In this study, we demonstrated that the antenatal administration of ritodrine and MgSO4 to mothers as a treatment for preterm delivery resulted in an increased serum potassium concentration in neonates born from these mothers. In addition, we revealed that neonates exposed to both ritodrine and MgSO4 exhibited enhanced metabolic pathways distinct from those observed in neonates exposed to either ritodrine or MgSO4 alone, using a comprehensive analysis of serum metabolites in umbilical cord blood. Recent research has reported that the combined use of ritodrine and MgSO4 in mothers is a risk factor for hyperkalemia in preterm infants6,7. The findings of this study confirmed that the antenatal administration of ritodrine and MgSO4 to mothers induced hyperkalemia in preterm infants. Furthermore, a metabolomics analysis revealed activation not only in amino acid biosynthesis, sugar metabolism, and glycolysis/gluconeogenesis, but also in a distinctive citrate cycle in the neonatal group exposed to both ritodrine and MgSO4. Therefore, this study suggests a synergistic effect of ritodrine and MgSO4, potentially inducing distinctive metabolic changes and triggering neonatal hyperkalemia.
The significantly increased citric acid observed in the both ritodrine and MgSO4 group was produced in the citrate cycle through aldol condensation of oxaloacetic acid and acetyl CoA, the final products of the preceding turn of the cycle 14. Acetyl-CoA originates from glucose through the glycolytic pathway 14. Ritodrine functions as a β2-AR agonist. The stimulation of hepatic β2 adrenergic receptors by ritodrine activates hepatic adenylate cyclase, promoting hepatic gluconeogenesis and glycogenesis, thereby inducing hyperglycemia15,16. Prolonged glucose stimulation induces citrate synthesis in the mitochondria via the glycolysis pathway, leading to increased cytoplasmic and extracellular citrate17. The administration of MgSO4 to pregnant women results in an increased concentration of magnesium within the fetal serum and intracellular spaces, which is facilitated by the ease with which MgSO4 traverses the placenta18. The elevation in intracellular magnesium levels facilitates the uptake of glucose into the cell via Glut4, a component of the glycolytic pathway19. Additionally, magnesium serves as a cofactor for enzymes in the glycolysis pathway, including hexokinase, phosphofructokinase, phosphoglycerate kinase, and enolase20,21. In our study, neonates with antenatal exposure to both ritodrine and MgSO4 exhibited significant activation of metabolic pathways, including the citrate cycle, branched-chain amino acids, alanine, and fatty acid synthesis, derived from metabolites generated during glycolysis. Therefore, the synergistic effect of both ritodrine and MgSO4 suggests that they activate glycolysis and the derived metabolic routes.
Glycolysis regulates cell membrane ion transporters (pumps, exchangers, and channels) and modulates the intracellular distribution of potassium ions22. Adenosine triphosphate (ATP) is produced through three processes: glycolysis, the citrate cycle, and oxidative phosphorylation, starting from intracellular glucose23. The cell membrane features Na-K ATPase and ATP-sensitive K channels, with an increase in intracellular ATP levels, leading to elevated intracellular potassium concentrations22,24. Generally, stimulation of β2 adrenergic receptors by ritodrine involves the activation of Na-K ATPase pumps on the cell membrane, facilitating the intracellular transition of potassium25. The rebound following the cessation of ritodrine is known to cause the release of potassium from intracellular spaces into the serum 26–29. As approximately 98% of potassium resides intracellularly, even a slight efflux of intracellular potassium results in a significant increase in serum potassium concentration 25. The rebound of potassium after the injection of insulin or thiopentone has also been reported to induce the uptake of potassium into cells, indicating that rapid changes in mechanisms regulating potassium distribution in the body are risk factors for hyperkalemia30. In our study, neonates exposed to both ritodrine and MgSO4 may have experienced an enhanced influx of potassium into cells due to the activation of Na-K ATPase pumps by ritodrine coupled with increased metabolic pathways related to glycolysis. Therefore, neonates exposed to both ritodrine and MgSO4 may have a heightened quantity of potassium redistribution from intracellular to serum compartments following the discontinuation of these medications, potentially increasing their susceptibility to postnatal hyperkalemia.
The levels of citric acid in the serum of umbilical cord blood were positively correlated with the highest potassium values within the first 48 h of life, suggesting its potential as a marker for the early detection of neonatal hyperkalemia (Table 4). However, citric acid is not routinely analyzed in the blood of preterm infants immediately after birth. In our investigation, the serum phosphorus levels immediately after birth demonstrated a positive correlation with the citric acid levels in the serum of umbilical cord blood and the highest potassium values within the initial 48 h postpartum (Table 4). The presence of hypermagnesemia induced by the administration of MgSO4 inhibits parathyroid hormone secretion and induces hyperphosphatemia in the fetus31. Furthermore, ritodrine-induced insulin promotes the reabsorption of phosphate in the proximal tubules32. Thus, the elevation in serum levels of phosphorus and citric acid due to the influence of ritodrine and MgSO4 may occur through distinct mechanisms. However, our investigation revealed a clear positive correlation between serum phosphorus levels and citric acid levels (Table 4). Consequently, serum levels of phosphorus and citric acid immediately after birth may independently serve as potential predictors of the onset of neonatal hyperkalemia. The prediction of neonatal hyperkalemia would facilitate the early initiation of glucose-insulin therapy, a treatment for hyperkalemia, and assist in decision-making in relation to the introduction of early caffeine therapy, which has recently been reported to have preventive effects against neonatal hyperkalemia33. These early interventions may mitigate the risk of fatal arrhythmias due to hyperkalemia and potentially improve neonatal outcomes.
The present study was associated with several limitations. First, it was a retrospective analysis conducted at a single institution, and was limited to the analysis of the serum of umbilical cord blood from a subset of cases. Additionally, pregnant women who received both ritodrine and MgSO4 had longer durations of drug administration and higher dosages than those who received ritodrine or MgSO4 alone. This discrepancy in the drug administration parameters may have influenced the outcomes of this study. Furthermore, the study did not assess neonatal blood magnesium concentrations or urinary potassium excretion rates. Prospective randomized controlled trials are necessary to eliminate potential bias and elucidate the remaining issues.
The present study revealed that neonates exposed to both ritodrine and MgSO4 may experience synergistic effects of these drugs, leading to the activation of glycolysis and the derived metabolic routes, potentially inducing hyperkalemia. Citric acid levels in the serum of umbilical cord blood or serum phosphorus levels immediately after birth may serve as predictors of neonatal hyperkalemia. The early prediction of neonatal hyperkalemia would facilitate the timely introduction of preventive or therapeutic drugs for hyperkalemia. Furthermore, our findings hold the potential to contribute to future drug development aimed at preventing neonatal hyperkalemia by targeting molecules involved in glycolysis and the citrate cycle.