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Introduction: Given that reports on severe diazoxide (DZX) toxicity are increasing, we aimed to understand if the short-term clinical outcomes of small-for-gestational-age (SGA) infants with hyperinsulinemic hypoglycemia (HH) managed primarily by supportive care, termed watchful waiting (WW), are different from those treated with DZX., Method: A real-life observational cohort study was conducted from 1 September 2014 to 30 September 2020. The WW or DZX management decision was based on clinical and biochemical criteria. We compared central line duration (CLD), postnatal length of stay (LOS), and total intervention days (TIDs) among SGA-HH infants treated with DZX versus those on a WW approach. Fasting studies determined the resolution of HH., Result: Among 71,836 live births, 11,493 were SGA, and 51 SGA infants had HH. There were 26 and 25 SGA-HH infants in the DZX and WW groups, respectively. Clinical and biochemical parameters were similar between groups. The median day of DZX initiation was day 10 of life (range 4-32), at a median dose of 4 mg/kg/day (range 3-10). All infants underwent fasting studies. Median CLD [DZX, 15 days (6-27) vs. WW, 14 days (5-31), P = 0.582] and postnatal LOS [DZX, 23 days (11-49) vs. WW, 22 days (8-61), P = 0.915] were comparable. Median TID was >3-fold longer in the DZX than the WW group [62.5 days (9-198) vs. 16 days (6-27), P < 0.001]., Conclusion: CLD and LOS are comparable between WW and DZX groups. Since fasting studies determine the resolution of HH, physicians should be aware that clinical intervention of DZX-treated SGA-HH patients extends beyond the initial LOS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chandran, Jaya-Bodestyne, Rajadurai, Saffari, Chua and Yap.)

Hyperinsulinemic hypoglycemia (HH) has the potential to cause acute neurologic dysfunction and neurodevelopmental impairment. Parieto-occipital neuronal injuries have been reported in hypoglycemic infants, but intraparenchymal hemorrhage is rare. On day 5 of life, a late preterm infant was transferred to our care with recurrent asymptomatic hypoglycemia. Prior to arrival, plasma glucose levels were at a median of 1.25 mmol/L (22.5 mg/dL) in the first 6 hours of life, and he required a glucose infusion rate (GIR) of 22.6 mg/kg/min. Hyperinsulinism was confirmed in the presence of detectable insulin, low ketones, and fatty acid when hypoglycemic. A left grade 4 intraventricular hemorrhage (IVH) was noted in the cranial ultrasound scan during the workup for sepsis on the day of admission. However, magnetic resonance imaging of the brain on day 7 of life revealed extensive bilateral IVH. On day 9, he was initiated on diazoxide, and HH resolved within 48 to 72 hours, allowing increment of feeds while weaning GIR. Ventricular drain for post-hemorrhagic ventriculomegaly was advised but not performed. At 3 months, post-hemorrhagic ventriculomegaly was stable, and there were early signs of neurodevelopmental delay. After discontinuing diazoxide at 4 months of age, he passed an 8-hour fasting study confirming the resolution of HH. Severe hypoglycemia has been associated with cerebral hyperperfusion in preterm infants and potentially could cause IVH. Close monitoring and prompt intervention in preterm infants to prevent severe hypoglycemia are paramount. In addition to long-term neurodevelopmental follow-up, infants with recurrent hypoglycemia may benefit from neuroimaging and thereby early intervention if required.

Hyperinsulinaemic hypoglycaemia in small-for-gestational age infants usually presents in the first two postnatal days. We present a preterm, small-for-gestational age infant who had hyperinsulinaemic hypoglycaemia on day 13 of life. A female twin infant weighing 1390 g was born at 32(+6) weeks of gestation. Her glycaemic profile was normal till day 13 of life, after which she was noted to be lethargic and hypoglycaemic and had hyperinsulinism, hypoketonaemia and hypofattyacidaemia, requiring high glucose infusion rate to maintain normoglycaemia, while negative for septic markers and metabolic screen. Initially, there was no response to diazoxide and the genetic studies for ABCC8 and KCNJ11 gene mutations were negative. Delayed response to diazoxide was followed by complete resolution of hypoglycaemia in 5 months. This case highlights the importance of glucose monitoring in small-for-date infants for hypoglycaemia till they achieve full feeds and gain weight. Early recognition and appropriate management of hypoglycaemia in this group of infants have important implications for neurodevelopmental outcome.

