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Neonatal Hyperinsulinism: When Hypoglycemia Is Something More

Courtney Grassham, APRN
Kimberly Brown, RN BSN

Hypoglycemia is a common occurrence in the neonatal intensive care unit (NICU). It can be both a reason for admittance to the unit and a symptom of an underlying problem. There are, however, many gray areas in relation to hypoglycemia. Despite numerous years of research, the medical community has multiple definitions of hypoglycemia.

Two major consensus statements, by the American Academy of Pediatrics (AAP) and the Pediatric Endocrine Society (PES), have been issued on the topic. Both include the underlying belief that transient hypoglycemia should resolve by 48 hours after birth, but they define hypoglycemia differently. AAP defines hypoglycemia as a glucose level of < 25 mg/dL at less than 4 hours of age, < 35 mg/dL from 4–24 hours of age, < 45 mg/dL from 24–48 hours of age, and < 60 mg/dL at more than 48 hours of age. PES defines hypoglycemia as < 50 mg/dL from birth to 48 hours of life and < 60 mg/dL at more than 48 hours of life. Gray areas of defining hypoglycemia can make it more difficult to define prolonged hypoglycemia (Hubbard & Hay, 2021).

Hypoglycemia can be caused by inadequate glycogen stores, hyperinsulinism, growth hormone deficiency, cortisol deficiency, inborn errors of metabolism, birth-related stress, or a combination of these causes.

Hyperinsulinism may be indicated if the infant requires a glucose infusion rate (GIR) of more than 8–10 mg/kg/min, if you are unable to wean glucose despite appropriate enteral feeds, or if hypoglycemia persists for more than 5–7 days (Casertano, 2021). 

Hyperinsulinism Types and Diagnosis

Hyperinsulinism can be transient or congenital.

Transient hyperinsulinism is more commonly found in infants born to mothers who are diabetic or received sulfonylureas during labor and infants who experienced perinatal asphyxia or are small for gestational age, or were born to mothers who received sulfonylureas during labor. The hallmark of transient hyperinsulinism is that, though it may require medication, it will usually resolve in weeks to months. Infants with transient hyperinsulinism will not have a recurrence of hypoglycemia after it resolves. Recent studies have shown that a significant number of infants with transient hyperinsulinism are discharged home without medication therapy (Thornton, 2021).

Congenital hyperinsulinism is the most common cause of recurrent and persistent hypoglycemia in infants and children. The diagnosis of congenital hyperinsulinism is dependent on a critical lab evaluation of samples collected when the infant is hypoglycemic with a plasma glucose < 50. The labs obtained include insulin, plasma beta-hydroxybutyrate, free fatty acids, blood gas, lactate, cortisol, growth hormones and possibly a thyroid screening. Lab results suspicious for a congenital hyperinsulinism diagnosis include a low beta-hydroxybutyrate level, low levels of free fatty acids, and the presence of either an elevated or detectable insulin level (Casertano, 2021; Sims, 2021; Thornton, 2021).

Another step in the diagnostic process is a glucagon challenge test. A glucagon challenge should only be undertaken with consultation from a pediatric endocrinologist. There are different methods for the challenge, and it is important to ensure the use of the correct dose and lab timing for interpretation. If there is an increase in glucose of > 30 mg/dl after the glucagon is administered, it is indicative of hyperinsulinism as the cause of the hypoglycemia. The glucagon can be given intravenously (IV) or intramuscularly (IM), and the IV route is often preferred, because a rescue of a dextrose bolus may be given if there is not an increase in glucose level after the glucagon.

Treatment Options

Hyperinsulinism can be treated with medicines, diet, or surgery depending on the cause. Dietary modifications include adjusting the caloric density of the supplied formula/breast milk or administering additional carbohydrates. Increased caloric density, while a viable option for infants who are small for gestational age, may not be practical for the term infant of a diabetic mother, because the baby does not need the extra calories.

Medication-based therapy for hyperinsulinism includes the use of glucagon, diazoxide, and somatostatin receptor analogs. It is important for the NICU nurse to remember that once the diagnosis of hyperinsulinism is made, IV dextrose boluses rarely should be used, because the glucose surge will increase insulin release, perpetuating the cycle.

Glucagon, which can be given IM or via continuous IV drip, works by causing glycogenolysis and gluconeogenesis. Glucagon may be used with octreotide after diazoxide treatment failure or in the diagnostic phase.

Diazoxide works as an ATP-sensitive potassium channel agonist and is the only FDA-approved treatment for congenital hyperinsulinism. There is a risk of pulmonary hypertension and fluid overload with diazoxide treatment, so infants should have an echocardiogram and chest radiograph before the initiation of treatment. Due to the risk of fluid overload, diazoxide is usually administered with Diuril (chlorothiazide). There is a significant side effect associated with diazoxide: hypertrichosis, or excessive hair growth, which can be prevalent on the face but typically resolves when the medication is stopped. There is a subgroup of congenital hyperinsulinism patients who are genetically disposed to be nonresponsive to diazoxide. This is why one of the first genetic screenings done after a diagnosis of hyperinsulinism is to test for this subgroup.

Octreotide, the somatostatin analog used in neonates, must be used with caution in premature infants as it is associated with an increased occurrence of necrotizing enterocolitis.

If medication therapy fails, infants should be evaluated for surgical intervention (Sims, 2021).

Neurological Sequelae

Recurrent hypoglycemia is cause for concern, as there is no clear point that correlates with neurological sequelae. Studies have shown that the most severe hypoglycemia in infants did not correspond to the most severe brain injury. Recent studies have also shown that up to 40% of infants with congenital hyperinsulinism develop an adverse neurological outcome (Heckmann & Wudy, 2021).

For neonatal nurses, this raises the concern of what lasting impact each recurrent hypoglycemic episode has on the developing brain. Neurological sequelae that have been linked to hyperinsulinism include epilepsy, motor deficits, speech problems, and cognitive deficits. The neurological sequelae can also cause atrophy and infarcts in the occipital and parietal regions of the brain. The risk of long-term neurological problems is similar whether the congenital hyperinsulinism is responsive to medication or to surgery (Sims, 2021).

The identification and management of prolonged hypoglycemia in infants is an area that is continuing to evolve. A lot of progress has been made over the past 20 years, and more infants are receiving treatment than ever. It is hoped that treatment advances will reduce the number of infants affected by neurological sequelae from hypoglycemia.


Heckmann, M., & Wudy, S. A. (2021). Light on the horizon? Will continuous glucose monitoring allow for better management of congenital hyperinsulinism? The Journal of Clinical Endocrinology & Metabolism, 107(3), e1305–e1307.
Hubbard, E. M., & Hay, W. W., Jr. (2021). The term newborn: Hypoglycemia. Clinics in Perinatology, 48(3), 665–679.
Sims, K. (2021). Congenital hyperinsulinism. NeoReviews, 22(4), e230–e240.
Thornton, P. S. (2021). Recent updates in the management of infants and children with hyperinsulinism. Current Opinion in Pediatrics, 33(4), 424–429.

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