads to brain injury and impacts development is unknown. Less than 2.6mmol/L is the most widely used threshold in neonates for intervention to raise blood glucose. This is based on evidence currently available.

Persistently low blood sugar (<1mmol/L for >1 hour) is associated with neurological dysfunction and carries a high risk for cerebral injury which leads to adverse neurodevelopmental outcomes through widespread white matter injury. There is also evidence emerging in the literature that blood glucose levels < 2mmol/L can also impact development.

Risk factors

Risk factors for neonatal hypoglycaemia can be grouped into maternal and neonatal factors.

Maternal factorsMaternal diabetes (poorly controlled diabetes makes baby to be more likely affected)
Certain medication use during pregnancy e.g. beta blockers
Neonatal factorsSmall for gestational age babies (SGA)/ birth weight ≤ 10th percentile for gestational age
Large for gestational age babies (LGA)/ birth weight ≥ 90th percentile for gestational age
Prematurity (<37 weeks gestation)
Perinatal stress such as birth asphyxia, sepsis, hypothermia
Congenital causes such as congenital hyperinsulinism, congenital adrenal hyperplasia and Beckwith- Wiedemann syndrome
Inborn errors of metabolism
Polycythaemia
Rhesus haemolytic disease
Poor feeding due to other issue, e.g. Prader Willi syndrome presents with small floppy baby not feeding, or babies with T21 can have a poor suck and low tone and don’t always feed well

Signs and symptoms

The clinical presentation of neonatal hypoglycaemia is variable. While an otherwise healthy infant may remain completely asymptomatic with very low blood glucose levels, other infants may appear seriously unwell. Symptoms are unspecific but appearance of them should rouse suspicion of hypoglycaemia in the differential diagnosis. Manifestations include:

Sweating

Feeding difficulties or disinterest in feeding

Weak or high-pitched cry

Tremors

Hypothermia

Irritability

Lethargy/ stupor

Hypotonia (floppy baby)

Cyanosis

Episodes of apnoea, grunting or tachypnoea

Seizures

hypoglycaemia 2

Other conditions that could lend themselves to hypoglycaemia would be jaundice [(makes babies sleepy and therefore, they have reduced feeds and are more prone to hypoglycaemia and hypernatraemic dehydration) with reduced urine output]

Hypothermia can also cause hypoglycaemia in babies, so in any hypothermic neonate you should check a blood glucose.

Differential Diagnosis

As there is such a wide list of differentials for neonatal hypoglycaemia, using your sings, symptoms, history, and investigation results will help narrow down this list and will guide your management.

Differentials include:

Management

The British Association of Perinatal Medicine (BAPM) provides comprehensive guidelines for the management of neonatal hypoglycaemia in full-term infants. The key aspects of these guidelines include:

Identification:
  • Risk factors: Infants at risk should be identified, such as those who are small or large for gestational age, preterm, infants of diabetic mothers and those with perinatal stress (identified through poor cord gases with raised lactates, or prolonged foetal bradycardia prior to delivery)
  • Screening: Blood glucose monitoring is recommended for all at risk infants, with the first measurement taking place 2-4 hours after birth and then regular pre-feed blood glucose monitoring until stable. Discharge can be considered after two consecutive blood glucose measurements >2.6mmol/L and a satisfactory feeding assessment. However, values <2.6 mmol/L warrant further monitoring and interventions depending on the level and presence of abnormal clinical signs.
Prevention of separation:

Efforts should be made to manage hypoglycaemia without avoidable separation of mother and baby to promote bonding and breastfeeding.

This means reviewing the baby regularly and putting in place a good feeding plan to prevent hypoglycaemia and reduce preventable admissions to NICU.

Treatment:

Feeding support:

  • In the absence of abnormal clinical signs and if pre-feed glucose levels are between 2.0-2.5mmol, feeding support is offered (after treating hypoglycaemia with dextrose gel). Early and frequent feeding is crucial; you should observe a breastfeed for good attachment and effective feeding. Breast feeding should be encouraged and supplemental feeds should be considered if necessary

Glucose gels:

  • If glucose levels are between 1.0-2.6mmol/l infants should be supplemented and subjected to a review by a neonatal doctor. The baby should be gievn a dose of 40% buccal glucose 200mg/kg (0.5ml/kg), and then a feed, and blood glucose levels should be checked again, after 30-60 minutes. If blood glucose (BG) levels remain between 1.0-2.6mmol, the baby should be assessed as soon as possible and given a second dose of buccal gel. The BG levels should be reviewed after a further 30-60 minutes. 
  • A normal feed amount for a baby on day 1 of life would be 50-60ml/kg/day, so the volume of one feed would be the total 24-hour volume divided by 8 to give a 3 hourly amount. (e.g. in a 2.5kg baby, one feed would be 12.5-19ml)

Feeding support:

  • If blood glucose levels normalise following dex gel and a feed, then continued feeding support is crucial to help maintain stable blood glucose levels. Early and frequent feeding is crucial; breast feeding should be encouraged and the midwifery team can observe a breastfeed for good attachment and effective feeding. Supplemental feeds should be considered if necessary.