Diazoxide (DZX) remains the first-line medication for the treatment of prolonged and persistent forms of hyperinsulinemic hypoglycemia (HH). In nearly 40%–50% of cases of HH, the genetic mechanism is unidentified. Almost half of the infants with permanent or genetic causes are DZX sensitive, but hypersensitivity to DZX is extremely rare, and the mechanism is poorly understood. Here, we report for the first time a case of DZX hypersensitivity in a neonate with HH who inherited a novel HNF1A variant from the mother. A term, male large-for-gestational-age infant of a diabetic mother presented with early onset of severe, recurrent hypoglycemia. Critical blood samples when hypoglycemic confirmed HH. Diazoxide was initiated at conventional doses of 5 mg/kg/day, which resulted in hyperglycemia (blood glucose, 16.6 mmol/L) within 48 h. Glucose infusion was rapidly weaned off. DZX was withheld and eventually stopped. Following 3 days of milk feeds alone with a normal glucose profile, suspecting a resolution of HH, he underwent a 6-h fasting study and passed. While on glucose monitoring in the hospital, he again developed hypoglycemic episodes, and the critical blood samples confirmed HH. DZX was restarted at a lower dose of 3 mg/kg/day, which required further down-titration to 0.7 mg/kg/day before steady euglycemia was obtained. No more episodes of hypo or hyperglycemia occurred, and he passed a safety fasting study before discharge. Molecular genetic testing identified a novel HNF1A mutation in the mother–child dyad, whereas the father tested negative. We concluded that the HH phenotype due to this novel HNF1A mutation can be mutation specific and require a very low dose of DZX. Clinicians should observe closely for the risk of diabetic ketoacidosis and hyperglycemic hyperosmolar state while initiating DZX therapy. [ABSTRACT FROM AUTHOR]

Purpose: Molecular basis of various forms of hyperinsulinemic hypoglycemia, involving defects in key genes regulating insulin secretion, are being increasingly reported. However, the management of medically unresponsive hyperinsulinism still remains a challenge as current facilities for genetic diagnosis and appropriate imaging are limited only to very few centers in the world. We aim to provide an overview of spectrum of clinical presentation, diagnosis and management of hyperinsulinism. Methods: We searched the Cochrane library, MEDLINE and EMBASE databases, and reference lists of identified studies. Conclusions: Analysis of blood samples, collected at the time of hypoglycemic episodes, for intermediary metabolites and hormones is critical for diagnosis and treatment. Increased awareness among clinicians about infants 'at-risk' of hypoglycemia, and recent advances in genetic diagnosis have made remarkable contribution to the diagnosis and management of hyperinsulinism. Newer drugs like lanreotide (long acting somatostatin analogue) and sirolimus (mammalian target of rapamycin (mTOR) inhibitor) appears promising as patients with diffuse disease can be treated successfully without subtotal pancreatectomy, minimizing the long-term sequelae of diabetes and pancreatic insufficiency. Newer insights in understanding the molecular and histological basis and improvements in imaging and surgical techniques will modify the approach to patients with congenital hyperinsulinism. [ABSTRACT FROM AUTHOR]

Glucose is an essential substrate for mammalian cells; in particular, the brain needs glucose continuously as a primary source of energy. Hypoglycemia is the most common biochemical finding in the neonatal period. However, despite the common occurrence, there is still controversy on the definition of hypoglycemia in the newborn period. This has led to the development of guidelines designed to identify infants "at-risk" and the implementation of an "operational threshold" for physicians to consider intervention. In healthy term infants, the optimal hormonal and metabolic adaptations during the immediate neonatal period ensure an adequate energy substrate for the vital organs, whereas the abnormal glucose homeostasis observed in preterm and growth-retarded infants is multifactorial in origin. For these high-risk infants, it is important to identify, screen, and prevent significant hypoglycemia. Detailed investigations are warranted in infants with severe and persistent hypoglycemia. Neonatal hypoglycemia is a major cause of brain injury. The speculated mechanisms of cellular injury include excitatory neurotoxins active at N-methyl-D-aspartate receptors, increased mitochondrial free radical generation with initiation of apoptosis and altered cerebral energetic characteristics. This hypoglycemic brain injury predominantly affects parieto-occipital regions causing cognitive, sensory, psychomotor, and behavioral deficits in children. This state of the art review article covers the fetal--neonatal metabolic adaptation, glucose homeostasis in normal and abnormal conditions, management strategies, and late neurological sequelae of hypoglycemia. [ABSTRACT FROM AUTHOR]

Hyperinsulinaemic hypoglycaemia in small-for-gestational age infants usually presents in the first two postnatal days. We present a preterm, small-for-gestational age infant who had hyperinsulinaemic hypoglycaemia on day 13 of life. A female twin infant weighing 1390 g was born at 32+6 weeks of gestation. Her glycaemic profile was normal till day 13 of life, after which she was noted to be lethargic and hypoglycaemic and had hyperinsulinism, hypoketonaemia and hypofattyacidaemia, requiring high glucose infusion rate to maintain normoglycaemia, while negative for septic markers and metabolic screen. Initially, there was no response to diazoxide and the genetic studies for ABCC8 and KCNJ11 gene mutations were negative. Delayed response to diazoxide was followed by complete resolution of hypoglycaemia in 5 months. This case highlights the importance of glucose monitoring in small-for-date infants for hypoglycaemia till they achieve full feeds and gain weight. Early recognition and appropriate management of hypoglycaemia in this group of infants have important implications for neurodevelopmental outcome. [ABSTRACT FROM AUTHOR]