What are the common causes of neonatal hypoglycemia?

Causes of Hypoglycemia in Newborns

Neonatal hypoglycemia is primarily caused by hyperinsulinism in three major forms: transitional hyperinsulinism affecting all normal newborns, perinatal stress-induced hyperinsulinism in high-risk infants, and genetic congenital hyperinsulinism. 1, 2

Primary Mechanism: Hyperinsulinism

The overwhelming majority of neonatal hypoglycemia cases result from dysregulated pancreatic insulin secretion rather than other metabolic or hormonal causes 1, 2. This represents a fundamental shift in understanding from older approaches that focused solely on numerical glucose thresholds without considering underlying mechanisms.

1. Transitional Hyperinsulinism (Normal Newborns)

• All normal newborns experience transitional hypoglycemia in the first few days after birth due to persistence of the low fetal glucose threshold for insulin secretion 1
• The mechanism involves decreased trafficking of ATP-sensitive potassium channels to beta-cell plasma membranes, likely resulting from the hypoxemic state of fetal life 1
• This form is self-limited and resolves within the first few postnatal days 1

2. Perinatal Stress-Induced Hyperinsulinism (High-Risk Infants)

This affects approximately 1 in 1,200 newborns and represents an exaggeration of normal transitional hyperinsulinism 1. The following risk factors predispose infants to this form:

Maternal Factors

• Infants of diabetic mothers are the most common at-risk group, with prevalence of 10-40% in infants of mothers with type 1 diabetes 3
• Maternal hyperglycemia induces fetal hyperinsulinism that persists 24-48 hours postpartum while maternal glucose supply ceases immediately after birth 3
• Maternal diabetes as a screening indication has increased from 20.1% in 2004 to 41.7% in 2018 3

Fetal Growth Abnormalities

• Large for gestational age (LGA) infants (>90th percentile) comprise 26.2% of screened infants 4
• Small for gestational age (SGA) infants (<10th percentile) comprise 24.5% of screened infants and have limited glycogen stores 4, 3
• Low birth weight (<2500g) and **high birth weight** (>4500g) infants are at risk 4

Gestational Age Abnormalities

• Preterm infants (<37 weeks) comprise 13.2% of screened infants and have limited glycogen and fat stores, inability to generate glucose via gluconeogenesis, higher metabolic demands due to relatively larger brain size, and inability to mount counter-regulatory responses 4, 5
• Nearly 30-60% of high-risk preterm infants develop hypoglycemia requiring immediate intervention 5
• Post-term infants (>42 weeks) may have depleted glycogen reserves 4, 3

Perinatal Stress

• Perinatal asphyxia is a major risk factor requiring glucose screening 6
• More severe and prolonged exposure to perinatal hypoxemia exaggerates the low fetal glucose threshold for insulin release 1

3. Genetic Congenital Hyperinsulinism

This affects approximately 1 in 10,000-40,000 newborns and reflects permanent genetic defects in beta-cell insulin regulation 1, 7.

KATP Channel Mutations (Most Common)

• KCNJ11 gene (Kir6.2 subunit): autosomal dominant mutations causing permanent or transient neonatal diabetes with intrauterine growth restriction, possible developmental delay and seizures 8
• ABCC8 gene (SUR1 subunit): autosomal dominant mutations with similar presentation to KCNJ11 8
• 30-50% of patients with KATP-related neonatal diabetes respond to high-dose oral sulfonylureas instead of insulin 8

Insulin Gene Mutations

• INS gene mutations are the second most common cause of permanent neonatal diabetes 8
• These mutations cause intrauterine growth restriction and require insulin therapy 8
• Most mutations are dominantly inherited, requiring genetic counseling 8

Other Genetic Causes

• 6q24 chromosome (PLAGL1, HYMA1): causes transient neonatal diabetes with intrauterine growth restriction, macroglossia, and umbilical hernia 8
• GATA6 gene: causes permanent diabetes with pancreatic hypoplasia and cardiac malformations 8
• HNF4A-MODY: may present with large birth weight and transient neonatal hypoglycemia 8
• EIF2AK3 gene (Wolcott-Rallison syndrome): causes permanent diabetes with epiphyseal dysplasia and pancreatic exocrine insufficiency 8
• FOXP3 gene (X-linked): causes IPEX syndrome with autoimmune diabetes 8

Critical Diagnostic Recommendation

All infants diagnosed with diabetes in the first 6 months of life should have immediate genetic testing for neonatal diabetes, regardless of current age 8. This is because:

• Autoimmune type 1 diabetes rarely occurs before 6 months of age 8
• 80-85% of neonatal diabetes cases have an underlying monogenic cause 8
• Correct genetic diagnosis determines whether sulfonylureas (rather than insulin) can be used for treatment 8

Common Pitfall to Avoid

The traditional approach of screening based solely on risk factors for transient hypoglycemia (maternal diabetes, prematurity, birth weight) will not reliably detect infants with genetic causes such as fatty acid oxidation disorders, which are not associated with these risk factors 8. However, the most common genetic cause—congenital hyperinsulinism—often presents with large for gestational age status and will be captured by standard screening criteria 8.