NICU Admission

Neonates who have a pre-feed BG < 1.0mmol/L, those who are displaying clinical signs consistent with hypoglycaemia, or those with three or more episodes of hypoglycaemia, should be admitted to a neonatal unit as soon as possible, and appropriate investigations for persistent hypoglycaemia should be commenced.

In the neonatal unit efforts should be made to obtain IV access and a 2.5ml/kg 10% glucose bolus should be given, followed by an infusion of 10% glucose 60ml/kg/day or regular NGT feeds of formula.

If there are any risk factors for sepsis present alongside severe or persistent hypoglycaemia then antibiotics should be considered

If you are unable to obtain immediate IV access, I.M glucagon 200mcg/kg can be administered. It is important to note that regular breast feeding should not stop unless there is a clinical contraindication or the infant is too sick to feed. BG should be checked regularly, ideally after 30 minutes, and managed as per the following:

Blood glucose levelBG < 1.0mmol/L or abnormal clinical signsBG between 1.0-2.5mmol/L and no abnormal clinical signsBG > 2.6mmol/L
ManagementGive IV 10% glucose 2.5ml/kg Increase glucose delivery rate by 2mg/kg/minute*
Recheck BG after 30 minutes Repeat if BG < 1.0mmol/L or there are abnormal clinical signs
Increase glucose delivery rate by 2mg/kg/minute*
Continue to feed if no contraindication
Recheck BG after 30 minutes
Slowly wean off IV infusion Continue enteral feeds
Monitor BG until infant is on full enteral feeds and blood glucose levels are > 2.5mmol/L or 3.0mmol/L in cases of hyperinsulinism

Glucose Infusion rate (GIR) is calculated from the concentration and rate of dextrose running to the baby. There is a handy calculator here: https://starship.org.nz/health-professionals/calculators/glucose-calculator/. (or you can calculate it yourself using the formula below)

If glucose infusion rate > 8mg/kg/min, test for hyperinsulinism (with hypo screen)

You can increase the GIR by increasing the concentration of dextrose running, e.g. from 10 to 12.5, 15, 20 or even 50%. 10% and 12.5% dextrose can run peripherally, but for 15% and above, you need central access such as an umbilical venous catheter. You can also increase the GIR by increasing the rate of fluids, but in a newborn baby there is a risk of fluid overloading above 60-75ml/kg/day.

hypoglycaemia 5

In babies who have transient hypoglycaemia, e.g. those born to diabetic mothers or who are SGA, and are admitted to NICU for IV fluids, as blood glucose levels normalise IV fluids are slowly weened as feeds are introduced, while monitoring blood glucose.

Hyposcreens

As per BAPM guidelines, a hypoglycaemia screen is indicated for any neonate with:

  • More than 2 measurements of BG < 2.0mmol/L within the first 48 hours after birth,
  • Severe hypoglycaemia (< 1.0mmol/L) at any time,
  • Signs of neurological dysfunction and blood glucose < 2.6mmol/L

A hypoglycaemia screen is a set of diagnostic tests performed to identify the underlying causes of persistent or recurrent hypoglycaemic episodes. It is essential to perform during an episode of hypoglycaemia to capture relevant biochemical data

Components of a hypoglycaemic screen:

  • Blood glucose: to measure the current glucose level
  • Insulin: detectable insulin levels during hypoglycaemic episodes suggest hyperinsulinism as a cause
  • Growth hormone: to evaluate for growth hormone deficiency associated with pituitary dysfunction
  • Cortisol: to assess adrenal function; low levels may indicate adrenal insufficiency
  • Lactate: elevated levels can indicate disorders of gluconeogenesis, glycogenolysis or sepsis
  • Beta-hydroxybutyrate (ketones): low levels indicate impaired ketogenesis, which is common in hyperinsulinism
  • Free Fatty Acids (FFA): low levels may also suggest hyperinsulinism
  • Amino acids: abnormal profiles may be seen in certain metabolic conditions, e.g. low alanine levels are seen in Ketotic hypoglycaemia and starvation, and high levels of alanine is seen in lactic acidosis. Other anomalies in plasma amino acids can be due to inborn errors of metabolism.
  • Acyl-carnitine profile to screen for fatty acid oxidation disorders
  • Ammonia: raised in urea cycle disorders, Reyes syndrome and fatty acid oxidation disorders.
  • Urine organic acids to detect organic acidaemias
  • The flow chart below gives a basic interpretation of an abnormak hyposcreen
hypoglycaemia 3

If there are abnormalities on the hypo screen and blood sugars are difficult to maintain in a normal range, then the endocrine team should be consulted.

Management of congenital hyperinsulinism

Management of CHI involves a multidisciplinary approach to stabilise blood glucose levels and address the underlying condition. The management typically includes medical therapy, dietary interventions, and in some cases, surgery.

In the setting of acute hypoglycaemia, the aim is to maintain blood glucose levels above 3.5mmol/L. Initially, children are managed with an IV bolus of 2.5ml/kg of 10% glucose, followed by a continuous infusion to prevent rebound hypoglycaemia. Alternatively, if IV therapy is not immediately available, intramuscular, or subcutaneous glucagon can be administered.

