Exploring the long-term impacts of neonatal hypoglycemia to determine a safe threshold for glucose concentrations

Abstract

Hypoglycemia and impaired metabolic transition are frequently observed in neonates during the first 24-48 h after birth [1, 2]. Severe (< 36 mg/dL or 2 mmol/L) and recurrent (3 or more episodes) hypoglycemia can cause neurological injury and developmental delays. The ambiguity regarding a threshold blood glucose concentration remains due to differing values proposed by various professional organizations. This poses a challenge in diagnosing neonatal hypoglycemia in addition to using a single blood glucose value, which in itself is not entirely reflective of various key molecular processes uncovered by in vitro or pre-clinical studies. The symptoms of hypoglycemia can also be present in conditions other than hypoglycemia, e.g., sepsis and polycythemia, and in many cases, hypoglycemia is clinically unrecognized. Therefore, early screening of at-risk and otherwise healthy-appearing neonates is essential. Continuous glucose monitoring and early interventions such as glucose gel, breast and formula feeding, and intravenous glucose administration are utilized to prevent long-term neurological impairments. However, the safe limits of serum glucose that will prevent neuroglycopenia and neural injury are elusive. The impact of early screening and available therapies on neurodevelopmental outcomes remains uncertain due to the absence of a robust clinical design and combining all causes of neonatal hypoglycemia without making further distinctions from other conditions. This review highlights the controversies in definitions and the most recent information on long-term neurodevelopmental outcomes that may impact the early management of NH.Conclusion: Optimizing the definitions and treatment of neonatal dysglycemia is crucial for preventing hypoglycemia-related brain injury. Continuous glucose monitoring technology in neonates offers a promising approach for real-time screening and early intervention. What is Known: • There is ongoing debate regarding the optimal glucose threshold for intervention and prevention of hypoglycemia-induced brain injury. This suggests brain injury may be incurred over a range rather than a single blood glucose concentration. What is New: • Recent studies suggest that glucose concentrations between 36 mg/dL (2 mmol/L) and 47 mg/dL (2.6 mmol/L) are acceptable in asymptomatic neonates. However, neurological injury was observed in early school age with glucose values of <36 mg/dl (<2 mmol/L) and in mid-childhood of <30-36 mg/dL (<1.7 -2 mmol/L). This suggests brain injury may be incurred over a range rather than a single blood glucose concentration. • Continuous glucose monitoring (CGM) highlights real-time glucose measurement and glycemic lability in neonates. Its use may mitigate long-term neurologic injury by improving early recognition and treatment.

Keywords: Continuous glucose monitoring; Glucose; Neurodevelopmental outcomes; Newborn; Threshold.

Fig. 1

Maternal and neonatal factors affecting glucose homeostasis: differentiating transient and persistent causes of hypoglycemia

Fig. 2

A Plasma glucose concentration in healthy term infants from birth to 120 hours is shown in the graph, and the table below the graph shows a comparison of plasma and interstitial glucose concentrations at the corresponding time intervals. The CGM (Medtronics, Minimed, California) was placed soon after birth to measure interstitial glucose continuously for 5 days. Plasma glucose equivalent concentrations are reported from intermittent heel stick samples obtained 60-90 minutes after birth, every 3-4 hours for the first day, and then every 12 hours for 4 days (before feeding when possible). (data from Harris et al; J Pediatr 2020;223:34-41 (GLOW study). B The bar graph showing 10th (in black bars) and 90th (in grey bars) percentile data for interstitial glucose derived from the continuous glucose monitoring (CGM) in Healthy Term Infants at < 48 hours and greater than 72 hours of age. (data from Harris et al; J Pediatr 2020;223:34-41 (GLOW study)

Fig. 3

Treatment Strategies for newborn infants at high-risk of Hypoglycemia