The normal blood glucose levels of newborns vary between individuals and are influenced by factors such as birth weight, gestational age, age in days, glycogen stores, feeding methods, energy availability, and the presence of medical conditions. Asymptomatic hypoglycemia exists, and the relationship between blood glucose levels and long-term neurological outcomes remains unclear. Currently, there is no universally accepted international diagnostic standard for neonatal hypoglycemia. In general, neonatal hypoglycemia is defined as blood glucose levels <2.2 mmol/L (40 mg/dL).
Etiology and Pathogenesis
Neonatal hypoglycemia can be classified as transient or persistent.
Transient Hypoglycemia
This refers to hypoglycemia that lasts for a short duration, typically not exceeding the neonatal period.
Insufficient Glycogen Stores and Gluconeogenesis
After birth, glycogen serves as the primary energy source within the first hour. Glycogen storage occurs mainly during the last 4–8 weeks of pregnancy, so preterm and small-for-gestational-age infants often have reduced energy reserves. The smaller the gestational age, the lower the glycogen stores, while energy demands after birth are relatively higher. Additionally, enzyme activity related to gluconeogenesis is low in neonates. Intrauterine distress also reduces glycogen reserves. Even in term neonates, the immaturity of key gluconeogenic enzymes within the first 24 hours postpartum, combined with delayed feeding (beyond 6–8 hours), causes about 30% of neonates to experience blood glucose levels below 2.78 mmol/L (50 mg/dL), with 10% dropping below 1.67 mmol/L (30 mg/dL).
Increased Glucose Consumption
In stressful conditions such as asphyxia or severe infections, catecholamine secretion increases, and levels of glucagon and cortisol rise. This initially raises blood glucose levels, followed by rapid glycogen consumption, leading to hypoglycemia. Anaerobic glycolysis, which increases glucose utilization, also contributes to hypoglycemia. Additionally, conditions like hypothermia or congenital heart disease often result in insufficient caloric intake and increased glucose utilization, which may cause hypoglycemia.
Hyperinsulinemia
This refers to transient elevations in insulin levels, commonly seen in the following situations:
- Infants of diabetic mothers: Maternal hyperglycemia induces compensatory hyperplasia of fetal pancreatic beta cells, leading to excess insulin production. Upon birth and the abrupt cessation of maternal glucose supply, hypoglycemia occurs.
- Neonatal hemolytic disease: Red blood cell destruction releases glutathione, which stimulates increased insulin secretion.
Persistent Hypoglycemia
This refers to hypoglycemia that persists into infancy or childhood.
Congenital Hyperinsulinism (CH)
This is typically associated with genetic defects.
Endocrine Deficiencies
These include congenital hypopituitarism, congenital adrenal hyperplasia, glucagon deficiency, and growth hormone deficiency.
Inherited Metabolic Disorders
These include:
- Carbohydrate Metabolism Disorders: Such as glycogen storage diseases type I and III and galactosemia.
- Fatty Acid Metabolism Disorders: Such as medium-chain acyl-CoA dehydrogenase deficiency.
- Amino Acid Metabolism Disorders: Such as branched-chain amino acid metabolism abnormalities or leucine metabolism defects.
Clinical Manifestations
Asymptomatic Hypoglycemia
No clinical symptoms may be present. Studies indicate that asymptomatic hypoglycemia is 10–20 times more common than symptomatic cases. Diagnosis primarily depends on blood glucose monitoring.
Symptomatic Hypoglycemia
Affected neonates may exhibit symptoms such as lethargy, poor feeding, feeding difficulties, cyanosis, apnea, pallor, hypothermia, or even coma. Other possible symptoms include irritability, restlessness, tremors, hyperreflexia, a high-pitched cry, or seizures.
Auxiliary Examinations
Blood Glucose Measurement
Bedside glucometers are often used for rapid measurement, usually utilizing blood samples from the infant’s heel. Portable glucose testing devices have demonstrated good correlation with actual blood glucose concentrations, with deviations generally not exceeding 10–15%. However, these deviations may become more pronounced at glucose concentrations below 2.2 mmol/L. Bedside testing is commonly used for dynamic monitoring, while confirmatory diagnosis necessitates laboratory measurement of standard blood glucose levels. Treatment should commence based on bedside findings of hypoglycemia.
Other Laboratory Tests
Persistent hypoglycemia may warrant further investigations of blood insulin, glucagon, triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), growth hormone, cortisol, and amino acids or organic acids in blood and urine.
Imaging and Pathological Examinations
In cases of hyperinsulinemia, pancreatic ultrasound or CT scans may be utilized. If glycogen storage disease is suspected, liver biopsy may be performed to assess hepatic glycogen content and enzyme activity.
Treatment
Since the threshold of hypoglycemia causing brain injury remains uncertain, timely treatment is required regardless of symptomatic status.
Asymptomatic Hypoglycemia in Infants Able to Feed
Affected newborns may be fed while closely monitoring blood glucose levels. If hypoglycemia is not corrected, intravenous glucose infusion at a rate of 6–8 mg/(kg·min) is warranted. Blood glucose should be monitored hourly, and the glucose infusion rate adjusted based on glucose measurements. After stabilization for 24 hours, glucose administration is gradually tapered off.
Symptomatic Hypoglycemia
An initial dose of 10% glucose at 200 mg/kg (2 mL/kg) may be administered via intravenous injection at a rate of 1.0 mL per minute. This is followed by maintenance infusion at a rate of 6–8 mg/(kg·min) to prevent rebound hypoglycemia. Blood glucose should be monitored hourly, with the infusion rate adjusted as needed. After 24 hours of normal glucose levels, the infusion rate is gradually reduced, and glucose is discontinued within 48–72 hours. For prolonged hypoglycemia, hydrocortisone at 5 mg/kg may be given via intravenous injection every 12 hours, or prednisone at 1–2 mg/(kg·d) may be administered orally for a duration of 3–5 days to induce increased gluconeogenic enzyme activity. In very low birth weight preterm infants with poor glucose tolerance, infusion rates exceeding 6–8 mg/(kg·min) may lead to hyperglycemia.
Persistent Hypoglycemia
For congenital hyperinsulinism (CH), diazoxide is the first-line treatment, with a dosage of 5–20 mg/kg per day divided into three oral doses. If ineffective, second-line medications such as somatostatin analogs (e.g., octreotide at 5–25 μg/(kg·d) via intravenous injection) may be considered. Intravenous glucagon at 0.02 mg/kg, or continuous intravenous infusion at 1–20 μg/(kg·h), is another alternative, though glucagon is primarily used as a short-term treatment. If medical therapy for CH is ineffective, surgical intervention may be necessary.
Infants with congenital metabolic disorders require specialized dietary therapy.
Prevention
Avoidance of high-risk factors for hypoglycemia, such as cold stress, is essential. High-risk infants should undergo regular blood glucose monitoring.
For newborns who are able to feed, early feeding is recommended.
For those unable to tolerate enteral feeding, intravenous infusion of 10% glucose can be used. The appropriate infusion rate depends on the infant’s condition:
- Term appropriate-for-gestational-age infants: 3–5 mg/(kg·min).
- Preterm appropriate-for-gestational-age infants: 4–6 mg/(kg·min).
- Small-for-gestational-age infants: 6–8 mg/(kg·min).
These rates approximate the endogenous hepatic glycogen production rate.