The first line treatment for CHI is diazoxide. Diazoxide is an oral medication taken three times daily. It works by activating the ATP sensitive potassium channel on the pancreatic beta-cells, thereby reducing insulin secretion. To avoid diazoxide associated fluid retention, chlorothiazide is usually prescribed alongside.

To assess the responsiveness of diazoxide, you can measure the blood glucose, insulin, and ketone levels; after initiating diazoxide, blood glucose levels should be stable and within the target range, insulin levels should decrease to appropriate levels for the blood glucose concentration and presence of normal ketone levels (beta-hydroxybutyrate) indicates the suppression of hyperinsulinaemia.

Babies starting diazoxide should be assessed with an echo beforehand as it can cause fluid overload and congestive heart failure. 

A dose of diazoxide > 7mg/kg/day with no resolution of hypoglycaemia generally means that the patient is diazoxide unresponsive and warrants further discussion or referral to a specialist CHI centre.  

Diazoxide unresponsive patients should be referred for a genetic analysis for the ABCC8 and KCNJ11 mutations as well as a 18F-DOPA PET-CT scan. Patients positive for the ABCC8 or KCNJ11 mutations should be commenced on high calorie diets and frequent feeds and trialled with octreotide before being referred for surgical management. Depending on the results of the scan, patients may require a curative lesionectomy for focal forms of CHI, or a subtotal pancreatectomy for diffuse forms.

Octreotide is a somatostatin analogue, used as second line therapy in children who are unresponsive to diazoxide. It acts on somatostatin receptor 5 (SSR5) to inhibit cAMP mediated insulin release. It can be given as subcutaneous injections with up to 8 doses per day, or a continuous IV infusion.

hypoglycaemia 4

Overall

If you remember anything from this article let it be to follow local guidelines for monitoring for and managing hypoglycaemia in neonates.

Hypoglycaemia should be recognised and managed early through identifying risk factors and monitoring closely. This is to prevent hypoglycaemic brain damage and developmental impairment.

Severe refractory hypoglycaemia should be investigated early with a hypoglycaemia screen, while the baby is hypoglycaemic (if you struggle to get bloods from the baby the most important tests are insulin, c-peptide and ketones) and should be managed agressively with increasing dextrose concentrations until blood sugar is in normal range and stable.

References

Abramowski A, W. R. (2023, September 4). Neonatal hypoglycemia. Retrieved from National Library of Medicine: https://www.ncbi.nlm.nih.gov/books/NBK537105/

al, M. G. (2023, October ). Standardised practices in the networked management of congenital hyperinsulinism: a UK national collaborative consensus. Retrieved from Frontiers in Endocrinology: https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1231043/full

Alegra, T. (2024, June). Metabolic presentations 3: Galactossaemia . Retrieved from Don’t Forget The Bubbles: https://dontforgetthebubbles.com/metabolic-presentations-3-galactossaemia/

BAPM, B. A. (October, 2017). Identification and Management of neonatal hypoglycaemia in the full term infant. Framework for practice. Retrieved from https://hubble-live-assets.s3.eu-west-1.amazonaws.com/bapm/file_asset/file/37/Identification_and_Management_of_Neonatal_Hypoglycaemia_in_the__full_term_infant_-_A_Framework_for_Practice_revised_Oct_2017.pdf

Diva D. De Leon, J. B. (2024, June). International Guidelines for the Diagnosis and Management of Hyperinsulinism. Retrieved from Karger: https://doi.org/10.1159/000531766

Dr Abiramy Saravanamuthu, D. P. (n.d.). Sweet Nothings: Neonatal Hypoglycaemia. Retrieved from Paedatric FOAMed: https://www.paediatricfoam.com/2017/04/neonatal-hypoglycaemia/

Hegde VS, S. T. (2024, January ). Hereditary fructose intolerance. Retrieved from National library of medicine : https://www.ncbi.nlm.nih.gov/books/NBK559102/

Robert C. Tasker, R. J. (2013). Oxford Handbook of Paediatrics, 2nd Edition. Oxford University Press.

Rose Wilson, R. (2023, February ). Neonatal Hypoglycaemia. Retrieved from rch.org.au: https://www.rch.org.au/rchcpg/hospital_clinical_guideline_index/Neonatal_hypoglycaemia/

Safer Care Victoria . (2019, May). Congenital adrenal hyperplasia (CAH) in neonates. Retrieved from https://www.safercare.vic.gov.au/best-practice-improvement/clinical-guidance/neonatal/congenital-adrenal-hyperplasia-cah-in-neonates#:~:text=Congenital%20adrenal%20hyperplasia%20(CAH)%20is,pressure%20and%20essential%20for%20life

Shien Chen Lee, E. S. (n.d.). Hypoglycaemia in adrenal insufficiency . Retrieved from Frontiers: https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1198519/full

Written by Nikhita Rathod, 5th year medical student

Edited by Dr Bex Evans, Paediatric Registrar

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