Neonatal hypoglycemia is a common metabolic disorder. Hypoglycemia symptoms can be non-specific, such as poor feeding, irritability, apnea, and hypothermia, or even absent. Therefore, screening neonates at risk of hypoglycemia, and planning the appropriate management of the hypoglycemic neonate, is an essential aspect of neonatal care [1–3]. The Pediatric Endocrine Society defines neonatal hypoglycemia as a pre-prandial blood glucose level <50 mg/dL in the first 48 hours after birth, followed by levels <60 mg/dL [4]. Another study defined hypoglycemia as blood glucose levels <50 mg/dL at any time in the setting of congenital hyperinsulinism (CHI) [5].

CHI is the most common cause of persistent neonatal hypoglycemia; it is characterized by inappropriate insulin secretion by pancreatic beta-cells [3,6]. Profound hypoglycemia due to CHI can lead to brain injury, since the brain depends on glucose as an oxidative fuel [7,8]. Neurodevelopmental delay due to hyperinsulinism has been reported in 30%–50% of cases of persistent hyperinsulinism (PHI) and transient hyperinsulinism (THI) [6,9]. Unlike monogenic forms of CHI, THI is usually related to perinatal stress in prematurity, and may be seen in small for gestational age (SGA) infants, infants of diabetic mothers, and cases of birth asphyxia [6]. Therefore, early recognition of neonates at-risk and prompt glucose testing are needed to prevent poor outcomes.

Here, we report the case of a SGA premature infant with persistent hypoglycemia due to THI that was successfully treated with oral diazoxide in the neonatal intensive care unit (NICU).

A preterm girl was delivered via cesarean section at 34+0 weeks of gestation to a 38-year-old mother. The mother gave birth after severe preeclampsia with a breech presentation and intrauterine growth retardation on prenatal examination. The baby was a second-born twin (first-born twin’s birth weight: 2,300 g) and her birth weight, birth length, and head circumference were 1,070 g (<3rd percentile), 75 cm (<10th percentile), and 27.5 cm (<10th percentile), respectively. Her Apgar score was 5 at 1 minute and 7 at 5 minutes. She was admitted to our NICU for further evaluation and treatment. Nasal intermittent positive-pressure ventilation was applied just after admission due to tachypnea and mild chest retraction. There were no other abnormalities on physical examination. Point-of-care (POC) glucose measured within 1 hour after birth was 24 mg/dL. An intravenous bolus of 10% dextrose in water at 2 mL/kg was given and the glucose subsequently rose to 31 mg/dL. Trophic feeding was started with premature formula milk and total parenteral nutrition, with a glucose infusion rate (GIR) of 6.5 mg/kg/min, to maintain normoglycemia. Even though hypoglycemia among premature infants usually resolves within 72 hours after birth, she needed GIR as high as 7–12 mg/kg/min although a feeding volume of 100 mL/kg/day was reached on day of life (DOL) 10. The feeding volume had increased to 150 mL/kg/day at DOL 17, but the pre-prandial glucose levels ranged from 35 to 100 mg/dL, so she could not be weaned from the parenteral glucose infusion. On DOL 18, critical samples were obtained under suspicion of hyperinsulinemic hypoglycemia when the pre-prandial POC glucose was 52 mg/dL. This revealed serum glucose of 54 mg/dL, insulin of 6.45 μU/mL (normal range, >1 μU/mL [depending on the sensitivity of the insulin assay]), cortisol of 2.08 μg/dL (normal range, 1–24 μg/dL), and growth hormone (GH) of 19.0 ng/mL (normal range, 5–40 mg/mL). Blood ketone, lactate, ammonia, and abdominal ultrasonography result were all normal. A genetic analysis for CHI was performed on DOL 18, and the ABCC8, KCNJ11, GCK, GLUD1, HNF4A, HADH, and UCP2 genes were normal. On DOL 20, oral diazoxide was started at 12 mg/kg/day (divided into three doses) under a diagnosis of hyperinsulinemia hypoglycemia. The effect of diazoxide was dramatic and the intravenous glucose fluid was successfully tapered and stopped 7 days after starting oral diazoxide. Fifteen days after starting the oral diazoxide, the blood glucose level was 113 mg/dL and insulin was 1.16 U/mL, so we reduced the diazoxide to 6 mg/kg/day (in two doses). On DOL 49 (29 days after beginning the oral diazoxide), the diazoxide dosage was tapered to 1.3 mg/kg/day, once a day. Finally, on DOL 52, the oral diazoxide was stopped and normoglycemia was maintained with preterm infant formula and breast milk (Fig. 1). Brain magnetic resonance imaging during the NICU admission was normal. While on diazoxide, mild hirsutism appeared on her forehead, but it gradually improved after discontinuing the oral diazoxide. She was discharged from the NICU on DOL 63, with a weight of 2.14 kg. We taught the parents to perform POC glucose measurements at home at least 2 or 3 times a day before meals, to prevent hypoglycemic events after discharge. The patient has not received any additional treatment since discharge and hypoglycemia has not recurred. Although her weight is still between the 5th and 10th percentiles for her age, she is now 27 months of age, healthy, and showing normal neurological development.

