Serum Arginine Deficiency Is Associated with Early Pulmonary Hypertension in Premature Infants

Background: Fetal circulation bypasses the lungs as gas exchange is performed by the placenta. After delivery, the transition from fetal to neonatal circulation involves many physiologic changes driven by nitric oxide (NO) produced by pulmonary vascular endothelial cells. The NO synthesis pathway relies on the availability of L-arginine (Arg), a conditionally essential amino acid. Previous studies have shown serum Arg is significantly decreased in term infants with pulmonary hypertension (PH), with significant clinical improvement after Arg supplementation.

Objectives: The treatment of PH in premature neonates by inhaled NO (iNO) is contentious. The objective of this study was to assess Arg concentrations in premature infants with PH to determine the utility of future clinical trials in alternative therapies for PH.

Design/Methods: This is a retrospective cohort study, including infants born at 21-32 weeks’ gestational age (GA) from one tertiary center from 2021-2025. Infants were divided in 3 groups: acute PH (aPH, clinical and echocardiographic (echo) evidence of PH with iNO treatment in the first 7 postnatal days), transitional PH (tPH, echo diagnosis of PH without clinical symptoms) or control (no PH diagnosis, matched by GA, birthweight and sex to aPH cohort). Demographic data and echo markers of PH, right ventricular systolic pressure (RVSP) and systolic eccentricity index (sEI), were determined by review of the electronic medical record. Arg was measured in residual clinical serum specimens from the time of PH diagnosis by a commercially available kit. Demographic data were assessed by ANOVA and Chi square. Arg differences were determined by Kruskal-Wallace. Linear regression was used to assess the relationship of Arg with RVSP and sEI.

Results: 51 infants were included with no significant demographic differences between the groups. Infants with aPH had significantly lower serum Arg levels compared to controls (23.57+/-21.07 vs 67.19+/-56.2 umol/L, p=0.0077) at the time of PH diagnosis. Infants with tPH had intermediate levels (39.33+/-33.52 umol/L), but not different when compared to either group (Fig1). A trend in Arg deficiency and worsening aPH severity by increasing RVSP was appreciated (Fig2).

Conclusions: Premature infants with aPH have significantly decreased Arg as compared to healthy matched controls, suggesting that Arg deficiency may contribute to aPH in this population. Our study suggests Arg supplementation is a promising potential therapeutic to aid the transition from fetal to neonatal circulation.