Neonatal hypoglycemia triggered by maternal ritodrine administration is caused by inhibition of gluconeogenesis in the neonatal liver in rodents.

Neonatal hypoglycemia, a known risk factor for neurodevelopmental impairment, may result from maternal exposure to ritodrine, a β2-adrenergic agonist used as a tocolytic agent to prevent preterm labor. We established a rodent model of ritodrine-induced neonatal hypoglycemia to elucidate mechanisms underlying this adverse effect. Ritodrine administration to pregnant rodents (dams) significantly decreased plasma glucose levels in their offspring (pups) 3 h after birth, compared with the phosphate-buffered saline (PBS) group. Although plasma insulin concentrations were significantly lower in the ritodrine group at birth, no significant differences were observed thereafter, suggesting this hypoglycemia is insulin-independent. Since blood glucose levels are regulated by a balance between peripheral glucose utilization and hepatic glucose production, we first assessed peripheral glucose uptake by measuring 2-deoxyglucose incorporation in the pup limbs. No significant differences were observed between the ritodrine and PBS groups. We next investigated whether the observed hypoglycemia was due to impaired hepatic glucose production. Hepatic glycogen content at birth was comparable between the two groups. Liver-targeted metabolomic analysis revealed that the rapid decline in gluconeogenesis (GNG)-related metabolites seen between 2 and 3 h after birth in the PBS group was absent in the ritodrine group. Furthermore, during GNG substrate tolerance tests, pups in the ritodrine group exhibited significantly lower blood glucose levels than those in the PBS group. Finally, hepatic expression of genes encoding gluconeogenic enzymes was significantly reduced in the ritodrine group. Overall, our findings demonstrate that ritodrine-induced neonatal hypoglycemia is caused by suppression of hepatic gluconeogenic enzyme expression in an insulin-independent manner.