This study adhered to the tenets of the Helsinki Declaration by the Research Ethics Committee of the Institutional Review Board (IRB) of Soonchunhyang University College of Medicine, Cheonan, Korea (IRB approval no., 2022-03-031). The patient provided written informed consent for the publication of clinical details and images.

Hyperinsulinism is a condition involving dysregulated insulin secretion from pancreatic beta-cells, in both the persistent and transient forms of the disease [9]. PHI is commonly called congenital hyperinsulinism (CHI), and genetic mutations such as ABCC8 and KCNJ11 in pancreatic beta-cells cause abnormal insulin secretion, which usually results in persistent hypoglycemia in neonates [3]. In transient hyperinsulinemic hypoglycemia (THH), hypoglycemia typically resolves completely in a few days or months [10]. Perinatal stress, such as prematurity, birth asphyxia, maternal diabetes mellitus, and intrauterine growth restriction/SGA, are known causes of THH [6,10]. SGA is defined as a birth weight less than the 10th percentile, as in our patient, who was also born preterm. SGA infants cannot generate alternative fuels, such as ketone bodies. Arya et al. [11] studied the relationship between hyperinsulinism and SGA in 27 SGA infants with hyperinsulinemic hypoglycemia and sequenced the ABCC8/KCNJ11 genes, but found no mutations in any infant. This implies that for babies with risk factors for developing hyperinsulinemia, early recognition and rapid correction are mandatory before performing genetic testing. Since hyperinsulinemia can induce abnormal neurodevelopmental outcomes, its effects on infants with THH are also being studied. Avatapalle et al. [8] reported that abnormal neurodevelopment was evident in one third of children with previous THI or PHI, and Shah et al. [12] found an association between early transient hypoglycemia and lower academic achievement at 10 years of age.

A diagnosis of hyperinsulinemic hypoglycemia is suggested by the following: glucose infusion requirement >6–8 mg/kg per min; plasma glucose <50 mg/dL; detectable insulin (>1 μIU/mL) with increased C-peptide (>0.5 ng/mL); low insulin-like growth factor-binding protein 1 (<125 ng/mL); abnormally low plasma free fatty acids (<0.5 mmol/L); and ketone bodies (β-hydroxybutyrate <1.1 mmol/L); and the absence of ketonuria [3]. Other laboratory tests might also be helpful, such as GH and cortisol, which reflect pituitary gland deficiency, as well as lactate, ammonia, and free fatty acids, which reflect other metabolic conditions. We did not test for C-peptide in our critical sample, although it has recently shown diagnostic promise for hyperinsulinism. Detectable insulin levels with a GIR as high as 12 mg/kg/min supported our diagnosis. Since insulin is unstable in the circulation due to its short half-life (6 minutes), it cannot be used as the sole diagnostic parameter for hyperinsulinism [9,11]. Therefore, it is necessary to establish a critical sample list for diagnosing hyperinsulinism when hypoglycemia is present (serum glucose 45–55 mg/dL; typically, <50 mg/dL).

Oral diazoxide is the only drug approved currently by the US Food and Drug Administration for the treatment of hyperinsulinemic hypoglycemia. It opens the KATP (adenosine triphosphate–sensitive potassium) channels on pancreatic beta-cells, which inhibits insulin secretion [3]. The recommended dose is 5–15 mg/kg per day orally, divided into two or three doses, while monitoring for possible side effects such as hypertrichosis, fluid retention, and bone marrow suppression [3,6]. If a neonate requires continuous dextrose support after 5 days of maximum diazoxide treatment, it is considered diazoxide-unresponsive and further genetic evaluation is required. The majority of SGA and premature infants with hyperinsulinism are diazoxide-responsive [6]. Therefore, treatment should be continued until the hypoglycemia resolves. In summary, we report a premature SGA infant with THH and no abnormal genetic mutations who was successfully treated with oral diazoxide. Long-term close monitoring is planned to evaluate catch-up growth and confirm normal development without neurological complications.